AIP Familial Isolated Pituitary Adenomas

Clinical characteristics: AIP familial isolated pituitary adenoma (AIP-FIPA) is defined as the presence of an AIP germline pathogenic variant in an individual with a pituitary adenoma (regardless of family history).

The most commonly occurring pituitary adenomas in this disorder are growth hormone-secreting adenomas (somatotropinoma), followed by prolactin-secreting adenomas (prolactinoma), growth hormone and prolactin co-secreting adenomas (somatomammotropinoma), and nonfunctioning pituitary adenomas (NFPA). Rarely TSH-secreting adenomas (thyrotropinomas) are observed. Clinical findings result from excess hormone secretion, lack of hormone secretion, and/or mass effects (e.g., headaches, visual field loss). Within the same family, pituitary adenomas can be of the same or different type. Age of onset in AIP-FIPA is usually in the second or third decade.

Diagnosis/testing: The diagnosis of AIP-FIPA is established in a proband with a pituitary adenoma by identification of a heterozygous germline pathogenic variant in AIP by molecular genetic testing.

Management: Treatment of manifestations: Pituitary adenomas identified in those with AIP-FIPA are generally treated in the same manner as pituitary adenomas of unknown cause: they can be treated by medical therapy (somatostatin analogs, growth hormone receptor antagonists, and dopamine agonists), surgery, and/or radiotherapy. Although surgery is usually performed in persons with AIP-FIPA, it often does not fully control the tumor; thus, medical therapy and radiotherapy following surgery may be required to control hormone output and tumor growth. AIP-FIPA adenomas often do not respond well to first-generation somatostatin analog, while data suggest that they may respond better to second-generation multi-ligand agonists. Prolactinomas are treated with dopamine agonist therapy or surgery and can be aggressive and difficult to treat. NFPA is treated with surgery and if necessary radiotherapy.

Prevention of secondary complications: Expert management for hypopituitarism which can be due to tumor size, surgery, or radiotherapy. Persons on glucocorticoid replacement therapy need to increase their steroid dose when ill or stressed.

Surveillance: In asymptomatic individuals: annual growth assessment and evaluation for signs/symptoms of pituitary adenoma and pubertal development from age four years until adulthood. Continue annual evaluation for signs and symptoms of pituitary adenoma until age 30 years and then every five years between ages 30 and 50 years. Annual pituitary function tests (serum IGF-1, prolactin, estradiol/testosterone, LH, FSH, TSH, free T4) beginning at age four years until age 30; pituitary MRI at age ten years and repeated (every 5 years has been suggested) or as necessary based on clinical and biochemical parameters until age 30 years. Starting at age 30 to 50 years surveillance can be relaxed.

In symptomatic individuals: annual clinical assessment and pituitary function tests (serum IGF-1, spot growth hormone, prolactin, estradiol/testosterone, LH, FSH, TSH, free T4, and morning cortisol); if indicated annual dynamic testing to evaluate for hormone excess or deficiency (e.g., glucose tolerance test, insulin tolerance test); pituitary MRI with frequency depending on clinical status, previous extent of the tumor, and treatment modality. Clinical monitoring of secondary complications of the tumor and/or its treatment (e.g., diabetes mellitus, hypertension, osteoarthritis, hypogonadism, osteoporosis); in those with acromegaly, colonoscopy at age 40 years and repeated every three to ten years depending on the number of colorectal lesions and IGF-1 levels.

Evaluation of relatives at risk: Family members at risk for AIP-FIPA warrant molecular genetic testing for the family-specific pathogenic variant to identify those who harbor the variant and thus require surveillance for pituitary adenomas.

Genetic counseling: AIP-FIPA is inherited in an autosomal dominant manner. Each child of an individual with AIP-FIPA has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the AIP pathogenic variant of an affected family member has been identified; however, because AIP-FIPA demonstrates reduced penetrance, the finding of an AIP pathogenic variant prenatally does not allow accurate prediction of whether a tumor will develop, or the type of adenoma, age of onset, prognosis, or availability and/or outcome of treatment.