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Evidence for Genetic Heterogeneity in Male Pseudohermaphroditism due to Leydig Cell Hypoplasia¹

Research Unit in Developmental Biology, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (J.C.Z., P.C., J.P.M.); and the Department of Genetics, Hospital General de México, Secretaría de Salud, Faculty of Medicine, Universidad Nacional Autónoma de México (J.C.Z., S.K.-A.), Mexico, D.F., Mexico

Address all correspondence and requests for reprints to: Juan Pablo Méndez, M.D., Coordinación de Investigación Médica, Unidad de Investigación Médica en Biología del Desarrollo, Avenida Cuauhtémoc 330, Apartado Postal 73–032, Colonia Doctores, C.P. 06725, Mexico, D.F., Mexico. E-mail: jpmb{at}servidor.unam.mx

Leydig cell aplasia or hypoplasia is a rare form of male pseudohermaphroditism resulting from inadequate fetal testicular Leydig cell differentiation. Affected individuals presented a wide phenotypic spectrum, ranging from complete female external genitalia to males with micropenis. Recessive mutations in the LH receptor gene have been identified as responsible for the condition. The majority of these mutations are point mutations and have been located in exon 11 of the gene. In this study, we report the molecular characterization of the LH receptor gene in three siblings with Leydig cell hypoplasia. After sequencing the 11 exons of the gene, no deleterious mutations were detected in any patient. However, we identified a previously described polymorphism in exon 11. In patients 1 and 3 DNA sequencing revealed a C to T substitution at nucleotide 1065; both patients were homozygous GAT/GAT at codon 355. In contrast, patient 2 was homozygous GAC/GAC, whereas the father and one unaffected sister were heterozygous GAC/GAT at this polymorphic site. These results exclude that Leydig cell hypoplasia in this family is due to a mutation in the LH receptor gene and provide evidence that defects in other loci may also result in failure of Leydig cell differentiation, demonstrating, for the first time, that Leydig cell hypoplasia is a genetically heterogeneous condition. . Subsequently, male phenotypic development is under the control of three fetal hormones that exert their effects on the genital primordium. The first event is Mullerian duct regression, which depends on the effect of the Sertoli cell-synthesized Mullerian inhibiting hormone. Immediately thereafter, testosterone (synthesized in Leydig cells) stimulates Wolffian duct proliferation while 5-dihydrotestosterone (synthesized at the target cell level) virilizes external genitalia. Fetal Leydig cell differentiation and testosterone synthesis occur in a similar fashion as in the adult; however, as fetal LH is not yet available at this point in time, trophoblastically produced hCG takes over the LH actions. hCG/LH requires the presence of membrane-located hCG/LH receptors in Leydig cells (2).

Male pseudohermaphroditism (MPH) encompasses a group of disorders that can arise from a variety of conditions, including abnormalities of androgen end-organ response, enzymatic defects in androgen bioynthesis, defective Mullerian duct regression, and abnormal testicular differentiation. Leydig cell agenesis or hypoplasia, which has an autosomal recessive inheritance pattern, is a well defined form of MPH resulting from inadequate fetal testicular Leydig cell differentiation (3–14). Individuals with this condition exhibit a wide clinical spectrum that ranges from phenotypic females to males with micropenis (14, 15). Mullerian derivatives are always absent, and vas deferens with epididymis are occasionally found (3, 4, 6, 9). The hormonal profile in these patients is characterized by low levels of serum testosterone (basal and hCG-stimulated) and elevated levels of LH (16).

Recently, a number of mutations in the LH receptor gene have been characterized in familial and sporadic cases of Leydig cell agenesis or hypoplasia (17–26). The majority of these mutations were found in affected homozygotes, although compound heterozygosity has been identified in two cases (20, 23). In vitro expression studies of the mutated receptors demonstrated impaired or absent ligand binding and cAMP production in response to hCG stimulation, confirming the inactivating effect of these mutations in LH receptor activity (17–26).

Here we report the molecular findings regarding the LH receptor gene in a familial case of MPH due to Leydig cell hypoplasia. Our data exclude that mutations in the LH receptor gene are the cause of this disorder in this particular family and demonstrate, for the first time, that Leydig cell hypoplasia is a genetically heterogeneous condition.

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