X-linked acrogigantism (ORPHA:300373)
A rare, genetic pituitary disease characterized by infantile-onset, rapid and excessive acceleration of linear growth and body size due to mixed growth hormone (GH)- and prolactin-secreting adenomas and/or pituitary hyperplasia. Patients present with gigantism and may have associated acromegalic features (e.g. coarse facial features, frontal bossing, prognathism, increased interdental space) as well as marked enlargement of hands and feet, soft tissue swelling, increased appetite and acanthosis nigricans.
Epidemiology
To date, less than 40 cases have been described worldwide. It accounts for 10% of cases of pituitary gigantism with a known genetic cause.
Clinical description
The onset of disease is in early infancy and may even be present as early as the neonatal period. Pituitary adenoma and/or hyperplasia leads to hypersecretion of GH and insulin-like growth factor 1 (IGF-1). Prolactin secretion is elevated in almost all cases and approximately one third of patients have elevated circulating levels of hypothalamic growth hormone releasing hormone (GHRH). Elevated GH and IGF-1 lead to increased growth in infants, that is usually apparent in the first 12 months of life, and a diagnosis is made usually by the age of 3 years. Increased height and weight are associated with marked increases in hand and foot sizes. Pituitary adenomas are usually macroadenomas (>10 mm diameter) at diagnosis. Height increases in affected children can be very marked in comparison with their peers (Z scores >+5 to +8.7 SDS).
Etiology
The disorder is caused by a GH and prolactin secreting pituitary adenoma and/hyperplasia. Patients with X-linked acrogigantism have a duplication on chromosome Xq26.3 that includes the gene GPR101, which is highly overexpressed in pituitary adenoma tissue.
Diagnostic methods
Diagnostic methods include array comparative genomic hybridization (aCGH) and digital droplet PCR as genetic tests.
Differential diagnosis
In early childhood pituitary gigantism due to a growth hormone secreting pituitary adenoma can be associated with other conditions like AIP germline mutations, McCune-Albright syndrome, and rarely MEN1 syndrome, or Carney complex. For familial X-LAG, the main differential diagnosis is familial isolated pituitary adenomas (FIPA).
Antenatal diagnosis
Prenatal diagnosis is possible.
Genetic counseling
The condition is X-linked dominant; however most cases occur sporadically. X-linked mother-to-son transmission has been reported in three cases; no cases of paternal transmission has been identified to date. Where there is vertical transmission, the Xq26.3 duplication occurs constitutively in the germline; in contrast, sporadic male cases exhibit somatic mosaicism. Genetic counseling should be proposed to individuals having the germline disease-causing Xq26.3 duplication informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
The disorder usually requires a multimodal therapeutic approach combining surgery, medical therapy and rarely radiotherapy. As the anterior pituitary can be extensively affected by adenoma and hyperplasia, early effective treatment to lower growth hormone and IGF-1 to normal levels can be challenging. In many cases, radical neurosurgery is required to widely resect affected anterior pituitary tissue. Residual tumor tissue can lead to long-term growth hormone and IGF-1 over-secretion and continued overgrowth; medical therapy with a growth hormone antagonist (pegvisomant) is usually effective. In X-linked acrogigantism, hormonal control with a somatostatin analog therapy is usually unsuccessful. Control of elevated prolactin levels can be achieved using a low-dose dopamine agonist. Hypopituitarism, involving multiple hormonal axes, and diabetes insipidus are possible post-surgical complications.
Prognosis
Without effective intervention, pituitary gigantism worsens in severity and expansion of the pituitary adenoma continues. Early diagnosis and effective treatment in X-linked acrogigantism can lead to normal adult height. Unmanaged hypopituitarism may lead to morbidity.

                            Last update: 
                            November 2019


                            - Expert reviewer(s): 
                            Pr Albert BECKERS  - Dr Adrian DALY