Novel mutations of the LHCGR gene in two families with 46,XY DSD causing Leydig cell hypoplasia I.

PURPOSE: Leydig cell hypoplasia is a rare autosomal recessive 46,XY disorder of sexual development (DSD). It is caused by homozygous or compound heterozygous inactivating mutations in the human luteinizing hormone/chorionic gonadotropin hormone receptor (LHCGR) gene. In Leydig cell hypoplasia type I, patients are characterized by predominantly female external genitalia, which usually go unrecognized until the age of puberty. METHODS: This study reports three patients descending from two unrelated families. We performed clinical, hormonal, histopathological, molecular, and bioinformatics studies for the studied cases. RESULTS: All investigations suggested 46,XY DSD and Leydig cell hypoplasia. Molecular analysis showed two novel homozygous inactivating mutations (p.Glu148Ter and p.Leu104Pro) within the extracellular domain of the LHCGR gene. CONCLUSION: Although the mutations of the LHCGR gene are distributed heterogeneously, without hotspot or recurrent mutations, about one fifth of the reported mutations worldwide have been detected in Arab patients. This is probably due to the high consanguinity rate in these populations, which increases the percentage of autosomal recessive disorders and the homozygous LHCGR gene mutations.

Unique karyotype: mos 46,X,dic(X;Y)(p22.33;p11.32)/ 45,X/45,dic(X;Y)(p22.33;p11.32) in an Egyptian patient with Ovotesticular disorder of sexual development.

Ovotesticular disorder of sexual development (OT-DSD) is an unusual form of DSD, characterized by the coexistence of testicular and ovarian tissue in the same individual. In this report, we present clinical, cytogenetic and molecular data of an Egyptian patient with ambiguous genitalia and OT-DSD, who had a unique karyotype comprising 3 different cell lines: mos 46,X,dic(X;Y)(p22.33;p11.32)/45,X/ 45,dic(X;Y)(p22.33;p11.32). This mosaic karyotype probably represents 2 different events: abnormal recombination between the X and Y chromosomes during paternal meiosis and postzygotic abnormality in mitotic segregation of the dic(X;Y) chromosome, resulting in a mosaic karyotype. The presence of the sex-determining region Y (SRY) gene explains the development of testicular tissue. On the other hand, other factors, including the presence of a 45,X cell line, partial SRY deletion, X inactivation pattern, and position effect, could be contributed to genital ambiguity. Explanation of the patient's phenotype in relation to the genotype is discussed with a literature review. We conclude that FISH analysis with X- and Y-specific probes and molecular analysis of the SRY gene are highly recommended and allow accurate diagnosis for optimal management of cases with ambiguous genitalia.