A number sign (#) is used with this entry because of evidence that susceptibility to multiple types of pituitary adenoma (PITA5) is conferred by heterozygous mutation in the CDH23 gene (605516) on chromosome 10q21.

Both familial and sporadic pituitary adenomas have been found to be caused by germline mutation in the CDH23 gene. Familial pituitary adenoma types include growth hormone (GH)-secreting and nonfunctional tumors. Sporadic pituitary adenoma types include GH-secreting, nonfunctional, prolactin (PRL)-secreting, adrenocorticotropin (ACTH)-secreting, thyroid-stimulating hormone (TSH)-secreting, and plurihormonal (GH and TSH) tumors.

For a general description and a discussion of genetic heterogeneity of pituitary adenomas, see PITA1 (102200).

Zhang et al. (2017) reported a family in which 4 individuals developed pituitary adenomas. Two patients had GH-secreting tumors and underwent surgical resection, whereas the other 2 patients had nonfunctional tumors with occasional headaches and did not undergo surgery. Subsequently, 3 additional families in which more than 2 individuals had either GH-secreting or nonfunctional pituitary tumors were identified. Finally, 15 patients with apparently sporadic pituitary tumors associated with CDH23 mutations were identified. The tumor types among these patients varied, and included 1 nonfunctional, 3 PRL-secreting, 2 GH-secreting, 4 ACTH-secreting, 1 glomus tumor, 3 TSH-secreting, and 1 plurihormonal (GH and TSH).

The transmission pattern of pituitary adenomas in the families reported by Zhang et al. (2017) was consistent with autosomal dominant inheritance with incomplete penetrance.

In affected members of 4 unrelated families with both functional growth hormone-secreting and nonfunctional pituitary adenomas, Zhang et al. (2017) identified germline heterozygous missense mutations in the CDH23 gene (605516.0016-605516.0019). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There was evidence of age-dependent or incomplete penetrance. Whole-exome sequencing of 125 individuals with sporadic pituitary adenoma identified CDH23 mutations in 15 individuals (12.0%); 13 had heterozygous mutations and 2 had homozygous mutations. The tumor types in these patients varied. All mutations identified occurred at highly conserved residues in the EC domains of CDH23, and were predicted to adversely affect calcium binding or protein folding. Functional studies of the variants were not performed. Compared to pituitary adenomas with wildtype CDH23, those associated with CDH23 mutations were smaller in diameter and less invasive. Heterozygous, putatively functional variants in the CDH23 gene were found in 2 (0.8%) of 260 control individuals.