GNAS1 Mutation and Cbfa1 Misexpression in a Child with Severe Congenital Platelike Osteoma Cutis

Abstract

We evaluated a 7-year-old girl with severe platelike osteoma cutis (POC), a variant of progressive osseous heteroplasia (POH). The child had congenital heterotopic ossification of dermis and subcutaneous fat that progressed to involve deep skeletal muscles of the face, scalp, and eyes. Although involvement of skeletal muscle is a prominent feature of POH, heterotopic ossification has not been observed in the head, face, or extraocular muscles. The cutaneous ossification in this patient was suggestive of Albright hereditary osteodystrophy (AHO); however, none of the other characteristic features of AHO were expressed. Inactivating mutations of the GNAS1 gene, which encodes the ␣-subunit of the stimulatory G protein of adenylyl cyclase, is the cause of AHO. Mutational analysis of GNAS1 using genomic DNA of peripheral blood and of lesional and nonlesional tissue from our patient revealed a heterozygous 4-base pair (bp) deletion in exon 7, identical to mutations that have been found in some AHO patients. This 4-bp deletion in GNAS1 predicts a protein reading frameshift leading to 13 incorrect amino acids followed by a premature stop codon. To investigate pathways of osteogenesis by which GNAS1 may mediate its effects, we examined the expression of the obligate osteogenic transcription factor Cbfa1/RUNX2 in lesional and uninvolved dermal fibroblasts from our patient and discovered expression of bone-specific Cbfa1 messenger RNA (mRNA) in both cell types. These findings document severe heterotopic ossification in the absence of AHO features caused by an inactivating GNAS1 mutation and establish the GNAS1 gene as the leading candidate gene for POH.

Adipose Tissue Derived Stem Cells Secretome: Soluble Factors and Their Roles in Regenerative Medicine

“…The first is characterized by ectopic bone formation within the subcutaneous adipose layer of the skin [4,[6][7][8]. Closer observations to these ectopic formations also revealed the presence of osteoblasts and chondrocytes, in addition to adipocytes [6], which were a clear indication of the presence of a multipotent stem cell population within the adipose tissue.…”

Adipose-Derived Stem Cells for Regenerative Medicine

“…Children with a rare disease known as progressive osseous heteroplasia (POH) present to clinicians as a result of symptoms related to the formation of ectopic bone within their subcutaneous adipose layer of their skin. [5][6][7] Histological analysis of these lesions demonstrates the presence of osteoblasts and chondrocytes in addition to adipocytes. 5 POH is an autosomal dominant inherited defect associated with mutations in the GNAS1 gene, responsible for the coupling of transmembrane hormone receptors to adenylate cyclase.…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…Osteoma cutis is associated with normal serum levels of calcium and phosphorus throughout life, which suggests that the mutation is on the paternal GNAS allele 41,58,59,[80][81][82] .…”

“…Surgical removal of the ectopic ossifications can be performed when the lesions are well delimited. This is rarely the case in patients with POH, but it can be effective in those with osteoma cutis and in superficial lesions associated with PPHP or PHP1A with successful long-term results 58,59,81,241 . In most cases, surgical resection is followed by recurrence or complications 3,83,[242][243][244][245] .…”