Rare Variant of PTH1R Mutation in an Indian Family.

INTRODUCTION: Murk Jansen metaphyseal chondrodysplasia is an extremely rare form of skeletal dysplasia. It is caused by the mutation in PTH1R gene (1). MATERIALS: A 13 year old boy presented with history of progressive bowing of both legs since 5 years of age. He had no history of development delay, seizures, renal stones or abdominal distension. On examination, he was having prominent upper face, prominent tip of nose, long philtrum, small mandible and severe bowing of legs with deformed knee joint. His bone mineral profile came out to be normal. His skeletal survey showed severe metaphyseal dysplasia of long bones of lower limb. His genetic testing revealed heterozygous mutation in PTH1R gene, c.1562G>A variant in exon 16. On extended evaluation, his father and paternal grandmother were also having similar phenotype, however not as severely affected as the index case. RESULT: Murk Jansen metaphyseal chondrodysplasia is characterized by severe short stature, short bowed limbs, clinodactyly and dysmorphic facies with metabolic derangement of hypercalcemia and hypophosphatemia (2). The variant present in our patient has not been reported anywhere yet, hence revealing a new molecular mechanism to an already known rare disease. CONCLUSION: Molecular diagnosis of skeletal dysplasia is of paramount importance as they are a clinically heterogenous group with varied presentation with non-specific radiological findings, however with different treatment and prognostic implications. References Nampoothiri S, Fernández-Rebollo E, Yesodharan D, et al. Jansen metaphyseal chondrodysplasia due to heterozygous H223R PTH1R mutations with or without overt hypercalcemia. J Clin Endocrinol Metab 2016;101(11):4283-4289. Schipani E, Langman CB, Parfitt AM, et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone- related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med 1996;335(10):708-714.

Whole exome sequencing, clinical exome or targeted gene panels: what to choose for suspected lethal skeletal dysplasia (short rib thoracic dysplasia type IV).

Lethal skeletal dysplasias (SDs) are a heterogeneous group of rare but important genetic disorders characterised by abnormal growth and development of bone and cartilage. The phenotypic variation of SD highlights the complex aetiology for this group of disorders. Short rib polydactyly syndrome (SRPS) types I-IV are a group of rare congenital autosomal recessive types of SD.We report a case of a non-consanguineous couple whose two successive pregnancies were diagnosed with multiple congenital anomalies in fetuses suggestive of lethal SD (likely SRPS type IV) at 24 and 19 weeks period of gestation, respectively. Pregnancy was terminated, and the whole exome sequencing of the abortus for genetic analysis in the second pregnancy confirmed an autosomal recessive type of short rib thoracic dysplasia-4 (SRTD-4) also called SRPS in homozygous condition. Our case is unique as it was also associated with cystic hygroma which is a rare association with SRPS/SRTD-4.