Acromegaly (ORPHA:963)
A rare acquired endocrine disease related to excessive production of growth hormone (GH) and characterized by progressive somatic disfigurement (mainly involving the face and extremities) and systemic manifestations.
Epidemiology
Worldwide, the prevalence is 1/7,500 to 1/35,800. The annual incidence is 1/91,000 to 1/526,000.
Clinical description
Due to its insidious onset and slow progression, acromegaly is often diagnosed from four to more than ten years after its onset, and is most often diagnosed in middle age (average age 40-50 years). The main clinical features are broadened extremities (hands and feet), widened, thickened and stubby fingers, and thickened soft tissue. The facial aspect is characteristic and includes a widened and thickened nose, prominent cheekbones, forehead bulges, thick lips and marked facial lines. The forehead and overlying skin is thickened, sometimes leading to frontal bossing. There is a tendency towards mandibular overgrowth with prognathism, maxillary widening, tooth separation and jaw malocclusion. The disease also has rheumatologic, cardiovascular, respiratory and metabolic consequences which determine its prognosis.
Etiology
In the majority of cases, acromegaly is related to a pituitary adenoma, either purely GH-secreting (60%) or mixed. In very rare cases, acromegaly is due to ectopic secretion of growth hormone-releasing hormone (GHRH), responsible for pituitary hyperplasia. The gene aryl hydrocarbon receptor interacting protein, AIP (11q13.3), has been identified as a major susceptibility factor, particularly when acromegaly begins in childhood or adolescence. Acromegaly may also be part of multiple endocrine neoplasia syndromes such as MEN1 (MEN1; gene MEN1, 11q13), Carney complex (gene  PRKAR1A , 17q24.2) or familial isolated pituiatary adenoma (FIPA; gene AIP, 11q13.2). Very rarely it may be secondary to Xq26.3 chromosomal microduplications, responsible for X-linked acrogigantism due to Xq26 microduplication (XLAG), a very early-onset gigantism syndrome. Acromegaly may also be part of McCune-Albright syndrome.
Diagnostic methods
The clinical diagnosis is confirmed biochemically by detection of increased serum of insulin-like growth factor-I (IGF-I) concentrations (screening test) and an increased serum GH concentration not suppressed following an oral glucose tolerance test (OGTT; confirmation test). Assessment of tumor volume and extension is based on imaging studies. Echocardiography and sleep apnea testing are used to determine the clinical impact of acromegaly.
Differential diagnosis
Differential diagnosis includes other causes of acromegaly (FIPA, MEN1, Carney complex and XLAG) as well as pachydermoperiostosis and acromegaloid features of severe insulin resistance.
Genetic counseling
This form of acromegaly is sporadic; a causal genetic mutation has not been identified.
Management and treatment
Treatment is aimed at correcting (or preventing) tumor compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. Transsphenoidal surgery is often the first-line treatment. When surgery fails to correct GH/IGF-I hypersecretion, medical treatment with dopamine agonists and/or somatostatin analogs is proposed. The GH antagonist (pegvisomant) is used in patients that are resistant to somatostatin analogs. Radiotherapy may be discussed as a third line of treatment in cases of medical treatment failure.
Prognosis
Adequate hormonal disease control is achieved in most cases, allowing a life expectancy similar to that of the general population. However, even if patients are cured or well-controlled, sequelae (joint pain, deformities and altered quality of life) often remain.

                            Last update: 
                            December 2019


                            - Expert reviewer(s): 
                            Pr Philippe CHANSON