Progressive osseous heteroplasia (POH) is a progressive bone disorder in which bone forms (ossifies) within skin and muscle tissue. It usually becomes apparent in infancy with skin (cutaneous) ossification, which progresses to involvement of subcutaneous and deep tissues, including muscle. In some cases, it first becomes apparent later in childhood or in early adulthood. Ossification may cause pain and open sores (ulcers) in affected areas of the body. Joints may become involved over time, causing impaired mobility. POH is caused by a mutation in the GNAS gene and is inherited in an autosomal dominant manner. 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. 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.

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.

GNAS gene and has been thought to occur only when a mutation affects the paternally inherited copy of the gene.

The GNAS gene give the body instructions for making parts of protein complexes called G proteins, which trigger signaling pathways that influence the functions of cells. G proteins are believed to play a key role in signaling pathways that regulate bone development (osteogenesis), preventing bone from being produced outside the skeleton. GNAS mutations that cause POH are thought to disrupt G protein function, impairing its ability to regulate osteogenesis. As a result, bone is permitted to grow outside the skeleton, causing the features of POH.

Normal Function

The GNAS gene provides instructions for making one component, the stimulatory alpha subunit, of a protein complex called a guanine nucleotide-binding protein (G protein). Each G protein is composed of three proteins called the alpha, beta, and gamma subunits.

In a process called signal transduction, G proteins trigger a complex network of signaling pathways that ultimately influence many cell functions by regulating the activity of hormones. The G protein made with the subunit produced from the GNAS gene helps stimulate the activity of an enzyme called adenylate cyclase. This enzyme is involved in controlling the production of several hormones that help regulate the activity of endocrine glands such as the thyroid, pituitary gland, ovaries and testes (gonads), and adrenal glands. Adenylate cyclase is also believed to play a key role in signaling pathways that help regulate the development of bone (osteogenesis). In this way, the enzyme helps prevent the body from producing bone tissue in the wrong place (ectopic bone).

Health Conditions Related to Genetic Changes

McCune-Albright syndrome

At least three GNAS gene mutations have been identified in people with McCune-Albright syndrome, a disorder that affects the bones, skin, and several hormone-producing (endocrine) tissues. These mutations result in an abnormal version of the G protein that causes the adenylate cyclase enzyme to be constantly turned on (constitutively activated). Constitutive activation of the adenylate cyclase enzyme leads to over-production of several hormones, resulting in the signs and symptoms of McCune-Albright syndrome.

McCune-Albright syndrome is not inherited. The gene mutation that causes this disorder is described as somatic. Instead of being passed from parent to child, somatic mutations are acquired during a person's lifetime and are present only in certain cells. McCune-Albright syndrome is caused by a random mutation in the GNAS gene that occurs very early in development. As a result, some of the body's cells have a normal version of the GNAS gene, while other cells have the mutated version. This phenomenon is called mosaicism. The severity of this disorder and its specific features depend on the number and location of cells that have the mutated GNAS gene.

Primary macronodular adrenal hyperplasia

At least two mutations in the GNAS gene have been identified in people with primary macronodular adrenal hyperplasia (PMAH), a disorder that causes multiple lumps (nodules) to form in the adrenal glands, which are small hormone-producing glands located on top of each kidney. These nodules cause adrenal gland enlargement (hyperplasia) and result in production of higher-than-normal levels of the hormone cortisol. Cortisol normally helps maintain blood glucose levels, protects the body from physical stress, and suppresses inflammation. Increased cortisol levels can lead to weight gain in the face and upper body, fragile skin, bone loss, fatigue, and other health problems, which often occur in people with PMAH.

The GNAS gene mutations that cause PMAH are believed to result in an overactive G protein. Research suggests that the overactive G protein may increase levels of adenylate cyclase, which results in the overproduction of another compound called cyclic AMP (cAMP). An excess of cAMP may trigger abnormal cell growth and lead to the adrenal nodules characteristic of PMAH.

As in McCune-Albright syndrome, the GNAS gene mutations that cause PMAH are somatic mutations that are believed to occur early in embryonic development. Cells with the mutated GNAS gene can be found in both adrenal glands.

Progressive osseous heteroplasia

At least 14 GNAS gene mutations have been identified in people with progressive osseous heteroplasia. People normally inherit one copy of each gene from their mother and one copy from their father. For most genes, both copies are active, or "turned on," in all cells. For a small subset of genes, however, only one of the two gene copies is active. For some of these genes, only the copy inherited from a person's father (the paternal copy) is active, while for other genes, only the copy inherited from a person's mother (the maternal copy) is active. These differences in gene activation based on the gene's parent of origin are caused by a phenomenon called genomic imprinting.

The GNAS gene has a complex genomic imprinting pattern. In some parts of the body the maternal copy of the gene is active, while in others the paternal copy is active. Progressive osseous heteroplasia is caused by certain mutations that affect the paternal copy of the gene. These mutations disrupt the function of the G protein and impair its ability to regulate osteogenesis. Impaired regulation of osteogenesis results in the ectopic production of bony tissue in the skin and muscles seen in progressive osseous heteroplasia.

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Other disorders

Mutations in the GNAS gene also cause Albright hereditary osteodystrophy (AHO), which is characterized by short stature, obesity, unusually short fingers and toes (brachydactyly), ectopic development of bony tissue under the skin, and other skeletal abnormalities. When a mutation that causes AHO is inherited from a person's mother, the affected individual will usually have AHO accompanied by a resistance to multiple hormones (a condition called pseudohypoparathyroidism type Ia, or PHPIa). A paternally-inherited mutation can result in AHO without endocrine problems; this form of the condition is called pseudopseudohypoparathyroidism (PPHP).

Somatic mutations in the GNAS gene have been found in tumors of the endocrine glands and in fibrous lesions (dysplasia) that can occur in bones. These mutations are believed to result in an overactive G protein, which triggers abnormal cell growth. Because the cells with mutations are not as widespread in the body as in McCune-Albright syndrome (described above), the abnormal growth is confined to a particular gland or fibrous lesion.

Other Names for This Gene

• ADENYLATE CYCLASE STIMULATORY PROTEIN, ALPHA SUBUNIT
• adenylate cyclase-stimulating G alpha protein
• AHO
• C20orf45
• dJ309F20.1.1
• dJ806M20.3.3
• GNAS1
• GNAS1_HUMAN
• GNASXL
• GPSA
• Gs, ALPHA SUBUNIT
• GSA
• GSP
• guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1
• guanine nucleotide regulatory protein
• MGC33735
• NESP
• NESP55
• NEUROENDOCRINE SECRETORY PROTEIN 55
• PHP1A
• PHP1B
• POH
• SCG6
• secretogranin VI
• SgVI
• STIMULATORY G PROTEIN

Genomic Location

The GNAS gene is found on chromosome 20.

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.

People with POH can conceive and have children. 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.

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.

Parents may first notice small rice-sized particles of bone in the skin, causing the skin to feel rough and thick. As affected children age, bone formation may progress to subcutaneous tissue and into deeper structures including muscles, tendons and ligaments. It may cause pain and the development of open sores (ulcers) in affected areas of the body. Joints may become involved over time, causing impaired mobility.

As the condition progresses, it may cause restricted mobility of various joints, eventually "locking" the joints (ankylosis). Affected arms and legs may become malformed and may not grow their full length. If bone growth occurs around the spine, scoliosis may develop.

In some individuals, the condition affects a small area of the body; in others, large areas of the body are affected. The rate of progression also varies greatly among affected individuals and is unpredictable. However, most individuals experience a gradual progression of the condition.

GNAS gene. These disorders are characterized by additional features that are not associated with POH.

POH is diagnosed on the basis of three major criteria:

• superficial HO that progresses to deep connective tissue;
• two or fewer AHO features, excluding HO; and
• no parathyroid hormone (PTH) resistance (as in PHP)

In addition to these key diagnostic criteria, there are several findings that support the diagnosis of POH. These include:

• a GNAS mutation identified with genetic testing (present in almost two-thirds of POH patients)
• evidence for paternal inheritance
• a specific pattern of ossification seen on radiographic imaging
• a history of intrauterine growth retardation
• leanness
• age of onset younger than 1 year

One case report on the use of the bisphosphonate pamidronate in POH suggested stabilization of the condition, but it is unclear how applicable this may be to preventing new skin lesions. Treatment with a bisphosphonate is unlikely to have an effect on preexisting bone formation.

Important conservative approaches include physical therapy to preserve movement, and meticulous skin care to prevent the breakdown of skin. Special shoes, braces, and other devices to assist in walking and weight-bearing have been used to help people with POH involving the lower limbs.

Because progressive osseous heteroplasia (POH) is so rare, there is limited information about long-term outlook (prognosis). The progression of POH is highly variable even among members of the same family. In some individuals, it may progress extremely slowly; in others it may progress more rapidly. Most individuals experience a gradual progression of the condition. The degree of morbidity depends on the location and extent of abnormal bone formation, and in some cases, the condition results in severe disability. The condition may be associated with restricted movement of the arms and legs caused by "locking" of joints (ankyloses), pain, and secondary osteoporosis. POH may also restrict movement in the hips, jaw, shoulders, and/or other areas of the body. Despite the morbidity associated with POH, there is no known effect on the life span of affected individuals as it does not directly affect the internal organs.