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.

Late Onset Pompe's Disease: Clinical, Pathological & Molecular Analysis of Two Adolescent Patients.

INTRODUCTION: The estimated global prevalence of late onset Pompe's disease is 1/57000 live birth(1). We present the case of two patients diagnosed to have Pompe's disease with a rare association of cardiomyopathy. MATERIALS: Two siblings born out of non consanguineous marriage presented with proximal myopathy of 5 years duration. Patient 1 - 19 year female, there was atrophy and weakness of face, neck, girdle and limbs. Her Echocardiogram showed LV dilation with low ejection fraction, ECG showed LV hypertrophy with incomplete LBBB. Her CK-NAC values came to be 918 U/L. Patient 2 - 16 year male; progression, distribution and severity slightly different to his sister but had exertional dyspnea since last one year. His echocardiogram showed LV diastolic dysfunction, ECG showed short PR interval partial LBBB and his CK-NAC came to be 2347 U/L. His skeletal muscle biopsy showed deposition of glycogen. Genetic analysis revealed pathogenic mutation in GAA gene (c.2040G>A) in both patients. RESULT: Late onset Pompe disease is of less severity but progressive. The involvement of heart is less likely compared to infantile onset(2). It is also interesting that the same variant presents differently in both patients. CONCLUSION: Genetic diseases manifest as rare phenotype which in itself is a clinical puzzle. When rare disease present with a rare manifestation of itself, this pose a great diagnostic challenge. Pompe's disease is one of the very few inherited disorder which has definitive treatment- enzyme replacement therapy. Molecular characterization of the variant is absolutely necessary before initiating therapy. References Ausems MG, Verbiest J, Hermans MM, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 1999;7(6):713-716. Van der Beek NA, Soliman OI, Van Capelle CI, et al. Cardiac evaluation in children and adults with Pompe disease sharing the common c.-32-13T>G genotype rarely reveals abnormalities. J Neurol Sci 2008;275(1-2):46-50.