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Background: Thyroid Disorders represent the most common endocrinopathy in childhood and a preventable cause of growth delay and mental retardation. Clinical manifestations of hypothyroidism are highly variable depending upon etiology, duration, age and severity. True incidence of congenital hypothyroidism in Pakistan is unknown due to lack of community surveys and long awaited national newborn screening program for hypothyroidism. Objective: We aimed to determine the various etiological factors involved in the development of congenital hypothyroidism (CH) in cases coming to a tertiary care center. We also aimed to study the varied clinical presentation of congenitally hypothyroid cases to appreciate early detection and prompt diagnosis. Methodology: This was a descriptive cross-sectional study conducted in the Endocrine Section of Department of Pediatrics, Mayo Hospital, King Edward Medical University (KEMU), Lahore, from July 2012 to January 2019. A predesigned proforma was used to record clinical and biochemical parameters of the Patients. The diagnosis of CH was based on clinical, radiological, and biochemical features. Results: Out of 198 cases of permanent CH, 58.6% (116/198) were female. Among study patients, 33% (66/198) were under the age of 3 years, 32.2% (64/198) aged 3-11 months and 19.7% (39/198) between 1 - 3 years of age. The common clinical features at presentation were constipation 56.6%, unusual facies 53%, learning difficulties 42.4%, mental retardation 39.4%, short stature 38% and goiter 25.8% patients. Regarding aetiology, hormonal dysgenesis (56.5%) and iodine deficiency (26.6%) were found to be the common underlying factors. The association between age at diagnosis with various variables was computed using the Pearson chi-square test. Pvalue less than 0.05 was taken as statistically significant. Conclusion: The high prevalence of iodine deficiency among Patients of CH points towards variable aetiology and importance in community health. The study also emphasizes the need to explore clinical features at different age groups, which help in establishing early diagnosis of CH in the absence of national neonatal screening programs in Pakistan. [ABSTRACT FROM AUTHOR]

Objective Mutations in leptin receptor gene ( LEPR) result in early onset extreme adiposity. However, their prevalence in different populations is not known. Indeed, LEPR screening by gold standard Sanger sequencing has been limited by its large size and the cost. One-step PCR-based targeted enrichment could be an option for rapid and cost effective molecular diagnosis of monogenic forms of obesity. Methods The study is based on 39 unrelated severely obese Pakistani children, previously shown to be negative for leptin ( LEP) and melanocortin 4 receptor ( MC4R) gene mutations, from an initial cohort of 62 probands. Patient samples were analyzed by microdroplet PCR-enrichment (RainDance technologies) targeting coding exons of 26 obesity-associated genes combined with next generation sequencing. Hormone levels were analyzed by ELISA. Results The analysis revealed two novel homozygous LEPR mutations, an essential splice site mutation in exon 15 (c.2396-1 G>T), and a nonsense mutation in exon 10 (c.1675 G>A). Both probands had high leptin levels and were phenotypically indistinguishable from age-matched leptin-deficient subjects from the same population. Conclusions The two subjects carrying homozygous LEPR mutations, reported here for the first time in the Pakistani population, constitute 3% of the whole cohort of severely obese children (compared to 17% for LEP and 3% for MC4R). [ABSTRACT FROM AUTHOR]