Familial Isolated Pituitary Adenoma

Familial isolated pituitary adenoma is the occurrence of pituitary adenomas in two or more members of a family, without MEN1, Carney complex or another syndrome. It is called homogeneous if the tumour type is the same in all members and heterogeneous if it differs.

It accounts for about 2% of pituitary adenomas. AIP variants are found in about 15 to 20% of families, and in about 50% of homogeneous acromegaly or gigantism families. Inheritance is autosomal dominant with low penetrance (about 20%).

AIP-related tumours present earlier (often under 30 years), are larger, and cause gigantism, acromegaly or prolactinoma. They respond poorly to somatostatin analogues. Duplication at Xq26.3 (GPR101) causes X-linked acrogigantism, usually sporadic, from infancy.

Pathophysiology.

AIP encodes a co-chaperone of the aryl hydrocarbon receptor. Loss of function reduces its tumour suppressor action and somatostatin receptor signalling, and a second hit in the pituitary leads to tumour formation.

Most families have no identified gene, so other genes are likely.

• Features of the tumour type: acromegaly or gigantism (growth hormone), galactorrhoea and amenorrhoea (prolactin), Cushing disease, or mass effect (headache, visual field loss).
• Early onset, rapid growth in children, delayed puberty and hypopituitarism.

Red flags.

• Visual loss or apoplexy.
• Rapid childhood growth or onset in infancy.

• Family history: confirm adenomas in two or more first degree relatives or relatives within the extended family.
• Hormone assessment: IGF-1 with growth hormone suppression on an oral glucose test, prolactin, morning cortisol and cortisol suppression tests, thyroid function, LH, FSH, and sex steroids.
• Pituitary MRI with contrast, and visual fields for macroadenomas.
• AIP sequencing and deletion analysis; GPR101 duplication testing in infants with gigantism. Exclude MEN1 (calcium, parathyroid hormone, MEN1 sequencing), Carney complex and SDHx variants.
• Screening of AIP carriers: yearly height, weight and pubertal assessment, prolactin and IGF-1 from childhood (about age 4), and pituitary MRI from about age 10, repeated every 2 to 3 years or if hormones rise.

Differential diagnosis.

• MEN1, Carney complex, McCune-Albright syndrome and SDHx related tumours.
• Chance occurrence of unrelated sporadic adenomas in a family.
• Pituitary hyperplasia from ectopic growth hormone releasing hormone.

• Treat by tumour type: transsphenoidal surgery is first line for growth hormone and ACTH tumours and for macroadenomas with mass effect.
• Prolactinoma: cabergoline 0.25 mg twice weekly increased every 4 weeks to usual 0.25 to 1 mg twice weekly (maximum 3 mg weekly).
• Growth hormone excess: octreotide long acting 20 mg intramuscularly every 4 weeks or lanreotide 90 to 120 mg every 4 weeks, but response is often poor in AIP disease. Pasireotide long acting 40 mg every 4 weeks (raises glucose), pegvisomant 10 mg subcutaneously daily after a loading dose, and cabergoline 0.5 to 3 mg weekly are used. Radiotherapy for residual tumour.
• Replace pituitary hormone deficits: hydrocortisone first (15 to 25 mg daily in two or three divided doses).
• Genetic counselling: 50% chance of inheriting the variant, with low penetrance. Surveillance for carriers.

Special groups. Children: paediatric endocrine management with growth and pubertal assessment. Pregnancy: macroadenomas may enlarge; assess visual fields each trimester.

Monitoring. After treatment: IGF-1 or prolactin every 3 months then yearly, and MRI at 3 to 6 months then yearly.

Referral and escalation. Pituitary multidisciplinary team and clinical genetics; urgent review for visual loss.