ABSTRACT The authors present a case of Fragile X syndrome (FXS) in siblings from an Indian family with no developmental delay in previous generations. The boy presented with developmental delay, autistic features and defiant behaviours that raised clinical suspicion. He also had congenital diaphragmatic hernia (CDH). Social anxiety and difficulty in making friends were the subtle features in his sister with dull normal intelligence. FXS was confirmed by clinical features and DNA testing. Intervention was initiated for both the siblings. Screening siblings in FXS is important. CDH can be associated with FXS. Fragile X syndrome, FMR-1-related disorder, congenital diaphragmatic hernia, social anxiety INTRODUCTION Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability (ID) . FXS is more frequent in males. FXS is caused by an alteration in the Fragile X mental retardation 1 (FMR1) gene, which maps at the Xq27.3 band: >99% of individuals have a CGG expansion (>200 triplets) in the 5′ untranslated region of the gene, called a full mutation (FM). This causes a hypermethylated state of the FMR1 promoter that consequently inhibits FMR1 transcription causing loss or heavy reduction of FMR protein. The FMR protein plays a critical role in neuronal development. The clinical spectrum of FXS is wide. In boys, FXS usually manifests in the form of mild to moderate ID. Behaviour phenotype includes autistic features, social anxiety, attention deficit and sensory processing disorders. The girl with FXS may have intellectual potential ranging from normal intelligence to mild ID with behaviour phenotype of shyness, social anxiety, depression and mood lability . We report an unusual case of siblings (younger boy and older sister) with FXS with no family history of developmental delay. Furthermore, the boy had congenital diaphragmatic hernia (CDH). To our knowledge, association of CDH with FXS has not been reported before. CASE REPORT A 4-year-old boy (gestation: 38 weeks, birth weight: 3 kg) presented with speech delay and tantrums. He was the second child of non-consanguineous Indian parents with no family history of developmental delay in three generations. He had respiratory distress soon after birth, and was diagnosed to have left posterolateral CDH with persistent pulmonary hypertension. There were no other congenital anomalies. The ventilatory and oxygen requirements were minimal (peak inspiratory pressure: 16 cm H2O, positive end-expiratory pressure: 4 cm H2O, maximum oxygen requirement: 35%). He was operated on Day 5 of life, and extubated within 24 h of surgery. The blood gases were normal during the perioperative period with no hypotension or acidosis. Postoperative course was uneventful. Neurological examination was normal at discharge. He went home on the 10th day after surgery. The child’s developmental milestones were delayed. He started walking at the age of 2 years, and speaking only words but not using sentences at the age of 2.5 years. He had tantrums such as shouting and throwing himself down. General examination showed slightly large ears and narrow face. Hearing (brainstem evoked response audiometry) was normal. An intelligence test (IQ) assessment by Stanford–Binet test revealed mild ID. Behaviour assessment revealed social anxiety, defiant behaviours and sensory processing disorder. The Diagnostic Statistical Manual of mental disorders-V (DSM-V) criteria for autism were fulfilled. The clinical findings suggested possibility of FXS. A polymerase chain reaction (PCR) using specific primers (Repeat PCR) and triplet repeat primed PCR (TP-PCR) indicated >200 repeats suggesting FM and confirmed the diagnosis of FXS. Intervention was started in the form of speech therapy, sensory integration, structured routine and schooling. The family was counselled for behaviour modification. During one of the follow-up visits, he was accompanied by his 10-year-old sister. On behavioural assessment, she had social difficulties, social anxiety and difficulty in making friends. Her IQ and Wide Range Achievement Test (WRAT) assessment revealed dull normal intelligence (IQ: 85) with difficulty in mathematics and poor reading comprehension. Her genomic DNA analysis by PCR with amplification for FMR1 allele showed a normal allele (29 CGG repeats) and the other with >200 repeats suggestive of being carrier of a FM allele. She was commenced on remediation and social skills training in group therapy. DISCUSSION Our case has two siblings, both with FXS with no family history of ID in three generations and no history of consanguinity in parents. To our knowledge, it is rare to have two siblings to have FXS without family history of developmental delay in three generations. The boy also had CDH, which to our knowledge is previously unreported. Family history of ID is common in FXS. Stembalska et al.  reported two females from a family with history of ID in men from the previous generation. Sorensen et al.  reported FXS in siblings (brother and a sister) born to consanguineous parents. Chatterjee et al.  reported a male patient with ID and family history of ID. Previously reported associations of FXS include congenital heart defect, tracheoesophageal fistula, Poland anomaly and cleft lip or palate . Whether the CDH was a coincidental finding or an association in the case we have presented is difficult to prove. CDH has been associated with isochromosome 12p, trisomy 21, Wolf–Hirschhorn syndrome, Cornelia de Lange syndrome and Fryns syndrome . The characteristic dysmorphic features of FXS do not manifest until puberty in boys and girls do not have specific dysmorphic features in FXS. The social anxiety, defiance and sensory issues in the boy and the social anxiety in his sister were pointers to the diagnosis. Our clinical suspicion rested mainly on the developmental profile. The subtle presentation of the developmental issues was probably the reason why the diagnosis was delayed in the girl. TP-PCR test is the gold standard for first-level assessment. It allows the simultaneous amplification of both the full-length FMR1 alleles (using PCR primers flanking the repeated region); CGG triplets (using a third primer, complementary to the FMR1 triplet repeat region) in the same PCR reaction detecting the full range of FX-expanded alleles and minimizing need for Southern blot analysis [7, 8]. The limitation of our case report is that we were unable to test for maternal carrier status. In the Indian scenario, significant social stigma is associated with having a disabled child (in this case, a son with disability and a daughter with behavioural difficulties). Testing for maternal carrier status would have further increased the mother's stress, and inadvertently, a feeling of guilt with risk of straining her marital relation. Hence, we avoided this investigation. In summary, our experience suggests that screening of siblings in FXS is important, and CDH can be associated with FXS. Early diagnosis allows implementation of an appropriate therapeutic intervention programme for children with FXS and counselling for the family. Footnotes The authors certify that the article is original, is not under consideration by any other journal and has not been previously published. REFERENCES 1 Hersh JH , Saul RA ; Committee on Genetics . Health supervision for children with Fragile X syndrome . Pediatrics 2011 ; 127 : 994 – 1006 . Google Scholar Crossref Search ADS PubMed 2 Stembalska A , Łaczmańska I , Gil J , et al. Fragile X syndrome in females—a familial case report and review of the literature . Dev Period Med 2016 ; 20 : 99 – 104 . Google Scholar PubMed 3 Sorensen PL , Basuta K , Mendoza-Morales G , et al. A Fragile X sibship from a consanguineous family with a compound heterozygous female and partially methylated full mutation male . Am J Med Genet 2012 ; 158A : 1221 – 4 . Google Scholar Crossref Search ADS PubMed 4 Chatterjee C , Guha D , Das S , et al. Fragile X syndrome a case report of a family . Indian J Pathol Microbiol 2001 ; 44 : 499 – 502 . Google Scholar PubMed 5 Kidd SA , Lachiewicz A , Barbouth D , et al. Fragile X syndrome: a review of associated medical problems . Pediatrics 2014 ; 134 : 995 – 1005 . Google Scholar Crossref Search ADS PubMed 6 Holder AM , Klaassens M , Tibboel D , et al. Genetic factors in congenital diaphragmatic hernia . Am J Human Genet 2007 ; 80 : 825 – 45 . Google Scholar Crossref Search ADS 7 Chen L , Hadd A , Sah S , et al. An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for southern blot analysis . J Mol Diagn 2010 ; 12 : 589 – 600 . Google Scholar Crossref Search ADS PubMed 8 Lyon E , Laver T , Yu P , et al. A simple, high-throughput assay for Fragile X expanded alleles using triple repeat primed PCR and capillary electrophoresis . J Mol Diagn 2010 ; 12 : 505 – 11 . Google Scholar Crossref Search ADS PubMed © The Author . Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
Journal of Tropical Pediatrics – Oxford University Press
Published: Oct 1, 2018
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