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
Characteristics | Familial Isolated Pituitary Adenoma (FIPA) | Simplex Somatotropinoma1 |
|---|
AIP-FIPA | X-LAG | FIPA of unknown cause |
Clinical features | Typical age of onset (range)2 | Adolescence (age 4-24 yrs) |
Average number of affected family members3 | 3-4 | Usually simplex cases, but 3 families w/2-3 affected members have been described |
Male-to-female ratio4 | 1:1 to 2:1 | 1:3 |
Adenoma features | Somatotropinomas/somatomammotropinomas4 | 70%-80% |
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Source: GeneReviews — "AIP Familial Isolated Pituitary Adenomas"
