Clinical and Genetic Profile of Children With Short Stature Presenting to a Genetic Clinic in Northern India

Objective: To define the spectrum of genetic disorders in patients with short stature visiting the genetic out-patient department in a tertiary care hospital. Methods: A chart review was done for 455 individuals (10 months-16 yrs) with short stature, who were evaluated at the genetic clinic from 1 January, 2017 upto 31 October, 2018. 226 patients who needed detailed evaluation, the spectrum of genetic diagnosis is presented. Results: Proportionate short stature was identified in 63% individuals (n=142) of which 93 (65%) were recognizable syndromes such as Turner syndrome, and William syndrome, and RASopathies. In clinically undefined syndromes (39, 27%), a diagnosis could be made by karyotype (n=3/10), chromosomal microarray (6/12) and exome sequencing (1/6). In the 84 children in the disproportionate short stature group (37%), lysosomal storage disorders (LSDs) (45%, n=38) were identified by enzyme analysis in 86.8% and skeletal dysplasias (44%, n=37) identified by skeletal survey in 89% cases. Conclusions: In undefined syndromic short stature, chromosomal microarray may be the first investigation of choice if phenotyping is not suggestive of a specific genetic syndrome. Exome sequencing can be useful in identifying newer genes among idiopathic and familial short stature cohorts.

Prenatal presentation of a rare genetic disorder: a clinical, autopsy and molecular correlation

Walker Warburg syndrome (WWS) lies at the severe end of the spectrum of the congenital muscular dystrophies. WWS is a congenital disorder of the O-glycosylation that disrupts in the post-translation modification of dystroglycan proteins. WWS is characterized by the involvement of the central nervous system and rarely by multisystem involvement. Next-generation sequencing discovered that multiple genes are associated with this disorder. FKTN is the rarest cause of WWS. We describe a clinical-autopsy report of a molecularly- confirmed WWS case presenting with ventriculomegaly, agenesis of the corpus callosum with a novel phenotype of Dandy-Walker malformation and unilateral multi-cystic kidney. The whole-exome sequencing confirmed a homozygous variant (c.411C>A) in the FKTN gene with a premature termination codon. This case emphasizes the importance of detailed postnatal phenotyping through an autopsy in any pregnancy with antenatally identified malformations. Obstetricians, pediatricians as well as fetal medicine experts need to counsel the parents and focus on preserving the appropriate sample for genetic testing. WWS, though rare deserves testing especially in the presence of positive family history. Dandy-Walker malformation is a novel feature and expands the phenotypic spectrum.

Testing Modalities for Inborn Errors of Metabolism – What a Clinician Needs to Know?

The present century is being hailed as the century for genetic therapies, and inborn errors of metabolism is leading the way. As we gearourselves for treating children with genetic and metabolic disorders, the key is to recognize them early and accurately for best outcomes.In these changing times with advent of technology, clinicians are now more aware, exposed and well equipped with the armamentariumof diagnostic modalities. However, it is difficult to choose between the tests without a baseline knowledge about testing for genetic andmetabolic disorders. The key question for a clinician when dealing with a suspected metabolic disorder case is ‘what test to order’ and‘how to proceed.’ The current article provides a rational view on the various laboratory testing modalities available for diagnosis of inbornerrors of metabolism. The article provides details of the basic and advanced metabolic tests that can be ordered in appropriate settings

Ethylmalonic Encephalopathy in an Indian Boy.

Background: Ethylmalonic encephalopathy is a rare inborn error of metabolism characterized by neurodevelopmental delay / regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Case Characteristics: 4-year-old boy with developmental regression, chronic diarrhea, petechial spots and acrocyanosis. MRI brain showed T2W/FLAIR hyperintensities in bilateral caudate and putamen. Abnormal acyl-carnitine profile and metabolites on urinary GC-MS analysis suggested the diagnosis. Intervention: Sequencing of ETHE1 gene revealed mutations: c.488G>A and c.375+5G>T (novel). Message: EE is clinically-recognizable disorder with typical clinical features.

Lysinuric Protein Intolerance Presenting with Recurrent Hyperammonemic Encephalopathy.

Background: Lysinuric protein intolerance is an inherited disorder of transport of cationic amino acids, causing amino aciduria. Case characteristics: A 3-year-old boy with 12 month history of episodic change in behavior (decreased sleep, poor interaction), stunted growth and hyperammonemia. Outcome: Genetic analysis revealed a homozygous mutation, c.158C>T (p.Ser53Leu) in exon 1 of SLC7A7 gene.With appropriate management of hyperammonemia episodes, his neurodevelopmental outcome is normal. Message: Lysinusic protein intolerance is a potentially treatable disorder and should not to be missed.

Identification of a Novel TAZ Gene Mutation in a Family With X-Linked Dilated Cardiomyopathy Barth Syndrome

Abstract Mutations in the tafazzin (TAZ) gene on chromosome Xq28 are responsible for the Barth syndrome (BTHS) phenotype resulting in a loss of function in the protein tafazzin involved in the transacylation of cardiolipin, an essential mitochondrial phospholipid. TAZ gene was investigated in the proband in our study, who died of dilated cardiomyopathy at 8 months of age, and his family by sequencing to identify the genetic cause of BTHS. Molecular analysis revealed a novel mutation in exon 5 (c.520T>G) of the TAZ gene. This novel mutation c.520T>G, pW174G, was also found in female carriers (mother and grandmother of proband) in the family. Bioinformatic analysis was carried out to examine the effect of mutation in the gene and confirmed the deleterious effect of this single mutation to the protein structure. Protein modeling and 3-dimensional structure of TAZ protein demonstrated the significantly visible changes in mutated protein leading to BTHS phenotype. Prenatal diagnosis in a subsequent pregnancy showed a carrier female, and pregnancy was continued. Child is doing well at 1 year of age.

Mitochondrial DNA Depletion Syndrome Causing Liver Failure.

Background: Mitochondrial DNA depletion syndromes are disorders of Mitochondrial DNA maintenance causing varied manifestations, including fulminant liver failure. Case characteristics: Two infants, presenting with severe fatal hepatopathy. Observation: Raised serum lactate, positive family history (in first case), and absence of other causes of acute liver failure. Outcome: Case 1 with homozygous mutation, c.3286C>T (p.Arg1096Cys) in POLG gene and case 2 with compound heterozygous mutations, novel c.408T>G (p.Tyr136X) and previously reported c.293C>T (p.Pro98Leu), in MPV17 gene. Message: Mitochondrial DNA depletion syndrome is a rare cause of severe acute liver failure in children.