Clinical characteristics: AIP familial isolated pituitary adenoma (AIP-FIPA) is characterized by an increased risk of pituitary neuroendocrine tumors (PitNETs, also known as pituitary adenomas), including growth hormone (GH)-secreting PitNETs (somatotropinomas), prolactin-secreting PitNETs (prolactinomas), GH and prolactin cosecreting PitNETs (somatomammotropinomas), and clinically nonfunctioning PitNETs (NF-PitNETs). Rarely, thyroid-stimulating hormone (TSH)-secreting PitNETs (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, PitNETs can be of the same or different type. Age of diagnosis 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 PitNET by identification of a heterozygous germline pathogenic variant in AIP by molecular genetic testing.

Management: Treatment of manifestations: AIP-associated pituitary tumors are usually treated in the same manner as those of unknown genetic cause. Standard treatment of GH-producing microadenomas includes medical therapy (somatostatin receptor ligands [SRLs], GH receptor antagonists, and dopamine agonists), surgery, and/or radiotherapy. Large somatotropinomas are treated with transsphenoidal surgery, medical therapy, and/or radiotherapy. Cardiovascular and rheumatologic/orthopedic complications for individuals with acromegaly are managed as in other individuals with acromegaly. Prolactinomas are treated with dopamine agonist therapy or surgery. NF-PitNETs are treated with surgery and, if necessary, radiotherapy. Management of hypopituitarism (due to tumoral compression, surgery, or radiotherapy) should follow standard guidelines for endocrine care. 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 PitNETs and pubertal development from age four years until adulthood. Although development of new disease in a previously clinically screened person has not been observed in individuals age >30 years, 11 percent of individuals have been diagnosed at age >30 years. Therefore, annual evaluation for signs and symptoms of PitNETs should be carried out 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, thyroxine) 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. Pituitary MRI can be done in those with clinical or biochemical abnormality from age 30 to 50 years, but screening can be less frequent if laboratory tests are normal.

In symptomatic individuals: annual clinical assessment and pituitary function tests (serum IGF-1, spot GH, prolactin, estradiol/testosterone, LH, FSH, TSH, thyroxine, 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: Molecular genetic testing for the familial AIP pathogenic variant is appropriate for all at-risk relatives. Apparently asymptomatic individuals found to be heterozygous for a familial AIP pathogenic variant seem to benefit from targeted surveillance: PitNETs identified in asymptomatic individuals are significantly less invasive and are associated with better outcomes compared with PitNETs diagnosed in symptomatic individuals.

Genetic counseling: AIP-FIPA is inherited in an autosomal dominant manner with reduced penetrance. Almost all individuals reported to date with AIP-FIPA have a parent who is also heterozygous for the AIP pathogenic variant; because clinical penetrance of PitNETs in individuals with AIP pathogenic variants is approximately 15%-30%, a heterozygous parent may or may not be affected. Each child of an individual who is heterozygous for an AIP pathogenic variant has a 50% chance of inheriting the pathogenic variant. Once the AIP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. As AIP-FIPA demonstrates reduced penetrance, the finding of an AIP pathogenic variant prenatally does not allow accurate prediction of a tumor, the PitNET type, age of onset, prognosis, or availability and/or outcome of treatment.