GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis

We evaluated a 7-year-old girl with severe platelike osteoma cutie (POC), a variant of progressive osseous heteroplasia (POH), The child had congenita l heterotopic ossification of dermis and subcutaneous fat that progressed t o involve deep skeletal muscles of the face, scalp, and eyes. Although invo lvement of skeletal muscle is a prominent feature of POH, heterotopic ossif ication has not been observed in the head, face, or extraocular muscles. Th e cutaneous ossification in this patient was suggestive of Albright heredit ary osteodystrophy (AHO); however, none of the other characteristic feature s of AHO were expressed. Inactivating mutations of the GNAS1 gene, which en codes the cy-subunit of the stimulatory G protein of adenylyl cyclase, is t he cause of AHO. Mutational analysis of GNAS1 using genomic DNA of peripher al blood and of lesional and nonlesional tissue from our patient revealed a heterozygous 4-base pair (bp) deletion in exon 7, identical to mutations t hat have been found in some AHO patients. This 4-bp deletion in GNAS1 predi cts a protein reading frameshift leading to 13 incorrect amino acids follow ed by a premature stop codon, To investigate pathways of osteogenesis by wh ich GNAS1 may mediate its effects, we examined the expression of the obliga te osteogenic transcription factor Cbfa1/RUNX2 in lesional and uninvolved d ermal fibroblasts from our patient and discovered expression of bone-specif ic Cbfa1 messenger RNA (mRNA) in both cell types. These findings document s evere heterotopic ossification in the absence of AHO features caused by an inactivating GNAS1 mutation and establish the GNAS1 gene as the leading can didate gene for POH.