X-Linked Acrogigantism

Clinical characteristics: X-linked acrogigantism is the occurrence of pituitary gigantism in an individual heterozygous or hemizygous for a germline or somatic duplication of GPR101. X-linked acrogigantism is characterized by acceleration of linear growth in early childhood – in most cases during the first two years of life – due to growth hormone (GH) excess. Most individuals with X-linked acrogigantism present with associated hyperprolactinemia due to a mixed GH- and prolactin-secreting pituitary adenoma with or without associated hyperplasia; less commonly they develop diffuse hyperplasia of the GH- and prolactin-secreting pituitary cells without a pituitary adenoma. Most affected individuals are females. Growth acceleration is the main presenting feature; other frequently observed clinical features include enlargement of hands and feet, coarsening of the facial features, and increased appetite. Neurologic signs or symptoms are rarely present. Untreated X-linked acrogigantism can lead to markedly increased stature, with obvious severe physical and psychological sequelae.

Diagnosis/testing: The diagnosis of X-linked acrogigantism is established in an individual with pituitary gigantism and a germline or somatic duplication of GPR101 identified by molecular genetic testing.

Management: Treatment of manifestations:

1. In patients with radiologic evidence of a pituitary adenoma: transsphenoidal surgery should be considered as first-line treatment as it can provide long-term control of the disease (although often at the cost of permanent hypopituitarism) and prevent excessive tumor growth; in those with persistent disease, GH receptor antagonist treatment should be promptly initiated and tailored to growth velocity and IGF-1 levels.

2. In patients with radiologic evidence of hyperplasia without a pituitary tumor: first-line treatment with GH receptor antagonist should be considered as surgery (which is not usually recommended) can lead to disease remission only by means of a total hypophysectomy, invariably resulting in the need for lifelong pituitary hormone replacement treatment.

3. In patients with associated hyperprolactinemia: a dopamine agonist should be employed.

Surveillance: Intensive monitoring of height, growth velocity, and pituitary function tests. Repeat pituitary MRI (with frequency based on presence of hyperplasia/tumor, previous extent of the tumor, treatment modality, clinical status, and disease activity). Routine surveillance for complications of GH excess (based on recommendations for patients with acromegaly).

Genetic counseling: X-linked acrogigantism is inherited in an X-linked manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo GPR101 duplication; of note, all males who are simplex cases have had a somatic mosaic GPR101 duplication. In the three reported instances of familial X-linked acrogigantism, affected males inherited the GPR101 duplication from their affected mothers. Females with X-linked acrogigantism have a 50% chance of transmitting the GPR101 duplication in each pregnancy. While a male with a somatic mosaic GPR101 duplication that involves germ cells could theoretically transmit the duplication to his daughters, and a male with a germline GPR101 duplication will transmit the duplication to all of his daughters, to date male-to-female transmission has not been described. A male will not transmit the duplication to his sons. Offspring of either sex who inherit the GPR101 duplication will be affected. Once the GPR101 duplication has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.