Pituitary gigantism (ORPHA:99725)
A rare endocrine disease characterized by excessively tall stature and rapid growth velocity due to growth hormone excess from a pituitary adenoma/hyperplasia occurring before closure of the epiphyseal growth plates. Additional features may include pubertal delay, visual defects, headache, excessive appetite, hyperhidrosis, menstrual irregularity, prognathism, coarse facial features and large hands/feet.
Epidemiology
The epidemiology of pituitary gigantism is unknown. Among acromegaly populations, pediatric and adolescent onset cases are rare (<5%).
Clinical description
Disease onset is from early infancy to late adolescence as long as the epiphyseal growth plates remain open. Pituitary gigantism is associated with excessive height (>2 standard deviations over the population mean) and growth velocity. Pituitary gigantism predominantly affects males (78%), probably due to amplification by excess GH of greater pubertal height gain in males. Median age at first symptoms is approximately 14 years, but long delays in establishing a diagnosis give a median age at diagnosis of 21 years. The GH-secreting pituitary adenoma is usually a macroadenoma in pituitary gigantism. Patients develop symptoms related to tumor mass effects, deficiencies of other pituitary hormones and chronic excess of GH and insulin-like growth factor 1. Pituitary gigantism patients can have classical signs/symptoms of acromegaly (growth of hands/feet, facial changes, metabolic disease, cardiovascular effects and musculoskeletal disease).
Etiology
In nearly 50% of cases of pituitary gigantism the pituitary adenoma is caused by a known genetic abnormality such as: germline AIP mutations (29%), GPR101 duplications in X-linked acrogigantism syndrome (X-LAG; 10%), somatic mosaic activating mutations in GNAS in McCune-Albright syndrome (5%), germline mutations in MEN1 and PRKAR1A.
Diagnostic methods
Clinical assessment of overgrowth by physicians should lead to establishment of a diagnosis of elevated GH and insulin-like growth factor 1 (IGF1) by hormonal testing. MRI is also used.
Differential diagnosis
Gigantism and overgrowth can be due to an extensive range of normal and pathological conditions. Excess GH and IGF-1 from a pituitary adenoma/hyperplasia distinguishes pituitary gigantism from other forms of constitutional, familial or pathological tall stature/overgrowth.
Antenatal diagnosis
Germline mutations in AIP, MEN1, PRKAR1A can be inherited but are not usually screened for in prenatal testing strategies. In X-LAG related pituitary gigantism, chromosome Xq26.3 duplications can be passed from affected mother to affected son.
Genetic counseling
In AIP mutation carriers, 20% develop a pituitary macroadenoma in their life-time, as the disease is autosomal dominant with incomplete penetrance. Familial cases of gigantism have been described in familial isolated pituitary adenoma (FIPA) kindreds with AIP mutations, in X-LAG and in those with no known genetic cause. Pituitary gigantism is exceptionally rare in MEN1 and PRKAR1A mutation carriers. McCune Albright syndrome due to post-zygotic mosaicism for GNAS activating mutations is not inherited.
Management and treatment
The management of pituitary gigantism focuses on early and effective control of elevated GH and IGF-1 levels to limit final adult height. Patients with pituitary gigantism are usually have large and aggressive pituitary adenomas and these tumors can be relatively treatment-resistant. Multimodal therapy employs neurosurgery to resect the adenoma, usually in combination with medical therapy (somatostatin analogs, pegvisomant and dopamine agonists). Radiotherapy is reserved for individual cases. Replacement of deficient hormonal axes should be pursued. In cases where the patient has entered the pubertal growth spurt, some reduction in final height can be gained by orthopedic epiphysiodesis to destroy the growth plates at the knee joint.
Prognosis
Early diagnosis and rapid achievement of GH and IGF-1 control leads to lower final height in pituitary gigantism, which is a desirable outcome. Multimodal treatment can also lead to a high level of pituitary axis deficiencies, which require lifelong replacement. There are no formal outcome studies on life expectancy in patients with pituitary gigantism.

                            Last update: 
                            January 2020


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