Leydig Cell Hypoplasia, Type I

A number sign (#) is used with this entry because Leydig cell hypoplasia (LCH) types I and II, as well as luteinizing hormone resistance in females, are caused by inactivating mutations in the luteinizing hormone/choriogonadotropin receptor gene (LHCGR; 152790).

Description

Leydig cell hypoplasia is an autosomal recessive disorder in which loss of function of the LHCGR gene in the male prevents normal sexual development. Two types of LCH have been defined (Toledo, 1992). Type I, a severe form caused by complete inactivation of LHCGR, is characterized by complete 46,XY male pseudohermaphroditism, low testosterone and high LH levels, total lack of responsiveness to LH/CG challenge, lack of breast development, and absent development of secondary male sex characteristics. Type II, a milder form caused by partial inactivation of the gene, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias. Females with inactivating mutations in the LHCGR gene display a mild phenotype characterized by defective follicular development and ovulation, amenorrhea, and infertility (review by Themmen and Huhtaniemi, 2000).

Reviews

Arnhold et al. (2009) noted that the clinical manifestations of female patients with hypogonadotropic hypogonadism due to isolated LH deficiency (HH23; 228300) are very similar to those of women with hypergonadotropic hypogonadism due to inactivating mutations of the LH receptor: all have female external genitalia, spontaneous development of normal pubic hair and breasts at puberty, and normal to late menarche followed by oligoamenorrhea and infertility. Pelvic ultrasound shows a small or normal uterus and normal or enlarged ovaries with cysts. However, women with LHB (152780) mutations can be treated with luteinizing hormone or chorionic gonadotropin (CG; 118860) replacement therapy; women with LH receptor mutations are resistant to LH, and no treatment is effective in recovering their fertility.

Clinical Features

Leydig Cell Hypoplasia

Perez-Palacios et al. (1975, 1981) reported 3 46,XY sibs, 2 postpubertal and 1 prepubertal, with infantile female external genitalia and lack of breast development and sexual hair. Persistently elevated serum levels of gonadotropins with normal pituitary responsiveness to LRH was found. Testosterone levels were extremely low before and after gonadal stimulation with CG. The testes were small and cryptorchidic. Microscopic and ultrastructural examination revealed seminiferous tubules with absence of spermatogenesis and normal Sertoli cells. The interstitial spaces were mainly occupied by poorly differentiated cells, although in the postpubertal patients there were small and randomly distributed nodules of Leydig cells without crystaloids. Perez-Palacios et al. (1981) suggested that gonadotropin resistance was the underlying cause of the disorder. They suggested that the disorder may be the human homolog of the 'vet' rat (see ANIMAL MODEL section).

Berthezene et al. (1976) reported a case of gonadotropin resistance as a cause of male pseudohermaphroditism under the designation 'Leydig cell agenesis.' Characteristically, patients with this disorder have predominantly female external genitalia despite 46,XY chromosome constitution; no development of either male or female secondary sexual characteristics at puberty; presence of epididymis and vas deferens, and absence of uterus and fallopian tubes; low testosterone values despite elevated gonadotropin values; unresponsiveness to human chorionic gonadotropin stimulation; no abnormal step-up in testosterone-biosynthesis precursors; and only slightly smaller undescended testis with seminiferous tubules but without mature Leydig cells.

Saldanha et al. (1987) reported a kindred in which a typical patient with Leydig cell hypoplasia was the offspring of first-cousin parents. A sister had secondary amenorrhea due possibly to primary ovarian dysfunction. Analysis of 6 pedigrees led Saldanha et al. (1987) to conclude that the inheritance pattern is male-limited autosomal recessive.

El-Awady et al. (1987) described Leydig cell hypoplasia as the cause of male pseudohermaphroditism in 2 46,XY sibs whose parents were first cousins. The sibs were phenotypic females who had been raised as girls. Bilateral inguinal swellings had been noted in each soon after birth and both were operated on for herniotomy.

Wu and Chan (1999) noted that patients with the mild form of LCH present with male hypogonadism. Patients with the severe form present with male pseudohermaphroditism, with female external genitalia and cryptorchid testes. Mullerian derivatives are absent. Histologic examination of the testis shows absence of mature Leydig cells. Such patients have elevated plasma levels of LH, normal to elevated levels of follicle-stimulating hormone (FSH), and low levels of testosterone that do not respond to chorionic gonadotropin stimulation.

Luteinizing Hormone Resistance in Females

Luteinizing hormone stimulates the theca cells in normal women to produce androgen precursors for conversion to estradiol by granulosa cells during the follicular phase of the menstrual cycle. During the surge of LH levels in mid-cycle, it promotes follicular maturation and ovulation, and during the luteal phase, LH induces the formation of the corpus luteum and stimulates progesterone secretion. Thus, Latronico et al. (1996) stated that abnormalities in the LH receptor would be expected to result not only in abnormalities of male sexual development, but also in partial ovarian failure characterized by defective folliculogenesis, anovulation, absence of a luteal phase, delayed or incomplete feminization at puberty, amenorrhea, and infertility. Latronico et al. (1996) described a kindred in which this was indeed the case. In a sibship with 14 children, 3 brothers had male pseudohermaphroditism with Leydig cell hypoplasia and 1 sister had partial ovarian failure. Spontaneous gonadarche had occurred at the age of 13 years, and she had a single episode of vaginal bleeding at the age of 20 years. Her height and weight were normal, pubic hair development was Tanner stage 5, and the breasts and external genitalia were those of a normal woman. Her karyotype was 46,XX. Serum LH concentration was very high and serum estradiol concentration and progesterone concentration were low.

Toledo et al. (1996) evaluated a 46,XX sister of the two 46,XY male pseudohermaphrodites with Leydig cell hypoplasia described by Kremer et al. (1995). The patient presented with amenorrhea due to hypergonadotropic hypogonadism, but had structurally normal ovaries.

Wu and Chan (1999) noted that due to the late onset and milder disease phenotype, 46,XX females with homozygous or compound heterozygous inactivating mutations of LHR are difficult to identify unless an LCH male sib is found.

Inheritance

Consanguinity was noted in the case reported by Schwartz et al. (1981). Consanguinity in several other families (e.g., Saldanha et al., 1987 and El-Awady et al., 1987) supported autosomal recessive inheritance.

Molecular Genetics

Wu and Chan (1999) noted that missense, nonsense, insertion, and deletion mutations in the LHR gene have been found to reduce or abolish the signal transduction activity of the LHR, causing testicular and ovarian resistance to LH.

Leydig Cell Hypoplasia

In 46,XY sibs with pseudohermaphroditism, offspring of consanguineous parents, who presented with female external genitalia, primary amenorrhea, and lack of breast development, Kremer et al. (1995) identified homozygosity for an ala593-to-pro mutation in the LCGR gene (152790.0004).

Laue et al. (1995) demonstrated a nonsense mutation in the LCGR gene (152790.0007) in 2 46,XY 'sisters' with Leydig cell hypoplasia. The affected sibs were presumably compound heterozygotes. The father had the same mutation; the mother was presumed to have a different loss-of-function mutation which was not detected. In the family reported by Laue et al. (1995), Wu et al. (1998) identified a loss-of-function mutation in the mother (152790.0021).

Luteinizing Hormone Resistance in Females

In a 46,XX female with amenorrhea due to hypergonadotropic hypogonadism, but with structurally normal ovaries, Toledo et al. (1996) identified homozygosity for the same LHCGR mutation (152790.0004) that had been identified in her 2 brothers with LCH type I by Kremer et al. (1995). In vitro analysis of the mutant LH receptor in cultured human embryonic kidney 293 cells showed that the receptor is unable to stimulate adenylyl cyclase in response to CG. These results documented the existence of inherited LH resistance as a cause of primary amenorrhea in women.

In 4 sibs, 3 brothers with pseudohermaphroditism with Leydig cell hypoplasia and a sister with partial ovarian failure, Latronico et al. (1996) identified a homozygous missense mutation in the LHCGR gene (152790.0008).

Latronico and Arnhold (2012) reviewed inactivating mutations of the LH receptor in both men and women, stating that most female patients are ascertained as the sisters of probands with 46,XY disorders of sex development. However, they noted that Yariz et al. (2011) had identified an LHCGR mutation in 2 sisters undergoing in vitro fertilization procedures; the sisters had been diagnosed with 'empty follicle syndrome,' defined as the failure to retrieve oocytes from mature ovarian follicles after ovulation induction, despite apparently normal follicular development and estradiol levels. Latronico and Arnhold (2012) concluded that although LHCGR mutations are rare in comparison to other genetic and nongenetic causes of hypergonadotropic hypogonadism, they should be considered in patients with oligoamenorrhea and empty follicle syndrome.

Heterogeneity

Zenteno et al. (1999) studied the LHCGR gene in 3 sibs with Leydig cell hypoplasia. Sequencing of all 11 LHCGR exons detected no deleterious mutations in any patient. The authors did, however, identify a previously described polymorphism in exon 11 of patients 1 and 3: a C-to-T transition at nucleotide 1065; both patients were homozygous GAT/GAT at codon 355. In contrast, patient 2 was homozygous GAC/GAC, whereas the father and an unaffected sister were heterozygous GAC/GAT at this polymorphic site. Zenteno et al. (1999) concluded that Leydig cell hypoplasia in this family was not due to a mutation in the LHCGR gene and that defects in other genes may result in failure of Leydig cell differentiation. Furthermore, the authors stated that the results showed, for the first time, that Leydig cell hypoplasia is a genetically heterogeneous condition. It should be noted, however, that if this mutation perturbed a splicing enhancer element, their conclusion could be invalid.

Animal Model

Bardin et al. (1973) studied an inherited form of male pseudohermaphroditism in XY rats with female phenotype and vestigial testes (from which the designation 'vet' was derived). The testes were small with marked immaturity of the Leydig cells which correlated with undetectable plasma testosterone levels and elevated gonadotropins. They suggested a receptor defect.

History

Berg and Skre (1976) described a kindred in which males and females had what they termed hypergonadotropic hypogonadism, i.e., hypogonadism with elevated gonadotropins. They cited the report of Elliott et al. (see 233300) as representing the same condition. Possible linkage with Marinesco-Sjogren syndrome (248800) was found and criteria for concluding that linkage is the basis of concurrence of 2 rare recessives were proposed. Since both males and females were affected, the disorder was presumably distinct from gonadal dysgenesis, XX type (233300).