Clinical Guidance

To date, no genotype-phenotype correlations are evident as the clinical phenotype of the single individual harboring a smaller duplication (encompassing GPR101 only) was identical to the phenotype of other individuals whose duplications encompass GPR101 and the neighboring genes on Xq26.3 . While a limited number of simplex males with X-linked acrogigantism have been reported to date, no differences have been observed between individuals with germline duplications and those with somatic mosaic duplications .

Source: GeneReviews — "X-Linked Acrogigantism"

Penetrance

All heterozygous females and hemizygous males described to date were affected. In females who are simplex cases, the GPR101 duplications arose de novo as demonstrated by the normal dosage of GPR101 in samples from the unaffected parents. Moreover, in the three families described, all males who inherited the duplication from their affected mother were affected. Thus, based on currently available data the penetrance for X-linked acrogigantism appears to be 100%.

Source: GeneReviews — "X-Linked Acrogigantism"

Diagnostic Criteria

Suggestive Findings

X-linked acrogigantism should be suspected in an individual with early-onset pituitary gigantism, defined as acceleration of linear growth due to growth hormone (GH) excess. All individuals with X-linked acrogigantism reported to date have manifested the first signs of the disorder before age four years, with most manifesting the disease during the first two years of life.

Clinical findings

• Accelerated growth velocity (+2 SD) and/or abnormally tall stature (+2 SD, adjusted for parental height). Note: When available, country-specific growth curves should be employed.

• Other frequently observed clinical features of GH excess: acral enlargement, coarse facial features, and increased appetite (~1/3 of cases)

Laboratory findings

Source: GeneReviews — "X-Linked Acrogigantism"

Differential Diagnosis

Pituitary gigantism can be nonsyndromic or can be associated with other manifestations as part of a syndrome . Approximately 50% of all individuals with pituitary gigantism have a known predisposing genetic variant . The very young age at disease onset, female preponderance, and the absence of extrapituitary manifestations can help with the differential diagnosis of X-linked acrogigantism. Table 2. Disorders to Consider in the Differential Diagnosis of Pituitary Gigantism

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and further management needs in an individual diagnosed with X-linked acrogigantism, the following evaluations are recommended:

• Consultation with a specialist in pediatric endocrinology or endocrinology

• Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia.

• Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism.

• Visual field evaluation to assess for mass effects due to an expanding pituitary tumor. Young children may need informal testing (e.g., observing eye movements toward small objects in different areas of the visual field).

• Pituitary MRI for evidence of pituitary hyperplasia or a pituitary tumor. In case of a pituitary tumor, extrasellar extension should be evaluated.

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

GH Hypersecretion

Pituitary gigantism secondary to X-linked acrogigantism can be treated medically, surgically, and/or with radiotherapy. Pituitary adenoma. When MRI findings suggest the presence of a pituitary adenoma in patients with molecularly confirmed X-linked acrogigantism, either transsphenoidal surgery or GH receptor antagonist ...

Source: GeneReviews — "X-Linked Acrogigantism"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "X-Linked Acrogigantism"

Surveillance Guidelines

Patients with X-linked acrogigantism require the following:

• Intensive monitoring of height and growth velocity, and frequent clinical assessment for other manifestations of GH excess (including enlargement of the extremities, hyperhydrosis, headache, joint pain) and/or enlargement of a pituitary adenoma (visual field deficits)

• Intensive monitoring of pituitary function tests (spot GH, IGF-1, prolactin) to determine disease activity and response to treatment. Note: Frequency depends on control of GH excess, clinical status, compliance with treatment, treatment modality, and presence of comorbidities.

• Periodic evaluation of basal hormone tests (9 a.m. cortisol, TSH, fT4, LH, FSH, estradiol/testosterone), and, if necessary, dynamic testing (e.g., growth hormone stimulation tests, ACTH stimulation test) to evaluate for hypopituitarism. Note: Patients treated with radical neurosurgery and/or radiotherapy may develop GH deficiency and should receive GH replacement treatment as appropriate.

• Repeat pituitary MRI. Note: Frequency depends on previous extent of the tumor, treatment modality, clinical status, and disease activity.

The established guidelines regarding surveillance for associated comorbidities and risk of secondary neoplasms for patients with acromegaly should be applied to patients with X-linked acrogigantism. These include the following:

Source: GeneReviews — "X-Linked Acrogigantism"