31.5 Evaluation of a Newborn with DSD

31.5Evaluation of a Newborn with DSD

•The evaluation, diagnostic approach and management of a newborn with DSD involves a multidisciplinary team approach.

•This team include:

–Neonatologists

–Geneticists/genetic counselor

–Pediatric endocrinologists

–Pediatric surgeons

–Social worker

–Pediatric urologist

–Psychologist

•The most common disorder of sexual development (DSD), congenital adrenal hyperplasia (CAH), results in virilization of a 46,XX female.

•The clinician’s challenge is to distinguish CAH from other less common causes of ambiguous genitalia.

Classification of DSD

1. Sex chromosome DSD

•45,X0/46,XY Mixed gonadal dysgenesis (MGD)

•45,X0/46,XY Partial gonadal dysgenesis

•46,XX/XY or 45,X0/46,XY Ovotesticular DSD

•45,X0 or 45,X0/46,XY (Turner’s syndrome)

•Seminiferous tubule dysgenesis: Klinefelter’s syndrome (47,XXY)

2.46,XX (DSD)

•Androgen excess: (60–70 %)

–CAH (vast majority)

•21-Hydroxylase deficiency (95%)

•11β-Hydroxylase deficiency (5%)

•3β-Hydroxysteroid dehydrogenase deficiency

–Maternal androgens (very rare)

•Endogenous: Virilising tumours in the mother

•Exogenous (very rare)

•Disorders of ovarian development

–Ovotesticular DSD

–46,XX testicular DSD (SRY translocation)

–Pure gonadal dysgenesis (e.g. SOX9 duplication

•Meyer–Rokitansky syndrome (Müllerian aplasia)

3.46,XY DSD

•Disorders of testicular development

–Gonadal dysgenesis (Swyer syndrome = Pure, DAX-1 Duplication. SF-1 mutation)

–Ovotesticular DSD

–Bilateral vanishing testis/testicular regression syndromes

•Disorders of androgen synthesis or action

–Leydig cell agenesis, unresponsiveness

–Enzyme deficiency

•StAR deficiency (lipoid adrenal hyperplasia

•3β-Hydroxysteroid dehydrogenase deficiency

•17α-Hydroxylase deficiency

•17,20-Lyase deficiency

•17β-Hydroxysteroid oxidoreductase deficiency

•5α-Reductase deficiency

•Disorders of androgen-dependent target tissue

–CAIS (testicular feminisation)

–PAIS

•Persistent Müllerian duct syndrome

4.Others: Severe hypospadias and cryptorchidism, penile agenesis and cloacal exstrophy

•A detailed family history is essential; the following considerations should be kept in mind:

– A family history of genital ambiguity, infertility, or unexpected changes at puberty may suggest a genetically transmitted trait.

– Recessive traits tend to occur in siblings, whereas X-linked abnormalities tend to appear in males who are scattered sporadically across the family history.

– A history of early death of infants in a family may suggest a previously missed adrenogenital deficiency

– Maternal drug ingestion is important, particularly during the first trimester, when virilization may be produced exogenously in a gonadal female.

– Although extremely rare, a history of maternal virilization may suggest an androgen-producing maternal tumor (arrhenoblastoma)

•Sex assignment:

– It is important not to assign a sex immediately and delay it till after full evaluation.

–During the evaluation stage, the newborn is referred to as “baby,” not boy or girl.

–The family should be encouraged to delay naming the baby until the sex has been assigned.

•There are other factors that must be taken in consideration during this process including:

–The social and cultural background.

–Expectations of the parents.

–Religious factors.

•The parents are also involved, educated and should participate in the process and should understand that a children with a DSD can live normal live and function well in society.

•Although different DSDs may present with similar findings on physical examination, there are certain clinical and laboratory aspects that are important and will help define the type of DSD.

•It is important to rule out a malformation syndromes that may present as ambiguous genitalia (Fig. 31.12).

•Clinical evaluation of the gonads and external genitalia is very important:

–It is important to note the size and degree of differentiation of the phallus.

–Note the phallus length:

•A normal-term male penis is 3.5±0.7 cm.

•A length of less than 2.0 cm is considered abnormal.

•A normal-term female clitoris is less than 1.0 cm.

•Micropenis is thus defined as a stretch penile length of less than 2.0 cm in a term male infant, and clitoromegaly as a clitoris greater than 1.0 cm in a term female. In preterm infant males, the penile length is shorter.

–Note the position of the urethral meatus:

•Hypospadias associated with bifid scrotum or undescended testis suggests a DSD (Figs. 31.13 and 31.14).

•If the urethral opening is at the base of the phallus, it could be a urogenital sinus in a virilized female.

–Labioscrotal folds may be separated or be fused at the midline, giving an appearance of a scrotum.

–Newborns with 46XX DSD due to CAH may have hyperpigmented labioscrotal folds.

–The anogenital ratio:

•This is the distance between the anus and posterior fourchette divided by the distance between the anus and base of the clitoris/phallus.

•A ratio greater than 0.5 suggests virilization.

•In a fully virilized male the ratio is 1.0.

–Documentation of palpable gonads is also important:

•Although ovotestes have been reported to descend completely into the bottom of labioscrotal folds, in most patients, only testicular components descends fully.

•If clinical evaluation reveals palpable gonads in the inguinal area, the diagnoses of pure gonadal dysgenesis can be eliminated.

Fig. 31.12 A clinical photograph of a newborn with DSD. Note also the associated anorectal agenesis

Figs. 31.13 and 3.14 Clinical photographs showing severe degrees of hypospadias. Note the bifid scrotum also

•Impalpable gonads, even in an apparently fully virilized infant, should raise the possibility of a severely virilized 46XX DSD patient with CAH.

•The presence of two palpable gonads strongly favors the diagnosis of a 46XY DSD.

•The presence of only one palpable gonad suggests the diagnosis of mixed gonadal dysgenesis, although it does not rule out a 46 XX ovotesticular DSD.

31.6Diagnosis and Investigations

•The optimal care of patients with DSD requires a multidisciplinary team and begins in the newborn period.

•Some cases of DSD are obvious at birth while others are diagnosed during childhood or remain undiagnosed until a child reaches puberty.

•The investigations depend on the suspected type of DSD.

•The diagnostic evaluation of DSD includes:

–A complete CBC and electrolytes

–Hormone measurements

–Hormone stimulation tests

–Diagnostic radiological evaluations

•Ultrasonography shows the presence or absence of Müllerian/Wolfian structures and can locate the gonads and their echo texture.

•Ultrasonography also can identify associated malformations such as renal abnormalities.

–Cytogenetic and molecular studies

–Endoscopic, laparoscopic and gonadal biopsy

–Retrograde genitogram is performed for the anatomical outlining of the urogenital sinus and for localizing the position and entry of the urethra and vagina into the sinus.

–The genetic evaluation includes:

•Chromosomal analysis (Karyotype)

•FISH

•Specific molecular studies to screen the presence of mutations or gene dosage imbalance (AR, SRY, SF1, WT1, CYP21, SOX9, DAX-1, 17b hydroxysteroid dehydrogenase, 5a-reductase-2, and others). These are not readily avaliable.

•Current molecular diagnosis is limited by cost, accessibility, and quality control.

–Common findings suggesting DSD are:

•A male appearance with associated abnormalities of genitalia including:

–Severe hypospadias with bifid scrotum

–Undescended testis/testes with hypospadias

–Bilateral non-palpable testes

–Micropenis with chordee.

•A female appearance with associated abnormalities of genitalia including:

–Enlarged clitoris

–Posterior labial fusion

–An inguinal/labial mass.

–The location of the gonads and presence or absence of a uterus, will provide a provisional clinical diagnosis.

•If no gonads are palpable:

–46,XX DSD (with two ovaries) is the most commonly seen.

–MGD.

–The presence of a uterus and absence of palpable gonads in a virilized female primarily suggest a clinical

diagnosis of 21-hydroxylase deficiency.

–MGD, ovotesticular, and 46,XY DSD remain as diagnostic possibilities.

•If two gonads are palpable:

–46,XY DSD and ovotesticular DSD are the most likely diagnoses.

–Symmetrical external genitalia, with or without palpable gonads, and an absent uterus suggest an undervirilized XY male.

–The presence of a uterus and asymmetric external genitalia and palpable gonad(s) suggest gonadal dysgenesis with Y and ovotesticular DSD.

–A gonadal biopsy is required to classify the type of gonadal dysgenesis and ovotesticular DSD, to assess gonadal chromosomal mosaicism and to detect the presence of a gonadal tumor.

–Hormone measurements should include hCG and ACTH stimulation tests to assess testicular and adrenal steroid biosynthesis.

–The endocrine evaluation of patients with 46,XY DSDs and sex chromosome DSDs include assessment of testicular function by basal measurement of LH, FSH, inhibin B, Testesterone, Dihyrotestesterone (DHT), Anti-Mullerian hormone (AMH), and DHEAS.

–In patients with Testesterone synthesis defects, neonatal and post pubertal diagnosis is made based on basal steroid levels.

–Testesterone stimulation test:

•The stimulation of Testesterone production by hCG is used to determine abnormalities in Testesterone biosynthesis and also to document the presence of functioning testicular tissue.

•Testosterone and DHT should be measured at baseline and 72 h after hCG stimulation.

•The increase in the level of Testesterone should be at least threefold.

•A failure to respond to hCG in combination with elevated LH/FSH levels and low/undetectable value of AMH is

consistent with anorchia or gonadal dysgenesis.

•Androgen insensitivity should be considered in individuals with a 46,XY karyotype and with normal Testesterone biosynthesis.

•Patients with 5a-reductase deficiency have normal Testesterone levels, low or normal DHT levels and a high Testesterone/DHT ratio after hCG stimulation test.

–The testosterone level can help to determine whether the DSD is due to a lack of androgen or cortisone synthesis or rather due to a receptor defect.

–Anelevatedlevelof17-hydroxyprogesterone is diagnostic of CAH.

–Determining the levels of 11-deoxycortisol and deoxycorticosterone will help to make

a differential diagnosis between 21-hydroxylase and 11β-hydroxylase defi-

ciencies. If the levels are elevated, a diagnosis of 11β-hydroxylase deficiency could

be made, whereas low levels confirm 21-hydroxylase deficiency.

–The diagnosis of 17bHydroxysteroid dehydrogenase deficiency is made when a 10to 15-fold elevation is observed in the ratio of A/T.

–Inhibin B and AMH are useful markers for the presence of Sertoli cells and their assessment could help in the diagnosis of testis determination disorders.

–Serum AMH level:

•This is indicative of the presence of testicular tissue.

•In boys with bilateral cryptorchidism, serum AMH correlate with the presence of testicular tissue.

•Undetectable values are highly suggestive of absence of testicular tissue.

•In XY patients, AMH is low in those with DSD secondary to abnormal testicular determination (including complete and partial gonadal dysgenesis).

•AMH will be normal or elevated in patients with impaired Testesterone secretion.

•AMH level will be elevated during the first year of life and at puberty in those with androgen insensitivity.

•In 46,XX patients with DSDs, a high serum AMH level is indicative of the presence of testicular tissue.

–The diagnosis of 21-hydroxylase deficiency in 46,XX DSDs with two ovaries depends on:

•The detection of elevated 17-OHP levels either as a basal measurement or after a short ACTH stimulation test.

•High concentration of 11-deoxycortisol and deoxycortisol (DOC) with low levels of plasma renin activity (PRA).

•This will help differentiate 11hydroxylase from 21-hydroxylase deficiency.

–Study of androgen target cells:

•Defects in peripheral sensitivity to androgens may be responsible for genital ambiguity in male individuals with partial androgen insensitivity.

•Androgen receptor activity can be determined in fibroblasts grown from a genital skin biopsy sample.

•5-alpha reductase activity can be determined by this method.

–Chromosomal characteristics, gonadal histology and presence or absence uterus are taken into consideration in the classification of DSDs.

–In rare cases in which a definite diagnosis cannot be determined and in infants with intra-abdominal or nonpalpable testes in whom DSDs are considered, open or laparoscopic exploration with biopsy of the gonads could become necessary.

–In some cases, the differential diagnosis of DSD depends on the interpretation of the histologic features of the gonads.

–Infants with intra-abdominal or nonpalpable testes in whom the precise diagnosis is unavailable with karyotyping and serum study will require an open or laparoscopic exploration with bilateral deep longitudinal gonadal biopsies for histologic evaluation, which will determine the presence of ovotestes, streak gonads, or dysgenetic testes, thereby confirming the diagnosis.