Alka V. Ekbote

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Purpose:Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established.Methods:One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians.Results and Conclusion:We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.Genet Med 18 5, 483–493.

A descriptive analysis of 14 cases of progressive-psuedorheumatoid-arthropathy of childhood from south India: Review of literature in comparison with Juvenile Idiopathic Arthritis

BACKGROUND Progressive-psuedorheumatoid-arthropathy of childhood (PPAC) is an autosomal recessive single gene skeletal dysplasia involving joints. The gene attributed to its cause is WNT1-inducible-signaling pathway protein3 (WISP3). OBJECTIVE To study the clinical and radiographic presentation of PPAC in Indian patients and to compare with described features of PPAC and Juvenile Idiopathic Arthritis (JIA) from published literature. METHODS All cases (n = 14) of PPAC seen in the Rheumatology and Clinical Genetics outpatient clinic between 2008 and 2011 with classical, clinical, and radiological features were studied. The demographic and clinical data were obtained from medical records of the outpatient visits. RESULTS Slight female preponderance (57%) and history of consanguinity in parents (43%) was observed in this group. The median age at onset was 4.5 years (range from birth to 9 years of age). Early presentation below the age of 3 years was seen in 3/14 patients (21%) in this group. The growth of all the patients fell below the 3rd percentile for the age. Historically, hip joint involvement was the most common presenting feature; however, elbow, wrist, knees, feet, spine, shoulder joints and small joints, namely proximal interphalangeal (PIP), distal interphalangeal (DIP), metacarpophalangeal (MCP), metatarsophalangeal joints (MTP), and interphalangeal joints (IP) of the feet, were also involved, either clinically or radiologically in varying proportions. Platyspondyly was noted in all. Molecular analysis of the WISP3 gene identified mutations in all the 5 individuals in whom it was done. CONCLUSION This descriptive case series of PPAC from India reports distinctly differentiating clinical, radiological, and molecular markers in contrast with classically described features of JIA, its mimic. Early presentation (age of onset below 3 years) with involvement of interphalangeal joints seen in three patients (21%) was a unique finding, with missense WISP3 gene mutations in all of them. Timely diagnosis of this entity can spare the patient from unnecessary investigations and toxic medications.

Patient with Mutation in the Matrix Metalloproteinase 2 (MMP2) Gene - A Case Report and Review of the Literature

Torg and Winchester syndromes and patients reported by Al-AqeelSawairi as well as nodulosis-arthropathy-osteolysis (NAO) patients, patients with multicentric NAO share autosomal recessive inheritance. The common presenting symptomatology includes progressive osteolysis chiefly affecting the carpal, tarsal and interphalangeal joints. Here, we report a patient with Torg syndrome. Torg syndrome is caused by homozygous or compound heterozygous mutations in the matrix metalloproteinase 2 (MMP2) gene. MMP2 codes for a gelatinase that cleaves type IV collagen, a major component of basement membrane. The clinical presentation of our patient included moderate osteolysis of the small joints of the hands and knees, hirsutism, nodulosis sparing the palms and soles, corneal opacities and mild facial dysmorphism without gum hypertrophy. Genetic analysis showed that the patient was homozygous for a novel base variant c538 G>A (p.D180N) in the MMP2 gene. Both parents were carriers of the same mutated variant. Our patient had some previously unreported endocrine manifestations such as premature thelarche and elevated follicle-stimulating hormone levels.

Recurrent and novel GLB1 mutations in India.

GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme β-d-galactosidase. In this study, we report molecular findings in 50 Asian Indian families with GM1 gangliosidosis. We sequenced all the exons and flanking intronic sequences of GLB1 gene. We identified 33 different mutations (20 novel and 13 previously reported). The novel mutations include 12 missense (p.M1?, p.E129Q, p.G134R, p.L236P, p.G262E, p.L297F, p.Y331C, p.G414V, p.K493N, p.L514P, p.P597L, p.T600I), four splicing (c.246-2A>G, c.397-2A>G, c.552+1G>T, c.956-2A>G), three indels (p.R22Qfs*8, p.L24Cfs*47, p.I489Qfs*4) and one nonsense mutation (p.Q452*). Most common mutations identified in this study were c.75+2InsT (14%) and p.L337P (10%). Known mutations accounted for 67% of allele frequency in our cohort of patients, suggesting that these mutations in GLB1 are recurrent across different populations. Twenty three mutations were localized in the TIM barrel domain, β-domain 1 and β-domain 2. In silico sequence and structure analysis of GLB1 reveal that all the novel mutations affect the function and structure of the protein. We hereby report on the largest series of patients with GM1 gangliosidosis and the first from India.

Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy.

Multicentric osteolysis nodulosis and arthropathy (MONA) is an infrequently described autosomal recessive skeletal dysplasia characterized by progressive osteolysis and arthropathy. Inactivating mutations in MMP2, encoding matrix metalloproteinase‐2, are known to cause this disorder. Fifteen families with mutations in MMP2 have been reported in literature. In this study we screened thirteen individuals from eleven families for MMP2 mutations and identified eight mutations (five novel and three known variants). We characterize the clinical, radiographic and molecular findings in all individuals with molecularly proven MONA from the present cohort and previous reports, and provide a comprehensive review of the MMP2 related disorders.

A Case Report of Fibular Aplasia, Tibial Campomelia, and Oligosyndactyly (FATCO) Syndrome Associated With Klinefelter Syndrome and Review of the Literature

Limb development is a complex regulated development phenomenon involving multiple genes. Fibular Aplasia, Tibial Campomelia and Oligosyndactyly (FATCO) syndrome (MIM#246570) is a syndrome of unknown genetic basis and inheritance with variable expressivity and penetrance. Its counterpart, Fuhrmann syndrome or Femoral-Fibularaplasia-Campomelia and Oligosyndactyly are a result of defect in the WNT7a gene located on the 3p25. Former is proposed to be a development dysplasia of defective dorso-ventral polarity assignment and distal limb development. Ectrodactyly and fibular a/hypoplasia (EFA, MIM# 113310) share the full phenotypic spectrum of FATCO syndrome, whether they are allelic disorders or represent two variable presentations in the spectrum of the same disorder is not an established fact. We report here one Indian patient with findings of FATCO syndrome with associated Klinefelter syndrome. This is the first such report which is likely to be a co-incidental finding and has implications for genetic counseling. Levels of Evidence: Therapeutic, Level IV

Renal manifestations of tuberous sclerosis among children: an Indian experience and review of the literature

Objective The objective of this study was to describe the renal manifestations in children 0–18 years of age diagnosed with tuberous sclerosis complex (TSC) at a tertiary hospital in South India. Methods Data of children with TSC, who presented to Christian Medical College Vellore Hospital from January 2008 to January 2013, were analysed by a retrospective chart review. The cases were identified from outpatient records and underwent ultrasonography, urine analysis and examination of serum creatinine to recognize renal involvement. Results Twenty-five children with TSC were identified. Two children did not have imaging studies available and were excluded from the analysis. The age of the included children ranged from 5 days to 15 years with a median age of 8 years. Seventy-four per cent (17/23) were males. Ten of the 23 children had evidence of renal involvement (43.5%). Of the 10 children with renal involvement, 6 had angiomyolipoma (60%), 5 had renal cysts (50%) and 1 had suspected renal cell carcinoma. In two children both angiomyolipoma (AML) and cysts were noted. One child was found to have proteinuria. The rest of the children had no evidence of proteinuria and had normal creatinine clearance. Conclusion We conclude that all children with TSC should be screened for renal involvement and regular follow-up should be arranged.

Expanding the phenome and variome of skeletal dysplasia

PurposeTo describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.MethodsDetailed phenotyping and next-generation sequencing (panel and exome).ResultsOur analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello–Carey syndrome–like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.ConclusionBy expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Isoleucine deficiency in a neonate treated for maple syrup urine disease masquerading as acrodermatitis enteropathica

BackgroundSpecial diet with restricted branched-chain-amino-acids used for treating maple syrup urine disease can lead to specific amino acid deficiencies.Case characteristicsWe report a neonate who developed skin lesions due to isoleucine deficiency while using specialised formula.Intervention/OutcomeFeeds were supplemented with expressed breast milk. This caused biochemical and clinical improvement with resolution of skin lesions.MessageBreast milk is a valuable and necessary adjunct to specialized formula in maple syrup urine disease to prevent specific amino acid deficiency in the neonatal period.

De Barsy syndrome type B presenting with cardiac and genitourinary abnormalities.

Background De Barsy Syndrome type B (ICD – 10 Q87.7, OMIM 614438) is a rare cutis laxa syndrome with progeroid appearance because of a defect in the pyrroline-5-carboxylate reductase (PYCR1) gene. Pyrroline-5-carboxylate reductase (EC 1.5.1.2) catalyses the NAD(P)H-dependent conversion of pyrroline-5-carboxylate into proline. PYCR1 deficiency leads to an altered mitochondrial membrane potential, an increased fragmentation of the mitochondrial network and higher apoptosis rates upon oxidative stress. Prevalence is less than 1/10 00 000. Inheritance is autosomal recessive. Fewer than 100 cases have been reported so far, of which three were from India (Dimopoulou et al., 2013).