FAMILIAL ALBRIGHT HEREDITARY OSTEODYSTROPHY WITH HYPOPARATHYROIDISM -NORMAL STRUCTURAL G(S)ALPHA GENE

Albright's hereditary osteodystrophy (AHO) is a characteristic skeleta l phenotype, including short stature, obesity, round face, and brachyd actyly. AHO appears in patients with pseudohypoparathyroidism (PHP) wh o have resistance to PTH and in their eumetabolic family members who h ave pseudopseudohypoparathyroidism (PPHP). The differential diagnosis of AHO in families without PHP includes brachydactyly E, whose existen ce as a distinct entity has been questioned. We studied a patient with familial AHO who presented with hypocalcemia. To our surprise, PTH le vels were low, and the response to PTH administration was normal. This is the first case of familial AHO with hypoparathyroidism. The proban d's family included 22 affected subjects spanning 3 generations, who h ad variable degrees of AHO manifestations, with an autosomal dominant inheritance trait. The metacarpophalangeal pattern profile was typical of that of PHP-PPKP. As deficient activity and inactivating mutations of G(s) alpha were described in PHP as well as in PPHP, we measured t he biological activity of G(s) in family members, which was normal. To exclude subtle abnormalities in the G(s) alpha gene, we sequenced the entire coding region of G(s) alpha in the propositus, which was norma l. We conclude that hypocalcemia should be adequately evaluated even i n the presence of familial AHO, and that familial AHO can occur with a normal coding structural G(s) alpha gene. Identification of the molec ular defect in familial AHO without PHP will shed light on the pathoge nesis of AHO in general.