The child of uncertain sex

19.3 The child of uncertain sex



Jan Fairchild


Disorders of sexual development are congenital conditions in which the development of chromosomal, gonadal or phenotypic sex is atypical. This includes infants with a genital appearance that does not permit gender assignment:



• bilateral non-palpable testes


• perineal hypospadias with a bifid scrotum


• hypospadias and unilateral non-palpable gonad


• clitoromegaly


• posterior labial fusion


• a phenotypical female with a palpable gonad


• and those with discordant genitalia and sex chromosomes.


The birth of a child with a disorder of sexual development presents a psychosocial crisis for the family and may indicate an underlying medical condition such as congenital adrenal hyperplasia, which could be life-threatening if undiagnosed and untreated.


Disorders of sexual development (DSDs) are rare (1 in 4500), often complex, and always require urgent expert consultation. Optimal care requires an experienced multidisciplinary team.



Normal sexual differentiation


An understanding of normal sexual differentiation is essential in the evaluation of the child with a disorder of sexual development. Normal sexual development in the embryo consists of three related sequential processes:



1. Establishment of chromosomal sex at fertilization, with XY as male and XX as female


2. Determination of gonadal sex, when the bipotential gonad develops into a testis or an ovary


3. Development of phenotypic sex, as a result of gonadal differentiation and gonadal hormone production.



Internal genitalia


Up until about 7 weeks, male and female embryos develop in an identical fashion, with bipotential gonads and both wolffian and müllerian internal genital ducts present (Fig. 19.3.1).


image

Fig. 19.3.1 Normal prenatal development: internal genitalia.


In males, the presence of the sex-determining region on the Y chromosome (SRY gene) directs the bipotential gonad to become a testis. At least four other genes are also required for normal testicular development. By 7–8 weeks the testis has recognizable tubules and starts producing androgens, including testosterone from the Leydig cells and müllerian-inhibiting substance (MIS) from the Sertoli cells. Circulating hormone levels are low and masculinization of the internal genital ducts occurs by locally acting (exocrine) secretion of these hormones down the wolffian duct.


High levels of testosterone promote the ipsilateral development of the wolffian duct to become the epididymis, vas deferens and seminal vesicle. High levels of MIS lead to ipsilateral müllerian duct regression. This process occurs during a critical period between 8 and 12 weeks. The Leydig cells also produce a relaxin-like factor that, together with MIS and androgens, masculinizes the gubernaculum. The gubernaculum holds the testis near the inguinal ligament during early development and from 25 weeks it begins to elongate, steering the testis towards the scrotum.



image Clinical example


A healthy, full-term infant was born with ambiguous genitalia. On examination there was an enlarged clitoris (2 cm in length), posterior fusion of the labia, with a single opening visible, and no gonads were palpable. The genitalia were noted to be hyperpigmented. There was no history of consanguinity but a previous male sibling had died at 2 weeks of age after a vomiting illness.


Initial investigations confirmed that the baby’s chromosomes were 46,XX and pelvic ultrasonography showed the presence of a normal uterus and ovaries. The 17-hydroxyprogesterone level at 48 hours of age was markedly increased, confirming the diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Treatment with hydrocortisone was commenced. Daily electrolytes were normal until the 6th day of life, when hyperkalaemia developed, confirming the salt-wasting form of the condition. Fludrocortisone therapy was then added. The child was referred to a paediatric surgeon for consideration of corrective genital surgery. She will require lifelong replacement therapy and monitoring.


The hyperpigmentation was due to the adrenocorticotrophic hormone (ACTH) excess and resolved with adequate replacement therapy. It was likely that the previous male sibling had also had the condition, as it is inherited as an autosomal recessive trait. The genitalia of affected males are usually normal at birth apart from some hyperpigmentation, and affected male infants typically present with a salt-wasting crisis in the first few weeks of life. It is often confused with pyloric stenosis, which also presents at this age with vomiting and dehydration.


In females, the absence of testosterone and MIS leads to wolffian duct regression and müllerian duct preservation. The müllerian ducts develop into the uterus, fallopian tubes and upper vagina.



External genitalia


Up until about 8 weeks, the external genitalia of male and female embryos also have an identical appearance. Both sexes have a genital tubercle, two genital swellings and two genital folds (Fig. 19.3.2).


image

Fig. 19.3.2 Normal prenatal development: external genitalia.


In males, between 8 and 12 weeks, androgen action on the external genitalia results in the development of normal male genitalia. Circulating levels of testosterone are insufficient for this action but testosterone is converted in the periphery to dihydrotestosterone (DHT) by the enzyme 5α-reductase. Dihydrotestosterone binds to the androgen receptors much more strongly than testosterone, thereby amplifying its effect. The genital tubercle develops into the glans penis, the genital swellings fuse to form the scrotum, and the genital folds elongate and fuse to become the shaft of the penis and the penile urethra. The prostate forms in the wall of the urogenital sinus. With the exception of the phallus, circulating androgens masculinize the external genitalia only during a critical period between 8 and 12 weeks.


In females, in the absence of androgen, the genital tubercle forms the glans clitoris and the short female urethra. The genital swellings remain unfused and become the labia majora. The genital folds become the labia minora and the vaginal plate, a thickening of the posterior wall of the urogenital sinus, canalizes to form the lower vagina.



Evaluation of the child with a disorder of sexual development


The initial evaluation of the child with a disorder of sexual development should include a history, physical examination, urgent karyotype, ultrasound imaging of the internal anatomy, and assessment of adrenal and gonadal function.



History


A careful history should include:



• prenatal exposure to androgens


• maternal virilization during pregnancy


• family history of females who are childless or have amenorrhoea (complete androgen insensitivity)


• family history of unexplained infant deaths (congenital adrenal hyperplasia)


• consanguinity.



Physical examination


The physical examination should include:



• careful inspection of the external genitalia and palpation to determine the presence, location and symmetry of the gonads


• if both gonads are palpable and symmetrical they are almost always testes

Related posts:

  1. Sudden unexpected death in infancy
  2. Birth defects, prenatal diagnosis and teratogens
  3. Resuscitation
  4. The newborn infant: stabilization and examination

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Aug 4, 2016 | Posted by in PEDIATRICS | Comments Off on The child of uncertain sex

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