Alternative titles; symbolsTESTICULAR REGRESSION SYNDROME; TRSTESTICULAR REGRESSION, EMBRYONICXY GONADAL AGENESIS/DYSGENESIS SYNDROMEANORCHIA, FAMILIAL▼ Descript...
Alternative titles; symbols
SRXY11 is characterized by a genital phenotype that may range from predominantly female to predominantly male, including marked sex ambiguity depending on the duration of normal testicular function prior to the loss of testicular tissue. Approximately half of patients present with micropenis and bilateral cryptorchidism, and half present with female-appearing or ambiguous external genitalia (da Silva et al., 2019; McElreavey et al., 2020).
The testicular regression syndrome (TRS) was delineated by Sarto and Opitz (1973), who called it the XY gonadal dysgenesis syndrome. It is characterized primarily by the absence of gonads in an XY person. In most cases, uterus and fallopian tubes are absent but small tubular structures interpreted as mullerian or wolffian rudiments (or both) are present. The range of virilizing effects due to early testicular tissue extends from none in phenotypic females with only slightly hypoplastic normal external genitalia, well-formed but hypoplastic uterus, and well-formed tubes (De Marchi et al., 1981) to the anorchic phenotypic male (Edman et al., 1977). Most affected individuals lack a vagina but a urogenital sinus or pseudovaginal urethral outpouching is found. Partial labioscrotal fusion and clitoris enlargement are common, breast development is absent, and postpubertal eunuchoid habitus is the rule. Sometimes nongenital anomalies are present (summary by Rosenberg et al., 1984).
▼ Clinical Features
Abeyaratne et al. (1969) described 16 cases of apparently complete absence of testes in phenotypic males, including one pair of affected sibs. Ferrier (1969) examined twins, one of whom had anorchia, who were found through blood studies to be probably monozygotic. Familial occurrence was noted by Overzier and Linden (1956).
Bobrow and Gough (1970) also described 2 affected brothers. This familial disorder may be unilateral in a portion of cases. Hall et al. (1975) described anorchia in identical twins and in 2 brothers, and anorchia was unilateral in 3 and bilateral in 1.
Josso and Briard (1980) supported the suggestion that a more appropriate term would be embryonic testicular regression syndrome. They observed two 46,XY sibs with variable degrees of sexual ambiguity. The elder was a phenotypic male with micropenis. The younger, a phenotypic female with slight fusion of the genital folds and absent mullerian ducts, conformed to the usual criteria of true agonadism. Coexistence of anorchia and true agonadism in this sibship suggests that they are fundamentally the same and due to regression of the embryonic testis.
Rosenberg et al. (1984) reported a case of testicular regression in a virilized female and analyzed 20 cases from the literature. They described a 16-year-old 46,XY phenotypic female, born of nonconsanguineous parents and with 3 normal sibs, who had no breast development or pubic hair, slightly hypoplastic female external genitalia with enlarged clitoris and a small pseudovagina. Intravenous urography and urethral cystography showed a hypoplastic masculine urethra. On laparotomy no uterus or gonadal rudiments were observed, although rudiments of wolffian ducts were identified histologically. Basal levels of luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) were elevated, consistent with lack of gonadal tissue. Plasma testosterone, dihydrotestosterone, 17-hydroxyprogesterone, and androstenedione were all low; dehydroepiandrosterone (DHEA), predominantly of adrenal origin, was normal. The patient had no other anomalies. Rosenberg et al. (1984) favored autosomal recessive inheritance because of first-cousin parents in 1 instance, agreement with the recessive hypothesis (with sex limitation) on segregation analysis, and familial occurrence in 1 generation only.
De Grouchy et al. (1985) reported a Tunisian sibship of 10 that contained 3 XY sibs with the testicular regression syndrome and severe mental retardation. Since there was an XX sib also with mental retardation, 2 independent disorders may have been segregating in this kindred.
Parisi et al. (2002) described three 46,XY boys, including 2 brothers, with micropenis and poor phallic growth in response to both exogenous human chorionic gonadotropin (HCG) and testosterone therapy in the newborn period. They exhibited low neonatal testosterone levels that failed to respond to HCG stimulation, and had a distinctive gonadotropin profile with reduced LH levels and elevated FSH levels. They had small, cryptorchid testes with subsequent testicular regression and atrophy. In addition, all 3 boys developed microcephaly and mild learning delays. Parisi et al. (2002) noted that the phenotype of these 3 patients was reminiscent of testicular regression syndrome, but stated that patients with testicular regression syndrome have elevation of serum concentrations of both LH and FSH.
Oguz Kutlu et al. (2009) reported a 46,XY boy with testicular regression, born of first-cousin Turkish parents, who presented at 5 months of age with undescended testicles, micropenis, flat scrotum, microcephaly, and psychomotor delay. The patient's LH level was low-normal, and FSH was high. No response was obtained with the HCG stimulation test. Analysis of Sertoli cell function showed levels of inhibin B and anti-Mullerian hormone to be low. At 5 months of age, testicles were visualized bilaterally in the inguinal canals by ultrasound, but by 2 years of age, no testicular tissue was found during inguinal exploration. Oguz Kutlu et al. (2009) stated that the physical findings and laboratory results in this patient were identical to those of the 3 patients studied by Parisi et al. (2002).
Da Silva et al. (2019) studied 17 patients from 11 unrelated families with 46,XY gonadal dysgenesis (GD) and a mutation in the DHX37 gene. A diagnosis of embryonic testicular regression syndrome (ETRS) was given to 12 of the patients, 4 were designated as having partial gonadal dysgenesis (pGD), and the remaining patient was a 35-year-old woman with a history of previous gonadectomy and genitoplasty. All patients with ETRS had micropenis and absent or rudimentary gonads; of the 4 patients with pGD, 1 had female-appearing external genitalia, 2 had atypical external genitalia, and 1 exhibited micropenis. Histologic analysis reported in 15 patients showed wolffian derivatives present in all; of mullerian derivatives, rudimentary fallopian tubes were evident in 7 patients, but none had a uterus.
McElreavey et al. (2020) reported thirteen 46,XY individuals with mutations in the DHX37 gene, who presented a phenotypic spectrum ranging from phenotypic females to males with micropenis and bilateral or unilateral cryptorchidism. The authors noted that the majority of patients showed presence of wolffian and absence of mullerian structures, suggesting residual Sertoli and Leydig cell function during early testis formation. No gonadal tissue was present in 4 patients. Hormone analysis showed elevated LH and FSH, low or low-normal testosterone levels, and low anti-mullerian hormone (AMH; 600957). None of the patients exhibited other somatic anomalies.
Segregation analysis was consistent with a sex-limited autosomal dominant pattern in 8 families studied by da Silva et al. (2019), with maternal inheritance demonstrated in 5 of them. In 2 families, the mutation was shown to have arisen de novo, and in 1 family, the mutation was inherited from an asymptomatic father, suggesting incomplete penetrance.
▼ Molecular Genetics
By genetic analysis of 87 patients with 46,XY gonadal dysgenesis, da Silva et al. (2019) identified 17 patients from 11 unrelated families of varying nationalities who were heterozygous for 4 different missense mutations in the DHX37 gene: R308Q (617362.0006) in 4 patients from 2 Brazilian families (F1 and F2) and 3 sporadic Chinese American patients (F6, F7, and F8); R674W (617362.0007) in 3 patients from an Argentinian family (F4), 2 from a Chilean family (F3), and 2 sporadic Brazilian patients (F10 and F11); S595F (617362.0008) in a Brazilian aunt and nephew (F5); and T304M (617362.0009) in a Brazilian woman (F9). All 4 variants were located in the conserved DHX37 helicase core region. Segregation analysis, performed in 8 families, showed a sex-limited autosomal dominant pattern, with maternal inheritance in 5 families (F2, F3, F4, F5, and F11). In F1, the presence of the R308Q variant in the asymptomatic father suggested an autosomal dominant pattern of inheritance with incomplete penetrance. In 2 sporadic cases (F6 and F8), the confirmed paternity revealed a de novo status of the R308Q variant.
From a cohort of 145 patients of European ancestry with 46,XY disorders of sex differentiation (DSD), McElreavey et al. (2020) identified 13 patients diagnosed with gonadal dysgenesis or testicular regression syndrome who were heterozygous for missense mutations in the DHX37 gene, including the recurrent R308Q (617362.0006) and T304M (617362.0009) mutations and 6 other variants (see, e.g., R674Q, 617362.0010). All but 1 clustered within the functional RecA1 and RecA2 domains of the protein and involved highly conserved amino acids. Inheritance was reported in 6 families, and showed 1 maternally inherited variant and 5 families in which the mutation arose de novo. The authors noted that in their cohort, no DHX37 mutations were found in patients diagnosed with severe penoscrotal hypospadias or anorchia.
In 52 adult 46,XY women, Buonocore et al. (2019) sequenced the NR5A1 gene (184757) and analyzed targeted panels of DSD-associated and candidate genes. A likely pathogenic variant was identified in 16 (30.8%) of the patients in the cohort, including 4 patients who were designated as having partially virilized DSD and who had a heterozygous mutation in the DHX37 gene: the recurrent R308Q substitution was detected in 3 patients who had been previously reported by McElreavey et al. (2020), and a T477M substitution was found in the remaining patient, who exhibited mild virilization and an absent uterus.