Neuropsychological profile in a child with Buschke-Ollendorff syndrome: A case report

Neuropsychological profile in a child with Buschke-Ollendorff syndrome: A case report | 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 Neuropsychological profile in a child with Buschke-Ollendorff syndrome: A case report Marilina Covuccia, Eleonora Spinelli, Barbara Caravale This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4530118/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Buschke-Ollendorff syndrome (BOS) is a rare autosomal dominant genodermatosis caused by a mutation in the LEMD3 gene. While it primarily affects the skin with the development of connective tissue nevi, it can be associated with other conditions such as intellectual disability or developmental delay. These co-occurring conditions add complexity to the clinical picture and necessitate comprehensive evaluation and management strategies. Case report: We describe the clinical history of a 7-year-old male child diagnosed with BOS, exploring his neuropsychological profile and finding the presence of mild intellectual disability, impaired attentional abilities, and difficulties in language, motor coordination, and learning. Discussion Our findings support the hypothesis of the presence of neurodevelopmental disorders in children with BOS. However, further studies are needed to determine the existence and understand the nature of the possible link between these conditions. Buschke-Ollendorff syndrome Intellectual Disability Neurodevelopment Genetic syndrome 1. Introduction Buschke-Ollendorff syndrome (BOS) represents a rare and typically harmless type of autosomal dominant genodermatosis (Diotallevi et al., 2020 ). It arises from a heterozygous, loss-of-function germline mutation in the LEMD3 gene, situated on chromosome band 12q14. The LEMD3 gene encodes the LEM domain-containing protein 3, which serves as a suppressor of bone morphogenetic protein (BMP) signaling pathways and transforming growth factor beta (TGF-ß). Mutations in LEMD3 lead to hyperostosis and abnormalities in the formation of connective tissue, including elastin. Consequently, this condition manifests in skin lesions, such as elastomas, and/or bone lesions, such as osteopoikilosis (Salik et al., 2022). These lesions manifest progressively during childhood, although some regression may occur in adulthood. The estimated incidence of BOS is 1/20,000 (Diotallevi et al., 2020 ). In rare cases, other conditions reported alongside BOS included intellectual disability (ID) or developmental delay (DD) (Pope et al., 2016). A possible association between BOS and ID/DD has been highlighted only by Pope et al. In their retrospective study, three out of six (50%) patients showed attention deficit hyperactivity disorder or other developmental delays. Overall, the cohort of patients described in their case reports and case series exhibited a significantly lower incidence, accounting for just 5% (nine out of 164) (Pope et al., 2016). Intellectual disability is a complex condition with a prevalence in developing countries estimated to range from 10 to 15 per 1000 children, with a peak between the ages of 10 to 14 years (Lee et al., 2024). The research suggests that a substantial portion of cases may have genetic origins. Indeed genetic abnormalities can affect normal neurodevelopmental processes, leading to intellectual and adaptive behavior challenges (Lee et al., 2024). Here, we present the clinical history of a 7-year-old male child, diagnosed with BOS, whose neuropsychological profile we analyzed through the administration of standardized tests. 2. Case report 2.1. Clinical background The patient, a 7-year-old male child, was born prematurely at 34 weeks of gestational age via cesarean section, after a normal pregnancy, from healthy and non-consanguineous parents. No neonatal distress was reported. At age 4, he underwent an excisional skin biopsy of a yellowish nodular lesion in the sacral and gluteal regions, revealing a connective nevus-like hamartomatous lesion. Additionally, the child presented multiple nodular elastic lesions on the trunk and lower limbs. These clinical features prompted clinicians to conduct a Next Generation Sequencing (NGS) panel, which identified the presence of a heterozygous c.1444del (p. Cys482AlafsTer5) variant in the LEMD3 gene (inherited from his father), confirming the suspected diagnosis of BOS. Therefore, the child underwent neuroradiological evaluation (MRI of the spinal cord) to rule out the presence of spina bifida, which returned negative. He first presented at the age of 7, when he was in the second year of primary school, at our child neuropsychiatry outpatient clinic for a developmental evaluation due to a clinical history of expressive language problems. These included persistent dyslalia and unintelligible speech, with simple sentence structure and difficulty in storytelling, associated with difficulties in gross and fine motor coordination. In the school setting, the patient struggled to acquire reading and writing skills, showing attentional lability, and hyperactivity. He also exhibited poor autonomy in daily activities, infantile behaviors and recurrent episodes of secondary daytime enuresis. During the neurological examination, we observed right-beating horizontal nystagmus in horizontal gaze movements and chaotic movements in pursuit; hypo-eligible osteotendinous reflexes in the lower extremities; motor impairment in postural steps, gait, and cerebellar skills. Additionally, diffuse hamartomatous nodular lesions were observed bilaterally on the chest, back, and lower limbs, along with a snowy lesion at the intergluteal site. We completed a neuropsychological assessment to evaluate the patient's cognitive abilities, language, motor, and school learning levels. 2.2. Neuropsychological assessment The cognitive profile, assessed with the Wechsler Intelligence Scale for Children - IV Edition (WISC-IV) (Orsini A. et al., 2012 ), revealed a non-homogeneous pattern: the total intelligence quotient (IQ) fell well below the normal range (total IQ = 59), along with indexes of verbal comprehension (VCI = 58), working memory (WMI = 61) and processing speed (PSI = 68), whereas non-verbal reasoning skills were within the normal range (Perceptual Reasoning Index = 89). The non-verbal cognitive ability, measured by the Leiter International Performance Scale-Revised (Leiter-R) (Roid GH et al., 1997), was classified as average (short IQ = 95 and full-scale IQ = 96), with some difficulties in fluid reasoning tasks (IQ = 75). According to the Developmental Neuropsychological Assessment - Second Edition (NEPSY-II) (Korkman M et al., 2007 ), the patient exhibited general difficulties in Sustaining and Focusing Attention abilities, Working Memory, Impulsive Behavior, and Inhibition skills. Indeed, the patient scored below average in tests of Visual Attention (Standard score = 2), Inhibition (combined score in the naming test = 4), Auditory Attention (2nd-5th percentile), and response set (2nd-5th percentile). The assessment of language comprehension revealed deficits specifically at the morphosyntactic level, indicating difficulties in understanding complex sentences. This was evidenced by the Language Comprehension Assessment Tests (PVCL) (Rustioni M.L.D. et al., 2007), where the child scored a raw score that falls below the expected range for his age group of 6–7 years. Conversely, at the semantic level, he performed at an average level in both lexical production and comprehension as assessed by the Lexical Neuropsychological Test (TNL) (Cossu G., 2013 ). The verbal production consisted of simple sentences that were not syntactically connected and included numerous elisions, truncations, and syllabic inversions. The motor assessment, conducted using the Movement Assessment Battery for Children-Second Edition (Movement ABC-2) (Henderson et al., 2007 ), confirmed deficits in both gross and fine motor coordination as well as in balance (total score = 1st percentile for the age range 7–7,11 years; Manual Dexterity = 5th, Aiming and Catching = 9th and Balance = 1st percentiles). In the Developmental Test for Visual-Motor Integration (VMI) (Beery K. E., 1997), visual-motor difficulties also emerged (total VMI = 9th, Visual Perception = 14th, Motor coordination = 37th percentiles). In the drawing, the graphomotor trait appeared not adequate for his age. To evaluate the child's level of school skill acquisition, it was necessary to administer learning tests appropriate for first grade, as he could not handle those aligned with his current grade level. At the MT-3 tests (Cornoldi C. et al., 1995 ), a deficient performance in reading correctness was evident (< 5th percentile). This was confirmed by the tests from the battery for assessing developmental dyslexia and dysorthography - Second Edition (DDE-2) (Sartori G. et al., 2007), in which he scored lower than 2 SD below the mean in reading words and non-words. The child could not complete the writing tests due to his difficulties, but he achieved satisfactory performance on all tests related to calculation skills for the first grade. The Adaptive Behavior Assessment System - Second Edition (ABAS-2) (Harrison P. et al., 2003) administered to the parents, revealed an overall profile below average (CAG = 88), with practical skills (PAD = 88) below average, conceptual skills borderline (CAD = 78), and social skills in the average (SAD = 106). Based on the responses provided from the Child Behavior Checklist for Ages 6–18 (CBCL/6–18) (Achenbach, T. M. et al., 2001), clinically significant scores (pT > 70) emerged in the areas of anxiety/depression, somatic complaints, social problems, attention and hyperactivity problems, and oppositional-defiant behaviors. The Conners’ Parent Rating Scale-Revised (CPRS-R) (Conners, C. K., 1997) revealed the following concerns: clinically significant score for ‘Social Problems’ (pT = 73) and borderline scores (pT = 56–65) in the following areas: ‘Cognitive/Inattention Problems’, ‘Hyperactivity’, ‘Psychosomatic Problems’ and ‘Restlessness/Impulsivity’. The evaluation concluded that the child has been diagnosed with a mild intellectual disability, characterized by a non-homogeneous profile. This diagnosis was accompanied by significant challenges in several developmental areas: language production and comprehension, motor coordination, and learning. Moreover, the child has been identified as being at risk for an emotional-affective disorder. Considering this complex diagnosis, neuropsychomotor and speech rehabilitation therapies were recommended to improve language, motor and attention problems. According to the Italian school system, a support teacher and educator were suggested to assist the child in the school setting. 3. Discussion We have described a case diagnosed as mild intellectual disability with clinical manifestations including impaired attentional skills, and difficulties in expressive language and motor coordination in a patient with Buschke–Ollendorff syndrome (BOS), caused by a heterozygous variant in the LEMD3 gene. Up to 80% of cases of intellectual disability are suspected to be influenced by genetic factors (Amberger et al., 2015 ). Identifying potential genetic causes of neurodevelopmental disorders (NDDs) is crucial for understanding the molecular mechanisms behind their onset and establishing genotype-phenotype correlations to aid in monitoring progression and predicting future complications (Parenti et al., 2020). Although a genetic component is known to contribute to NDDs, including intellectual disability, and the genetic basis for several subtypes has been identified, the majority of cases have an unknown genetic origin (van Loo & Martens, 2007 ). As far as known in the literature, in our case, the association between BOS and cognitive delay has not yet been adequately studied. As previously mentioned, Pope et al. attempted to explore the potential link between BOS and cognitive or developmental delay in their systematic review, but additional research is needed to establish the existence and characteristics of such a connection (Pope et al., 2016). This would aid in recognizing possible difficulties related to neurodevelopmental disorders earlier. As in the case of our patient with BOS, neuropsychological difficulties were recognized later, leading to his referral to child neuropsychiatry at age 7, thereby delaying the diagnosis of cognitive impairment and initiation of specific rehabilitative therapy. Furthermore, he exhibited a moderate severity of intellectual disability, which often goes unnoticed until school age (Lee et al., 2024), further delaying diagnosis. Through this case description, we aim to emphasize the importance of early identification of NDDs in individuals with BOS. A comprehensive approach involving neuropsychological assessment and counseling is essential for optimizing cognitive functioning, mitigating potential complications, and improving overall outcomes and quality of life for those affected by BOS. Further investigation is warranted to determine the nature and existence of a possible link between LEMD3 mutation and neurodevelopmental disorders. By delving into these neurological aspects, we gain deeper insights into the multifaceted nature of BOS and its implications for neurological health and development. Declarations Author Contributions Marilina Covuccia, Eleonora Spinelli and Barbara Caravale planned the manuscript's conceptualization, writing, review, and editing. All authors reviewed the drafts and authorized the final version of the manuscript. Ethical Approval : The study was conducted in accordance with the Declaration of Helsinki, and Ethical review and approval were waived for this study due to the anonymization procedure used for reporting the clinical case which involved the extensive modification of all demographic details and relevant characteristics that could potentially identify the individual. Informed Consent Statement : parental consent to participate and to publish was obtained. Declaration of competing interest : The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflicts of Interest : The authors declare no conflicts of interest. Funding : This research received no external funding. References Diotallevi F, Martina E, Paolinelli M, Radi G, Simonetti O, Sapigni C et al (2020) Buschke-Ollendorff syndrome in a 6-year-old patient: clinical and histopathological aspects of a rare disease. Acta Dermatovenerol Alp Pannonica Adriat 29(1):31–33 Dangoisse C, Dupire G, Franck D, Labadens A, Salik D, Sass U et al (2022) Variable expressivity in Buschke-Ollendorff syndrome. Ann Dermatol Venereol 149(2):128–131 Dupuis L, Kannu P, Mendoza-Londono R, Pope V, Sajic D, So J et al (2016) Buschke-Ollendorff syndrome: a novel case series and systematic review. Br J Dermatol 174(4):723–729 Cascella M, Lee K, Marwaha R Intellectual Disability. In: StatPearls. Treasure Island (FL): 2024 . http://www.ncbi.nlm.nih.gov/books/NBK547654/ Orsini A, Pezzuti L, Picone L (2012) Wechsler intelligence scale for children IV Edizione Italiana. Firenze, Italy., Giunti, OS Miller LJ, Roid GH (1997) Leiter international performance scale-revised (Leiter-R). Wood Dale IL: Stoelting ;10 Korkman M, Kirk U, Kemp S (2007) NEPSY II: Clinical and interpretive manual. Harcourt Assessment, PsychCorp; Rustioni MLD Associazione «La Nostra Famiglia». Prove di Valutazione della Comprensione Linguistica - PVCL. Giunti O.S. Organizzazioni speciali. 2007. Cossu G (2013) TNL - Test Neuropsicologico Lessicale per l’età evolutiva. Hogrefe Editore Henderson SE, Sugden DA, Barnett AL (2007) Movement Assessment Battery for Children-Second Edition (Movement ABC-2). Harcourt Assessment., London Beery KE (1997) The Beery-Buktenica Developmental Test of Visual-Motor Integration: Administration, Scoring, and Teaching Manual. Modern Curriculum., Parsippany, NJ Cornoldi C, Colpo G, Gruppo MT (1995) MT-3 Clinica: Prove per la valutazione delle abilità di lettura e comprensione per la scuola media. Firenze, Italia: Edizioni Organizzazioni Speciali. Job R, Tressoldi, Sartori G P. E. DDE-2: Batteria per la valutazione della dislessia e della disortografia evolutiva-2: manuale / Giuseppe Sartori, Remo Job, Patrizio E. Tressoldi (2. ed). Giunti O. S., Organizzazioni speciali. 2007. Harrison P, Oakland T (2003) Adaptive Behavior Assessment System - Second Edition (ABAS-2). San Antonio, TX: The Psychological Corporation. Achenbach TM, Rescorla LA (2001) Child Behav Checkl Ages 6–18 (CBCL/6–18, ASEBA CBCL/6–18) Conners CK Conners’ Parent Rating Scale – Revised (CPRS-R). North Tonawanda, NY: Multi-Health Systems. 1997. Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A (2015) OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res 43:D789–798 Novarino G, Parenti I, Rabaneda LG, Schoen H (2020) Neurodevelopmental Disorders: From Genetics to Functional Pathways. Trends Neurosci 43(8):608–621 Martens GJM, van Loo KMJ (2007) Genetic and environmental factors in complex neurodevelopmental disorders. Curr Genomics 8(7):429–444 Additional Declarations No competing interests reported. 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Introduction","content":"\u003cp\u003eBuschke-Ollendorff syndrome (BOS) represents a rare and typically harmless type of autosomal dominant genodermatosis (Diotallevi et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). It arises from a heterozygous, loss-of-function germline mutation in the LEMD3 gene, situated on chromosome band 12q14. The LEMD3 gene encodes the LEM domain-containing protein 3, which serves as a suppressor of bone morphogenetic protein (BMP) signaling pathways and transforming growth factor beta (TGF-\u0026szlig;). Mutations in LEMD3 lead to hyperostosis and abnormalities in the formation of connective tissue, including elastin. Consequently, this condition manifests in skin lesions, such as elastomas, and/or bone lesions, such as osteopoikilosis (Salik et al., 2022). These lesions manifest progressively during childhood, although some regression may occur in adulthood. The estimated incidence of BOS is 1/20,000 (Diotallevi et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In rare cases, other conditions reported alongside BOS included intellectual disability (ID) or developmental delay (DD) (Pope et al., 2016). A possible association between BOS and ID/DD has been highlighted only by Pope et al. In their retrospective study, three out of six (50%) patients showed attention deficit hyperactivity disorder or other developmental delays. Overall, the cohort of patients described in their case reports and case series exhibited a significantly lower incidence, accounting for just 5% (nine out of 164) (Pope et al., 2016). Intellectual disability is a complex condition with a prevalence in developing countries estimated to range from 10 to 15 per 1000 children, with a peak between the ages of 10 to 14 years (Lee et al., 2024). The research suggests that a substantial portion of cases may have genetic origins. Indeed genetic abnormalities can affect normal neurodevelopmental processes, leading to intellectual and adaptive behavior challenges (Lee et al., 2024). Here, we present the clinical history of a 7-year-old male child, diagnosed with BOS, whose neuropsychological profile we analyzed through the administration of standardized tests.\u003c/p\u003e"},{"header":"2. Case report","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Clinical background\u003c/h2\u003e \u003cp\u003eThe patient, a 7-year-old male child, was born prematurely at 34 weeks of gestational age via cesarean section, after a normal pregnancy, from healthy and non-consanguineous parents. No neonatal distress was reported. At age 4, he underwent an excisional skin biopsy of a yellowish nodular lesion in the sacral and gluteal regions, revealing a connective nevus-like hamartomatous lesion. Additionally, the child presented multiple nodular elastic lesions on the trunk and lower limbs. These clinical features prompted clinicians to conduct a Next Generation Sequencing (NGS) panel, which identified the presence of a heterozygous c.1444del (p. Cys482AlafsTer5) variant in the \u003cem\u003eLEMD3\u003c/em\u003e gene (inherited from his father), confirming the suspected diagnosis of BOS. Therefore, the child underwent neuroradiological evaluation (MRI of the spinal cord) to rule out the presence of spina bifida, which returned negative. He first presented at the age of 7, when he was in the second year of primary school, at our child neuropsychiatry outpatient clinic for a developmental evaluation due to a clinical history of expressive language problems. These included persistent dyslalia and unintelligible speech, with simple sentence structure and difficulty in storytelling, associated with difficulties in gross and fine motor coordination. In the school setting, the patient struggled to acquire reading and writing skills, showing attentional lability, and hyperactivity. He also exhibited poor autonomy in daily activities, infantile behaviors and recurrent episodes of secondary daytime enuresis. During the neurological examination, we observed right-beating horizontal nystagmus in horizontal gaze movements and chaotic movements in pursuit; hypo-eligible osteotendinous reflexes in the lower extremities; motor impairment in postural steps, gait, and cerebellar skills. Additionally, diffuse hamartomatous nodular lesions were observed bilaterally on the chest, back, and lower limbs, along with a snowy lesion at the intergluteal site. We completed a neuropsychological assessment to evaluate the patient's cognitive abilities, language, motor, and school learning levels.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Neuropsychological assessment\u003c/h2\u003e \u003cp\u003eThe cognitive profile, assessed with the Wechsler Intelligence Scale for Children - IV Edition (WISC-IV) (Orsini A. et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2012\u003c/span\u003e), revealed a non-homogeneous pattern: the total intelligence quotient (IQ) fell well below the normal range (total IQ\u0026thinsp;=\u0026thinsp;59), along with indexes of verbal comprehension (VCI\u0026thinsp;=\u0026thinsp;58), working memory (WMI\u0026thinsp;=\u0026thinsp;61) and processing speed (PSI\u0026thinsp;=\u0026thinsp;68), whereas non-verbal reasoning skills were within the normal range (Perceptual Reasoning Index\u0026thinsp;=\u0026thinsp;89).\u003c/p\u003e \u003cp\u003eThe non-verbal cognitive ability, measured by the Leiter International Performance Scale-Revised (Leiter-R) (Roid GH et al., 1997), was classified as average (short IQ\u0026thinsp;=\u0026thinsp;95 and full-scale IQ\u0026thinsp;=\u0026thinsp;96), with some difficulties in fluid reasoning tasks (IQ\u0026thinsp;=\u0026thinsp;75). According to the Developmental Neuropsychological Assessment - Second Edition (NEPSY-II) (Korkman M et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2007\u003c/span\u003e), the patient exhibited general difficulties in Sustaining and Focusing Attention abilities, Working Memory, Impulsive Behavior, and Inhibition skills. Indeed, the patient scored below average in tests of Visual Attention (Standard score\u0026thinsp;=\u0026thinsp;2), Inhibition (combined score in the naming test\u0026thinsp;=\u0026thinsp;4), Auditory Attention (2nd-5th percentile), and response set (2nd-5th percentile).\u003c/p\u003e \u003cp\u003eThe assessment of language comprehension revealed deficits specifically at the morphosyntactic level, indicating difficulties in understanding complex sentences. This was evidenced by the Language Comprehension Assessment Tests (PVCL) (Rustioni M.L.D. et al., 2007), where the child scored a raw score that falls below the expected range for his age group of 6\u0026ndash;7 years. Conversely, at the semantic level, he performed at an average level in both lexical production and comprehension as assessed by the Lexical Neuropsychological Test (TNL) (Cossu G., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe verbal production consisted of simple sentences that were not syntactically connected and included numerous elisions, truncations, and syllabic inversions.\u003c/p\u003e \u003cp\u003eThe motor assessment, conducted using the Movement Assessment Battery for Children-Second Edition (Movement ABC-2) (Henderson et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2007\u003c/span\u003e), confirmed deficits in both gross and fine motor coordination as well as in balance (total score\u0026thinsp;=\u0026thinsp;1st percentile for the age range 7\u0026ndash;7,11 years; Manual Dexterity\u0026thinsp;=\u0026thinsp;5th, Aiming and Catching\u0026thinsp;=\u0026thinsp;9th and Balance\u0026thinsp;=\u0026thinsp;1st percentiles).\u003c/p\u003e \u003cp\u003eIn the Developmental Test for Visual-Motor Integration (VMI) (Beery K. E., 1997), visual-motor difficulties also emerged (total VMI\u0026thinsp;=\u0026thinsp;9th, Visual Perception\u0026thinsp;=\u0026thinsp;14th, Motor coordination\u0026thinsp;=\u0026thinsp;37th percentiles). In the drawing, the graphomotor trait appeared not adequate for his age.\u003c/p\u003e \u003cp\u003eTo evaluate the child's level of school skill acquisition, it was necessary to administer learning tests appropriate for first grade, as he could not handle those aligned with his current grade level. At the MT-3 tests (Cornoldi C. et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e1995\u003c/span\u003e), a deficient performance in reading correctness was evident (\u0026lt;\u0026thinsp;5th percentile). This was confirmed by the tests from the battery for assessing developmental dyslexia and dysorthography - Second Edition (DDE-2) (Sartori G. et al., 2007), in which he scored lower than 2 SD below the mean in reading words and non-words. The child could not complete the writing tests due to his difficulties, but he achieved satisfactory performance on all tests related to calculation skills for the first grade.\u003c/p\u003e \u003cp\u003eThe Adaptive Behavior Assessment System - Second Edition (ABAS-2) (Harrison P. et al., 2003) administered to the parents, revealed an overall profile below average (CAG\u0026thinsp;=\u0026thinsp;88), with practical skills (PAD\u0026thinsp;=\u0026thinsp;88) below average, conceptual skills borderline (CAD\u0026thinsp;=\u0026thinsp;78), and social skills in the average (SAD\u0026thinsp;=\u0026thinsp;106).\u003c/p\u003e \u003cp\u003eBased on the responses provided from the Child Behavior Checklist for Ages 6\u0026ndash;18 (CBCL/6\u0026ndash;18) (Achenbach, T. M. et al., 2001), clinically significant scores (pT\u0026thinsp;\u0026gt;\u0026thinsp;70) emerged in the areas of anxiety/depression, somatic complaints, social problems, attention and hyperactivity problems, and oppositional-defiant behaviors.\u003c/p\u003e \u003cp\u003eThe Conners\u0026rsquo; Parent Rating Scale-Revised (CPRS-R) (Conners, C. K., 1997) revealed the following concerns: clinically significant score for \u0026lsquo;Social Problems\u0026rsquo; (pT\u0026thinsp;=\u0026thinsp;73) and borderline scores (pT\u0026thinsp;=\u0026thinsp;56\u0026ndash;65) in the following areas: \u0026lsquo;Cognitive/Inattention Problems\u0026rsquo;, \u0026lsquo;Hyperactivity\u0026rsquo;, \u0026lsquo;Psychosomatic Problems\u0026rsquo; and \u0026lsquo;Restlessness/Impulsivity\u0026rsquo;.\u003c/p\u003e \u003cp\u003eThe evaluation concluded that the child has been diagnosed with a mild intellectual disability, characterized by a non-homogeneous profile. This diagnosis was accompanied by significant challenges in several developmental areas: language production and comprehension, motor coordination, and learning. Moreover, the child has been identified as being at risk for an emotional-affective disorder. Considering this complex diagnosis, neuropsychomotor and speech rehabilitation therapies were recommended to improve language, motor and attention problems. According to the Italian school system, a support teacher and educator were suggested to assist the child in the school setting.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eWe have described a case diagnosed as mild intellectual disability with clinical manifestations including impaired attentional skills, and difficulties in expressive language and motor coordination in a patient with Buschke\u0026ndash;Ollendorff syndrome (BOS), caused by a heterozygous variant in the LEMD3 gene.\u003c/p\u003e \u003cp\u003eUp to 80% of cases of intellectual disability are suspected to be influenced by genetic factors (Amberger et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIdentifying potential genetic causes of neurodevelopmental disorders (NDDs) is crucial for understanding the molecular mechanisms behind their onset and establishing genotype-phenotype correlations to aid in monitoring progression and predicting future complications (Parenti et al., 2020). Although a genetic component is known to contribute to NDDs, including intellectual disability, and the genetic basis for several subtypes has been identified, the majority of cases have an unknown genetic origin (van Loo \u0026amp; Martens, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). As far as known in the literature, in our case, the association between BOS and cognitive delay has not yet been adequately studied. As previously mentioned, Pope et al. attempted to explore the potential link between BOS and cognitive or developmental delay in their systematic review, but additional research is needed to establish the existence and characteristics of such a connection (Pope et al., 2016). This would aid in recognizing possible difficulties related to neurodevelopmental disorders earlier.\u003c/p\u003e \u003cp\u003eAs in the case of our patient with BOS, neuropsychological difficulties were recognized later, leading to his referral to child neuropsychiatry at age 7, thereby delaying the diagnosis of cognitive impairment and initiation of specific rehabilitative therapy. Furthermore, he exhibited a moderate severity of intellectual disability, which often goes unnoticed until school age (Lee et al., 2024), further delaying diagnosis.\u003c/p\u003e \u003cp\u003eThrough this case description, we aim to emphasize the importance of early identification of NDDs in individuals with BOS. A comprehensive approach involving neuropsychological assessment and counseling is essential for optimizing cognitive functioning, mitigating potential complications, and improving overall outcomes and quality of life for those affected by BOS.\u003c/p\u003e \u003cp\u003eFurther investigation is warranted to determine the nature and existence of a possible link between LEMD3 mutation and neurodevelopmental disorders. By delving into these neurological aspects, we gain deeper insights into the multifaceted nature of BOS and its implications for neurological health and development.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMarilina Covuccia, Eleonora Spinelli and Barbara Caravale planned the manuscript\u0026apos;s conceptualization, writing, review, and editing. All authors reviewed the drafts and authorized the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e:\u003c/strong\u003e The study was conducted in accordance with the Declaration of Helsinki, and Ethical review and approval were waived for this study due to the anonymization procedure used for reporting the clinical case which involved the extensive modification of all demographic details and relevant characteristics that could potentially identify the individual.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eInformed Consent Statement\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e:\u003c/strong\u003e parental consent to participate and to publish was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eDeclaration of competing interest\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e:\u003c/strong\u003e The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e:\u003c/strong\u003e The authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/em\u003e: This research received no external funding.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDiotallevi F, Martina E, Paolinelli M, Radi G, Simonetti O, Sapigni C et al (2020) Buschke-Ollendorff syndrome in a 6-year-old patient: clinical and histopathological aspects of a rare disease. Acta Dermatovenerol Alp Pannonica Adriat 29(1):31\u0026ndash;33\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDangoisse C, Dupire G, Franck D, Labadens A, Salik D, Sass U et al (2022) Variable expressivity in Buschke-Ollendorff syndrome. Ann Dermatol Venereol 149(2):128\u0026ndash;131\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDupuis L, Kannu P, Mendoza-Londono R, Pope V, Sajic D, So J et al (2016) Buschke-Ollendorff syndrome: a novel case series and systematic review. Br J Dermatol 174(4):723\u0026ndash;729\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCascella M, Lee K, Marwaha R Intellectual Disability. \u003cem\u003eIn: StatPearls. 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Prove di Valutazione della Comprensione Linguistica - PVCL. \u003cem\u003eGiunti O.S. Organizzazioni speciali. 2007.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCossu G (2013) TNL - Test Neuropsicologico Lessicale per l\u0026rsquo;et\u0026agrave; evolutiva. Hogrefe Editore\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHenderson SE, Sugden DA, Barnett AL (2007) Movement Assessment Battery for Children-Second Edition (Movement ABC-2). Harcourt Assessment., London\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeery KE (1997) The Beery-Buktenica Developmental Test of Visual-Motor Integration: Administration, Scoring, and Teaching Manual. Modern Curriculum., Parsippany, NJ\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCornoldi C, Colpo G, Gruppo MT (1995) MT-3 Clinica: Prove per la valutazione delle abilit\u0026agrave; di lettura e comprensione per la scuola media. Firenze, \u003cem\u003eItalia: Edizioni Organizzazioni Speciali.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJob R, Tressoldi, Sartori G P. E. DDE-2: Batteria per la valutazione della dislessia e della disortografia evolutiva-2: manuale / Giuseppe Sartori, Remo Job, Patrizio E. Tressoldi (2. ed). \u003cem\u003eGiunti O. S., Organizzazioni speciali. 2007.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarrison P, Oakland T (2003) Adaptive Behavior Assessment System - Second Edition (ABAS-2). \u003cem\u003eSan Antonio, TX: The Psychological Corporation.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAchenbach TM, Rescorla LA (2001) Child Behav Checkl Ages 6\u0026ndash;18 (CBCL/6\u0026ndash;18, ASEBA CBCL/6\u0026ndash;18)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConners CK Conners\u0026rsquo; Parent Rating Scale \u0026ndash; Revised (CPRS-R). North Tonawanda, \u003cem\u003eNY: Multi-Health Systems. 1997.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A (2015) OMIM.org: Online Mendelian Inheritance in Man (OMIM\u0026reg;), an online catalog of human genes and genetic disorders. Nucleic Acids Res 43:D789\u0026ndash;798\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNovarino G, Parenti I, Rabaneda LG, Schoen H (2020) Neurodevelopmental Disorders: From Genetics to Functional Pathways. Trends Neurosci 43(8):608\u0026ndash;621\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartens GJM, van Loo KMJ (2007) Genetic and environmental factors in complex neurodevelopmental disorders. Curr Genomics 8(7):429\u0026ndash;444\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Buschke-Ollendorff syndrome, Intellectual Disability, Neurodevelopment, Genetic syndrome","lastPublishedDoi":"10.21203/rs.3.rs-4530118/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4530118/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eBuschke-Ollendorff syndrome (BOS) is a rare autosomal dominant genodermatosis caused by a mutation in the LEMD3 gene. While it primarily affects the skin with the development of connective tissue nevi, it can be associated with other conditions such as intellectual disability or developmental delay. These co-occurring conditions add complexity to the clinical picture and necessitate comprehensive evaluation and management strategies.\u003c/p\u003e\u003ch2\u003eCase report:\u003c/h2\u003e \u003cp\u003eWe describe the clinical history of a 7-year-old male child diagnosed with BOS, exploring his neuropsychological profile and finding the presence of mild intellectual disability, impaired attentional abilities, and difficulties in language, motor coordination, and learning.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eOur findings support the hypothesis of the presence of neurodevelopmental disorders in children with BOS. However, further studies are needed to determine the existence and understand the nature of the possible link between these conditions.\u003c/p\u003e","manuscriptTitle":"Neuropsychological profile in a child with Buschke-Ollendorff syndrome: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-27 03:40:30","doi":"10.21203/rs.3.rs-4530118/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4ba532be-ef41-4a7a-b2ee-dfd2f320f249","owner":[],"postedDate":"June 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-29T00:23:30+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-27 03:40:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4530118","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4530118","identity":"rs-4530118","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}