Progressive osseous heteroplasia

Progressive osseous heteroplasia (POH) is a rare genetic disorder characterized by the formation of bone (heterotopic ossification) within the skin and deep connective tissues, including subcutaneous fat, skeletal muscle, tendons, ligaments, and fascia. The condition typically begins in infancy with superficial ossification presenting as small islands of bone within the skin (cutaneous osteoma cutis), which then progressively extends into deeper tissues during childhood. This progressive deep tissue ossification can lead to significant complications including joint ankylosis (fusion), limb length discrepancies, growth retardation of affected limbs, and severe restriction of movement. POH is caused by inactivating mutations in the GNAS gene, which encodes the alpha subunit of the stimulatory G protein (Gsα). The disease follows an autosomal dominant inheritance pattern, and notably, POH occurs almost exclusively when the mutant GNAS allele is inherited from the father (paternal inheritance), reflecting the complex imprinting of this genomic locus. POH must be distinguished from related conditions caused by GNAS mutations, including Albright hereditary osteodystrophy (AHO) and pseudohypoparathyroidism, as well as from fibrodysplasia ossificans progressiva (FOP), which involves a different gene (ACVR1) and different pattern of ossification. There is currently no cure for progressive osseous heteroplasia, and no medical therapy has been proven effective in preventing or reversing the heterotopic bone formation. Treatment is primarily supportive and symptomatic, focusing on physical therapy to maintain mobility and surgical excision of heterotopic bone when feasible, although recurrence after surgery is common. Management requires a multidisciplinary approach involving orthopedic surgeons, geneticists, and rehabilitation specialists to optimize quality of life and functional outcomes.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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