Rare association of 15q26 deletion syndrome and lymphangioleiomyomatosis: diagnostic and therapeutic challenge

Rare association of 15q26 deletion syndrome and lymphangioleiomyomatosis: diagnostic and therapeutic challenge | 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 Rare association of 15q26 deletion syndrome and lymphangioleiomyomatosis: diagnostic and therapeutic challenge Ivana Buha, Nikola Marić, Branka Bonaci-Nikolic, Mihailo Stjepanovic, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6272150/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Dec, 2025 Read the published version in Journal of Applied Genetics → Version 1 posted 5 You are reading this latest preprint version Abstract 15q26 deletion syndrome is a rare genetic condition caused by the deletion of terminal end of the long arm of chromosome 15 (Drayer's syndrome). Clinical presentation usually implies intrauterine growth restriction, postnatal growth failure, varying degrees of intellectual disability, developmental delay, typical facial appearance, brachydactyly and diaphragmatic hernia. Lymphangioleiomiomatosis (LAM) is a rare disease affecting multiple organs, which almost exclusively afflicts women. Typical presentation of LAM disease is pulmonary LAM, characterized by cyst-like destruction of pulmonary tissue, which leads to loss of pulmonary function, and if progresses further can lead to recurring pneumothoraxes. Association of these two rare diseases hasn’t been reported so far. Here we report a case of the simultaneous presence of 15q26 deletion syndrome and LAM disease in a 38-year-old female. She presented with short statue, brachydactyly, pes equinovarus, microcephaly and signs of intellectual disability from birth and early childhood. At the age of 23 she starts to suffer of recurring pneumothoraxes with gradual loss of pulmonary function. CT and pathohistological findings revealed the presence of pulmonary LAM and genetic testing revealed 15q26.2 microdeletion characteristic for 15q26 deletion syndrome. Successful treatment of LAM using mTOR inhibitor Sirolimus resulted in clinical and functional improvement. 15q26 deletion syndrome Lymphangioleiomiomatosis mTOR inhibition sirolimus pneumothorax Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction 15q26 deletion syndrome (OMIM#612626) is a rare genetic condition caused by the deletion of terminal end (qter) of the long arm of chromosome 15. It includes stunted growth, intellectual disability, developmental delay, typical facial appearance and diaphragmatic hernia (Santos et al. 2020 ). It was first revealed in 1977 by Drayer and al. (1977) describing two siblings with an intellectual disability and multiple congenital abnormalities. Later, more cases were described, mostly sporadic, with a variable clinical picture depending on the breakpoints and the genes contained within deleted region. As this region was later mapped and the genes located within were discovered, a clearer picture of the genotype-phenotype correlation was obtained. Lymphangioleiomyomatosis (LAM) (OMIM #606690) is a rare multisystem disease which is characterized by abnormal growth of smooth muscle cells primarily affecting the lungs and lymphatic system (LAM cells) and is frequently associated with renal angiomyolipomas (AMLs) (Glasgow et al 2008 ). Uncontrolled growth of LAM cells can lead to the loss of lung function (Taveira-Dasilva, Moss 2016 , McCormack 2008 ). LAM almost exclusively affects women and has one of the strongest gender predispositions of any extragenital human disease (Xu et al. 2020 ). Typical presentation of LAM disease implies destruction of pulmonary tissue caused by formation of fluid-filled cystic structures, which leads to loosing of pulmonary function usually accompanied with progressive dyspnea on exertion, pneumothoraxes, and chylous pleural effusions. Pulmonary manifestations are often mistakenly diagnosed as other respiratory disorders such as asthma, emphysema or COPD, leading to delays in diagnostic and treatment (Johnson et al. 2010 , Ryu et al. 2006 ). Association of these two rare diseases in one patient is rarity and to the best of our knowledge has not been reported so far. Results of clinical and molecular analysis are presented here, as well successful treatment using mTOR inhibition which resulted in clinical and functional improvement. Case presentation Female patient, 38 years of age, presented difficulty in breathing and fatigue, with significant loss of pulmonary function. Physical examination showed short statue (body hight 135 cm, TT 40 kg), typical facial dysmorphism (short palpebral fissures), brachydactyly with small thumb (Fig. 1 ), microcephaly, and signs of mild intellectual disability. She had pes equinovarus and atrioventricular septal defect present on birth, which had spontaneously closed when she was 4 years old. Due to recurring pneumothoraxes, which occurred five times (at age of 23, 24, 26, 32 and 35 respectively), patient had multiple computed tomography (CT) scans, all of which had shown diffuse ground glass lesions with multiple cysts with thin walls, indicative of LAM (Fig. 2 ). During four years of follow-up, the loss of lung function had been verified by performing pulmonary functional tests; the patient had restrictive disorder of ventilation: forced vital capacity (FVC) was falling from 82 to 54%, forced expiratory volume in 1st second (FEV1) from 78 to 46%, FEV1/FVC ratio from 81 to 65%, DLCOc from 41 to 16%, KCOc from 47 to 30%, measured at the age of 32 to 35 respectively. There were no signs of pulmonary hypertension (right ventricular systolic pressure was 29 mmHg). Examinations of several systems (eyes, lungs, heart, brain, skin, neurological) revealed that there are no elements for the existence of tuberous sclerosis complex (TSC). Definitive diagnosis was reached, at the age of 35 after pneumothorax, by performing video-assisted thoracoscopic surgery and atypical resection of lingual, whose pathohistological finding had shown pulmonary LAM (Fig. 3 ). These LAM cells were strongly positive for smooth muscle actin in the cytoplasm, HMB-45 in the cytoplasm, and progesterone receptor in the nuclei (immunoperoxidase stain). CT scan of the abdomen revealed several cists in the liver and retroperitoneum (Fig. 4 ). Due to short stature, brachydactyly, microcephaly and intellectual disability, the presence of another syndrome was proposed and molecular diagnostics was performed, after the diagnosis of LAM, at the age of 35. Genetic analysis The Whole Exome Sequencing (WES) analysis revealed 15q26.2-26.3 microdeletion. No germline mutations in TSC1 or TSC2 genes were detected. No other genetic findings were revealed, except 2 VUS variants in COL10A1 and JAG1 genes, with no certain correlation with clinical phenotype (detailed description is given in Supplementary material). To validate the findings from WES, molecular karyotyping was carried out utilizing the Agilent SurePrint G3 Human array kit on the CGH Microarray Platform. This analysis confirmed a deletion of approximately 5.6Mb in 15q26.2-26.3 genomic region. This deletion encompassed 23 protein-coding genes, and according to the OMIM database 8 of them were identified as disease-causing: ADAMTS17 (607511), ALDH1A3 (600463), CERS3 (615276), CHSY1 (608183), IGF1R (1147370), LINS1 (610350), MEF2A (600660), and NR2F2 (107773). Patient’s family members are without any signs of either of the diseases. Therapy Considering that the patient has LAM with a significant damage to the lungs, the treatment using mTOR inhibitor (Sirolimus) started at age of 35. Initial dose was 1 mg/24h, with further corrections, depending on the concentration of the drug in serum. The treatment has led to significant subjective improvement, as well as improvement of lung function parameters after one year of starting Sirolimus (FVC 83% of predictive value, FEV1 64% of predictive value, FEV1/FVC ratio 65%; TLCOc 27%, KCOc 34%). In the moment of writing this report, the patient is on the Sirolimus therapy for three years and did not have clinical worsening of either symptoms or recurrence of pneumothoraxes. The last concentration of Sirolimus in the serum was 7.4 ng/mL Discussion The association of 15q26 deletion syndrome and LAM, unpublished until now, was challenging in terms of establishing an accurate diagnosis and choosing the right treatment. Variation in clinical pictures of cases with 15q26 deletion syndrome described in the literature are due to the amount of DNA loss and affected genes. WES analysis in our patient discovered a copy number loss on chromosome chr15q26.2-26.3. As shown in a case with the same breakpoint region, (Ono et al. 2022 ) heterozygous deletion of genes IGF1R and NR2F2 could explain most of the phenotype. IGF1R plays an important role in skeletal and brain development, causing below-average height, facial dysmorphisms, skeletal deformations, microcephaly, speech delays and intellectual disability (Fang et al. 2009 , Abuzzahab et al. 2003 , Yang et al. 2018 ). NR2F2, also known as nuclear receptor subfamily 2 group F member 2 or COUP-TFII, belongs to the steroid/thyroid hormone superfamily of nuclear receptors. It plays a significant role in various developmental processes such as organogenesis, angiogenesis, cardiovascular development, and the establishment of ovary identity during early gonad development Bashamboo et al. 2018 , Carvalheira et al. 2019 ). Diseases associated with NR2F2 include congenital heart defects and 46,XX sex reversal Carvalheira et al. 2019 . Our patient had short stature, brachydactyly, pes equinovarus, heart malformations at birth and in early childhood, microcephaly and intellectual disability. She did not have signs of pulmonary hypertension and congenital bowing of long bones of the legs because she had deletion that encompassed IGF1R (Sivakumaran, Grebe 2023 ). LAM result from the proliferation of neoplastic cells, which, in many cases, have a smooth muscle cell phenotype. LAM cells have mutations in one of the tuberous sclerosis complex genes TSC1 or TSC2 (Krymskaya 2008 ). Dysregulation of the mTOR signaling pathway, caused by the mutations in these genes, is believed to be responsible for the proliferation of LAM cells. The mTOR pathway controls crucial aspects of cell size, proliferation, and survival (Jozwiak 2006 ). When the TSC1/TSC2 complex is not functional, uncontrolled mTOR activity triggers cell cycle progression and tumor formation. A lung biopsy is required for diagnosis in cases without germline TSC mutations. Our patient’s CT scan revealed widespread ground glass lesions containing multiple thin-wall cysts. Pathohistological analysis of VATS resected lingula identified pulmonary LAM. No germline TSC1 or TSC2 mutations were detected by WES, leaving the possibility that somatic mutations were presented in the cysts that weren’t explored. Currently, there is no clinical or serological prognostic factor of LAM. Deciphering the molecular foundation of LAM should result in better therapeutic targets and prognostic indicators. According to guidelines for diagnosis and management of LAM, patients with confirmed LAM and with FEV1 < 70% should be treated with an mTOR inhibitor (Sirolimus or Everolimus). Sirolimus has been confirmed to be effective for LAM, but the long-term effects are unknown. Generally, patients take Sirolimus 1–2 mg orally once daily. Optimal drugs serum level is 5–10 ng/ml. Our patient has been taking Sirolimus for the last three years (1–2 mg daily), with optimal drug serum levels. The patient has no respiratory symptoms or exacerbation at present and has a significant improvement in lung function. Association of two rare diseases, 15q26 deletion syndrome and lymphangioleiomyomatosis is curiosity and challenge, both for diagnostics and for the treatment. Our results of clinical and molecular diagnostics, as well as treatment, using mTOR inhibition resulted in clinical and functional improvement. Declarations Funding: This work was funded by the Ministry of Science, Technological Development and Innovation, Republic of Serbia, grant No. 451-03-66/2024-03/200042, 2024 and the Ministry of Education, Science and Technological Development, Republic of Serbia, Grant Number 451-03-68/2020-14/200110. Conflicts of Interest: The authors declare no conflict of interest. Author Contributions : Conceptualization, clinical examination IB, NM, MSt, SB, BBN, BM, AB; Data acquisition: MSt, BM, MSa, AB; analysis and interpretation of data IB, NM, BBN, MSa; writing—original draft, IB, SB, JJ, VS; writing—review and editing: IB, BBN, JJ, AZ, VS. All authors have read and agreed to the published version of the manuscript. Consent for participation and publication : The mother of patient provided written informed consent to obtain the images and clinical information to be published. Acknowledgments: The authors deeply appreciate the patient and her family for participating in the study and report. References Abuzzahab MJ, Schneider A, Goddard A et al (2003) IGF-I Receptor Mutations Resulting in Intrauterine and Postnatal Growth Retardation. N Engl J Med 349:2211-2222. doi:10.1056/NEJMoa010107 Bashamboo A, Eozenou C, Jorgensen A et al (2018) Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children. Am J Hum Genet 102:487-493. doi:10.1016/j.ajhg.2018.01.021 Carvalheira G, Malinverni AM, Moysés-Oliveira M et al (2019) The Natural History of a Man With Ovotesticular 46,XX DSD Caused by a Novel 3-Mb 15q26.2 Deletion Containing NR2F2 Gene. J Endocr Soc 3:2107-2113. doi:10.1210/js.2019-00241 Drayer N, Kamps W, Ten Kate L, Kuipers J, Gouw W (1977) Case report. Synd Ident 5:9-11 Fang P, Schwartz ID, Johnson BD et al (2009) Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay. J Clin Endocrinol Metab 94:1740-1747. doi:10.1210/jc.2008-1903 Glasgow CG, Taveira-DaSilva AM, Darling TN, Moss J (2008) Lymphatic Involvement in Lymphangioleiomyomatosis. Ann N Y Acad Sci 1131:206-214. doi:10.1196/annals.1413.018 Johnson SR, Cordier JF, Lazor R et al (2010) European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 35:14-26. doi:10.1183/09031936.00076209 Jozwiak J (2006) Hamartin and tuberin: working together for tumour suppression. Int J Cancer 118:1-5. doi:10.1002/ijc.21542 Krymskaya VP (2008) Smooth Muscle like Cells in Pulmonary Lymphangioleiomyomatosis. Proc Am Thorac Soc 5:119-126. doi:10.1513/pats.200705-061VS McCormack FX (2008) Lymphangioleiomyomatosis. Chest 133:507-516. doi:10.1378/chest.07-0898 Ono M, Tanaka M, Hiroshima S et al (2022) Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels. Endocrines 3 :92-99. doi:10.3390/endocrines3010008 Ryu JH, Moss J, Beck GJ et al (2006) The NHLBI Lymphangioleiomyomatosis Registry: Characteristics of 230 Patients at Enrollment. Am J Respir Crit Care Med 173:105-111. doi:10.1164/rccm.200409-1298OC Santos JFD, Acosta AX, Scheibler GG et al (2020) Case of 15q26-qter deletion associated with a Prader-Willi phenotype. Eur J Med Genet 63:103955. doi:10.1016/j.ejmg.2020.103955 Sivakumaran TA, Grebe TA (2023) 15q26.3 deletions distal to IGF1R cause growth retardation, congenital heart defect and skeletal anomalies: Case report and review of literature. Am J Med Genet A 191:2392-2397. doi: 10.1002/ajmg.a.63350 Taveira-Dasilva AM, Moss J (2016) Epidemiology, pathogenesis and diagnosis of lymphangioleiomyomatosis. Expert Opin Orphan Drugs 4:369-378. doi:10.1517/21678707.2016.1148597 Xu KF, Xu W, Liu S et al (2020) Lymphangioleiomyomatosis. Semin Respir Crit Care Med 41:256-268. doi:10.1055/s-0040-1702195 Yang L, Xu D Dan, Sun C Jun et al (2018) IGF1R Variants in Patients With Growth Impairment: Four Novel Variants and Genotype-Phenotype Correlations. J Clin Endocrinol Metab 103:3939-3944. doi:10.1210/jc.2017-02782 Cite Share Download PDF Status: Published Journal Publication published 04 Dec, 2025 Read the published version in Journal of Applied Genetics → Version 1 posted Editorial decision: Major Revisions Needed 20 Oct, 2025 Reviewers agreed at journal 12 Oct, 2025 Reviewers invited by journal 28 Mar, 2025 Editor assigned by journal 21 Mar, 2025 First submitted to journal 20 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6272150","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":435562989,"identity":"cd2a9e70-a697-461a-919e-e0e3e9985d69","order_by":0,"name":"Ivana Buha","email":"","orcid":"","institution":"University Clinical Center of Serbia Pulmonology Clinic: Univerzitetski klinicki centar Srbije Klinika za pulmologiju","correspondingAuthor":false,"prefix":"","firstName":"Ivana","middleName":"","lastName":"Buha","suffix":""},{"id":435562990,"identity":"bd7d7148-bc25-4832-b43b-edd2ad1a2f94","order_by":1,"name":"Nikola 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syndrome\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6272150/v1/f965ceec568973645949f5a6.jpg"},{"id":80813790,"identity":"aebea491-3958-4788-8643-8cef0baefc90","added_by":"auto","created_at":"2025-04-17 10:44:19","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52683,"visible":true,"origin":"","legend":"\u003cp\u003eCT finding of thorax a) and b) at the age of 35 had shown subcutaneous emphysema and bilaterally diffuse ground glass lesions with multiple cystic thin-walled changes of pansegmental distribution, of various sizes.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6272150/v1/f0a7f8b06fd291712f66e25c.jpg"},{"id":80814571,"identity":"3da0b3d2-73ca-41e2-840f-0d853d8eeddb","added_by":"auto","created_at":"2025-04-17 10:52:19","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":129808,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Histopathology of the lung show characteristic nodular smooth muscle cell–like infiltrates (H\u0026amp;E stain, x200) b) Higher magnification of the lung tissue revealing proliferation of spindle-shaped to epithelioid smooth muscle cells (LAM cells) (H\u0026amp;E stain, x400).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6272150/v1/3e8577c0d3042e77bbf78779.jpg"},{"id":80814573,"identity":"9b8463e9-ca21-408e-9f2f-0cbd81ae4afb","added_by":"auto","created_at":"2025-04-17 10:52:19","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":51011,"visible":true,"origin":"","legend":"\u003cp\u003eCT finding of abdomen at the age of 35 had shown a) liver of regular dimensions, with two cysts; b) also several cysts can be observed retroperitoneally\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6272150/v1/42c412004d7f087e828790c1.jpg"},{"id":97723926,"identity":"c158e01a-233f-4d1f-b7f6-3ee16d69272c","added_by":"auto","created_at":"2025-12-08 16:09:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":688627,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6272150/v1/15ad80ea-3917-40da-9534-8d99bddc651d.pdf"}],"financialInterests":"","formattedTitle":"Rare association of 15q26 deletion syndrome and lymphangioleiomyomatosis: diagnostic and therapeutic challenge","fulltext":[{"header":"Introduction","content":"\u003cp\u003e15q26 deletion syndrome (OMIM#612626) is a rare genetic condition caused by the deletion of terminal end (qter) of the long arm of chromosome 15. It includes stunted growth, intellectual disability, developmental delay, typical facial appearance and diaphragmatic hernia (Santos et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). It was first revealed in 1977 by Drayer and al. (1977) describing two siblings with an intellectual disability and multiple congenital abnormalities. Later, more cases were described, mostly sporadic, with a variable clinical picture depending on the breakpoints and the genes contained within deleted region. As this region was later mapped and the genes located within were discovered, a clearer picture of the genotype-phenotype correlation was obtained.\u003c/p\u003e \u003cp\u003eLymphangioleiomyomatosis (LAM) (OMIM #606690) is a rare multisystem disease which is characterized by abnormal growth of smooth muscle cells primarily affecting the lungs and lymphatic system (LAM cells) and is frequently associated with renal angiomyolipomas (AMLs) (Glasgow et al \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Uncontrolled growth of LAM cells can lead to the loss of lung function (Taveira-Dasilva, Moss \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2016\u003c/span\u003e, McCormack \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). LAM almost exclusively affects women and has one of the strongest gender predispositions of any extragenital human disease (Xu et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Typical presentation of LAM disease implies destruction of pulmonary tissue caused by formation of fluid-filled cystic structures, which leads to loosing of pulmonary function usually accompanied with progressive dyspnea on exertion, pneumothoraxes, and chylous pleural effusions. Pulmonary manifestations are often mistakenly diagnosed as other respiratory disorders such as asthma, emphysema or COPD, leading to delays in diagnostic and treatment (Johnson et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2010\u003c/span\u003e, Ryu et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2006\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAssociation of these two rare diseases in one patient is rarity and to the best of our knowledge has not been reported so far. Results of clinical and molecular analysis are presented here, as well successful treatment using mTOR inhibition which resulted in clinical and functional improvement.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eFemale patient, 38 years of age, presented difficulty in breathing and fatigue, with significant loss of pulmonary function. Physical examination showed short statue (body hight 135 cm, TT 40 kg), typical facial dysmorphism (short palpebral fissures), brachydactyly with small thumb (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), microcephaly, and signs of mild intellectual disability. She had pes equinovarus and atrioventricular septal defect present on birth, which had spontaneously closed when she was 4 years old. Due to recurring pneumothoraxes, which occurred five times (at age of 23, 24, 26, 32 and 35 respectively), patient had multiple computed tomography (CT) scans, all of which had shown diffuse ground glass lesions with multiple cysts with thin walls, indicative of LAM (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDuring four years of follow-up, the loss of lung function had been verified by performing pulmonary functional tests; the patient had restrictive disorder of ventilation: forced vital capacity (FVC) was falling from 82 to 54%, forced expiratory volume in 1st second (FEV1) from 78 to 46%, FEV1/FVC ratio from 81 to 65%, DLCOc from 41 to 16%, KCOc from 47 to 30%, measured at the age of 32 to 35 respectively. There were no signs of pulmonary hypertension (right ventricular systolic pressure was 29 mmHg).\u003c/p\u003e \u003cp\u003eExaminations of several systems (eyes, lungs, heart, brain, skin, neurological) revealed that there are no elements for the existence of tuberous sclerosis complex (TSC).\u003c/p\u003e \u003cp\u003eDefinitive diagnosis was reached, at the age of 35 after pneumothorax, by performing video-assisted thoracoscopic surgery and atypical resection of lingual, whose pathohistological finding had shown pulmonary LAM (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These LAM cells were strongly positive for smooth muscle actin in the cytoplasm, HMB-45 in the cytoplasm, and progesterone receptor in the nuclei (immunoperoxidase stain).\u003c/p\u003e \u003cp\u003eCT scan of the abdomen revealed several cists in the liver and retroperitoneum (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDue to short stature, brachydactyly, microcephaly and intellectual disability, the presence of another syndrome was proposed and molecular diagnostics was performed, after the diagnosis of LAM, at the age of 35.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGenetic analysis\u003c/h2\u003e \u003cp\u003eThe Whole Exome Sequencing (WES) analysis revealed 15q26.2-26.3 microdeletion. No germline mutations in TSC1 or TSC2 genes were detected. No other genetic findings were revealed, except 2 VUS variants in COL10A1 and JAG1 genes, with no certain correlation with clinical phenotype (detailed description is given in Supplementary material).\u003c/p\u003e \u003cp\u003eTo validate the findings from WES, molecular karyotyping was carried out utilizing the Agilent SurePrint G3 Human array kit on the CGH Microarray Platform. This analysis confirmed a deletion of approximately 5.6Mb in 15q26.2-26.3 genomic region. This deletion encompassed 23 protein-coding genes, and according to the OMIM database 8 of them were identified as disease-causing: ADAMTS17 (607511), ALDH1A3 (600463), CERS3 (615276), CHSY1 (608183), IGF1R (1147370), LINS1 (610350), MEF2A (600660), and NR2F2 (107773). Patient\u0026rsquo;s family members are without any signs of either of the diseases.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTherapy\u003c/h3\u003e\n\u003cp\u003eConsidering that the patient has LAM with a significant damage to the lungs, the treatment using mTOR inhibitor (Sirolimus) started at age of 35. Initial dose was 1 mg/24h, with further corrections, depending on the concentration of the drug in serum. The treatment has led to significant subjective improvement, as well as improvement of lung function parameters after one year of starting Sirolimus (FVC 83% of predictive value, FEV1 64% of predictive value, FEV1/FVC ratio 65%; TLCOc 27%, KCOc 34%). In the moment of writing this report, the patient is on the Sirolimus therapy for three years and did not have clinical worsening of either symptoms or recurrence of pneumothoraxes. The last concentration of Sirolimus in the serum was 7.4 ng/mL\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe association of 15q26 deletion syndrome and LAM, unpublished until now, was challenging in terms of establishing an accurate diagnosis and choosing the right treatment.\u003c/p\u003e \u003cp\u003eVariation in clinical pictures of cases with 15q26 deletion syndrome described in the literature are due to the amount of DNA loss and affected genes. WES analysis in our patient discovered a copy number loss on chromosome chr15q26.2-26.3. As shown in a case with the same breakpoint region, (Ono et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) heterozygous deletion of genes IGF1R and NR2F2 could explain most of the phenotype. IGF1R plays an important role in skeletal and brain development, causing below-average height, facial dysmorphisms, skeletal deformations, microcephaly, speech delays and intellectual disability (Fang et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2009\u003c/span\u003e, Abuzzahab et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2003\u003c/span\u003e, Yang et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). NR2F2, also known as nuclear receptor subfamily 2 group F member 2 or COUP-TFII, belongs to the steroid/thyroid hormone superfamily of nuclear receptors. It plays a significant role in various developmental processes such as organogenesis, angiogenesis, cardiovascular development, and the establishment of ovary identity during early gonad development Bashamboo et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2018\u003c/span\u003e, Carvalheira et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Diseases associated with NR2F2 include congenital heart defects and 46,XX sex reversal Carvalheira et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2019\u003c/span\u003e. Our patient had short stature, brachydactyly, pes equinovarus, heart malformations at birth and in early childhood, microcephaly and intellectual disability. She did not have signs of pulmonary hypertension and congenital bowing of long bones of the legs because she had deletion that encompassed IGF1R (Sivakumaran, Grebe \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLAM result from the proliferation of neoplastic cells, which, in many cases, have a smooth muscle cell phenotype. LAM cells have mutations in one of the tuberous sclerosis complex genes TSC1 or TSC2 (Krymskaya \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Dysregulation of the mTOR signaling pathway, caused by the mutations in these genes, is believed to be responsible for the proliferation of LAM cells. The mTOR pathway controls crucial aspects of cell size, proliferation, and survival (Jozwiak \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). When the TSC1/TSC2 complex is not functional, uncontrolled mTOR activity triggers cell cycle progression and tumor formation.\u003c/p\u003e \u003cp\u003eA lung biopsy is required for diagnosis in cases without germline TSC mutations. Our patient\u0026rsquo;s CT scan revealed widespread ground glass lesions containing multiple thin-wall cysts. Pathohistological analysis of VATS resected lingula identified pulmonary LAM. No germline TSC1 or TSC2 mutations were detected by WES, leaving the possibility that somatic mutations were presented in the cysts that weren\u0026rsquo;t explored.\u003c/p\u003e \u003cp\u003eCurrently, there is no clinical or serological prognostic factor of LAM. Deciphering the molecular foundation of LAM should result in better therapeutic targets and prognostic indicators. According to guidelines for diagnosis and management of LAM, patients with confirmed LAM and with FEV1\u0026thinsp;\u0026lt;\u0026thinsp;70% should be treated with an mTOR inhibitor (Sirolimus or Everolimus).\u003c/p\u003e \u003cp\u003eSirolimus has been confirmed to be effective for LAM, but the long-term effects are unknown. Generally, patients take Sirolimus 1\u0026ndash;2 mg orally once daily. Optimal drugs serum level is 5\u0026ndash;10 ng/ml. Our patient has been taking Sirolimus for the last three years (1\u0026ndash;2 mg daily), with optimal drug serum levels.\u003c/p\u003e \u003cp\u003eThe patient has no respiratory symptoms or exacerbation at present and has a significant improvement in lung function.\u003c/p\u003e \u003cp\u003eAssociation of two rare diseases, 15q26 deletion syndrome and lymphangioleiomyomatosis is curiosity and challenge, both for diagnostics and for the treatment. Our results of clinical and molecular diagnostics, as well as treatment, using mTOR inhibition resulted in clinical and functional improvement.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was funded by the Ministry of Science, Technological Development and Innovation, Republic of Serbia, grant No.\u0026nbsp;451-03-66/2024-03/200042, 2024 and the Ministry of Education, Science and Technological Development, Republic of Serbia, Grant Number 451-03-68/2020-14/200110.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e: Conceptualization, clinical examination IB, NM, MSt, SB, BBN, BM, AB; Data acquisition: MSt, BM, MSa, AB; analysis and interpretation of data IB, NM, BBN, MSa; writing—original draft, IB, SB, JJ, VS; writing—review and editing: IB, BBN, JJ, AZ, VS. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for participation and publication\u003c/strong\u003e:\u0026nbsp;The mother of patient provided written informed consent to obtain the images and clinical information to be published.\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e \u003cp\u003eThe authors deeply appreciate the patient and her family for participating in the study and report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAbuzzahab MJ, Schneider A, Goddard A et al (2003) IGF-I Receptor Mutations Resulting in Intrauterine and Postnatal Growth Retardation. N Engl J Med 349:2211-2222. doi:10.1056/NEJMoa010107\u003c/li\u003e\n\u003cli\u003eBashamboo A, Eozenou C, Jorgensen A et al (2018) Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children. Am J Hum Genet 102:487-493. doi:10.1016/j.ajhg.2018.01.021\u003c/li\u003e\n\u003cli\u003eCarvalheira G, Malinverni AM, Moys\u0026eacute;s-Oliveira M et al (2019) The Natural History of a Man With Ovotesticular 46,XX DSD Caused by a Novel 3-Mb 15q26.2 Deletion Containing NR2F2 Gene. J Endocr Soc 3:2107-2113. doi:10.1210/js.2019-00241\u003c/li\u003e\n\u003cli\u003eDrayer N, Kamps W, Ten Kate L, Kuipers J, Gouw W (1977) Case report. Synd Ident 5:9-11\u003c/li\u003e\n\u003cli\u003eFang P, Schwartz ID, Johnson BD et al (2009) Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay. J Clin Endocrinol Metab 94:1740-1747. doi:10.1210/jc.2008-1903\u003c/li\u003e\n\u003cli\u003eGlasgow CG, Taveira-DaSilva AM, Darling TN, Moss J (2008) Lymphatic Involvement in Lymphangioleiomyomatosis. Ann N Y Acad Sci 1131:206-214. doi:10.1196/annals.1413.018\u003c/li\u003e\n\u003cli\u003eJohnson SR, Cordier JF, Lazor R et al (2010) European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 35:14-26. doi:10.1183/09031936.00076209\u003c/li\u003e\n\u003cli\u003eJozwiak J (2006) Hamartin and tuberin: working together for tumour suppression. Int J Cancer 118:1-5. doi:10.1002/ijc.21542\u003c/li\u003e\n\u003cli\u003eKrymskaya VP (2008) Smooth Muscle like Cells in Pulmonary Lymphangioleiomyomatosis. Proc Am Thorac Soc 5:119-126. doi:10.1513/pats.200705-061VS\u003c/li\u003e\n\u003cli\u003eMcCormack FX (2008) Lymphangioleiomyomatosis. Chest 133:507-516. doi:10.1378/chest.07-0898\u003c/li\u003e\n\u003cli\u003eOno M, Tanaka M, Hiroshima S et al (2022) Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels. Endocrines 3 :92-99. doi:10.3390/endocrines3010008\u003c/li\u003e\n\u003cli\u003eRyu JH, Moss J, Beck GJ et al (2006) The NHLBI Lymphangioleiomyomatosis Registry: Characteristics of 230 Patients at Enrollment. Am J Respir Crit Care Med 173:105-111. doi:10.1164/rccm.200409-1298OC\u003c/li\u003e\n\u003cli\u003eSantos JFD, Acosta AX, Scheibler GG et al (2020) Case of 15q26-qter deletion associated with a Prader-Willi phenotype. Eur J Med Genet 63:103955. doi:10.1016/j.ejmg.2020.103955\u003c/li\u003e\n\u003cli\u003eSivakumaran TA, Grebe TA (2023) 15q26.3 deletions distal to IGF1R cause growth retardation, congenital heart defect and skeletal anomalies: Case report and review of literature. Am J Med Genet A 191:2392-2397. doi: 10.1002/ajmg.a.63350\u003c/li\u003e\n\u003cli\u003eTaveira-Dasilva AM, Moss J (2016) Epidemiology, pathogenesis and diagnosis of lymphangioleiomyomatosis. Expert Opin Orphan Drugs 4:369-378. doi:10.1517/21678707.2016.1148597\u003c/li\u003e\n\u003cli\u003eXu KF, Xu W, Liu S et al (2020) Lymphangioleiomyomatosis. Semin Respir Crit Care Med 41:256-268. doi:10.1055/s-0040-1702195\u003c/li\u003e\n\u003cli\u003eYang L, Xu D Dan, Sun C Jun et al (2018) IGF1R Variants in Patients With Growth Impairment: Four Novel Variants and Genotype-Phenotype Correlations. J Clin Endocrinol Metab 103:3939-3944. doi:10.1210/jc.2017-02782\u003c/li\u003e\n\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-applied-genetics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joag","sideBox":"Learn more about [Journal of Applied Genetics](https://www.springer.com/journal/13353)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/joag/default.aspx","title":"Journal of Applied Genetics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"15q26 deletion syndrome, Lymphangioleiomiomatosis, mTOR inhibition, sirolimus, pneumothorax","lastPublishedDoi":"10.21203/rs.3.rs-6272150/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6272150/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e15q26 deletion syndrome is a rare genetic condition caused by the deletion of terminal end of the long arm of chromosome 15 (Drayer's syndrome). Clinical presentation usually implies intrauterine growth restriction, postnatal growth failure, varying degrees of intellectual disability, developmental delay, typical facial appearance, brachydactyly and diaphragmatic hernia. Lymphangioleiomiomatosis (LAM) is a rare disease affecting multiple organs, which almost exclusively afflicts women. Typical presentation of LAM disease is pulmonary LAM, characterized by cyst-like destruction of pulmonary tissue, which leads to loss of pulmonary function, and if progresses further can lead to recurring pneumothoraxes. Association of these two rare diseases hasn\u0026rsquo;t been reported so far. Here we report a case of the simultaneous presence of 15q26 deletion syndrome and LAM disease in a 38-year-old female. She presented with short statue, brachydactyly, pes equinovarus, microcephaly and signs of intellectual disability from birth and early childhood. At the age of 23 she starts to suffer of recurring pneumothoraxes with gradual loss of pulmonary function. CT and pathohistological findings revealed the presence of pulmonary LAM and genetic testing revealed 15q26.2 microdeletion characteristic for 15q26 deletion syndrome. Successful treatment of LAM using mTOR inhibitor Sirolimus resulted in clinical and functional improvement.\u003c/p\u003e","manuscriptTitle":"Rare association of 15q26 deletion syndrome and lymphangioleiomyomatosis: diagnostic and therapeutic challenge","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 10:44:15","doi":"10.21203/rs.3.rs-6272150/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2025-10-20T05:05:24+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-10-12T08:39:19+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-29T00:18:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-21T14:14:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Applied Genetics","date":"2025-03-20T15:35:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-applied-genetics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joag","sideBox":"Learn more about [Journal of Applied Genetics](https://www.springer.com/journal/13353)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/joag/default.aspx","title":"Journal of Applied Genetics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"82064bad-d84c-4504-aa91-55e99f35a32d","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:03:20+00:00","versionOfRecord":{"articleIdentity":"rs-6272150","link":"https://doi.org/10.1007/s13353-025-01031-w","journal":{"identity":"journal-of-applied-genetics","isVorOnly":false,"title":"Journal of Applied Genetics"},"publishedOn":"2025-12-04 15:58:10","publishedOnDateReadable":"December 4th, 2025"},"versionCreatedAt":"2025-04-17 10:44:15","video":"","vorDoi":"10.1007/s13353-025-01031-w","vorDoiUrl":"https://doi.org/10.1007/s13353-025-01031-w","workflowStages":[]},"version":"v1","identity":"rs-6272150","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6272150","identity":"rs-6272150","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}