Pseudohypoparathyroidism (PHP) Ia is a rare condition associated with multiple hormone resistance and the Albright Hereditary Osteodystrophy (AHO) phenotype. Progressive osseous heteroplasia (POH) is characterized by progressive ossifications of dermal, skeletal muscle and deep connective tissue during childhood. Both PHP Ia and POH are caused by heterozygous inactivating mutations in the GNAS gene. Maternal inheritance of a GNAS mutation leads to an AHO phenotype with hormonal resistance (PHP Ia), whereas paternal inheritance leads to an AHO phenotype without the hormonal resistance (pseudopseudo-hypoparathyroidism). Pure POH (no other AHO features) is also caused by a paternal inheritance of GNAS mutations. Mutations that cause PHP Ia when maternally inherited can cause POH when paternally inherited. We present an unusual case of a boy with clinical features of both POH and PHP Ia, and a GNAS inactivating mutation.
Case presentation: The patient was referred at 1 month of age with a "knot on his leg". Plain radiographs revealed subcutaneous ossifications. PE at age 4 months included: length and weight >95%, a round face, short 4th metacarpals, and extensive subcutaneous ossifications of the lower limbs, buttocks, and back. Studies at age 4 months included an elevated TSH 12.4 mIU/l, free T4 0.86 ng/dl (0.8-2.3), PTH 61 pg/ml (10-65), calcium 9. 8 mg/dl (9.0-11.0), and phosphorus 6. 4 mg/dl (3.8-6.5). By age 16 months, the PTH was elevated at 126 pg/ml. Biopsies of the skin lesions demonstrated osteoma cutis consistent with POH. GNAS analysis revealed a heterozygous deletion in exon 7. The mutation was not detected in either parent.
Discussion: POH and PHP Ia are rare genetic disorders caused by loss of function mutations of the GNAS gene. POH and PHP Ia do not commonly occur in the same individual as they are associated with paternal versus maternal inheritance (imprinting) of an affected GNAS gene. Our patient has evidence of both severe POH and PHP Ia, apparently due to a de novo mutation in GNAS.