Clinical Guidance

Individuals with AIP truncating pathogenic variants may have a slightly earlier age of onset and diagnosis compared to those with non-truncating pathogenic variants .

Source: GeneReviews — "AIP Familial Isolated Pituitary Adenomas"

Penetrance

Studies on large families with AIP pathogenic variants show a clinical penetrance of PitNETs of approximately 23% (range: 15%-30%) [, , , ]. Although some families with AIP-FIPA can show high penetrance, the higher penetrance initially reported in some families is probably ascertainment bias due to insufficient information on all at-risk family members (e.g., lack of medical records, information on pituitary hormone testing, and/or imaging studies) .

Source: GeneReviews — "AIP Familial Isolated Pituitary Adenomas"

Diagnostic Criteria

Suggestive Findings

AIP familial isolated pituitary adenoma (AIP-FIPA) should be suspected in probands with the following:

• A pituitary neuroendocrine tumor (PitNET) diagnosed before age 18 years, especially a growth hormone (GH)-secreting PitNET, regardless of family history

• A pituitary macroadenoma (tumor 10 mm in diameter) diagnosed before age 30 years, especially a GH-secreting PitNET, regardless of family history

• A prolactin-secreting pituitary macroadenoma (tumor 10 mm in diameter) diagnosed before age 30 years, regardless of family history. A single individual with clinically presenting childhood-onset microadenoma (tumor 10 mm) has been identified in this setting .

Source: GeneReviews — "AIP Familial Isolated Pituitary Adenomas"

Differential Diagnosis

In children more often than in adults, pituitary neuroendocrine tumors (PitNETs) may be a manifestation of a genetic condition. PitNETs of genetic origin can be divided into isolated and syndromic categories. Familial Isolated Pituitary Adenomas (FIPA) FIPA is defined as a hereditary condition associated with PitNETs and no other features of a syndrome known to be associated with these tumors. X-linked acrogigantism (X-LAG), a second genetically characterized type of FIPA, is caused by duplication of GPR101. X-LAG, a highly penetrant disorder with female preponderance, is associated with pituitary hyperplasia or PitNET resulting in infant-onset growth hormone (GH) excess usually associated with hyperprolactinemia. Most individuals with X-LAG have a de novo duplication which is typically mosaic in males. Female-to-male transmission has been observed. Proposed associations requiring further validation. A single study reported germline heterozygous CDH23 variants in one third of families with FIPA and 12% of individuals with sporadic PitNETs from a single cohort. Cosegregation with the phenotype was proven in one family, but the variants were not functionally tested, and the findings have not been replicated in other cohorts . More recently, germline missense PAM variants were detected in a family with gigantism with reduced penetrance and were found to be overrepresented in individuals with sporadic PitNETs from two different cohorts . Loss of function was demonstrated in vitro for multiple variants . Families with FIPA of known or unknown cause can have homogeneous PitNET phenotypes (i.e., pituitary tumors of the same type) or heterogeneous phenotypes (i.e., pituitary tumors of different types). Aspects of FIPA that tend to differ between families with or without germline AIP pathogenic variant include: age of onset, number of persons affected in the family, male-to-female ratio, and typical adenoma types. Tumor variables may also include: size, aggressiveness, and response to treatment . Table 3. Comparison of Findings in Persons with Isolated PitNETs by Family History and Presence/Absence of a Germline AIP Pathogenic Variant

Management Guidelines

Recent clinical practice guidelines for pediatric pituitary neuroendocrine tumors (PitNETs), as well as acromegaly and prolactinoma, include management suggestions for hereditary pituitary tumors [, , , ]. Nevertheless, as no specific familial isolated pituitary adenoma (FIPA) guideline exists, the following recommendations also include the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with AIP-FIPA, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended (for details, see ).

Table 5.

AIP Familial Isolated Pituitary Adenoma: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

PitNET

| • LH, FSH, testosterone/estradiol

• Visual field eval

• Consultation w/endocrinologist

| DXA scan in those w/hypogonadism

Pituitary MRI | Beginning at age 10 yrs, or younger if PitNET is suspected

Somatotropinoma

(GH secreting) | • Evaluate for signs/symptoms of GH excess (e.g., stature, change in facial appearance, change in shoe size, ring size, headache, excessive sweating, joint pains, carpal tunnel syndrome).

• Spot serum GH, IGF-1

| • Review of serial photographs for acromegalic changes

• Measurement of parental heights

• OGTT in persons w/findings of acromegaly

• ACTH reserve if needed

Prolactinoma

| • Evaluate for manifestations of prolactin excess (e.g., menstrual history, galactorrhea, ...

Source: GeneReviews — "AIP Familial Isolated Pituitary Adenomas"

Therapies Under Investigation

The Genetics of Endocrine Tumours - Familial Isolated Pituitary Adenoma – FIPA study is actively recruiting individuals with FIPA or childhood-onset PitNET (NCT00461188). GH receptor antagonists block the action of endogenous GH, thereby controlling disease manifestations such as headaches, soft tissue enlargement, diabetes mellitus, hypertension, and high insulin-like growth factor 1 (IGF-1) levels. In two individuals with AIP-related PitNETs resistant to treatment with first-generation somatostatin receptor ligands (SRLs), pasireotide, a second-generation multiligand SRL with affinity to multiple somatostatin receptors, was shown to achieve long-term control of disease .

Source: GeneReviews — "AIP Familial Isolated Pituitary Adenomas"

Surveillance Guidelines

No formal guidelines regarding surveillance of persons with AIP-FIPA have been established. The following recommendations are based on expert opinion from the literature and on the authors' personal experience with more than 400 persons with symptomatic or asymptomatic AIP-FIPA.

Table 7.

AIP Familial Isolated Pituitary Adenoma: Recommended Surveillance

System/Concern | Evaluation | Frequency

PitNET

| • Measure height weight; calculate height velocity.

• Evaluate for signs/symptoms of PitNET evaluate pubertal development.

| Annually beginning at age 4 yrs until adulthood1

Evaluate for signs/symptoms of PitNET. | Annually until age 30 yrs every 5 yrs between ages 30 50 yrs; earlier if symptomatic

Serum IGF-1, prolactin, estradiol/testosterone, LH, FSH, TSH, free thyroxine | • Annually from age 4 to 30 yrs; to date, no secreting PitNETs have developed after age 30 in those w/normal findings at age 30 yrs.

• Blood tests if symptomatic after age 30 yrs

Pituitary MRI | • Baseline at age 10 yrs unless indicated earlier due to clinical findings

• Repeat MRI every 5 yrs until age 30 yrs (if clinical pituitary function tests remain normal)

• If clinical or biochemical abnormality: MRI can be performed between ages 30 50 yrs

FSH = follicle-stimulating hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; PitNETs = pituitary neuroendocrine tumors; TSH = thyroid-stimulating hormone

Source: GeneReviews — "AIP Familial Isolated Pituitary Adenomas"