Progressive osseous heteroplasia

Progressive osseous heteroplasia (POH) is a progressive bone disorder in which bone forms (ossifies) within skin and muscle tissue.^[1] It usually becomes apparent in infancy with skin (cutaneous) ossification, which progresses to involvement of subcutaneous and deep tissues, including muscle.^[1][2] In some cases, it first becomes apparent later in childhood or in early adulthood.^[1] Ossification may cause pain and open sores (ulcers) in affected areas of the body. Joints may become involved over time, causing impaired mobility.^[1] POH is caused by a mutation in the GNAS gene and is inherited in an autosomal dominant manner.^[1][2] In most cases, the mutation occurs randomly in a person with no family history of POH. In some cases, the mutation is inherited from a parent.^[3] There are currently no effective treatments for POH, and surgery to remove widespread lesions often results in recurrences or complications. However, well-circumscribed lesions can often be removed with successful, long-term results.^[2]

POH is thought to be part of a spectrum of related genetic disorders which include Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis. These disorders share the features of superficial ossification and being caused by mutations affecting the GNAS gene.^[2]

Progressive osseous heteroplasia (POH) is described as an autosomal dominant trait.^[1] This means that having a change (mutation) in only one copy of the responsible gene in each cell is enough to cause features of the condition. In most cases, the mutation occurs randomly (sporadically) for the first time in a person without a family history of POH. While a mutation that causes POH can be inherited, familial cases of POH are extremely rare.^[4]

People normally inherit one copy of each gene from each parent. For most genes, both copies are active, or "turned on." For some genes, however, only one of the two copies is active - either the maternal copy or the paternal copy. These differences in activation based on the gene's parent of origin are caused by a phenomenon called genomic imprinting. The gene responsible for POH (the GNAS gene) has a complex genomic imprinting pattern. In some cells the maternal copy is active, while in others the paternal copy is active. Progressive osseous heteroplasia is thought to occur when mutations affect the paternally inherited copy of the gene.^[1]

People with POH can conceive and have children.^[5] However, because it is an autosomal dominant condition, each child of a person with POH has a 50% chance to inherit the mutation that causes the condition. While POH occurs only when the mutated gene is inherited from the father, Albright's hereditary osteodystrophy (AHO) features can be associated with mutations inherited from either parent, and pseudohypoparathyroidism type 1A and/or AHO-associated obesity can occur when the mutated gene is inherited from the mother.^[3]

Due to the complexity of the genetics of POH and related conditions, people with questions about the genetics and inheritance of POH are encouraged to speak with a genetics professional.

In those with progressive osseous heteroplasia, the defective copy of the GNAS gene is inherited from the father. If a defective GNAS is inherited from the mother, individuals typically develop the related, yet distinct, disorder known as pseudohypoparathyrodism type 1a (PHP1a), which is usually seen in association with Albright's hereditary osteodystrophy (AHO). Thus, women with progressive osseous heteroplasia have a 50% chance of having children with PHP1a and AHO. To read more about these conditions, click on the links above.^[1]

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.