Neurological manifestations of Allgrove syndrome in patients carrying a potentially founder p.Ser263Pro variant of the AAAS gene

Neurological manifestations of Allgrove syndrome in patients carrying a potentially founder p.Ser263Pro variant of the AAAS gene | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neurological manifestations of Allgrove syndrome in patients carrying a potentially founder p.Ser263Pro variant of the AAAS gene Ewa Juścińska, Karolina Gadzalska, Paulina Jakiel, Michał Pietrusiński, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6962259/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jan, 2026 Read the published version in neurogenetics → Version 1 posted 12 You are reading this latest preprint version Abstract Allgrove syndrome is a rare, multisystem, autosomal recessive disorder characterized by the triad of symptoms: achalasia, alacrimia and ACTH-resistant adrenal insufficiency. Various and nonspecific neurological symptoms can also develop over time, “blurring” the typical course of this underdiagnosed condition. The incidence of Allgrove syndrome is unknown, Orphanet reports fewer than 100 published cases, but according to literature review, at least 206 patients have been already described. The pathogenic variant p.Ser263Pro is one of the most recurrent aberration affecting AAAS gene and have been reported in several families of Slavic origin. We investigated genotype-phenotype correlation in 206 patients with AS described in literature (including two novel Polish siblings carrying a homozygous p.Ser263Pro variant in the AAAS gene) and found that neurological symptoms were significantly more common among carriers of p.Ser236Pro variant (33 out of 34; 97.05%) as compared to other AAAS mutation carriers (133 out of172; 77.3%, p = 0.006). While the incidence of the classical clinical triad of AS was similar and observed in 110 out of 206 AS patients (53.4%) and in 18 out of 34 (52.9%) among p.Ser263Pro variant carriers. Furthermore our report supports the hypothesis of a founder mutation p.Ser263Pro of AAAS gene in a European Caucasian population, probably of Slavic origin- since 25out of 36 reported variant carriers were of Slavic origin (69.4%) and 17 out of 23(73.9%) who were homozygous for p.Ser263Pro mutation came from Slavic region. Summarizing, neurological manifestations of AS predominate in patients carrying a potentially founder p.Ser263Pro variant with the AAAS gene. Allgrove syndrome Triple A syndrome alacrimia achalasia adrenal insufficiency AAAS gene Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Allgrove syndrome (AS, Triple A syndrome) (OMIM #231550) is a rare, multisystem disorder characterized by the triad of symptoms: achalasia, alacrimia and ACTH-resistant adrenal insufficiency [ 1 ]. AS is one of two inherited ACTH resistance syndromes, beside the familial glycocorticoids deficiency (FGD) [ 2 , 3 ] and is usually diagnosed by early childhood. However patients may also develop symptoms during adulthood and then they show mainly neurological features [ 4 , 5 , 6 , 7 , 8 ] including: spasticity, peripheral neuropathy, hyperreflexia, optic atrophy, sensory impairment, myopathy/muscle weakness, developmental delay or dementia [ 9 , 10 , 11 , 12 ]. Rarity and non-specific clinical traits of late-onset forms of AS may contribute to delayed diagnosis [ 13 ]. The exact incidence of AS is unknown, according to Orphanet fewer than 100 cases have been published (ORPHA: 869), but we found at least 206 described patients in the literature. Allgrove syndrome is caused by homozygous or compound heterozygous, loss-of-function mutations in AAAS gene located on chromosome 12q13.13 (chr12:53307456–53324864) [ 14 ]. The AAAS mRNA is highly expressed in adrenal cortex, pituitary gland, esophagus gastroesophageal junction and neural tissue [ 15 ]. The AAAS gene consists of 16 exons and encodes a 546-amino-acid, 60-kDa protein ALADIN (acronym for: alacrima-achalasia-adrenal insufficiency-neurologic disorder), which belongs to the tryptophan aspartic acid (WD) repeat protein family and is component of the nuclear pore complexes (NPC) involved in nucleocytoplasmic transport, transmembrane signaling and cell division [ 16 , 17 ]. The precise function of ALADIN and molecular mechanisms leading to the wide range of AS-related phenotypical features remain only partly understood, but functional studies by Cronshaw et al show that mutated ALADIN proteins are mislocalized to the cytoplasm, instead of the wild-types bounded to NPCs [ 18 ]. In addition, Prasad et al described the role of ALADIN protein in maintenance of redox homeostasis in adrenal cells and inhibition of steroidogenesis [ 19 ]. The purpose of the study was to investigate possible genotype and phenotype correlations among carriers of p.Ser263Pro variant based on the review of already published patients diagnosed with Allgrove syndrome and exemplify the predominance of neurological symptoms in novel family case of twin brothers who carried biallelic pathogenic variant p.Ser263Pro in AAAS . Case description 40-year-old twins were referred to the Outpatient Clinical Genetics Department due to similar symptoms including: sensorimotor polyneuropathy, hemiparesis, dysphagia, defective tears formation, lower limb muscle weakness. Their cognitive functions remained relatively high. Electromyography revealed advanced form of axonal-demyelinating sensorimotor polyneuropathy in both patients. The first symptoms were observed in childhood as: late onset of walking, imbalance, gait abnormalities and reduced mobility compared to their peers. Another neurological features evolves over time and included: hypersensitivity to cold, sensory disturbances and paresthesia around the lower legs, feet and fingertips, difficulties with precise movements, slurred speech and swallowing disorders. Due to the worsening symptoms related with limited tear secretion, dry hands and mouth the brothers were primary diagnosed with Sjögren’s syndrome. The following clinical features were observed: very low muscle mass, atrophy of the intercostals muscles, hollow feet, toe deformities and wide-based gait. One brother also had refraction defect, farsightedness and astigmatism, while the other remains under the care of a rheumatologist due to Raynaud's sign. The patients were firstly tested for the most frequent form of inherited axonal-demyelinating sensorimotor polyneuropathy which is Charcot-Marie-Tooth type 1A using MLPA (Multiplex Ligation-dependent Probe Amplification). We searched for copy number variations (CNVs) involving PMP22 , COX10 and TEKT3 genes located in the region on chromosome 17p12 using SALSA MLPA probemix P033 Charcot-Marie-Tooth (chromosome 17p12) ( MRC Holland , Amsterdam, Netherlands) according to manufacturer protocol. In the analyzed region of chromosome 17 no microdeletions or microduplications were detected. Subsequently, whole exome sequencing (WES) was performed. Exomic regions and 37 genes of the mitochondrial genome (16,659 base pairs) were sequenced using NovaSeq 6000 on Illumina platform (2 x 100 base pairs). The results were analyzed using VariantStudio Software v.3.0 (Illumina), Integrative Genomics Viewer (IGV) v.2.3. and genetic, clinical and population databases: OMIM, dbSNP, ClinVar, Orphanet, ClinGen, HGMD and gnomAD. WES revealed in both brothers the presence of a homozygous missense variant: T > C transition at nucleotide position 787 in exon 8 on both alleles of the AAAS gene (c.787T > C) (12:53309624:T-C, GRCh38) (NM_015665.5) (Fig. 1). The identified SNV (single nucleotide variaton) has been previously reported in the literature in patients with Allgrove syndrome phenotype [ 20 – 26 ] and was presented in following databases: dbSNP (rs121918550), ClinVar: classified SNV as pathogenic/likely pathogenic (Variation ID: 5045), ClinGen (CA117228), Human Gene Mutation Database (HGMD, Public Entries): genotype was correlated with phenotype of Triple A syndrome (CM010150) and gnomAD v.4.1.0 with total allele frequency: 0.007622% (0.00007622) worldwide and 0.007034% (0.00007034) in European (non-Finnish) population. mtDNA and Y chromosome haplogroups were determined using the mtDNAserver and Yleaf algorithms [ 31 – 32 ]. The proband's maternal line (haplogroup H1) and paternal line (haplogroup R1a) confirm his European ancestry. The analyzed missense variant was located within third WD (tryptophan aspartic acid) repeat resulting in the replace of a polar serin with non-polar proline at amino acid position 263 of ALADIN protein (p.Ser263Pro) (NP_056480.1) (Fig. 2 ). The alteration in the third-WD repeat disrupts the formation of a typical form of beta-propeller structure, responsible for interactions with several proteins, including the NPC complex [ 18 , 33 ]. Functional studies regarding p.Ser263Pro mutation carried out by Milenković et al using HeLa cell lines confirmed the altered localization of mutant ALADIN to the cytosol caused by inhibition of the connection to the NPC complex [ 18 , 27 ]. Although the effect of the misfolded protein due to mutated third WD-repeat on the change in cellular localization has been proven, however, the impact of the function is still not completely understood. The in silico predictors indicates that this mutation disturbs the function of AAAS protein (MutationTaster: disease causing, PROVEAN and SIFT: damaging, REVEL: 0,844- pathogenic moderate, AlphaMissense: 0.985- likely pathogenic). The bioinformatic analysis of identified variant confirmed its pathogenicity as recommended by the American College of Medical Genetics and Genomics (ACMG). Variant segregation analysis using Sanger sequencing method revealed that healthy brother is a carrier of the heterozygous variant c.787T > C, parents denied genetic testing. The family history shows that examined brother, as well as parents, did not show any symptoms of achalasia, alacrymia, adrenal insufficiency or neurological symptoms similar to affected twins. Taking into consideration the numerous scientific reports describing the role of identified variant in Allgrove syndrome and the result of the segregation analysis performed on the healthy brother, the mode of autosomal recessive inheritance is the most probable (Fig. 3 ). Finally, both patients were diagnosed with Allgrove syndrome due to their clinical features and the presence of the homozygous p.Ser263Pro variant of the AAAS gene, allowing them to receive specialized medical care (endocrinologist, neurologist, ophthalmologist) and appropriate introduction of therapies: hydrocortisone replacement therapy to reduce the risk of potentially life-threatening adrenal insufficiency and artificial tears to avoid the discomfort associated with alacrimia. Genotype-phenotype correlation of p.Ser263Pro variant in the AAAS gene We reviewed the literature and found in total n = 206 patients diagnosed with Triple A syndrome, for whom phenotypic description was provided (Supplementary Table 1) [ 35 , 53 – 54 , 58 , 60 – 68 , 71 – 76 ]. Among 206 reported AS cases- 28 (13.6%) have not been genetically tested and diagnosed based only on clinical features- all of these patients have presented triad of symptoms: alacrimia, achalasia and adrenal insufficiency. The remaining 178 (86.4%) patients carried pathogenic or likely pathogenic variants in AAAS gene, in 34 out of 178 cases p.Ser236Pro was identified (n = 34/178, 19.1%). In this group there was n = 21 homozygous carriers of p.Ser263Pro variant and n = 13 compound heterozygous patients who carried single p.Ser263Pro variant of AAAS gene. Neurological symptoms including: progressive peripheral neuropathy (motor and sensory), mild mental retardation and developmental delay, learning difficulties, muscle weakness, hypotonia and muscle atrophy, gait disturbance, brisk tendon reflexes, hyperreflexia, optic atrophy were described in 33 out of 34 carriers of at least single p.Ser263Pro variant (both homo- and compound heterozygous) as compared to the n = 133 out of n = 172 remaining patients diagnosed with Triple A syndrome (p = 77.3%) (chi2 test p = 0.006). With respect to the possible founder origin of p.Ser263Pro variant of AAAS gene Dumic et al identified this alterations in five patients: one homozygous and four compound heterozygous (2 patients: p.Ser263Pro and p.Gly14fs and 2 other patients: p.Ser263Pro and p.Ser296Tyr), supporting the hypothesis that p.Ser263Pro may be a founder mutation in the Slavic population [ 22 ]. Moreover, molecular studies by Handschug et al detected the p.Ser263Pro mutation in four families: two Polish patients carrying the homozygous variant and two other patients with compound heterozygous mutations: p.Ser263Pro and on the second affected allele: Ser463fsTer (in a Polish family) and Gln15Lys (in a German family) [ 24 ]. Milenković et al further described three siblings from a Serbian family (a 12-year-old girl and 5, 3.5-year-old boys) who were compound heterozygotes in the AAAS gene: p.Ser263Pro and p.Val421GlyfsTer. They also described 17 patients with the p.Ser263Pro mutation, within this group, 12 out of 17 coming from the Slavic region [ 27 ]. Pripić et al reported another 3 cases carrying p.Ser263Pro variant- 1 homozygous and 2 heterozygous with respectively p.Gln15Lys and p.Gln387Ter on the other allele [ 20 ]. Recently, Cehic et al have described a case report of infant carrying p.Ser236Pro and p.Gln387Ter variants with triad, hyperpigmentation and neurological symptoms (generalized hypotonia, muscle weakness, developmental delay) observed. [ 78 ]. The origin of these 4 recently diagnosed patients remains unknown. In addition, to the best of our knowledge 23 out of 34 carriers of p.Ser263Pro variant (67.7%) already reported in literature, were of Slavic origin (Croatia: 10, Poland: 6, Serbia: 3, Slovenia: 2 Czech Republic: 1, Hungary: 1). Homozygous variant have been identified in 21 out of 34 cases- in which Slavic origin were confirmed in 15 patients (71.4%) (Croatia: 6, Poland: 5, Slovenia: 2, Hungary: 1, Czech Republic: 1) (Fig. 4 ). The remaining 13 patients carried heterozygous mutations: p.Gln15Lys (4 cases), p.Val421GlyfsTer5 (3 cases), p.Gln387Ter (2 cases), p.Ser296Tyr (2 cases), p.Phe464SerfsTer87, p.Pro426ThrfsTer15 and 8 out of 13 were Slavic origin (Croatia: 4, Serbia: 3, Poland: 1). In 4 out of 13 cases origin were not precisely described, one patient carrying p.Gln15Lys on the second allele came from German family. Our report presenting Polish twins with homozugous p.Ser263Pro supports the founder mutation hypothesis. Discussion Triple A syndrome is a rare, progressive disorder that varies in age of onset and severity of endocrine, gastrointestinal and neurological symptoms. The condition was firstly described by Jeremy Allgrove in 1978, who reported two pairs of siblings (3 boys and a girl aged 4–6 years) from separate families suffering from adrenal insufficiency, gastric achalasia and defective tear secretion [ 1 ]. AS is mainly diagnosed in early childhood, but in adult patients other clinical features, mainly neurological, may also occur [ 4 – 8 , 34 , 38 , 43 , 48 ]. This is a devastating disorder that affects patient’s quality of life and can potentially even be life-threatening due to adrenal insufficiency (episodes of hypoglycemia and seizures) and severe neurological impairment [ 36 , 39 – 42 , 45 , 69 ]. The diagnosis of AS may allow the indication of appropriate treatment that significantly improves patients’ quality of life: pharmacological glucocorticoid replacement therapy with hydrocortisone, surgical esophageal dilation, artificial tears due to insufficient tear production and symptomatic treatment of neurological symptoms [ 44 , 46 – 47 , 49 , 50 – 52 , 59 , 70 ]. Patients also require genetic counseling of entire family and multidisciplinary specialized medical care provided by endocrinologists, neurologists, gastroenterologists, ophthalmologists and surgeons [ 30 , 37 , 55 – 57 , 77 ]. We describe a Polish family with two adult (40-year-old) twin brothers who presented mainly neurological symptoms. Molecular studies revealed the presence of a pathogenic homozygous p.Ser263Pro variant of the AAAS gene, previously described in the literature in patients with the Allgrove syndrome phenotype [ 20 – 26 , 78 ]. According to our review of literature, neurological manifestations are very common among p.Ser263Pro carriers and may include: progressive peripheral neuropathy, muscle weakness, gait disturbance, optical atrophy and mild mental retardation. Interestingly, neurological symptoms have been presented in 33 out of 34 p.Ser263Pro carriers (97.1%), in opposite to “classical” triad, which were presented only in 18 out of 34 (52.9%). The remaining 16 patients showed at least one manifestation of the triad and except three cases- they all have presented alacrimia. In general, among 206 reported patients 166 presented neurological symptoms (80,5%) and all manifestation of classical triad have been observed in 110 out of 206 patients (53.4%). Milenković et al concluded that molecular genetic tests can play a supportive role in diagnosing Allgrove syndrome, but do not predict the phenotype [ 27 ]. Summarizing 32 years of experience in diagnosing AS, Milenković et al recommended molecular genetic testing and adrenal function testing in patients with alacrimia and at least one other feature of the condition [ 26 ]. Interestingly, the initial symptoms in our patients were neurological ones already present in childhood. Dumić et al also described a case of two siblings (a 3.5-year-old girl and a 5.5-year-old boy) with early onset of neurological symptoms and a compound heterozygous mutation consisting of p.Ser296Tyr and p.Ser263Pro variants. The authors pointed to the important role of discovering more patients with p.Ser263Pro, one of the most common mutations in the AAAS gene in the European Caucasian population, to find correlations with severity, age of onset and variability of symptoms in patients with Allgrove syndrome [ 25 ]. Vezzoli et al identified two novel variants of the AAAS gene in the Italian population– a frameshift substitution located in exon 8: p.Gly256TrpfsTer67 and a splice-site mutation in intron 11: c.997-2A > G [ 28 ]. In the past year, four studies reported patients with Allgrove syndrome: Yıldırım et al described 12 cases carrying biallelic variants in the AAAS gene, two of which were novel splice-site mutations: c.1250-1G > A and c.398_399 + 2del [ 12 ]. Naseer et al described a 17-year-old boy with clinical features of Allgrove syndrome (alacrimia, achalasia, dysphagia, weight loss, adrenal insufficiency with generalized hyperpigmentation and weakness) and significant improvement after hydrocortisone replacement therapy [ 29 ]. Gupta et al reported two another AS patients carrying: c.43C > A homozygous variant and one compound heterozygous: c.312dupA and c.307 + 4_307 + 7del [ 77 ]. Maaloul I. et al (2025) reported 14 homozygous carriers of c.1331 + 1G > A mutation and one c.856C > T, among which all presented classical AS triad and also hyperpigmentation, but neurological symptoms was observed in only 9 out of 15 cases [ 79 ]. Conclusions Our case report is further evidence supporting the pathogenicity of p.Ser263Pro variant in the AAAS gene which is probably a founder mutation in the European Caucasian population, possibly in the Slavic ethnic group. Molecular testing is recommended in patients with even scarce phenotypical features suggestive for Allgrove syndrome, since the whole triad of symptoms is not obligatory present in all the individuals with AS. Particularly in carriers of p.Ser263Pro variant the neurological phenotype may predominate. Abbreviations ACTH Adrenocorticotropic hormone AS Allgrove syndrome CNV Copy Number Variation EDTA Ethylenediaminetetraacetic acid disodium salt FGD Familial glucocorticoid deficiency MLPA Multiplex Ligation-dependent Probe Amplification NGS Next Generation Sequencing NPC Nuclear Pore Complex SNV Single Nucleotide Variation WES Whole Exome Sequencing Declarations Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. Additional information Informed consent was obtained from all individual participants included in the study. The authors have no financial or proprietary interests in any material discussed in this article. Funding Declaration No funding was received to assist with the preparation of this manuscript. The authors did not receive support from any organization for the submitted work. Author Contribution Conceptualization: Agata Pastorczak, Agnieszka Zmysłowska; Methodology: Tomasz Płoszaj, Michał Pietrusiński, Karolina Gadzalska; Formal analysis and investigation: Karolina Gadzalska, Paulina Jakiel, Monika Gorządek, Sebastian Skoczylas, Klaudia Starosz, Ewa Juścińska; Writing - original draft preparation: Ewa Juścińska; Writing - review and editing: Agata Pastorczak, Agnieszka Zmysłowska; Literature search: Ewa Juścińska; Supervision: Agata Pastorczak, Maciej Borowiec, Agnieszka Zmysłowska. All authors read and approved the final manuscript.Funding Declaration: No funding was received to assist with the preparation of this manuscript. The authors did not receive support from any organization for the submitted work.Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. Additional information: Informed consent was obtained from all individual participants included in the study. The authors have no financial or proprietary interests in any material discussed in this article. Data Availability Data is provided within the manuscript or supplementary information files. References Allgrove J, Clayden GS, Grant DB, Macaulay JC (1978) Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. ;1(8077):1284-6. 10.1016/s0140-6736(78)91268-0 . PMID: 78049 Metherell LA, Chan LF, Clark AJ (2006) The genetics of ACTH resistance syndromes. Best Pract Res Clin Endocrinol Metab. ;20(4):547 – 60. doi: 10.1016/j.beem.2006.09.002. PMID: 17161331 Cooray SN, Chan L, Metherell L, Storr H, Clark AJL (2008) Adrenocorticotropin resistance syndromes. Endocr Dev. ;13:99–116. 10.1159/000134828 . PMID: 18493136 Vallet AE, Verschueren A, Petiot P, Vandenberghe N, Nicolino M, Roman S, Pouget J, Vial C (2012) Neurological features in adult Triple-A (Allgrove) syndrome. J Neurol 259(1):39–46. 10.1007/s00415-011-6115-9 Epub 2011 Jun 9. PMID: 21656342 Gaiani F, Gismondi P, Minelli R, Casadio G, de'Angelis N, Fornaroli F, de'Angelis GL, Manfredi M (2020) Case report of a familial triple: a syndrome and review of the literature. Medicine (Baltimore). ;99(22):e20474. 10.1097/MD.0000000000020474 . PMID: 32481456 Pedreira CC, Zacharin MR (2004) Allgrove syndrome: when a recognisable paediatric disorder occurs in adulthood. Med J Aust. ;180(2):74 – 5. 10.5694/j.1326-5377.2004.tb05803.x . PMID: 14723589 Gilio F, Di Rezze S, Conte A, Frasca V, Iacovelli E, Marini Bettolo C, Gabriele M, Giacomelli E, Pizzuti A, Pirro C, Fattapposta F, Habib FI, Prencipe M, Inghilleri M (2007) Case report of adult-onset Allgrove syndrome. Neurol Sci. ;28(6):331-5. 10.1007/s10072-007-0848-3 . Epub 2008 Jan 4. PMID: 18175081 Kimber J, McLean BN, Prevett M, Hammans SR (2003) Allgrove or 4 A syndrome: an autosomal recessive syndrome causing multisystem neurological disease. J Neurol Neurosurg Psychiatry 74(5):654–657. 10.1136/jnnp.74.5.654 PMID: 12700313; PMCID: PMC1738415 Brown B, Agdere L, Muntean C et al (2016) Alacrima as a harbinger of adrenal insufficiency in a child with Allgrove (AAA) syndrome. Am J Case Rep 17:703–706 Grant DB, Barnes ND, Dumic M, Ginalska-Malinowska M, Milla PJ, von Petrykowski W, Rowlatt RJ, Steendijk R, Wales JH, Werder E (1993) Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child 68(6):779–782. 10.1136/adc.68.6.779 PMID: 8333772; PMCID: PMC1029374 Shah SWH, Butt AK, Malik K, Alam A, Shahzad A, Khan AA, AAA, Syndrome (2017 Nov-Dec) Case Report of a Rare Disease. Pak J Med Sci 33(6):1512–1516. 10.12669/pjms.336.13684 PMID: 29492088; PMCID: PMC5768854 Yıldırım R, Unal E, Tekmenuray-Unal A, Taş FF, Özalkak Ş, Çayır A, Özbek MN (2023) The clinical and laboratory features of patients with triple A syndrome: a single-center experience in Turkey. Endocrine. ;79(2):376–383. 10.1007/s12020-022-03206-5 . Epub 2022 Oct 4. PMID: 36194344 Salmaggi A, Zirilli L, Pantaleoni C, De Joanna G, Del Sorbo F, Koehler K, Krumbholz M, Huebner A, Rochira V (2008) Late-onset triple A syndrome: a risk of overlooked or delayed diagnosis and management. Horm Res 70(6):364–372 Epub 2008 Oct 27. PMID: 18953174 Weber A et al (1996) Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet 5(12):2061–2066 Cho AR, Yang KJ, Bae Y et al (2009) Tissue-specific expression and subcellular localization of ALADIN, the absence of which causes human triple A syndrome. Exp Mol Med 41:381–386. https://doi.org/10.3858/emm.2009.41.6.043 Angela Huebner AM, Kaindl KP, Knobeloch H, Petzold P, MannK.Koehler (2004) The Triple A Syndrome Is Due to Mutations in ALADIN, a Novel Member of the Nuclear Pore Complex. Endocr Res 30(4):891–899. 10.1081/ERC-200044138 Huebner A, Mann P, Rohde E, Kaindl AM, Witt M, Verkade P, Jakubiczka S, Menschikowski M, Stoltenburg-Didinger G, Koehler K (2006) Mice lacking the nuclear pore complex protein ALADIN show female infertility but fail to develop a phenotype resembling human triple A syndrome. Mol Cell Biol 26(5):1879–1887 PMID: 16479006; PMCID: PMC1430267 Cronshaw JM, Matunis MJ (2003) The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci U S A 100(10):5823–5827. 10.1073/pnas.1031047100 Epub 2003 May 2. PMID: 12730363; PMCID: PMC156285 Prasad R, Metherell LA, Clark AJ, Storr HL (2013) Deficiency of ALADIN impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis. Endocrinology. ;154(9):3209-18. doi: 10.1210/en.2013-1241. Epub 2013 Jul 3. PMID: 23825130; PMCID: PMC3958737 Prpic I, Huebner A, Persic M, Handschug K, Pavletic M (2003) Triple A syndrome: genotype–phenotype assessment. Clin Genet 63:415–417. https://doi.org/10.1034/j.1399-0004.2003.00070.x Houlden H, Smith S, De Carvalho M, Blake J, Mathias C, Wood NW, Reilly MM (2002) Clinical and genetic characterization of families with triple A (Allgrove) syndrome. Brain. ;125(Pt 12):2681-90. 10.1093/brain/awf270 . PMID: 12429595 Dumic M, Barišic N, Kusec V et al (2012) Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome. Eur J Pediatr 171:1453–1459. https://doi.org/10.1007/s00431-012-1745-1 Brooks BP, Kleta R, Stuart C, Tuchman M, Jeong A, Stergiopoulos SG, Bei T, Bjornson B, Russell L, Chanoine JP, Tsagarakis S, Kalsner L, Stratakis C (2005) Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000–2005. Clin Genet. ;68(3):215 – 21. 10.1111/j.1399-0004.2005.00482.x . PMID: 16098009 Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A (2001) Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. ;10(3):283 – 90. 10.1093/hmg/10.3.283 . PMID: 11159947 Dumić M, Barišić N, Rojnić-Putarek N et al (2011) Two siblings with triple A syndrome and novel mutation presenting as hereditary polyneuropathy. Eur J Pediatr 170:393–396. https://doi.org/10.1007/s00431-010-1314-4 Milenkovic T, Zdravkovic D, Savic N et al (2010) Triple A syndrome: 32 years experience of a single centre (1977–2008). Eur J Pediatr 169:1323–1328. https://doi.org/10.1007/s00431-010-1222-7 Milenković T, Koehler K, Krumbholz M, Zivanović S, Zdravković D, Huebner A (2008) Three siblings with triple A syndrome with a novel frameshift mutation in the AAAS gene and a review of 17 independent patients with the frequent p.Ser263Pro mutation. Eur J Pediatr. ;167(9):1049-55. 10.1007/s00431-007-0640-7 . Epub 2008 Jan 3. PMID: 18172684 Vezzoli V, Duminuco P, Pogliaghi G, Saccone M, Cangiano B, Rosatelli MC, Meloni A, Persani L, Bonomi M (2020) Two novel truncating variants of the AAAS gene causative of the triple A syndrome. J Endocrinol Invest 43(7):973–982. 10.1007/s40618-020-01180-1 Epub 2020 Jan 14. PMID: 31939195 Naseer A, Salih HA, Bhat S, Honnani SS (2024) A Rare Case of Allgrove Syndrome. Indian J Pediatr 91(1):104. 10.1007/s12098-023-04840-1 Epub 2023 Sep 16. PMID: 37715075 Flokas ME, Tomani M, Agdere L, Brown B (2019) Triple A syndrome (Allgrove syndrome): improving outcomes with a multidisciplinary approach. Pediatr Health Med Ther 10:99–106 PMID: 31695556; PMCID: PMC6718240 Weissensteiner H, Forer L, Fuchsberger C, Schöpf B, Kloss-Brandstätter A, Specht G, Kronenberg F, Schönherr S (2016) Nucleic Acids Res 44(W1):W64–W69. 10.1093/nar/gkw247 Epub 2016 Apr 15. PMID: 27084948; PMCID: PMC4987870 mtDNA-Server: next-generation sequencing data analysis of human mitochondrial DNA in the cloud Ralf A, Montiel González D, Zhong K, Kayser M, Yleaf (2018) Software for Human Y-Chromosomal Haplogroup Inference from Next-Generation Sequencing Data. Mol Biol Evol. ;35(5):1291–1294. 10.1093/molbev/msy032 . Erratum in: Mol Biol Evol. 2018;35(7):1820. doi: 10.1093/molbev/msy080. PMID: 29518227 Krumbholz M, Koehler K, Huebner A (2006) Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome - shedding light on an unexpected splice mutation. Biochem Cell Biol. ;84(2):243-9. 10.1139/o05-198 . PMID: 16609705 Nakamura K, Yoshida K, Yoshinaga T, Kodaira M, Shimojima Y, Takei Y, Morita H, Kayanuma K, Ikeda S (2010) Adult or late-onset triple A syndrome: case report and literature review. J Neurol Sci 297(1–2):85–88 Epub 2010 Aug 1. PMID: 20674935 Razavi Z, Taghdiri MM, Eghbalian F, Bazzazi N (2010) Premature Loss of Permanent Teeth in Allgrove (4A) Syndrome in Two Related Families. Iran J Pediatr 20(1):101–106 PMID: 23056690; PMCID: PMC3446014 Kilicli F, Acibucu F, Senel S, Dokmetas HS (2012) Allgrove syndrome. Singapore Med J. ;53(5):e92-4. PMID: 22584989 Bizzarri C, Benevento D, Terzi C, Huebner A, Cappa M, Triple A (2013) (Allgrove) syndrome: an unusual association with syringomyelia. Ital J Pediatr 39:39. 10.1186/1824-7288-39-39 PMID: 23800107; PMCID: PMC3704905 Sanyal D, Bhattacharjee S (2013) A case of late-onset allgrove syndrome presenting with predominant autonomic dysfunction. Ann Indian Acad Neurol 16(2):266–268. 10.4103/0972-2327.112494 PMID: 23956580; PMCID: PMC3724090 Alakeel A, Raynaud C, Rossi M, Reix P, Jullien D, Souillet AL (2015) Syndrome d'Allgrove [Allgrove syndrome]. Ann Dermatol Venereol. ;142(2):121-4. French. 10.1016/j.annder.2014.11.012 . Epub 2014 Dec 30. PMID: 25554662 Derrar R, Boutimzine N, Laghmari A, Alouane A, Daoudi R (2015) Alacrymie congénitale révélant un syndrome d'Allgrove: à propos de trois cas [Congenital alacrima revealing a Allgrove syndrome: report of three cases]. Pan Afr Med J. ;20:359. French. 10.11604/pamj.2015.20.359.4717 . PMID: 26185551; PMCID: PMC4495791 Misgar RA, Pala NA, Ramzan M, Wani AI, Bashir MI, Laway BA (2015) Allgrove (Triple A) Syndrome: A Case Report from the Kashmir Valley. Endocrinol Metab (Seoul) 30(4):604–606. 10.3803/EnM.2015.30.4.604 Epub 2015 Sep 10. PMID: 26354489; PMCID: PMC4722417 Li W, Gong C, Qi Z, Wu DI, Cao B (2015) Identification of AAAS gene mutation in Allgrove syndrome: A report of three cases. Exp Ther Med 10(4):1277–1282. 10.3892/etm.2015.2677 Epub 2015 Aug 10. PMID: 26622478; PMCID: PMC4578041 Jerie M, Vojtech Z, Malikova H, Prochazkova S, Vackova Z, Rolfs A (2016) Allgrove syndrome with prominent neurological symptoms. Case Report. Neuro Endocrinol Lett 37(3):184–188 PMID: 27618595 Kallabi F, Belghuith N, Aloulou H, Kammoun T, Ghorbel S, Hajji M, Gallas S, Chemli J, Chabchoub I, Azzouz H, Ben Chehida A, Sfaihi L, Makni S, Amouri A, Keskes L, Tebib N, Ben Becher S, Hachicha M, Kamoun H (2016) Clinical and Genetic Characterization of 26 Tunisian Patients with Allgrove Syndrome. Arch Med Res 47(2):105–110. 10.1016/j.arcmed.2016.04.004 Epub 2016 Apr 28. PMID: 27133709 Vahedi M, Fathi S, Allahbakhshi H (2016) Edentulous child with Allgrove syndrome: a rare case report. Korean J Pediatr 59(11):456–459. 10.3345/kjp.2016.59.11.456 Epub 2016 Nov 18. PMID: 27895694; PMCID: PMC5118506 van Tellingen V, Finken MJ, Israëls J, Hendriks YM, Kamp GA, van Santen HM (2016) Poorly Controlled Congenital Hypothyroidism due to an Underlying Allgrove Syndrome. Horm Res Paediatr 86(6):420–424. 10.1159/000446604 Epub 2016 Jun 3. PMID: 27255745; PMCID: PMC5296928 Berrani H, Meskini T, Zerkaoui M, Merhni H, Ettair S, Sefiani A, Mouane N (2018) Clinical and molecular report of c.1331 + 1G > A mutation of the AAAS gene in a Moroccan family with Allgrove syndrome: a case report. BMC Pediatr 18(1):184. 10.1186/s12887-018-1161-4 PMID: 29866068; PMCID: PMC5987581 de Freitas MRG, Orsini M, Araújo APQC, João Abraão L Jr, Barbosa GM, França MC, Correia L, Bastos VH, Trajano E, da Sant'Anna M Jr (2018) Allgrove syndrome and motor neuron disease. Neurol Int 10(2):7436 PMID: 30069287; PMCID: PMC6050446 Kurnaz E, Duminuco P, Aycan Z, Savaş-Erdeve Ş, Muratoğlu Şahin N, Keskin M, Bayramoğlu E, Bonomi M, Çetinkaya S (2018) Clinical and genetic characterisation of a series of patients with triple A syndrome. Eur J Pediatr 177(3):363–369. 10.1007/s00431-017-3068-8 Epub 2017 Dec 19. PMID: 29255950 Nakamura J, Hikichi T, Inoue H, Watanabe K, Kikuchi H, Takagi T, Suzuki R, Sugimoto M, Konno N, Waragai Y, Asama H, Takasumi M, Sato Y, Irie H, Obara K, Ohira H (2018) Per-oral endoscopic myotomy for esophageal achalasia in a case of Allgrove syndrome. Clin J Gastroenterol 11(4):273–277. 10.1007/s12328-018-0819-7 Epub 2018 Jan 30. PMID: 29383495 Akram S, Khan MA, Rehman A (2018) Allgrove syndrome: case report of 7 years old boy from Bahawalpur. J Pak Med Assoc 68(8):1260–1262 PMID: 30108399 Lu C, Lee TA, Pan DH, Pereira EM, Zhou P (2019) Clinical course of a unique case of Allgrove syndrome and challenges of hypoglycemia management. AACE Clin Case Rep 5(6):e357–e361. 10.4158/ACCR-2019-0210 PMID: 31967070; PMCID: PMC6873850 Bitetto G, Ronchi D, Bonato S, Pittaro A, Compagnoni GM, Bordoni A, Salani S, Frattini E, Lopez G, Cribiù FM, Corti S, Comi GP, Bresolin N, Di Fonzo A (2019) Loss of the nucleoporin Aladin in central nervous system and fibroblasts of Allgrove Syndrome. Hum Mol Genet. ;28(23):3921–3927. 10.1093/hmg/ddz236 . PMID: 31600784 Gupta S, Dayal D (2020) Allgrove Syndrome and a Novel Mutation of AAAS Gene in a Boy. Indian Pediatr. ;57(1):82. PMID: 31937715 Polat R, Ustyol A, Tuncez E, Guran T (2020) A broad range of symptoms in allgrove syndrome: single center experience in Southeast Anatolia. J Endocrinol Invest 43(2):185–196. 10.1007/s40618-019-01099-2 Epub 2019 Aug 21. PMID: 31435881 Zheng H, Iyer RS, Pacheco MC, Soares JJ, Johnson K, Len M, Ambartsumyan L (2020) Respiratory infections and chronic cough due to triple A (Allgrove) syndrome. Clin Case Rep 8(3):437–440 PMID: 32185032; PMCID: PMC7069866 Yadav P, Kumar D, Bohra GK, Garg MK (2020) Triple A syndrome (Allgrove syndrome) - A journey from clinical symptoms to a syndrome. J Family Med Prim Care 9(5):2531–2534. 10.4103/jfmpc.jfmpc_237_20 PMID: 32754538; PMCID: PMC7380807 Jabbour S, Hamel P, Soucy JF, Ospina LH, Allgrove Syndrome (2020) A Report of New Pathological Variants in the AAAS Gene. Cornea. ;39(6):782–783. doi: 10.1097/ICO.0000000000002287. PMID: 32073457 Rizzo R, Balassone V, Torroni F, De Angelis P, Dall'Oglio L (2020) Peroral endoscopic myotomy in a child with Triple A syndrome (Allgrove syndrome). VideoGIE 5(6):235–237. 10.1016/j.vgie.2020.02.007 PMID: 32529155; PMCID: PMC7276969 Jayant SS, Gupta R, Agrawal K, Das L, Dutta P, Bhansali A, Triple A (2021) (Allgrove) syndrome due to AAAS gene mutation with a rare association of amyotrophy. Horm (Athens) 20(1):197–205. 10.1007/s42000-020-00217-7 Epub 2020 Jul 22. PMID: 32700293 Volkova NI, Davidenko IY, Reshetnikov IB, Brovkina SS (2020) [Allgrove syndrome: how to suspect the problem? Endocrinologists experience]. Probl Endokrinol (Mosk). ;66(1):64–69. Russian. 10.14341/probl10296 . PMID: 33351314 Miyazawa H, Kimura M, Yonezawa H, Maeda T (2021) Sporadic Triple A (Allgrove) Syndrome with Novel Tandem Mutations. Intern Med 60(5):799–802. 10.2169/internalmedicine.5201-20 Epub 2020 Oct 21. PMID: 33087664; PMCID: PMC7990642 Alhassoun M, Almakadma AH, Almustanyir S, AlLehibi A, Alotaibi N, Triple AM, Disorder (2021) Allgrove Syndrome Cureus 13(8):e17476. 10.7759/cureus.17476 PMID: 34513526; PMCID: PMC8405170 Rivera-Suazo Y, Espriu-Ramírez MX, Trauernicht-Mendieta SA, Rodríguez L (2021 Oct-Dec) Allgrove syndrome in a toddler: Alacrima and achalasia, with no adrenal insufficiency. Rev Gastroenterol Mex (Engl Ed). 86(4):441–443 Epub 2021 Aug 18. PMID: 34417164 Weiman DI, Gillespie MK, Hartley T, Osmond M, Ito Y, Care4Rare Canada Consortium, Boycott KM, Kernohan KD, Lines M, McMillan HJ (2021) Neurophysiological Characteristics of Allgrove (Triple A) Syndrome: Case Report and Literature Review. Child Neurol Open 8:2329048X211031059. 10.1177/2329048X211031059 PMID: 34796249; PMCID: PMC8594529 AlOmran HA, Busaleh F, Alhashim Z, AlHelal M, Alsaleh Y, AlJabri A, AlGhadeer ZA, AlHejji FY, AlMazeedi M, Al Dandan AM (2021) Mineralocorticoid Deficiency as an Early Presenting Symptom of Allgrove Syndrome With Novel Mutation: A Case Report. Cureus 13(11):e19316. 10.7759/cureus.19316 PMID: 34900490; PMCID: PMC8648336 Hanino N, Swed S, Zakkor MD, Hindawy A, Alibrahim H, Alhussein H (2021) Allgrove syndrome: Case report of 18 years old male:the first case report from Syria. Ann Med Surg (Lond) 72:103009 PMID: 34820119; PMCID: PMC8600000 Kronenberg G, Guillery SPE, Harms L, Kunte H (2021) The Classic Triad of Triple A (Allgrove) Syndrome. Neurol Clin Pract 11(6):e916–e917. 10.1212/CPJ.0000000000001010 PMID: 34992981; PMCID: PMC8723963 Agarwal A, Das A, Pandit AK, Radhakrishnan DM, Rajan R, Faruq M, Srivastava AK (2022 May-Jun) Allgrove Syndrome: A Frequently Under-Diagnosed ALS Mimic. Ann Indian Acad Neurol 25(3):500–501. 10.4103/aian.aian_594_21 Epub 2021 Oct 22. PMID: 35936640; PMCID: PMC9350801 Botella García J, Lázaro-Rodríguez V, de la Paz MF (2022) The use of topical cyclosporine A 0.05% as treatment for primary alacrimia in Allgrove syndrome. Eur J Ophthalmol 32(1):NP9–NP11. 10.1177/1120672120945109 Epub 2020 Jul 22. PMID: 32698619 Soares MC, Lins OG, Lima de Carvalho JR et al (2022) Allgrove syndrome with amyotrophy. Pract Neurol 22:213–215. 10.1136/practneurol-2021-003192 Macke EL, Morales-Rosado JA, Macklin-Mantia SK, Schmitz CT, Oskarsson B, Klee EW, Wierenga KJ (2022) Functional validation of a novel AAAS variant in an atypical presentation of Allgrove syndrome. Mol Genet Genomic Med 10(7):e1966. 10.1002/mgg3.1966 Epub 2022 May 15. PMID: 35570467; PMCID: PMC9266593 Eid M, Chreitah A, Aljanati O, Mohammed A, Melhem I, Alkilany Z (2022) A rare case of Allgrove Syndrome associated with growth hormone deficiency in an 8-year-Old child: A case report. Ann Med Surg (Lond) 81:104352 PMID: 36147172; PMCID: PMC9486606 Alhalabi M, Alsayd S, Alboushi E (2022) Allgrove syndrome: a case report. Oxf Med Case Rep 2022(10):omac104. 10.1093/omcr/omac104 PMID: 36299673; PMCID: PMC9589468 Bitetto G, Lopez G, Ronchi D, Pittaro A, Melzi V, Peverelli E, Cribiù FM, Comi GP, Mantovani G, Di Fonzo A (2023) SCARB1 downregulation in adrenal insufficiency with Allgrove syndrome. Orphanet J Rare Dis 18(1):152. 10.1186/s13023-023-02763-w PMID: 37331934; PMCID: PMC10278336 Vigano' M, Mantero V, Basilico P, Pirro F, Ronchi D, Di Fonzo A, Salmaggi A (2023) Don't forget Allgrove syndrome in adult patients as a bulbar-ALS mimicker. Neurol Sci 44(10):3703–3705. 10.1007/s10072-023-06961-z Epub 2023 Jul 17. PMID: 37458842 Gupta J, Chowdhury SR, Jauhari P, Ragunathan K, Chakrabarty B, Jain V, Gulati S (2024) Child Neurology: Allgrove Syndrome: An Intriguing Etiology of Motor Neuron Disease in Children. Neurology 102(4):e208049. 10.1212/WNL.0000000000208049 Epub 2024 Jan 25. PMID: 38271654 Cehic Maja M, Katarina V, Rade M, Tatjana K, Gordana T, Sladjana PZ, Sanja C, Dimitrije P, Aleksandra (2024) Huebner Angela, Koehler Katrin, Quitter Friederike Very early and severe presentation of Triple A syndrome – case report and review of the literature. Front Endocrinol Volume 15–2024. 10.3389/fendo.2024.1431383 Maaloul I, Aloulou H, Bessghaier W, Ameur SB, Chabchoub I, Khalfallah R, Kamoun H, Morel Y, Kamoun T Primary adrenal insufficiency in children excluding congenital adrenal hyperplasia: insights from 33-year single-center experience in Tunisia. Arch Pediatr. 2025 Jan 27:S0929-693X(25)00019 – 3. doi: 10.1016/j.arcped.2024.10.010. Epub ahead of print. PMID: 39875217 Additional Declarations No competing interests reported. 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in IGV software (Integrative Genomic Viewer \u003cbr\u003e\n(chr12: 53,703,408) (Total coverage: 116, A (ref.): 0 (0%) \u0026gt; G (alt.): 116 (100%)) \u003cbr\u003e\n \u003cstrong\u003eb. \u003c/strong\u003eThe localization of identified variant in UCSC Genome Browser (chr12 q13.13)(rs121918550 A/G). \u003cbr\u003e\n \u003cstrong\u003ec.\u003c/strong\u003e The graphic from GeneBank (\u003cem\u003eHomo sapiens\u003c/em\u003e, NCBI Reference Sequence: NP_ 056480.1) shows amino acid sequence of ALADIN protein- the position of the identified mutation p.Ser263Pro in WD-3 (TGA-TGG: UCA-CCA: Ser-Pro) is indicated by an arrow and highlight.\u003c/p\u003e","description":"","filename":"floatimage12.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6962259/v1/8de8a45851f114b82bd4516f.jpeg"},{"id":87360856,"identity":"8ea515a6-0c2b-425c-9004-dfcc543d9f18","added_by":"auto","created_at":"2025-07-23 05:49:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":120288,"visible":true,"origin":"","legend":"\u003cp\u003eThe scheme of \u003cem\u003eAAAS\u003c/em\u003e gene displaying pathogenic/likely pathogenic variants reported in the literature.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6962259/v1/28ebbace15f4b62ff6eb70b4.png"},{"id":87360860,"identity":"3280c21f-bc49-4b34-ac78-0dac8247de3f","added_by":"auto","created_at":"2025-07-23 05:49:44","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":154466,"visible":true,"origin":"","legend":"\u003cp\u003ePedigree of the family with autosomal recessive inheritance pattern of c.787T\u0026gt;C variant in \u003cem\u003eAAAS\u003c/em\u003e gene. Square and circle symbols represent males and females respectively. Black-filled symbols indicates members with Allgrove syndrome and half shaded square represents the healthy carrier of the heterozygous variant. The abbreviation N/A (not available) refers to lack of possibility of testing unaffected parents.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6962259/v1/dda3c05df27fb465727d197c.jpeg"},{"id":87362821,"identity":"f922011f-07f9-4232-8502-e6510233f77b","added_by":"auto","created_at":"2025-07-23 05:57:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":96994,"visible":true,"origin":"","legend":"\u003cp\u003eThe chart summarizing origin of patients carrying the c.787T\u0026gt;C p.(Ser263Pro) variant in \u003cem\u003eAAAS\u003c/em\u003egene and diagnosed with Allgrove syndrome who have been reported in the literature (N=34/206).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6962259/v1/925114a6b91359ce84c8f4be.png"},{"id":100069428,"identity":"db3e394d-f276-4ac6-a952-33fda1ef932b","added_by":"auto","created_at":"2026-01-12 16:13:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1680055,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6962259/v1/e1c2b033-4d1d-41b9-a3e8-b9dc01c098c9.pdf"},{"id":87360859,"identity":"a15de94c-a97f-45cd-8666-ecfbc31568f6","added_by":"auto","created_at":"2025-07-23 05:49:44","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":74578,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable1finalAPv323.06.202515.07.docx","url":"https://assets-eu.researchsquare.com/files/rs-6962259/v1/bdc514d9b97376df33cceb1e.docx"},{"id":87362820,"identity":"b7545d94-4cb6-4df3-a74a-b953ad9796fb","added_by":"auto","created_at":"2025-07-23 05:57:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23153,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable218.04.202515.07.docx","url":"https://assets-eu.researchsquare.com/files/rs-6962259/v1/e86372bd04e070ed6f6df2fd.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neurological manifestations of Allgrove syndrome in patients carrying a potentially founder p.Ser263Pro variant of the AAAS gene","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAllgrove syndrome (AS, Triple A syndrome) (OMIM #231550) is a rare, multisystem disorder characterized by the triad of symptoms: achalasia, alacrimia and ACTH-resistant adrenal insufficiency [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. AS is one of two inherited ACTH resistance syndromes, beside the familial glycocorticoids deficiency (FGD) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and is usually diagnosed by early childhood. However patients may also develop symptoms during adulthood and then they show mainly neurological features [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] including: spasticity, peripheral neuropathy, hyperreflexia, optic atrophy, sensory impairment, myopathy/muscle weakness, developmental delay or dementia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Rarity and non-specific clinical traits of late-onset forms of AS may contribute to delayed diagnosis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The exact incidence of AS is unknown, according to Orphanet fewer than 100 cases have been published (ORPHA: 869), but we found at least 206 described patients in the literature. Allgrove syndrome is caused by homozygous or compound heterozygous, loss-of-function mutations in \u003cem\u003eAAAS\u003c/em\u003e gene located on chromosome 12q13.13 (chr12:53307456–53324864) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The \u003cem\u003eAAAS\u003c/em\u003e mRNA is highly expressed in adrenal cortex, pituitary gland, esophagus gastroesophageal junction and neural tissue [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The \u003cem\u003eAAAS\u003c/em\u003e gene consists of 16 exons and encodes a 546-amino-acid, 60-kDa protein ALADIN (acronym for: alacrima-achalasia-adrenal insufficiency-neurologic disorder), which belongs to the tryptophan aspartic acid (WD) repeat protein family and is component of the nuclear pore complexes (NPC) involved in nucleocytoplasmic transport, transmembrane signaling and cell division [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The precise function of ALADIN and molecular mechanisms leading to the wide range of AS-related phenotypical features remain only partly understood, but functional studies by Cronshaw et al show that mutated ALADIN proteins are mislocalized to the cytoplasm, instead of the wild-types bounded to NPCs [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In addition, Prasad et al described the role of ALADIN protein in maintenance of redox homeostasis in adrenal cells and inhibition of steroidogenesis [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe purpose of the study was to investigate possible genotype and phenotype correlations among carriers of p.Ser263Pro variant based on the review of already published patients diagnosed with Allgrove syndrome and exemplify the predominance of neurological symptoms in novel family case of twin brothers who carried biallelic pathogenic variant p.Ser263Pro in \u003cem\u003eAAAS\u003c/em\u003e.\u003c/p\u003e"},{"header":"Case description","content":"\u003cp\u003e40-year-old twins were referred to the Outpatient Clinical Genetics Department due to similar symptoms including: sensorimotor polyneuropathy, hemiparesis, dysphagia, defective tears formation, lower limb muscle weakness. Their cognitive functions remained relatively high. Electromyography revealed advanced form of axonal-demyelinating sensorimotor polyneuropathy in both patients. The first symptoms were observed in childhood as: late onset of walking, imbalance, gait abnormalities and reduced mobility compared to their peers. Another neurological features evolves over time and included: hypersensitivity to cold, sensory disturbances and paresthesia around the lower legs, feet and fingertips, difficulties with precise movements, slurred speech and swallowing disorders.\u003c/p\u003e\u003cp\u003eDue to the worsening symptoms related with limited tear secretion, dry hands and mouth the brothers were primary diagnosed with Sjögren’s syndrome. The following clinical features were observed: very low muscle mass, atrophy of the intercostals muscles, hollow feet, toe deformities and wide-based gait. One brother also had refraction defect, farsightedness and astigmatism, while the other remains under the care of a rheumatologist due to Raynaud's sign.\u003c/p\u003e\u003cp\u003eThe patients were firstly tested for the most frequent form of inherited axonal-demyelinating sensorimotor polyneuropathy which is Charcot-Marie-Tooth type 1A using MLPA (Multiplex Ligation-dependent Probe Amplification). We searched for copy number variations (CNVs) involving \u003cem\u003ePMP22\u003c/em\u003e, \u003cem\u003eCOX10\u003c/em\u003e and \u003cem\u003eTEKT3\u003c/em\u003e genes located in the region on chromosome 17p12 using SALSA MLPA probemix P033 Charcot-Marie-Tooth (chromosome 17p12) (\u003cem\u003eMRC Holland\u003c/em\u003e, Amsterdam, Netherlands) according to manufacturer protocol. In the analyzed region of chromosome 17 no microdeletions or microduplications were detected. Subsequently, whole exome sequencing (WES) was performed. Exomic regions and 37 genes of the mitochondrial genome (16,659 base pairs) were sequenced using NovaSeq 6000 on Illumina platform (2 x 100 base pairs). The results were analyzed using VariantStudio Software v.3.0 (Illumina), Integrative Genomics Viewer (IGV) v.2.3. and genetic, clinical and population databases: OMIM, dbSNP, ClinVar, Orphanet, ClinGen, HGMD and gnomAD. WES revealed in both brothers the presence of a homozygous missense variant: T \u0026gt; C transition at nucleotide position 787 in exon 8 on both alleles of the \u003cem\u003eAAAS\u003c/em\u003e gene (c.787T \u0026gt; C) (12:53309624:T-C, GRCh38) (NM_015665.5) (Fig.\u0026nbsp;1). The identified SNV (single nucleotide variaton) has been previously reported in the literature in patients with Allgrove syndrome phenotype [\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] and was presented in following databases: dbSNP (rs121918550), ClinVar: classified SNV as pathogenic/likely pathogenic (Variation ID: 5045), ClinGen (CA117228), Human Gene Mutation Database (HGMD, Public Entries): genotype was correlated with phenotype of Triple A syndrome (CM010150) and gnomAD v.4.1.0 with total allele frequency: 0.007622% (0.00007622) worldwide and 0.007034% (0.00007034) in European (non-Finnish) population. mtDNA and Y chromosome haplogroups were determined using the mtDNAserver and Yleaf algorithms [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e–\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The proband's maternal line (haplogroup H1) and paternal line (haplogroup R1a) confirm his European ancestry.\u003c/p\u003e\u003cp\u003eThe analyzed missense variant was located within third WD (tryptophan aspartic acid) repeat resulting in the replace of a polar serin with non-polar proline at amino acid position 263 of ALADIN protein (p.Ser263Pro) (NP_056480.1) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The alteration in the third-WD repeat disrupts the formation of a typical form of beta-propeller structure, responsible for interactions with several proteins, including the NPC complex [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Functional studies regarding p.Ser263Pro mutation carried out by Milenković et al using HeLa cell lines confirmed the altered localization of mutant ALADIN to the cytosol caused by inhibition of the connection to the NPC complex [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Although the effect of the misfolded protein due to mutated third WD-repeat on the change in cellular localization has been proven, however, the impact of the function is still not completely understood. The \u003cem\u003ein silico\u003c/em\u003e predictors indicates that this mutation disturbs the function of AAAS protein (MutationTaster: disease causing, PROVEAN and SIFT: damaging, REVEL: 0,844- pathogenic moderate, AlphaMissense: 0.985- likely pathogenic). The bioinformatic analysis of identified variant confirmed its pathogenicity as recommended by the American College of Medical Genetics and Genomics (ACMG).\u003c/p\u003e\u003cp\u003eVariant segregation analysis using Sanger sequencing method revealed that healthy brother is a carrier of the heterozygous variant c.787T \u0026gt; C, parents denied genetic testing. The family history shows that examined brother, as well as parents, did not show any symptoms of achalasia, alacrymia, adrenal insufficiency or neurological symptoms similar to affected twins. Taking into consideration the numerous scientific reports describing the role of identified variant in Allgrove syndrome and the result of the segregation analysis performed on the healthy brother, the mode of autosomal recessive inheritance is the most probable (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Finally, both patients were diagnosed with Allgrove syndrome due to their clinical features and the presence of the homozygous p.Ser263Pro variant of the \u003cem\u003eAAAS\u003c/em\u003e gene, allowing them to receive specialized medical care (endocrinologist, neurologist, ophthalmologist) and appropriate introduction of therapies: hydrocortisone replacement therapy to reduce the risk of potentially life-threatening adrenal insufficiency and artificial tears to avoid the discomfort associated with alacrimia.\u003c/p\u003e\u003cp\u003e\u003cb\u003eGenotype-phenotype correlation of p.Ser263Pro variant in the\u003c/b\u003e \u003cb\u003eAAAS\u003c/b\u003e \u003cb\u003egene\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe reviewed the literature and found in total n = 206 patients diagnosed with Triple A syndrome, for whom phenotypic description was provided (Supplementary Table\u0026nbsp;1) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e–\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan additionalcitationids=\"CR61 CR62 CR63 CR64 CR65 CR66 CR67\" citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e–\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan additionalcitationids=\"CR72 CR73 CR74 CR75\" citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e–\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]. Among 206 reported AS cases- 28 (13.6%) have not been genetically tested and diagnosed based only on clinical features- all of these patients have presented triad of symptoms: alacrimia, achalasia and adrenal insufficiency. The remaining 178 (86.4%) patients carried pathogenic or likely pathogenic variants in \u003cem\u003eAAAS\u003c/em\u003e gene, in 34 out of 178 cases p.Ser236Pro was identified (n = 34/178, 19.1%). In this group there was n = 21 homozygous carriers of p.Ser263Pro variant and n = 13 compound heterozygous patients who carried single p.Ser263Pro variant of \u003cem\u003eAAAS\u003c/em\u003e gene. Neurological symptoms including: progressive peripheral neuropathy (motor and sensory), mild mental retardation and developmental delay, learning difficulties, muscle weakness, hypotonia and muscle atrophy, gait disturbance, brisk tendon reflexes, hyperreflexia, optic atrophy were described in 33 out of 34 carriers of at least single p.Ser263Pro variant (both homo- and compound heterozygous) as compared to the n = 133 out of n = 172 remaining patients diagnosed with Triple A syndrome (p = 77.3%) (chi2 test p = 0.006).\u003c/p\u003e\u003cp\u003eWith respect to the possible founder origin of p.Ser263Pro variant of \u003cem\u003eAAAS\u003c/em\u003e gene Dumic et al identified this alterations in five patients: one homozygous and four compound heterozygous (2 patients: p.Ser263Pro and p.Gly14fs and 2 other patients: p.Ser263Pro and p.Ser296Tyr), supporting the hypothesis that p.Ser263Pro may be a founder mutation in the Slavic population [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Moreover, molecular studies by Handschug et al detected the p.Ser263Pro mutation in four families: two Polish patients carrying the homozygous variant and two other patients with compound heterozygous mutations: p.Ser263Pro and on the second affected allele: Ser463fsTer (in a Polish family) and Gln15Lys (in a German family) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Milenković et al further described three siblings from a Serbian family (a 12-year-old girl and 5, 3.5-year-old boys) who were compound heterozygotes in the \u003cem\u003eAAAS\u003c/em\u003e gene: p.Ser263Pro and p.Val421GlyfsTer. They also described 17 patients with the p.Ser263Pro mutation, within this group, 12 out of 17 coming from the Slavic region [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Pripić et al reported another 3 cases carrying p.Ser263Pro variant- 1 homozygous and 2 heterozygous with respectively p.Gln15Lys and p.Gln387Ter on the other allele [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Recently, Cehic et al have described a case report of infant carrying p.Ser236Pro and p.Gln387Ter variants with triad, hyperpigmentation and neurological symptoms (generalized hypotonia, muscle weakness, developmental delay) observed. [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]. The origin of these 4 recently diagnosed patients remains unknown. In addition, to the best of our knowledge 23 out of 34 carriers of p.Ser263Pro variant (67.7%) already reported in literature, were of Slavic origin (Croatia: 10, Poland: 6, Serbia: 3, Slovenia: 2 Czech Republic: 1, Hungary: 1). Homozygous variant have been identified in 21 out of 34 cases- in which Slavic origin were confirmed in 15 patients (71.4%) (Croatia: 6, Poland: 5, Slovenia: 2, Hungary: 1, Czech Republic: 1) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The remaining 13 patients carried heterozygous mutations: p.Gln15Lys (4 cases), p.Val421GlyfsTer5 (3 cases), p.Gln387Ter (2 cases), p.Ser296Tyr (2 cases), p.Phe464SerfsTer87, p.Pro426ThrfsTer15 and 8 out of 13 were Slavic origin (Croatia: 4, Serbia: 3, Poland: 1). In 4 out of 13 cases origin were not precisely described, one patient carrying p.Gln15Lys on the second allele came from German family. Our report presenting Polish twins with homozugous p.Ser263Pro supports the founder mutation hypothesis.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTriple A syndrome is a rare, progressive disorder that varies in age of onset and severity of endocrine, gastrointestinal and neurological symptoms. The condition was firstly described by Jeremy Allgrove in 1978, who reported two pairs of siblings (3 boys and a girl aged 4\u0026ndash;6 years) from separate families suffering from adrenal insufficiency, gastric achalasia and defective tear secretion [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. AS is mainly diagnosed in early childhood, but in adult patients other clinical features, mainly neurological, may also occur [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. This is a devastating disorder that affects patient\u0026rsquo;s quality of life and can potentially even be life-threatening due to adrenal insufficiency (episodes of hypoglycemia and seizures) and severe neurological impairment [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR40 CR41\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. The diagnosis of AS may allow the indication of appropriate treatment that significantly improves patients\u0026rsquo; quality of life: pharmacological glucocorticoid replacement therapy with hydrocortisone, surgical esophageal dilation, artificial tears due to insufficient tear production and symptomatic treatment of neurological symptoms [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan additionalcitationids=\"CR51\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. Patients also require genetic counseling of entire family and multidisciplinary specialized medical care provided by endocrinologists, neurologists, gastroenterologists, ophthalmologists and surgeons [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan additionalcitationids=\"CR56\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]. We describe a Polish family with two adult (40-year-old) twin brothers who presented mainly neurological symptoms. Molecular studies revealed the presence of a pathogenic homozygous p.Ser263Pro variant of the \u003cem\u003eAAAS\u003c/em\u003e gene, previously described in the literature in patients with the Allgrove syndrome phenotype [\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]. According to our review of literature, neurological manifestations are very common among p.Ser263Pro carriers and may include: progressive peripheral neuropathy, muscle weakness, gait disturbance, optical atrophy and mild mental retardation. Interestingly, neurological symptoms have been presented in 33 out of 34 p.Ser263Pro carriers (97.1%), in opposite to \u0026ldquo;classical\u0026rdquo; triad, which were presented only in 18 out of 34 (52.9%). The remaining 16 patients showed at least one manifestation of the triad and except three cases- they all have presented alacrimia. In general, among 206 reported patients 166 presented neurological symptoms (80,5%) and all manifestation of classical triad have been observed in 110 out of 206 patients (53.4%).\u003c/p\u003e\u003cp\u003eMilenković et al concluded that molecular genetic tests can play a supportive role in diagnosing Allgrove syndrome, but do not predict the phenotype [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Summarizing 32 years of experience in diagnosing AS, Milenković et al recommended molecular genetic testing and adrenal function testing in patients with alacrimia and at least one other feature of the condition [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eInterestingly, the initial symptoms in our patients were neurological ones already present in childhood. Dumić et al also described a case of two siblings (a 3.5-year-old girl and a 5.5-year-old boy) with early onset of neurological symptoms and a compound heterozygous mutation consisting of p.Ser296Tyr and p.Ser263Pro variants. The authors pointed to the important role of discovering more patients with p.Ser263Pro, one of the most common mutations in the \u003cem\u003eAAAS\u003c/em\u003e gene in the European Caucasian population, to find correlations with severity, age of onset and variability of symptoms in patients with Allgrove syndrome [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Vezzoli et al identified two novel variants of the \u003cem\u003eAAAS\u003c/em\u003e gene in the Italian population\u0026ndash; a frameshift substitution located in exon 8: p.Gly256TrpfsTer67 and a splice-site mutation in intron 11: c.997-2A\u0026thinsp;\u0026gt;\u0026thinsp;G [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In the past year, four studies reported patients with Allgrove syndrome: Yıldırım et al described 12 cases carrying biallelic variants in the \u003cem\u003eAAAS\u003c/em\u003e gene, two of which were novel splice-site mutations: c.1250-1G\u0026thinsp;\u0026gt;\u0026thinsp;A and c.398_399\u0026thinsp;+\u0026thinsp;2del [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Naseer et al described a 17-year-old boy with clinical features of Allgrove syndrome (alacrimia, achalasia, dysphagia, weight loss, adrenal insufficiency with generalized hyperpigmentation and weakness) and significant improvement after hydrocortisone replacement therapy [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Gupta et al reported two another AS patients carrying: c.43C\u0026thinsp;\u0026gt;\u0026thinsp;A homozygous variant and one compound heterozygous: c.312dupA and c.307\u0026thinsp;+\u0026thinsp;4_307\u0026thinsp;+\u0026thinsp;7del [\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]. Maaloul I. et al (2025) reported 14 homozygous carriers of c.1331\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A mutation and one c.856C\u0026thinsp;\u0026gt;\u0026thinsp;T, among which all presented classical AS triad and also hyperpigmentation, but neurological symptoms was observed in only 9 out of 15 cases [\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur case report is further evidence supporting the pathogenicity of p.Ser263Pro variant in the \u003cem\u003eAAAS\u003c/em\u003e gene which is probably a founder mutation in the European Caucasian population, possibly in the Slavic ethnic group. Molecular testing is recommended in patients with even scarce phenotypical features suggestive for Allgrove syndrome, since the whole triad of symptoms is not obligatory present in all the individuals with AS. Particularly in carriers of p.Ser263Pro variant the neurological phenotype may predominate.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACTH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Adrenocorticotropic hormone\u003c/p\u003e\n\u003cp\u003eAS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Allgrove syndrome\u003c/p\u003e\n\u003cp\u003eCNV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Copy Number Variation\u003c/p\u003e\n\u003cp\u003eEDTA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Ethylenediaminetetraacetic acid disodium salt\u003c/p\u003e\n\u003cp\u003eFGD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Familial glucocorticoid deficiency\u003c/p\u003e\n\u003cp\u003eMLPA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Multiplex Ligation-dependent Probe Amplification\u003c/p\u003e\n\u003cp\u003eNGS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Next Generation Sequencing\u003c/p\u003e\n\u003cp\u003eNPC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Nuclear Pore Complex\u003c/p\u003e\n\u003cp\u003eSNV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Single Nucleotide Variation\u003c/p\u003e\n\u003cp\u003eWES \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Whole Exome Sequencing\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting interests:\u003c/h2\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study. The authors have no financial or proprietary interests in any material discussed in this article.\u003c/p\u003e\n\u003ch2\u003eFunding Declaration\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003e\u003c/strong\u003eNo funding was received to assist with the preparation of this manuscript. The authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eConceptualization: Agata Pastorczak, Agnieszka Zmysłowska; Methodology: Tomasz Płoszaj, Michał Pietrusiński, Karolina Gadzalska; Formal analysis and investigation: Karolina Gadzalska, Paulina Jakiel, Monika Gorządek, Sebastian Skoczylas, Klaudia Starosz, Ewa Juścińska; Writing - original draft preparation: Ewa Juścińska; Writing - review and editing: Agata Pastorczak, Agnieszka Zmysłowska; Literature search: Ewa Juścińska; Supervision: Agata Pastorczak, Maciej Borowiec, Agnieszka Zmysłowska. All authors read and approved the final manuscript.Funding Declaration: No funding was received to assist with the preparation of this manuscript. The authors did not receive support from any organization for the submitted work.Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. Additional information: Informed consent was obtained from all individual participants included in the study. The authors have no financial or proprietary interests in any material discussed in this article.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAllgrove J, Clayden GS, Grant DB, Macaulay JC (1978) Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. ;1(8077):1284-6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0140-6736(78)91268-0\u003c/span\u003e\u003cspan address=\"10.1016/s0140-6736(78)91268-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 78049\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMetherell LA, Chan LF, Clark AJ (2006) The genetics of ACTH resistance syndromes. Best Pract Res Clin Endocrinol Metab. ;20(4):547\u0026thinsp;\u0026ndash;\u0026thinsp;60. doi: 10.1016/j.beem.2006.09.002. PMID: 17161331\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCooray SN, Chan L, Metherell L, Storr H, Clark AJL (2008) Adrenocorticotropin resistance syndromes. Endocr Dev. ;13:99\u0026ndash;116. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000134828\u003c/span\u003e\u003cspan address=\"10.1159/000134828\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 18493136\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVallet AE, Verschueren A, Petiot P, Vandenberghe N, Nicolino M, Roman S, Pouget J, Vial C (2012) Neurological features in adult Triple-A (Allgrove) syndrome. J Neurol 259(1):39\u0026ndash;46. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00415-011-6115-9\u003c/span\u003e\u003cspan address=\"10.1007/s00415-011-6115-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2011 Jun 9. PMID: 21656342\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGaiani F, Gismondi P, Minelli R, Casadio G, de'Angelis N, Fornaroli F, de'Angelis GL, Manfredi M (2020) Case report of a familial triple: a syndrome and review of the literature. Medicine (Baltimore). ;99(22):e20474. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MD.0000000000020474\u003c/span\u003e\u003cspan address=\"10.1097/MD.0000000000020474\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 32481456\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePedreira CC, Zacharin MR (2004) Allgrove syndrome: when a recognisable paediatric disorder occurs in adulthood. Med J Aust. ;180(2):74\u0026thinsp;\u0026ndash;\u0026thinsp;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5694/j.1326-5377.2004.tb05803.x\u003c/span\u003e\u003cspan address=\"10.5694/j.1326-5377.2004.tb05803.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 14723589\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGilio F, Di Rezze S, Conte A, Frasca V, Iacovelli E, Marini Bettolo C, Gabriele M, Giacomelli E, Pizzuti A, Pirro C, Fattapposta F, Habib FI, Prencipe M, Inghilleri M (2007) Case report of adult-onset Allgrove syndrome. Neurol Sci. ;28(6):331-5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10072-007-0848-3\u003c/span\u003e\u003cspan address=\"10.1007/s10072-007-0848-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2008 Jan 4. PMID: 18175081\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKimber J, McLean BN, Prevett M, Hammans SR (2003) Allgrove or 4 A syndrome: an autosomal recessive syndrome causing multisystem neurological disease. J Neurol Neurosurg Psychiatry 74(5):654\u0026ndash;657. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/jnnp.74.5.654\u003c/span\u003e\u003cspan address=\"10.1136/jnnp.74.5.654\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 12700313; PMCID: PMC1738415\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrown B, Agdere L, Muntean C et al (2016) Alacrima as a harbinger of adrenal insufficiency in a child with Allgrove (AAA) syndrome. Am J Case Rep 17:703\u0026ndash;706\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGrant DB, Barnes ND, Dumic M, Ginalska-Malinowska M, Milla PJ, von Petrykowski W, Rowlatt RJ, Steendijk R, Wales JH, Werder E (1993) Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child 68(6):779\u0026ndash;782. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/adc.68.6.779\u003c/span\u003e\u003cspan address=\"10.1136/adc.68.6.779\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 8333772; PMCID: PMC1029374\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShah SWH, Butt AK, Malik K, Alam A, Shahzad A, Khan AA, AAA, Syndrome (2017 Nov-Dec) Case Report of a Rare Disease. Pak J Med Sci 33(6):1512\u0026ndash;1516. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.12669/pjms.336.13684\u003c/span\u003e\u003cspan address=\"10.12669/pjms.336.13684\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 29492088; PMCID: PMC5768854\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYıldırım R, Unal E, Tekmenuray-Unal A, Taş FF, \u0026Ouml;zalkak Ş, \u0026Ccedil;ayır A, \u0026Ouml;zbek MN (2023) The clinical and laboratory features of patients with triple A syndrome: a single-center experience in Turkey. Endocrine. ;79(2):376\u0026ndash;383. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12020-022-03206-5\u003c/span\u003e\u003cspan address=\"10.1007/s12020-022-03206-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2022 Oct 4. PMID: 36194344\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSalmaggi A, Zirilli L, Pantaleoni C, De Joanna G, Del Sorbo F, Koehler K, Krumbholz M, Huebner A, Rochira V (2008) Late-onset triple A syndrome: a risk of overlooked or delayed diagnosis and management. Horm Res 70(6):364\u0026ndash;372 Epub 2008 Oct 27. PMID: 18953174\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWeber A et al (1996) Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet 5(12):2061\u0026ndash;2066\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCho AR, Yang KJ, Bae Y et al (2009) Tissue-specific expression and subcellular localization of ALADIN, the absence of which causes human triple A syndrome. Exp Mol Med 41:381\u0026ndash;386. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3858/emm.2009.41.6.043\u003c/span\u003e\u003cspan address=\"10.3858/emm.2009.41.6.043\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAngela Huebner AM, Kaindl KP, Knobeloch H, Petzold P, MannK.Koehler (2004) The Triple A Syndrome Is Due to Mutations in ALADIN, a Novel Member of the Nuclear Pore Complex. Endocr Res 30(4):891\u0026ndash;899. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1081/ERC-200044138\u003c/span\u003e\u003cspan address=\"10.1081/ERC-200044138\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuebner A, Mann P, Rohde E, Kaindl AM, Witt M, Verkade P, Jakubiczka S, Menschikowski M, Stoltenburg-Didinger G, Koehler K (2006) Mice lacking the nuclear pore complex protein ALADIN show female infertility but fail to develop a phenotype resembling human triple A syndrome. Mol Cell Biol 26(5):1879\u0026ndash;1887 PMID: 16479006; PMCID: PMC1430267\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCronshaw JM, Matunis MJ (2003) The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci U S A 100(10):5823\u0026ndash;5827. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1073/pnas.1031047100\u003c/span\u003e\u003cspan address=\"10.1073/pnas.1031047100\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2003 May 2. PMID: 12730363; PMCID: PMC156285\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePrasad R, Metherell LA, Clark AJ, Storr HL (2013) Deficiency of ALADIN impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis. Endocrinology. ;154(9):3209-18. doi: 10.1210/en.2013-1241. Epub 2013 Jul 3. PMID: 23825130; PMCID: PMC3958737\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePrpic I, Huebner A, Persic M, Handschug K, Pavletic M (2003) Triple A syndrome: genotype\u0026ndash;phenotype assessment. Clin Genet 63:415\u0026ndash;417. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1034/j.1399-0004.2003.00070.x\u003c/span\u003e\u003cspan address=\"10.1034/j.1399-0004.2003.00070.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoulden H, Smith S, De Carvalho M, Blake J, Mathias C, Wood NW, Reilly MM (2002) Clinical and genetic characterization of families with triple A (Allgrove) syndrome. Brain. ;125(Pt 12):2681-90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/brain/awf270\u003c/span\u003e\u003cspan address=\"10.1093/brain/awf270\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 12429595\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDumic M, Barišic N, Kusec V et al (2012) Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome. Eur J Pediatr 171:1453\u0026ndash;1459. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00431-012-1745-1\u003c/span\u003e\u003cspan address=\"10.1007/s00431-012-1745-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrooks BP, Kleta R, Stuart C, Tuchman M, Jeong A, Stergiopoulos SG, Bei T, Bjornson B, Russell L, Chanoine JP, Tsagarakis S, Kalsner L, Stratakis C (2005) Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000\u0026ndash;2005. Clin Genet. ;68(3):215\u0026thinsp;\u0026ndash;\u0026thinsp;21. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1399-0004.2005.00482.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1399-0004.2005.00482.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 16098009\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHandschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A (2001) Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. ;10(3):283\u0026thinsp;\u0026ndash;\u0026thinsp;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/hmg/10.3.283\u003c/span\u003e\u003cspan address=\"10.1093/hmg/10.3.283\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 11159947\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDumić M, Barišić N, Rojnić-Putarek N et al (2011) Two siblings with triple A syndrome and novel mutation presenting as hereditary polyneuropathy. Eur J Pediatr 170:393\u0026ndash;396. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00431-010-1314-4\u003c/span\u003e\u003cspan address=\"10.1007/s00431-010-1314-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMilenkovic T, Zdravkovic D, Savic N et al (2010) Triple A syndrome: 32 years experience of a single centre (1977\u0026ndash;2008). Eur J Pediatr 169:1323\u0026ndash;1328. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00431-010-1222-7\u003c/span\u003e\u003cspan address=\"10.1007/s00431-010-1222-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMilenković T, Koehler K, Krumbholz M, Zivanović S, Zdravković D, Huebner A (2008) Three siblings with triple A syndrome with a novel frameshift mutation in the AAAS gene and a review of 17 independent patients with the frequent p.Ser263Pro mutation. Eur J Pediatr. ;167(9):1049-55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00431-007-0640-7\u003c/span\u003e\u003cspan address=\"10.1007/s00431-007-0640-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2008 Jan 3. PMID: 18172684\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVezzoli V, Duminuco P, Pogliaghi G, Saccone M, Cangiano B, Rosatelli MC, Meloni A, Persani L, Bonomi M (2020) Two novel truncating variants of the AAAS gene causative of the triple A syndrome. J Endocrinol Invest 43(7):973\u0026ndash;982. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40618-020-01180-1\u003c/span\u003e\u003cspan address=\"10.1007/s40618-020-01180-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2020 Jan 14. PMID: 31939195\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNaseer A, Salih HA, Bhat S, Honnani SS (2024) A Rare Case of Allgrove Syndrome. Indian J Pediatr 91(1):104. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12098-023-04840-1\u003c/span\u003e\u003cspan address=\"10.1007/s12098-023-04840-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2023 Sep 16. PMID: 37715075\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFlokas ME, Tomani M, Agdere L, Brown B (2019) Triple A syndrome (Allgrove syndrome): improving outcomes with a multidisciplinary approach. Pediatr Health Med Ther 10:99\u0026ndash;106 PMID: 31695556; PMCID: PMC6718240\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWeissensteiner H, Forer L, Fuchsberger C, Sch\u0026ouml;pf B, Kloss-Brandst\u0026auml;tter A, Specht G, Kronenberg F, Sch\u0026ouml;nherr S (2016) Nucleic Acids Res 44(W1):W64\u0026ndash;W69. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/nar/gkw247\u003c/span\u003e\u003cspan address=\"10.1093/nar/gkw247\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2016 Apr 15. PMID: 27084948; PMCID: PMC4987870 mtDNA-Server: next-generation sequencing data analysis of human mitochondrial DNA in the cloud\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRalf A, Montiel Gonz\u0026aacute;lez D, Zhong K, Kayser M, Yleaf (2018) Software for Human Y-Chromosomal Haplogroup Inference from Next-Generation Sequencing Data. Mol Biol Evol. ;35(5):1291\u0026ndash;1294. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/molbev/msy032\u003c/span\u003e\u003cspan address=\"10.1093/molbev/msy032\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Erratum in: Mol Biol Evol. 2018;35(7):1820. doi: 10.1093/molbev/msy080. PMID: 29518227\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKrumbholz M, Koehler K, Huebner A (2006) Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome - shedding light on an unexpected splice mutation. Biochem Cell Biol. ;84(2):243-9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1139/o05-198\u003c/span\u003e\u003cspan address=\"10.1139/o05-198\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 16609705\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNakamura K, Yoshida K, Yoshinaga T, Kodaira M, Shimojima Y, Takei Y, Morita H, Kayanuma K, Ikeda S (2010) Adult or late-onset triple A syndrome: case report and literature review. J Neurol Sci 297(1\u0026ndash;2):85\u0026ndash;88 Epub 2010 Aug 1. PMID: 20674935\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRazavi Z, Taghdiri MM, Eghbalian F, Bazzazi N (2010) Premature Loss of Permanent Teeth in Allgrove (4A) Syndrome in Two Related Families. Iran J Pediatr 20(1):101\u0026ndash;106 PMID: 23056690; PMCID: PMC3446014\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKilicli F, Acibucu F, Senel S, Dokmetas HS (2012) Allgrove syndrome. Singapore Med J. ;53(5):e92-4. PMID: 22584989\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBizzarri C, Benevento D, Terzi C, Huebner A, Cappa M, Triple A (2013) (Allgrove) syndrome: an unusual association with syringomyelia. Ital J Pediatr 39:39. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/1824-7288-39-39\u003c/span\u003e\u003cspan address=\"10.1186/1824-7288-39-39\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 23800107; PMCID: PMC3704905\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSanyal D, Bhattacharjee S (2013) A case of late-onset allgrove syndrome presenting with predominant autonomic dysfunction. Ann Indian Acad Neurol 16(2):266\u0026ndash;268. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/0972-2327.112494\u003c/span\u003e\u003cspan address=\"10.4103/0972-2327.112494\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 23956580; PMCID: PMC3724090\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlakeel A, Raynaud C, Rossi M, Reix P, Jullien D, Souillet AL (2015) Syndrome d'Allgrove [Allgrove syndrome]. Ann Dermatol Venereol. ;142(2):121-4. French. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.annder.2014.11.012\u003c/span\u003e\u003cspan address=\"10.1016/j.annder.2014.11.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2014 Dec 30. PMID: 25554662\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDerrar R, Boutimzine N, Laghmari A, Alouane A, Daoudi R (2015) Alacrymie cong\u0026eacute;nitale r\u0026eacute;v\u0026eacute;lant un syndrome d'Allgrove: \u0026agrave; propos de trois cas [Congenital alacrima revealing a Allgrove syndrome: report of three cases]. Pan Afr Med J. ;20:359. French. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.11604/pamj.2015.20.359.4717\u003c/span\u003e\u003cspan address=\"10.11604/pamj.2015.20.359.4717\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 26185551; PMCID: PMC4495791\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMisgar RA, Pala NA, Ramzan M, Wani AI, Bashir MI, Laway BA (2015) Allgrove (Triple A) Syndrome: A Case Report from the Kashmir Valley. Endocrinol Metab (Seoul) 30(4):604\u0026ndash;606. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3803/EnM.2015.30.4.604\u003c/span\u003e\u003cspan address=\"10.3803/EnM.2015.30.4.604\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2015 Sep 10. PMID: 26354489; PMCID: PMC4722417\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi W, Gong C, Qi Z, Wu DI, Cao B (2015) Identification of AAAS gene mutation in Allgrove syndrome: A report of three cases. Exp Ther Med 10(4):1277\u0026ndash;1282. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3892/etm.2015.2677\u003c/span\u003e\u003cspan address=\"10.3892/etm.2015.2677\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2015 Aug 10. PMID: 26622478; PMCID: PMC4578041\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJerie M, Vojtech Z, Malikova H, Prochazkova S, Vackova Z, Rolfs A (2016) Allgrove syndrome with prominent neurological symptoms. Case Report. Neuro Endocrinol Lett 37(3):184\u0026ndash;188 PMID: 27618595\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKallabi F, Belghuith N, Aloulou H, Kammoun T, Ghorbel S, Hajji M, Gallas S, Chemli J, Chabchoub I, Azzouz H, Ben Chehida A, Sfaihi L, Makni S, Amouri A, Keskes L, Tebib N, Ben Becher S, Hachicha M, Kamoun H (2016) Clinical and Genetic Characterization of 26 Tunisian Patients with Allgrove Syndrome. Arch Med Res 47(2):105\u0026ndash;110. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.arcmed.2016.04.004\u003c/span\u003e\u003cspan address=\"10.1016/j.arcmed.2016.04.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2016 Apr 28. PMID: 27133709\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVahedi M, Fathi S, Allahbakhshi H (2016) Edentulous child with Allgrove syndrome: a rare case report. Korean J Pediatr 59(11):456\u0026ndash;459. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3345/kjp.2016.59.11.456\u003c/span\u003e\u003cspan address=\"10.3345/kjp.2016.59.11.456\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2016 Nov 18. PMID: 27895694; PMCID: PMC5118506\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan Tellingen V, Finken MJ, Isra\u0026euml;ls J, Hendriks YM, Kamp GA, van Santen HM (2016) Poorly Controlled Congenital Hypothyroidism due to an Underlying Allgrove Syndrome. Horm Res Paediatr 86(6):420\u0026ndash;424. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000446604\u003c/span\u003e\u003cspan address=\"10.1159/000446604\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2016 Jun 3. PMID: 27255745; PMCID: PMC5296928\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBerrani H, Meskini T, Zerkaoui M, Merhni H, Ettair S, Sefiani A, Mouane N (2018) Clinical and molecular report of c.1331\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A mutation of the AAAS gene in a Moroccan family with Allgrove syndrome: a case report. BMC Pediatr 18(1):184. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12887-018-1161-4\u003c/span\u003e\u003cspan address=\"10.1186/s12887-018-1161-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 29866068; PMCID: PMC5987581\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Freitas MRG, Orsini M, Ara\u0026uacute;jo APQC, Jo\u0026atilde;o Abra\u0026atilde;o L Jr, Barbosa GM, Fran\u0026ccedil;a MC, Correia L, Bastos VH, Trajano E, da Sant'Anna M Jr (2018) Allgrove syndrome and motor neuron disease. Neurol Int 10(2):7436 PMID: 30069287; PMCID: PMC6050446\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKurnaz E, Duminuco P, Aycan Z, Savaş-Erdeve Ş, Muratoğlu Şahin N, Keskin M, Bayramoğlu E, Bonomi M, \u0026Ccedil;etinkaya S (2018) Clinical and genetic characterisation of a series of patients with triple A syndrome. Eur J Pediatr 177(3):363\u0026ndash;369. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00431-017-3068-8\u003c/span\u003e\u003cspan address=\"10.1007/s00431-017-3068-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2017 Dec 19. PMID: 29255950\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNakamura J, Hikichi T, Inoue H, Watanabe K, Kikuchi H, Takagi T, Suzuki R, Sugimoto M, Konno N, Waragai Y, Asama H, Takasumi M, Sato Y, Irie H, Obara K, Ohira H (2018) Per-oral endoscopic myotomy for esophageal achalasia in a case of Allgrove syndrome. Clin J Gastroenterol 11(4):273\u0026ndash;277. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12328-018-0819-7\u003c/span\u003e\u003cspan address=\"10.1007/s12328-018-0819-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2018 Jan 30. PMID: 29383495\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAkram S, Khan MA, Rehman A (2018) Allgrove syndrome: case report of 7 years old boy from Bahawalpur. J Pak Med Assoc 68(8):1260\u0026ndash;1262 PMID: 30108399\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu C, Lee TA, Pan DH, Pereira EM, Zhou P (2019) Clinical course of a unique case of Allgrove syndrome and challenges of hypoglycemia management. AACE Clin Case Rep 5(6):e357\u0026ndash;e361. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4158/ACCR-2019-0210\u003c/span\u003e\u003cspan address=\"10.4158/ACCR-2019-0210\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 31967070; PMCID: PMC6873850\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBitetto G, Ronchi D, Bonato S, Pittaro A, Compagnoni GM, Bordoni A, Salani S, Frattini E, Lopez G, Cribi\u0026ugrave; FM, Corti S, Comi GP, Bresolin N, Di Fonzo A (2019) Loss of the nucleoporin Aladin in central nervous system and fibroblasts of Allgrove Syndrome. Hum Mol Genet. ;28(23):3921\u0026ndash;3927. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/hmg/ddz236\u003c/span\u003e\u003cspan address=\"10.1093/hmg/ddz236\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 31600784\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta S, Dayal D (2020) Allgrove Syndrome and a Novel Mutation of AAAS Gene in a Boy. Indian Pediatr. ;57(1):82. PMID: 31937715\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePolat R, Ustyol A, Tuncez E, Guran T (2020) A broad range of symptoms in allgrove syndrome: single center experience in Southeast Anatolia. J Endocrinol Invest 43(2):185\u0026ndash;196. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40618-019-01099-2\u003c/span\u003e\u003cspan address=\"10.1007/s40618-019-01099-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2019 Aug 21. PMID: 31435881\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZheng H, Iyer RS, Pacheco MC, Soares JJ, Johnson K, Len M, Ambartsumyan L (2020) Respiratory infections and chronic cough due to triple A (Allgrove) syndrome. Clin Case Rep 8(3):437\u0026ndash;440 PMID: 32185032; PMCID: PMC7069866\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYadav P, Kumar D, Bohra GK, Garg MK (2020) Triple A syndrome (Allgrove syndrome) - A journey from clinical symptoms to a syndrome. J Family Med Prim Care 9(5):2531\u0026ndash;2534. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/jfmpc.jfmpc_237_20\u003c/span\u003e\u003cspan address=\"10.4103/jfmpc.jfmpc_237_20\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 32754538; PMCID: PMC7380807\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJabbour S, Hamel P, Soucy JF, Ospina LH, Allgrove Syndrome (2020) A Report of New Pathological Variants in the AAAS Gene. Cornea. ;39(6):782\u0026ndash;783. doi: 10.1097/ICO.0000000000002287. PMID: 32073457\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRizzo R, Balassone V, Torroni F, De Angelis P, Dall'Oglio L (2020) Peroral endoscopic myotomy in a child with Triple A syndrome (Allgrove syndrome). VideoGIE 5(6):235\u0026ndash;237. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.vgie.2020.02.007\u003c/span\u003e\u003cspan address=\"10.1016/j.vgie.2020.02.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 32529155; PMCID: PMC7276969\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJayant SS, Gupta R, Agrawal K, Das L, Dutta P, Bhansali A, Triple A (2021) (Allgrove) syndrome due to AAAS gene mutation with a rare association of amyotrophy. Horm (Athens) 20(1):197\u0026ndash;205. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s42000-020-00217-7\u003c/span\u003e\u003cspan address=\"10.1007/s42000-020-00217-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2020 Jul 22. PMID: 32700293\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVolkova NI, Davidenko IY, Reshetnikov IB, Brovkina SS (2020) [Allgrove syndrome: how to suspect the problem? Endocrinologists experience]. Probl Endokrinol (Mosk). ;66(1):64\u0026ndash;69. Russian. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.14341/probl10296\u003c/span\u003e\u003cspan address=\"10.14341/probl10296\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 33351314\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiyazawa H, Kimura M, Yonezawa H, Maeda T (2021) Sporadic Triple A (Allgrove) Syndrome with Novel Tandem Mutations. Intern Med 60(5):799\u0026ndash;802. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2169/internalmedicine.5201-20\u003c/span\u003e\u003cspan address=\"10.2169/internalmedicine.5201-20\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2020 Oct 21. PMID: 33087664; PMCID: PMC7990642\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlhassoun M, Almakadma AH, Almustanyir S, AlLehibi A, Alotaibi N, Triple AM, Disorder (2021) Allgrove Syndrome Cureus 13(8):e17476. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.17476\u003c/span\u003e\u003cspan address=\"10.7759/cureus.17476\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 34513526; PMCID: PMC8405170\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRivera-Suazo Y, Espriu-Ram\u0026iacute;rez MX, Trauernicht-Mendieta SA, Rodr\u0026iacute;guez L (2021 Oct-Dec) Allgrove syndrome in a toddler: Alacrima and achalasia, with no adrenal insufficiency. Rev Gastroenterol Mex (Engl Ed). 86(4):441\u0026ndash;443 Epub 2021 Aug 18. PMID: 34417164\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWeiman DI, Gillespie MK, Hartley T, Osmond M, Ito Y, Care4Rare Canada Consortium, Boycott KM, Kernohan KD, Lines M, McMillan HJ (2021) Neurophysiological Characteristics of Allgrove (Triple A) Syndrome: Case Report and Literature Review. Child Neurol Open 8:2329048X211031059. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/2329048X211031059\u003c/span\u003e\u003cspan address=\"10.1177/2329048X211031059\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 34796249; PMCID: PMC8594529\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlOmran HA, Busaleh F, Alhashim Z, AlHelal M, Alsaleh Y, AlJabri A, AlGhadeer ZA, AlHejji FY, AlMazeedi M, Al Dandan AM (2021) Mineralocorticoid Deficiency as an Early Presenting Symptom of Allgrove Syndrome With Novel Mutation: A Case Report. Cureus 13(11):e19316. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.19316\u003c/span\u003e\u003cspan address=\"10.7759/cureus.19316\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 34900490; PMCID: PMC8648336\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHanino N, Swed S, Zakkor MD, Hindawy A, Alibrahim H, Alhussein H (2021) Allgrove syndrome: Case report of 18 years old male:the first case report from Syria. Ann Med Surg (Lond) 72:103009 PMID: 34820119; PMCID: PMC8600000\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKronenberg G, Guillery SPE, Harms L, Kunte H (2021) The Classic Triad of Triple A (Allgrove) Syndrome. Neurol Clin Pract 11(6):e916\u0026ndash;e917. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1212/CPJ.0000000000001010\u003c/span\u003e\u003cspan address=\"10.1212/CPJ.0000000000001010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 34992981; PMCID: PMC8723963\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAgarwal A, Das A, Pandit AK, Radhakrishnan DM, Rajan R, Faruq M, Srivastava AK (2022 May-Jun) Allgrove Syndrome: A Frequently Under-Diagnosed ALS Mimic. Ann Indian Acad Neurol 25(3):500\u0026ndash;501. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/aian.aian_594_21\u003c/span\u003e\u003cspan address=\"10.4103/aian.aian_594_21\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2021 Oct 22. PMID: 35936640; PMCID: PMC9350801\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBotella Garc\u0026iacute;a J, L\u0026aacute;zaro-Rodr\u0026iacute;guez V, de la Paz MF (2022) The use of topical cyclosporine A 0.05% as treatment for primary alacrimia in Allgrove syndrome. Eur J Ophthalmol 32(1):NP9\u0026ndash;NP11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/1120672120945109\u003c/span\u003e\u003cspan address=\"10.1177/1120672120945109\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2020 Jul 22. PMID: 32698619\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSoares MC, Lins OG, Lima de Carvalho JR et al (2022) Allgrove syndrome with amyotrophy. Pract Neurol 22:213\u0026ndash;215. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/practneurol-2021-003192\u003c/span\u003e\u003cspan address=\"10.1136/practneurol-2021-003192\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMacke EL, Morales-Rosado JA, Macklin-Mantia SK, Schmitz CT, Oskarsson B, Klee EW, Wierenga KJ (2022) Functional validation of a novel AAAS variant in an atypical presentation of Allgrove syndrome. Mol Genet Genomic Med 10(7):e1966. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/mgg3.1966\u003c/span\u003e\u003cspan address=\"10.1002/mgg3.1966\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2022 May 15. PMID: 35570467; PMCID: PMC9266593\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEid M, Chreitah A, Aljanati O, Mohammed A, Melhem I, Alkilany Z (2022) A rare case of Allgrove Syndrome associated with growth hormone deficiency in an 8-year-Old child: A case report. Ann Med Surg (Lond) 81:104352 PMID: 36147172; PMCID: PMC9486606\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlhalabi M, Alsayd S, Alboushi E (2022) Allgrove syndrome: a case report. Oxf Med Case Rep 2022(10):omac104. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/omcr/omac104\u003c/span\u003e\u003cspan address=\"10.1093/omcr/omac104\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 36299673; PMCID: PMC9589468\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBitetto G, Lopez G, Ronchi D, Pittaro A, Melzi V, Peverelli E, Cribi\u0026ugrave; FM, Comi GP, Mantovani G, Di Fonzo A (2023) SCARB1 downregulation in adrenal insufficiency with Allgrove syndrome. Orphanet J Rare Dis 18(1):152. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13023-023-02763-w\u003c/span\u003e\u003cspan address=\"10.1186/s13023-023-02763-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 37331934; PMCID: PMC10278336\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVigano' M, Mantero V, Basilico P, Pirro F, Ronchi D, Di Fonzo A, Salmaggi A (2023) Don't forget Allgrove syndrome in adult patients as a bulbar-ALS mimicker. Neurol Sci 44(10):3703\u0026ndash;3705. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10072-023-06961-z\u003c/span\u003e\u003cspan address=\"10.1007/s10072-023-06961-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2023 Jul 17. PMID: 37458842\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta J, Chowdhury SR, Jauhari P, Ragunathan K, Chakrabarty B, Jain V, Gulati S (2024) Child Neurology: Allgrove Syndrome: An Intriguing Etiology of Motor Neuron Disease in Children. Neurology 102(4):e208049. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1212/WNL.0000000000208049\u003c/span\u003e\u003cspan address=\"10.1212/WNL.0000000000208049\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2024 Jan 25. PMID: 38271654\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCehic Maja M, Katarina V, Rade M, Tatjana K, Gordana T, Sladjana PZ, Sanja C, Dimitrije P, Aleksandra (2024) Huebner Angela, Koehler Katrin, Quitter Friederike Very early and severe presentation of Triple A syndrome \u0026ndash; case report and review of the literature. Front Endocrinol Volume 15\u0026ndash;2024. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fendo.2024.1431383\u003c/span\u003e\u003cspan address=\"10.3389/fendo.2024.1431383\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaaloul I, Aloulou H, Bessghaier W, Ameur SB, Chabchoub I, Khalfallah R, Kamoun H, Morel Y, Kamoun T Primary adrenal insufficiency in children excluding congenital adrenal hyperplasia: insights from 33-year single-center experience in Tunisia. Arch Pediatr. 2025 Jan 27:S0929-693X(25)00019\u0026thinsp;\u0026ndash;\u0026thinsp;3. doi: 10.1016/j.arcped.2024.10.010. Epub ahead of print. PMID: 39875217\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"neurogenetics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nege","sideBox":"Learn more about [neurogenetics](https://link.springer.com/journal/10048)","snPcode":"10048","submissionUrl":"https://submission.nature.com/new-submission/10048/3","title":"neurogenetics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Allgrove syndrome, Triple A syndrome, alacrimia, achalasia, adrenal insufficiency, AAAS gene","lastPublishedDoi":"10.21203/rs.3.rs-6962259/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6962259/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAllgrove syndrome is a rare, multisystem, autosomal recessive disorder characterized by the triad of symptoms: achalasia, alacrimia and ACTH-resistant adrenal insufficiency. Various and nonspecific neurological symptoms can also develop over time, \u0026ldquo;blurring\u0026rdquo; the typical course of this underdiagnosed condition. The incidence of Allgrove syndrome is unknown, Orphanet reports fewer than 100 published cases, but according to literature review, at least 206 patients have been already described. The pathogenic variant p.Ser263Pro is one of the most recurrent aberration affecting \u003cem\u003eAAAS\u003c/em\u003e gene and have been reported in several families of Slavic origin. We investigated genotype-phenotype correlation in 206 patients with AS described in literature (including two novel Polish siblings carrying a homozygous p.Ser263Pro variant in the \u003cem\u003eAAAS\u003c/em\u003e gene) and found that neurological symptoms were significantly more common among carriers of p.Ser236Pro variant (33 out of 34; 97.05%) as compared to other \u003cem\u003eAAAS\u003c/em\u003e mutation carriers (133 out of172; 77.3%, p\u0026thinsp;=\u0026thinsp;0.006). While the incidence of the classical clinical triad of AS was similar and observed in 110 out of 206 AS patients (53.4%) and in 18 out of 34 (52.9%) among p.Ser263Pro variant carriers. Furthermore our report supports the hypothesis of a founder mutation p.Ser263Pro of \u003cem\u003eAAAS\u003c/em\u003e gene in a European Caucasian population, probably of Slavic origin- since 25out of 36 reported variant carriers were of Slavic origin (69.4%) and 17 out of 23(73.9%) who were homozygous for p.Ser263Pro mutation came from Slavic region. Summarizing, neurological manifestations of AS predominate in patients carrying a potentially founder p.Ser263Pro variant with the \u003cem\u003eAAAS\u003c/em\u003e gene.\u003c/p\u003e","manuscriptTitle":"Neurological manifestations of Allgrove syndrome in patients carrying a potentially founder p.Ser263Pro variant of the AAAS gene","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 05:49:39","doi":"10.21203/rs.3.rs-6962259/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-11T11:28:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-11T10:58:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-07T11:15:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-26T12:26:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"188723585719903815484404549154093412476","date":"2025-07-20T09:02:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196998211062593704392663356689386786433","date":"2025-07-18T09:14:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"107058488069730309148219426900155695728","date":"2025-07-17T04:06:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76482666979719441702760182803641380937","date":"2025-07-16T22:36:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-16T08:18:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-16T07:58:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-16T07:57:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"neurogenetics","date":"2025-06-24T06:31:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"neurogenetics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nege","sideBox":"Learn more about [neurogenetics](https://link.springer.com/journal/10048)","snPcode":"10048","submissionUrl":"https://submission.nature.com/new-submission/10048/3","title":"neurogenetics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fe7556f2-7dc3-4dd2-805b-577b6f28b9c3","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:06:25+00:00","versionOfRecord":{"articleIdentity":"rs-6962259","link":"https://doi.org/10.1007/s10048-025-00870-3","journal":{"identity":"neurogenetics","isVorOnly":false,"title":"neurogenetics"},"publishedOn":"2026-01-07 15:59:16","publishedOnDateReadable":"January 7th, 2026"},"versionCreatedAt":"2025-07-23 05:49:39","video":"","vorDoi":"10.1007/s10048-025-00870-3","vorDoiUrl":"https://doi.org/10.1007/s10048-025-00870-3","workflowStages":[]},"version":"v1","identity":"rs-6962259","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6962259","identity":"rs-6962259","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}