Presentation and Diagnosis of Turner Syndrome

In the prenatal period, fetuses with 45,X DSD and its variants frequently have intrauterine growth restriction. Suspicion for Turner syndrome should be raised if the presence of large septate cystic hygromas, nuchal thickening, short femur, total body lymphangiectasia, or cardiac defects is detected by ultrasound. At birth, Turner syndrome babies often have low birth weights; 30% of babies will present with lymphedema of the upper and lower extremities ( Fig. 16.6 ), an extension of the lymphangiectasia in utero, which disappears in the first few months of life. Additionally, the presence of a webbed neck (pterygium colli) (see Fig. 16.5 ) and dysmorphic features including a high-arched palate, low-set prominent ears, low posterior hairline, epicanthal folds, micrognathia, hypoplastic nail beds, or hypoplastic fourth and fifth metacarpals at birth should raise the suspicion for 45,X DSD. Turner syndrome patients may have increased carrying angle of the arms (cubitus valgus), shield-like chest with wide-set nipples, hearing loss, and a higher frequency of cardiovascular disease such as coarctation of the aorta. Furthermore, the incidence of renal anomalies is between 30% and 50%, the most common finding being a horseshoe kidney, followed by abnormal vasculature.

Lymphedema in the lower extremities of an infant with Turner syndrome.

During adolescence, the most common presentation is short stature, amenorrhea, and lack of secondary sexual characteristics. Patients may also have any of the other characteristics mentioned above. 45,X patients have normal intelligence. Depending on the degree of GD, up to 30% of Turner patients undergo some degree of spontaneous puberty.

Diagnosis is made by karyotype, which will show in a 45,X or mosaic variant of cells. If the karyotype appears normal but the presentation is suggestive of Turner syndrome, a fluorescent in situ hybridization (FISH) or chromosomal microarray study should be done because there may be a cryptic deletion in the pseudoautosomal region in one of the X chromosomes. Typically patients with 45,X or 46,XX with a chromosomal abnormality in one X chromosome have more prominent phenotypic features than those who are a mosaic.

Management of Turner Syndrome

For most patients with 45,X DSD, the greatest concern is for short stature and secondary sexual development. The treatment of both of these should be carefully titrated. For cases diagnosed in childhood, the use of low-dose anabolic steroid coupled with growth hormone has been shown to increase final adult height with increased beneficial effects compared to those who started therapy late. Optimal duration and timing of the steroid treatment is still under investigation. At the onset of the age of puberty, high-dose estrogen and progesterone should be given to promote the development of secondary sex characteristics. Estrogens and progesterone should be taken throughout life to prevent complications, such as osteoporosis.

In young patients diagnosed with Turner syndrome, spontaneous puberty is a good indicator of the presence of functional ovarian tissue. Overall, it is estimated that 2% to 5% of patients with Turner syndrome have the potential for spontaneous pregnancy.

A frequent question from families concerns fertility. Despite progress in egg preservation techniques, which could provide hope for fertility in women with Turner syndrome, pregnancies (conceived with either autologous or donated oocytes) carry a high risk of life-threatening cardiovascular complications (aortic dissection, severe hypertension). A complete cardiac assessment is recommended prior to consideration of pregnancy, as well as close monitoring during pregnancy and in the postpartum period.

Presentation and Diagnosis of Klinefelter Syndrome

Klinefelter syndrome is largely undiagnosed in the general population. In early life, Klinefelter may be diagnosed in boys with behavioral disorders, abnormally small testes, and long legs ( Fig. 16.7 ). The presence of only long lower extremities distinguishes Klinefelter syndrome from the other forms of eunuchoidism that results in equally long upper and lower extremities. In patients with Klinefelter syndrome, IQ typically falls in the normal range; however, it tends to be below that of other siblings. Most patients present in adolescence with small firm testes and hypogonadism with varying degrees of androgen deficiency. In later life, many males present at infertility centers with azoospermia.

Klinefelter syndrome.

(A) Phenotypic male with XXY. Note the long lower extremities as compared with the upper extremities. (B) Well-virilized patient with gynecomastia. (C) Testicular biopsy of patient in (B). Note marked hyalinization of seminiferous tubules and Leydig cell hyperplasia.

(From Grumbach, MM, Conte FA: Disorders of sex differentiation. In Wilson JS, Foster DW, Kronenberg HM, Larsen PR, editors: Williams Textbook of Endocrinology . Philadelphia, 1998, WB Saunders, p 1368.)

Diagnosis of Klinefelter syndrome is performed by lymphocyte karyotype or chromosomal microarray. Some mosaic cases will only be detected by karyotype of skin fibroblasts and occasionally of testicular biopsy specimens.

Management of Klinefelter Syndrome

Early detection of Klinefelter allows for early intervention for cognitive and behavioral disorders. Current studies are underway exploring the role of androgen replacement therapy in childhood, to help with cognitive and behavioral disabilities. Replacement of androgens also allows for development of masculine secondary sex characteristics, improved self-esteem, and increased libido, strength, and bone mineral density. With regard to fertility, testicular mosaicism is an important factor in determining spermatogenesis and the potential for fertility. The vast majority of 47,XXY patients are azoospermic but, since the advent of surgical testicular sperm extraction and intracytoplasmic sperm injection (ICSI) technology, have the potential to be fertile. It should be noted that there is a higher rate of sex chromosomal hyperploidy and autosomal aneupoloidy in the sperm of Klinefelter patients. However, the risk of passing sex chromosome aneuploidy to the offspring remains unclear. Regardless, preimplantation genetic diagnosis (PGD) or fetal karyotype can identify chromosomal abnormalities in the progeny. Using testicular sperm extraction technology, sperm can be successfully extracted from the testes and injected into a donor oocyte, with a reported fertility success of up to 50%, a dramatic change from the near complete historical infertility of Klinefelter patients.

Etiology and Pathophysiology of Pure/Complete Gonadal Dysgenesis

XY GD is a result of abnormal testis development in utero. There are three types of GD, pure (or complete), partial, or mixed, all of which can be differentiated by the extent of normal testicular tissue within the gonad and karyotype of the individual. In pure/complete GD, individuals have intraabdominal, bilateral, fibrous streaks that do not secrete AMH or testosterone. Phenotypically, pure XY GD individuals are unambiguously phenotypic females (previously known as Swyer syndrome) but usually internally possess hypoplastic müllerian structures.

Given the primary importance of SRY in human testes determination, it is surprising that mutations in SRY only account for approximately 15% of all 46,XY DSD with pure GD. This suggests the existence of many other genes involved in primary human sex determination. SRY is a transcription factor, but its mechanism of action remains incompletely understood. For instance, it is still unclear whether it acts as an activator or repressor, and its only identified and confirmed target is SOX9, another transcription factor from the Sox (Sry-box) family of genes. This interaction is mediated by the testis-specific Sox9 enhancer, TESCO, and by TESCO-independent mechanisms. To date, there are more than 50 verified mutations within the SRY gene. Mutations that result in streak gonads primarily occur within the HMG box, and cause reduced DNA binding, alterations in DNA bending, or prevents nuclear import of the SRY protein. Larger cytogenetic deletions of Yp that include SRY have also been implicated in XY GD.

Steroidogenic factor 1 (SF1, encoded by the gene NR5A1 ) is an orphan nuclear receptor necessary for adrenal and testicular development. Interactions between NR5A1/SF1 and the transcription factors GATA-binding protein 4 (GATA4) and friend of GATA 2 (FOG2) appear to be necessary for SRY expression in developing testes. Recent studies have underlined the importance of SF1 in testicular development, and nearly 15% of isolated XY GD can be attributed to SF1 haploinsufficiency. However, SF1 mutations with XY GD and adrenal hypoplasia congenita have been reported, which reflect the role of SF1 also in adrenal development. Together, mutations or deletions of SRY and SF1 account for 30% of XY GD, indicating that other genes critical to the testes determination cascade still remain to be discovered.

Exome sequencing has now shown that MAP3K1 variants are frequent in 46,XY DSD patients and may be an underestimated cause. Mutations in genes involved in testis sex determination (SOX9, WT-1, DHH, DMRT1) and duplications of putative “anti-testis” genes (WNT-4, DAX1) are responsible for a minority of all XY GD. Many are also associated with other syndromic features, which are outlined in Table 16.3 .

Etiology and Pathophysiology of Partial or Mixed Gonadal Dysgenesis

Like many developmental disorders, there is a wide range in phenotypic variability in patient presentation. When testes dysgenesis does not involve the entirety of both gonads and the external genital phenotype is ambiguous rather than typical female, the condition is called partial GD . The internal genitalia display varying degrees of wolffian and müllerian development, which correspond with the proportion of the gonads that is dysgenetic or “streak.” The medical literature is often confusing in regard to the difference between “partial” and “mixed” GD, which are often used interchangeably. Partial XY GD refers to intermediate stages of dysgenetic testes, between streak gonads and normal testes, and usually has a 46,XY, nonmosaic karyotype. Mixed XY GD typically refers to a situation in which one gonad is a streak gonad while the opposite gonad is partially dysgenic or a normal testis. Mosaicism for 45,X/46,XY is the most frequent cause of mixed GD, although a minority have a 46,Xi (Yq) karyotype. The evidence of the variable phenotypic spectrum of individuals with 45,X/46,XY mosaicism was reported in a series of 10 45,X/46,XY patients in which four individuals were undervirilized males with bilateral testis, three were diagnosed with mixed GD and genital ambiguity, and three were diagnosed with Turner syndrome. Although not proven, there is preliminary evidence that the percentage of normal testicular tissue and phenotypic maleness are correlated with an increase in the proportion of gonadal Y chromosome.

Familial cases of pure and partial 46,XY GD have been reported. In some of these cases, SRY mutations present with phenotypic variability in which the father and male relatives are phenotypically normal and fertile, while their XY offspring have GD. From these cases, it is clear that autosomal genetic modifiers influence the sex determination cascade and ultimate phenotypic appearance of the individual. There are also cases of fathers who are mosaic for mutant and normal SRY transmitting the mutation to their XY female daughters. Presumably, the normal father’s mosaicism reflects a postzygotic mutation event. These unique cases provide more hints about the molecular basis of sex determination. This is particularly relevant because the genetic cause of about half of 46,XY GD remains unknown.

Presentation and Diagnosis of Gonadal Dysgenesis

Pure XY GD presents as a phenotypic female with normal or tall stature, bilateral streak gonads, delayed puberty, amenorrhea, small or normal müllerian structures, and without signs of Turner syndrome. If patients are not diagnosed at birth (e.g., when in utero karyotype does not match the phenotypic sex at birth) most patients will be diagnosed during adolescence due to pubertal delay and primary amenorrhea. Patients can rarely present with an abdominal or pelvic mass, which is often a gonadoblastoma. Occasionally, XY GD can be part of a constellation of other symptoms, outlined in Table 16.3 .

Individuals with partial or mixed 46,XY GD typically present at birth with varying degrees of masculinization of external and internal genitalia. Depending on the percent of testicular tissue, dysgenetic testes can be found anywhere along the line of testes descent, from the abdomen, and in cases of normal testes, in the scrotum. However, the streak gonad in mixed 46,XY GD is always abdominally located. Patients with partial 46,XY GD usually have female external genitalia with some degree of virilization, such as clitoromegaly or a bifid scrotum ( Fig. 16.8 ). Uterus and fallopian tubes are usually well formed, but occasionally may be hypoplastic. In mixed GD, the development of wolffian and müllerian structures and the virilization of external genitalia correlate with the degree of development of the ipsilateral testis resulting in asymmetric virilization of the external or internal genitalia and unilateral cryptorchidism. Pelvic ultrasound can often detect the presence or absence of male or female internal genitalia and, in the case of mixed XY GD, asymmetry in development of the müllerian and wolffian structures. There are rare reported cases of patients presenting with premature adrenarche in an otherwise unambiguous female, due to a testosterone-producing gonadal tumor.

External genitalia of infant with 45,X/46,XY mosaicism.

Note enlarged phallus, labioscrotal fusion, and gonadal bulges (histologically, testes) in labioscrotum.

Isolated 46,XY pure GD is considered in an adolescent with primary amenorrhea and sexual immaturity with a full female external phenotype, while partial or mixed GD should be considered more likely in the differential diagnosis of a 46,XY patient with ambiguous genitalia. The biochemical changes in complete, partial, and mixed GD are outlined in Table 16.4 .

The major criteria for the diagnosis of pure, partial, or mixed GD are the appearance and histology of both gonads. Therefore, the ultimate diagnosis of any of the forms of GD, particularly the distinction between mixed and partial GD, requires biopsy of both gonads. Because the risk of gonadoblastoma in these patients is elevated, precise diagnosis of the type of GD is usually determined after prophylactic or therapeutic gonadectomy. In pure 46,XY GD both gonads are streak gonads. Partial GD is defined by bilateral dysgenetic gonads, whereas mixed GD typically has one streak gonad. Karyotype of peripheral leukocytes shows 46,XY in pure and partial GD, and mosaic 45,X/46,XY is frequent in mixed GD. However, if there is a streak gonad on one side and a normal testis contralaterally, but the peripheral karyotype is 46,XY, cryptic mosaicism can often be revealed within the gonad.

Once a presumptive diagnosis is made in 46,XY patients, FISH for SRY or for Yp can be performed. Only a minority of cases of XY GD can be explained by complete or partial SRY deletion or mutation, or SF1 mutation. The majority of patients are 46,XY and positive for SRY and SF1 . Sequencing of the SRY or SF1 open reading frames for mutations is only positive in up to 30% of 46,XY pure GD. Certain isolated and syndromic forms of XY GD can be diagnosed molecularly with cytogenetics, chromosomal microarrays, or sequencing of known genes (see Table 16.4 ). For example, 46,XY DSD in conjunction with congenital heart disease may increase the suspicion for a GATA4 mutation. However, next-generation sequencing is now available in the clinical realm to replace this sequential guesswork and should be prioritized as a diagnostic tool to identify etiology.

In addition, whole-genome chromosomal microarray studies have identified many rare copy number variants associated with patients with 46,XY GD and 46,XX testicular and ovotesticular DSD, including deletions and duplications in and around SOX3 , GATA4 , WWOX , and DMRT1 . Deletions or duplications in the upstream promoter region of SOX9 are associated with isolated and familial cases of 46,XY GD and 46,XX testicular DSD.

If a mutation or translocation involving SRY is found, the father should be tested for a possible familial mutation because SRY mutations can result in a full spectrum of phenotypes, from 46,XY fertile males to ambiguous individuals to females with partial and pure GD. Due to potential autosomal modifiers, it is very difficult to predict the risk of recurrence of a GD phenotype in XY offspring.

Management of XY Gonadal Dysgenesis

The major concern in the treatment of patients with XY GD is the risk of gonadoblastoma, a mixed germ-cell, sex-cord tumor. The risk of gonadoblastoma formation in XY GD patients increases with age and has been estimated to be as high as 30% by 30 years of age. Due to the high risk of gonadoblastoma formation, patients typically undergo prophylactic or therapeutic gonadectomy in the first decade of life. Patients are followed with regular ultrasounds every 6 months starting at age 2 until gonadectomy can be performed. With the advent of laparoscopic techniques, the invasiveness of these surgeries is decreasing and the results are improving.

In patients with XY pure GD, genitals and gender identity are unambiguously female. There are no reported cases of gender dysphoria. In patients with partial or mixed GD, the degree of genital masculinization can be used for initial gender assignment. However, issues of gender identity do arise in partial and mixed GD and are outlined further in the management section.

To complete secondary sex development, sex steroid replacement should be initiated at puberty. Sex steroid replacement is essential not only for development of secondary sex characteristics, but also growth spurt and normal accrual of bone mineral density. Height, weight, and bone density should be monitored regularly. Furthermore, a dual-energy x-ray absorptiometry (DEXA) scan for bone density should be performed prior to induction of puberty with exogenous hormone replacement, and yearly thereafter for the first 2 years. As long as the first three DEXA scans are reported as normal, they can be done every 2 to 3 years.

Because a normal uterus is often present, hysterectomies are not common to preserve childbearing potential with in vitro fertilization methods. Despite this, most patients do not carry successful pregnancies for unknown reasons. Mixed XY GD individuals with more masculinization of the external genitalia are often raised as males and consequently require lifetime testosterone therapy, through intramuscular injections or transdermal patches or gel.

Differential Diagnosis: Testicular Regression Syndrome

Testicular regression syndrome (TRS), also known as vanishing testes , results from an insult after initial testes determination, most likely vascular thrombosis or testicular torsion. Internal and external genitalia are variably developed, which presumably depends on when the loss of fetal testes occurred. Rarely, patients can present in adulthood as females with primary amenorrhea. Typically TRS is characterized by primitive epididymis and spermatic cord in the presence of a fibrous nodule with hemosiderin deposition rather than the streak or dysgenetic gonads seen in 46,XY GD. The presence of spermatic cord structures, the absence of müllerian derivatives, and typical male external phenotype suggest viable testes existed early in development, and imply a late fetal or early neonatal regression. Diagnostic criteria are outlined in Table 16.4 .

The incidence of TRS has been estimated at 5% of males presenting with cryptorchidism and as high as 12% of cryptorchid patients older than 1 year. Correct diagnosis of TRS versus 46,XY GD is essential because of significant malignant potential of abdominal or dysgenetic testes. Mutational analysis of SF1 as a cause of TRS did not find any association between mutations in SF1 and TRS and the etiology of TRS remains unknown. Although the condition is thought to be rather frequent, optimal management remains unclear. No reports of testicular germ cell tumors in TRS have been published, suggesting that excision of the remnant gonad may be unnecessary.

Congenital Lipoid Adrenal Hyperplasia

Mutations in genes encoding proteins involved in the initial enzymatic regions of steroidogenesis, such as steroidogenic acute regulatory protein (StAR) and cytochrome P450 side chain cleavage (P450scc, also known as CYP11A1) , result in global silencing of adrenal and gonadal steroidogenesis. The accumulation of cholesterol in the adrenals and gonads ultimately results in primary adrenal and gonadal failure. StAR protein transports cholesterol across the inner and outer mitochondrial membranes of steroidogenic cells. P450scc catalyzes the initial reaction in all steroidogenic tissues, the conversion of cholesterol to pregnenolone (see Fig. 16.9 ). On adrenal histology, patients with mutations in StAR protein or P450scc have lipid vacuoles. However, patients with STAR mutations have adrenal hyperplasia, whereas patients with P450SCC mutations typically do not exhibit adrenal enlargement.

3β-Hydroxysteroid Dehydrogenase Deficiency

This rare variant of CAH can have a wide spectrum of phenotypes, from classical presentation (salt-wasting, with a range of female external genitalia to ambiguous genitalia in genetic XY individuals) to nonclassical (no salt-wasting and later presentation). Rare defects in adrenal and gonadal 3β-hydroxysteroid dehydrogenase (HSD3B2) affect the synthesis of three major adrenal steroid hormones: cortisol, aldosterone, and testosterone synthesis. The resulting phenotype is adrenal insufficiency in XX and XY patients but genital ambiguity only in XY patients.

17α-Hydroxylase/17,20-Lyase Deficiency

Biosynthesis of adrenal and sex hormones requires cytochrome P450 17α-hydroxylase/17,20-lyase (P450C17) encoded by the CYP17A1 gene. Here, a single protein, P450C17, catalyzes two steps in the steroidogenic pathway, both of which are essential for sex steroid and glucocorticoid synthesis. Mutations in this gene ultimately result in decreased cortisol synthesis with shunting of steroidogenesis toward a mineralocorticoid precursor that has mineralocorticoid activity (see Fig. 16.9 ). Isolated cases of 17,20-lyase deficiency are caused by mutations in Cytochrome b5 (CYB5A), a gene that promotes the specific allosteric interaction between CYP17A1 and POR.

P450 Oxidoreductase Deficiency

Cytochrome POR deficiency is a recently characterized cause of CAH that affects the enzymatic activity of all microsomal P450 enzymes, including the steroidogenic enzymes P450c17, P450c21, and P450aro. As POR is a flavoprotein required for the action of all microsomal p450 enzymes (see Fig. 16.9 ), POR deficiency causes partial enzymatic activity loss in multiple enzymes. Therefore, POR deficiency presents with a wide range of phenotypes and is particularly difficult to diagnose using serum hormone levels and the definitive diagnosis is made by gene sequencing. Partial enzymatic deficiencies in 21α-hydroxylase account for the CAH phenotype and virilization in XX individuals, while partial 17α-hydroxylase deficiency accounts for undervirilization of XY individuals. Aromatase deficiency secondary to POR deficiency is the likely cause of virilization of mothers carrying fetuses with POR deficiency.

In addition to the genital phenotype, some POR deficiency patients present with a complex skeletal phenotype known as Antley-Bixler syndrome (ABS). These skeletal malformations include, but are not limited to, craniosynostosis, radiohumeral synostosis, midface hypoplasia, and choanal stenosis.

17β-Hydroxysteroid Dehydrogenase Deficiency

The17βHSD3 enzyme is a member of the 17β-HSD family, and catalyzes the conversion of Δ4A to testosterone in the testes (see Fig. 16.9 ). This is a rare cause of 46,XY DSD, with less than 30 reported cases in the literature.

5α-Reductase Type 2 Deficiency

SRD5A2 deficiency results from a defect in the enzyme that converts testosterone to DHT. DHT is responsible for the differentiation of male external genitalia (see Fig. 16.2 ). Peripheral conversion of testosterone to DHT is an irreversible reaction catalyzed by the two isoenzymes of 5α-reductase, SRD5A1 and SRD5A2. During puberty, the SRD5A1 isozyme is active in skin fibroblasts. During fetal development, the SRD5A2 isozyme is expressed in the genital skin tissue and male accessory sex organs. Mutations in SRD5A2 result in undermasculinized external genitalia (e.g., micropenis, perineal hypospadias). Examination of internal genitalia demonstrates normally differentiated wolffian ducts, with no müllerian structures, in addition to a blind vaginal pouch. Adrenal and gonadal biosynthesis remains normal.

Isolated 46,XY Disorders/Differences of Sex Development With Apparently Normal Testosterone Levels

Mastermind-like domain containing 1 (MAMLD1) is expressed during fetal Leydig cell development and important in modulation of fetal testosterone synthesis. Nonsense mutations in MAMLD1 have been identified in several patients with isolated 46,XY DSD with severe hypospadias and microphallus. Mutations in MAMLD1 result in a decrease in MAMLD1’s transactivating properties and a reduced testosterone and CYP17A1 expression in vitro. Specific polymorphisms in MAMLD1 have also been associated with hypospadias.

Partial and Complete Androgen Insensitivity Syndrome

In the presence of normal gonads and steroid biosynthesis, mutations in the steroid hormone receptors can also mute the effects of circulating steroid on specific tissues. Mutations in the AR, which is located on the X chromosome, result in AIS. Both testosterone and DHT can bind to AR and transcriptionally activate downstream genes. AR plays important roles in the differentiation of male internal and external genitalia and in the maintenance of spermatogenesis. Currently, there is an estimated incidence of 1 : 20,400 live-born XY individuals, in whom more than 300 mutations have been identified.

AIS is characterized by a range of phenotypes in 46,XY individuals, from unambiguous XY female, termed complete AIS (CAIS), to phenotypic XY males. In CAIS, the major reproductive manifestation is amenorrhea, typically presenting at puberty, and the associated infertility. At the other extreme is minimal AIS (MAIS) in which phenotypically male patients often present with infertility, gynecomastia, or hypospadias. Patients who exhibit various degrees of genital ambiguity are referred to as PAIS. CAIS is generally associated with a complete absence of androgen binding and AR activation. Beyond this, there is almost no correlation between the percentage of residual AR activity and phenotype, suggesting that other genetic modifiers can modulate the phenotype. Even within families, the phenotype resulting from the same mutation can vary between PAIS and CAIS.

The majority of mutations resulting in AIS are caused by single amino acid substitutions, which account for approximately 90% of the cases. Mutations are found throughout the gene, with the majority of mutations located within the ligand-binding domain. Exon 1 rarely possesses a causative mutation. The majority of cases are inherited, but 30% of all AIS cases are de novo mutations, which is consistent with other X-linked traits.

In familial PAIS, and in both familial and sporadic CAIS, mutations in AR exonic sequences are found in 85% to 90% of cases. In contrast, detectable mutations in AR account for only 10% to 15% of sporadic cases with hormonal profile and clinical presentation suggestive of de novo PAIS, and the molecular defect in these cases is unknown. Although the genotypes causing CAIS are consistent in phenotypic presentation, in PAIS there is phenotypic variability among affected individuals carrying the same mutation, and many individuals carrying a working diagnosis of PAIS will not have AR mutations. The term PAIS should be reserved for individuals in whom causative AR mutations have been found.

Leydig Cell Hypoplasia

Leydig cell hypoplasia (LCH) or aplasia is a disorder caused by inactivating mutations of the joint G protein-coupled receptor for human luteinizing hormone and choriogonadotropin (LHCGR). It is characterized by impaired Leydig cell differentiation and testosterone production. In utero, placental hCG stimulates Leydig cells to produce testosterone, resulting in male internal and external genitalia. LH takes over during the third trimester of gestation and neonatal life to complete Leydig cell development and continue testosterone production.

Over 20 inactivating mutations of LHCGR have been identified, scattered throughout the gene, that cause variable degrees of loss of receptor activity. More severe mutations resulting in truncation, decreased surface expression, or decreased coupling efficiency are usually associated with unambiguous female phenotype. Partial inactivating mutations often result in an undervirilized phenotype such as micropenis or hypospadias. One specific mutation highlights the differential binding sites of hCG and LH to the same receptor. A splice variant resulting in the absence of exon 10 was described in an 18-year-old male who presented with normal male phenotype, pubertal delay, small testicles, and delayed bone age. The receptor’s response to hCG was normal, inferred from normal fetal sex development. However, LHCGR was not activated by LH, resulting in delayed puberty and bone age.

Persistent Müllerian Duct Syndrome

During the critical time in sex differentiation, between weeks 10 and 12 of gestation, testicular AMH causes the regression of the müllerian derivatives. Inactivating mutations in AMH or AMH receptor type II (AMHR2) in XY individuals can prevent this regression, resulting in both male and female internal genitalia, with typical male external genitalia.