Search

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.

Objective: To examine the common and specific clinical features, mutation spectrum and genotype-phenotype correlation in Noonan syndrome and related RASopathies., Participants: Records of 30 patients with clinical diagnosis of Noonan syndrome and related RASopathies presenting over a six-year period at a tertiary care medical genetics centre were reviewed. Detailed clinical phenotype evaluation and genetic testing (PTPN11 sequencing or next generation sequencing) was done. The genetic results were used to classify the patients., Results: Noonan syndrome was confirmed in 22 patients, 5 had cardiofaciocutaneous syndrome and 3 had Noonan syndrome like disorder with loose anagen hair. The molecular diagnosis was confirmed in 27 patients. Mutations in PTPN11 gene were confirmed in 57.8 % patients. Developmental delay, cardiac defects, ectodermal abnormalities and coarse face was the predominant phenotype. Noonan syndrome like disorder with loose anagen hair was clinically identifiable by the sparse, slow growing hair and caused by one recurrent SHOC2, c.4A>G mutation., Conclusion: Noonan syndrome and other RASopathies should be suspected in patients with short stature, cardiac defects, typical facial dysmorphism with or without ectodermal involvement.

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.

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.

Objective: Gaucher disease in India has been reported only in a few case reports from India. The aim of the study was to assess the response to enzyme replacement therapy in Indian patients with Gaucher disease., Design: Retrospective analysis of patients receiving CHO-derived recombinant macrophage-targetted glucocorebrosidase., Setting: Five centers from India with experience in treating lysosomal storage disorders., Patients: The diagnosis of Gaucher disease was confirmed by low glucocerebrosidase levels, though it was first made on splenectomy in 8 and on bone marrow examination in 9 patients. Twenty five of 52 patients diagnosed with Gaucher disease (17 Type I, 8 mild Type III) received treatment for >6 months. Indications for treatment included symptomatic anemia, thrombo-cytopenia, organomegaly, bone disease or mild neurological symptoms leading to impairment of quality of life. Patients with significant neurological involvement were excluded. The drug infusions were given intravenously every 15 days., Main Outcome Measures: Hemoglobin, platelet counts, liver and spleen volumes and growth parameters., Results: 22 of the 25 children who survived were analyzed. After 6 months of treatment, the mean (range) increase in hemoglobin was 1.5 (-3.4 to 6.1) g/dL (P=0.01) and in platelet count was 32 x 10(9)/L (-98.5 x 109 to 145.5 x10(9))/L (P=0.02). The mean (range) increase in weight was 3 kg (-5.6 to 10.5) (P=0.04) and in height was 7.1 cm (0 to 26.5) (P=0.0003). Liver size decreased by a mean (range) of 38.5% (- 5.5 to 86.7) (P=0.0003) and the spleen size by 34.8% (0 to 91.7) (P=0.004). All patients had improvement in bone pains and in 2 patients, neurological symptoms improved with others remaining static., Conclusions: This is the first reported cohort of patients in India reporting our experience with imiglucerase enzyme replacement therapy for treatment of Gaucher Disease in India.

Congenital hyperinsulinism is the most frequent cause of severe, persistent hypoglycemia in infancy and childhood. We report a 2.5 year old girl with severe congenital hyperinsulinism. Mutation analysis showed that the child is a compound heterozygote for two missense mutations in the ABCC8 gene.

Objective: To study the clinical and biochemical spectrum of Gaucher disease., Design: Assay of beta glucosidase enzyme in leucocytes in patients with splenomegaly, and in chorionic villi for prenatal diagnosis., Setting: Hospital-based., Subjects: Of 13 cases of Gaucher disease, aged 1-6 years, 9 were identified at Delhi and 4 at Bombay., Results: The enzyme beta-glucosidase was 0.65 nmol/h/mg of protein or less in all the cases in Delhi, and 2.5 nmol/h/mg of protein or less in Bombay. All cases except one belonged to type 1 (hepatosplenomegaly), while one case was of type 2 (neuronopathic). Prenatal diagnosis was carried out in one family and the fetus was found to be affected., Conclusion: In children with hepatosplenomegaly and increased acid phosphatase, assay of beta-glucosidase enzyme confirms the diagnosis of Gaucher disease. Diagnosis of the disease is important because enzyme replacement therapy is available and prenatal diagnosis is possible.

Homocystinuria was diagnosed in 15 (0.59%) cases on screening 2560 children for aminoacidopathies. The commonest presenting features were ectopia lentis (95%) and mental retardation (86%). Other features included, dental anomalies (40%), osteoporosis (40%), behavioral problems (33%) and arachnodactyly (13%). Diagnosis was confirmed by iodoplatinate staining of one dimensional paper chromatography of urine. All the 15 cases of homocystinuria were first treated with high dose oral pyridoxine. Only one case responded to pyridoxine therapy. All the other patients were started on a low methionine, High cysteine diet with folate supplementation. Only one patient showed a complete response to dietary therapy. Nonavailability and high cost of the commercially available methionine-free, cysteine-supplemented diet and late diagnosis were responsible for the poor response in the majority of our patients.

Forty five case of Turner syndrome diagnosed in the Genetics Clinic, between January 1986 and December 1993, were analyzed. The most commonly observed karyotype was 45, X (44.4%), followed by 45, X/46, XX mosaicism (24.4%). Less frequently demonstrated karyotypes were 45, X/46, X, i (Xq) mosaicism and 46, X, i (Xq) (13.3%). Mosaicism for chromosome was seen in 6.7% of patients. Patients with 45, X karyotype had short stature (85%), dysmorphic facies (60%), delayed appearance of secondary sexual characters (100%) and primary amennorhea (100%). Those with 45, X/46, XX mosaicism were less often dysmorphic and presented with either primary or secondary amenorrhea. Patients with 45, X karyotype were younger at diagnosis and had a significantly shorter mean adult height than those with 45, X/46, XX mosaicism. The phenotype in patients with other karyotypic abnormalities was similar to the 45, X group. Short stature and primary or secondary amenorrhea occurring together in a female strongly suggests the possibility of Turner syndrome, which should be confirmed by chromosomal analysis.

The clinical features of 20 patients of Martin Bell syndrome were analyzed in order to derive diagnostic features in younger patients. The characteristic clinical features comprising long face, large ears and macro-orchidism were commoner in children more than 10 years old than in prepubertal children. This study shows that younger the patient, fewer the classical features exhibited. Hyperactivity was the most useful feature for diagnosis of the younger patient with Martin Bell syndrome.

We evaluated the utility of echocardiography in assessing the frequency and nature of cardiac malformations in children with Down syndrome. Fifty cases of chromosomally proven Down syndrome were studied. A physical examination, electro cardiogram, radiograph of chest and two-dimensional echocardiography was performed on all patients. Twenty-two (44%) children had heart diseases. Endocardial-cushion-defect was the commonest anomaly, followed by ventricular septal defect. Three children with heart disease were asymptomatic and had normal X-ray films of chest and ECGs. The prevalence and specific type of congenital heart disease in this study is comparable to the studies using invasive means for diagnosis. The study further suggests that clinical examination of the cardiovascular system alone may not be sufficient in detecting heart disease. Two-dimensional echocardiography offers an excellent non-invasive tool for diagnosing cardiac malformations in Down syndrome.

Of 1000 pregnant women studied, consanguinity was observed in 30.8%, with a higher frequency among women from rural areas, and among Hindus. In the consanguineous group, first cousin marriages were present in 47.4%, and uncle niece marriages in 23.4% of women. Coefficient of inbreeding was highest in Harijans (0.0258), followed by non-Brahmins (0.0220) and Brahmins (0.0204). Fertility was not influenced by consanguinity. There was a significantly higher rate of still births and infant mortality in consanguineous matings as compared with non-consanguineous. Total morbidity was higher in the consanguineous group as compared with the non-consanguineous (p less than 0.01), especially that due to neonatal infections and jaundice. There was no significant difference in the prevalence of congenital malformations, chromosomal and genetic disorders between the two groups, although the number of abnormal births in this group was small.

Cytogenetic studies were carried out in 645 patients with Down syndrome. Free trisomy of chromosome 21 was present in 600 cases (93%). Translocation karyotypes were observed in 26 cases (4%). Seventeen patients (2.6%) had mosaicism. Two (0.3%) patients had additional karyotypic abnormalities along with trisomy 21.

Prenatal diagnosis of chromosomal disorders was carried out in 144 samples of amniotic fluid during 1986-1989. The commonest indication was pregnancy in women having a previous child with Down syndrome. Cultures were successful in 104 (72.2%) of 144 cases. Three (2.9%) abnormal karyotypes were detected. Of 53 women who had a previous child with Down syndrome, recurrence of trisomy 21 occur d in one (1.9%); while considering all abnormal karyotypes, there were three recurrences (2.9%).