Cryptorchidism, Unilateral Or Bilateral
A number sign (#) is used with this entry because of evidence that cryptorchidism can be caused by heterozygous mutation in the insulin-like-3 gene (INSL3; 146738) on chromosome 19p13.
DescriptionCryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Clinical FeaturesBishop et al. (1979) pointed out that renal anomalies such as renal agenesis are often associated with the familial form of cryptorchidism.
Czeizel et al. (1981) found that mothers of index cases had shorter menses and delayed menarche, and stated that 'pituitary hypogonadism of mothers seems to be a predisposing factor for undescended testes in their sons.'
In 8 patients with mutations in either the INSL3 or LGR8 (RXFP2; 606655) genes, Ferlin et al. (2003) found different phenotypes ranging from normozoospermia to complete azoospermia and from bilateral cryptorchidism to retractile testes. The endocrine function of the testis appeared normal in all patients.
InheritanceCorbus and O'Conor (1922) found several reports of families with multiple generations affected. Perrett and O'Rourke (1969) described ipsilateral (right-sided) cryptorchidism in 8 males in 4 generations. Pardo-Mindan et al. (1975) reported 2 families suggesting autosomal dominant or, as they correctly indicated, Y-linked inheritance.
Czeizel et al. (1981) confirmed undescended testis in 1.5 to 4.0% of fathers and 6.2% of brothers. The family clustering fitted a gaussian-additive-multifactorial-threshold model. Heritability in first-degree male relatives was estimated to be 0.67 plus or minus 0.16. Bilateral (more severe) cryptorchidism was associated with a higher recurrence risk for brothers. The nosologic identity of unilateral and bilateral cryptorchidism was borne out by the study.
Molecular GeneticsTomboc et al. (2000) used SSCP analysis to screen the coding regions of the INSL3 gene in genomic DNA samples obtained from 145 formerly cryptorchid patients and 36 adult male controls. Two mutations and several polymorphisms were identified. The authors concluded that the frequency of INSL3 gene mutations as a cause of cryptorchidism is low, because only 2 of 145 (1.4%) formerly cryptorchid patients were found to have mutations: arg49 to ter (R49X; 146738.0005), which was likely to be pathogenetic because it was found in a boy with undescended right testis and history of incarcerated right inguinal hernia, and pro69 to leu (P69L; 146738.0002), which was found in an 8-month-old baby with nonpalpable intraabdominal right testis.
Canto et al. (2003) studied genomic DNA from 150 patients with idiopathic cryptorchidism. A heterozygous asn86-to-lys mutation (146738.0001) in the INSL3 gene was found in 1 patient whose mother was a heterozygous carrier of the mutation and whose father was homozygous wildtype.
Ferlin et al. (2003) sequenced the INSL3 and LGR8 genes in 87 patients with corrected cryptorchidism and 80 controls and found 3 mutations in the INSL3 gene (146738.0002-146738.0004) in 4 patients and 1 LGR8 mutation (606655.0001) in 4. The authors concluded that INSL3-LGR8 mutations are frequently associated with human cryptorchidism and are maternally inherited. The only clinical consequence of alterations of the INSL3-LGR8 system seemed to be failure of the testis to descend normally into the scrotum during embryonic development, without affecting the spermatogenic and endocrine components of the testis itself.
Associations Pending Confirmation
For discussion of a possible association between cryptorchidism and mutation in the LGR8 gene, see 606655.0001.
Animal ModelMale Insl3 knockout mice exhibit bilateral abdominal cryptorchidism (Nef and Parada, 1999; Zimmermann et al., 1999).
Overbeek et al. (2001) described mice with a transgene insertional mutation, crsp, causing high, intraabdominal cryptorchidism in homozygous males. The authors identified a candidate gene within a 550-kb deleted region, which they dubbed Great (G-protein-coupled receptor affecting testis descent). This gene was later identified as the murine ortholog of LGR8. Gorlov et al. (2002) described a targeted mutation in Great causing cryptorchidism in homozygous male mice.