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Editor—Albright hereditary osteodystrophy (AHO) is an autosomal dominant disorder characterised by short stature, a round face with a low, flat nasal bridge, brachymetaphalangism, particularly of the fourth and fifth digits, obesity, subcutaneous calcification, and variable degrees of mental retardation. Patients may show end organ resistance to parathyroid hormone (PTH), known as pseudohypoparathyroidism type Ia (PHPIa). Patients with PHPIa may have hypocalcaemia, hyperphosphataemia, and raised PTH levels and show an absent or blunted cAMP response to exogenous PTH.1Resistance to other hormones such as thyroid stimulating hormone (TSH) and luteinising hormone have also been reported. Other patients with AHO have a normal biochemical profile with a normal cAMP response to a PTH infusion, known as pseudopseudohypoparathyroidism (PPHP).
PHPIa and PPHP both result from inactivating mutations of theGNAS1 gene on chromosome 20. The PHPIa and PPHP phenotypes have been observed to segregate within the same family and thus represent variable expressivity of the same mutation. There is an apparent parent of origin effect: PHPIa usually results from maternal inheritance of a GNAS1 mutation while paternal transmissions give rise to offspring with PPHP.2 GNAS1 has 13 exons and mutations associated with AHO occur throughout the gene.3-8 The new mutation rate atGNAS1 is unknown, but de novo occurrence of mutations has been proven in a number of families5-7 (our own unpublished observations). We now describe a family comprising two affected sibs whose presentation was complicated by gastrointestinal symptoms not previously associated with Albright hereditary osteodystrophy. Neither parent showed any features of AHO.
Patient 1 was born at term to non-consanguineous Cypriot parents. She developed persistent diarrhoea on the second day of life, resulting in episodes of dehydration, metabolic acidosis, and failure to thrive. At 4 months of age, her barium meal was normal …