Familial Isolated Pituitary Adenoma via the AIP Gene

Familial Isolated Pituitary Adenomas (FIPAs) are tumors that occur in the pituitary gland that have a familial origin (two or more related members), and represent approximately 2% of pituitary adenomas (Beckers et al. 2013). They are classified as either growth hormone-secreting adenomas (somatotropinoma), prolactin-secreting adenomas (prolactinoma), growth hormone and prolactin co-secreting adenomas (somatomammotropinoma), gonadotropinomas, ACTH-secreting adenomas, thyrotropinomas and non-functioning pituitary adenomas (NFPAs) (Guaraldi and Salvatori 2011; Beckers et al. 2013). TSH-secreting adenomas (causing hyperthyroidism) and ACTH-secreting adenomas (causing Cushing disease) are rarely observed (Korbonits and Kumar 2012). Interestingly, the adenomas within a family can show tumor heterogeneity (i.e. different types of pituitary adenomas) (Guaraldi and Salvatori 2011). Clinical findings result from excess hormone secretion, lack of hormone secretion or mass effects of the tumor. Individuals with these adenomas may exhibit agromegaly and pituitary gigantism due to somatotropinomas; amenorrhea, sexual problems, galactorrhea, infertility, visual field defects, and headaches due to prolactinomas; and bitemporal hemianopia and hypogonadism due to NFPAs (Korbonits and Kumar 2012).

FIPAs are inherited in an autosomal dominant manner, and are caused by pathogenic variants in the AIP gene in 20% of cases. Importantly, pathogenic AIP variants have an incomplete penetrance of 15-30% (Korbonits and Kumar 2012). AIP encodes a protein that has a role in subcellular trafficking, transactivation and nuclear receptor stability (Chahal et al. 2010). It is thought to be a tumor suppressor, as inactivating AIP germline mutations and loss of the normal allele is observed in FIPAs (Guaraldi and Salvatori 2011). AIP-related FIPAs are larger, more aggressive, have an earlier course of disease, and are resistant to somatostatin analogs compared to individuals without a pathogenic AIP variant. Individuals with NFPAs are more common in families without an AIP mutation (Chahal et al. 2010; Salvatori et al. 2014). Approximately 70% of AIP pathogenic variants result in a truncated protein (Korbonits and Kumar 2012). Pathogenic variants are located throughout the gene and include nonsense, missense, small insertions and deletions, indels, splice site and gross deletions (Human Gene Mutation Database).

An AIP pathogenic variant is observed in 20% of individuals with FIPA. Sporadic pituitary adenoma patients have a pathogenic AIP variant in 2% of cases (Chahal et al 2010). Sanger sequencing is able to detect 90% of causative mutations in individuals with AIP-related FIPAs (Korbonits and Kumar 2012).

This test provides full coverage of all coding exons of the AIP gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.