Early Assessment of Ambiguous Genitalia

LEADING ARTICLE 401 Determination of sex (through duplication of Xp21) and Arch Dis Child: first published as 10.1136/adc.2002.011312 on 21 April 2004. Downloaded from ....................................................................................... Wnt4 (through duplication of 1p35), have been associated with impaired gonadal development and undervirilisa- Early assessment of ambiguous tion in a small number of karyotypic 46 XY males. genitalia Mutations or duplications in the various genes responsible for gonadal A L Ogilvy-Stuart, C E Brain differentiation and the subsequent development of the internal and exter- ................................................................................... nal genital phenotype genes may be responsible for gonadal dysgenesis and A multidisciplinary problem in some cases complete sex reversal (table 1). o discover that there is uncertainty the differentiation of the gonad. The Wnt4 is also expressed in the about the sex of one’s newborn differentiation of the gonad in turn Mu¨llerian ducts and in the absence of Tbaby is devastating and often determines the development of both anti-Mu¨llerian hormone (AMH) (also incomprehensible for most parents. It the internal genital tracts and the known as Mu¨llerian inhibiting sub- is paramount that clear explanations external genitalia and thus phenotypic stance) and testosterone, Mu¨llerian and investigations are commenced sex, which occurs later in development structures develop, while the Wolffian promptly, and that no attempt is made (from about 5–6 weeks of gestation). ducts involute.4 AMH promotes regres- to guess the sex of the baby. Extreme Both male and female genitalia differ- sion of Mu¨llerian structures and as the sensitivity is required, and ideally the entiate from the same structures along only source of AMH in the fetus is the baby should be managed in a tertiary the urogenital ridge. At about 4 weeks testes, the absence of a uterus in a baby centre by a multidisciplinary team after fertilisation, primordial germ cells with ambiguous genitalia is evidence including a paediatric endocrinologist migrate from the yolk sac wall to the that there has been functional testicular and a paediatric urologist. Early involve- urogenital ridge that develops from the tissue (Sertoli cell) present. Testosterone ment of a clinical psychologist with mesonephros. The urogenital ridge also produced from Leydig cells promotes experience in this field should be man- contains the cells that are the precursors differentiation of the Wolffian ducts and datory. Other professionals including for follicular or Sertoli cells and steroid hence the internal male genitalia (vas geneticists and gynaecologists may also producing theca and Leydig cells. The deferens, epididymis, and seminal vesi- become involved. There must be access ‘‘indifferent’’ gonads form on the geni- cles). to specialist laboratory facilities and tal ridges. Testosterone is converted to dihydro- experienced radiologists. The incidence The development of the fetal adrenals testosterone [DHT] by the enzyme 5a- of genital ambiguity that results in the and gonads occur in parallel, as before reductase. DHT masculinises the exter- child’s sex being uncertain is 1 per migration, the potential steroidogenic nal genitalia from about 6 weeks gesta- 4500,1 although some degree of male cells of both originate from the meso- tion, and the degree of masculinisation undervirilisation, or female virilisation nephros. There are many genes and is determined by the amount of fetal may be present in as many as 2% of live transcription factors that are expressed androgen present (irrespective of http://adc.bmj.com/ births.2 in both tissues (for example, SF1 and source) and the ability of the tissues to Parents require reassurance that DAX1), and hence mutations in these respond to the androgens. either a male or female gender will genes may affect both adrenal and Defects in any part of this pathway definitely be assigned. However the gonadal development (fig 1). In addi- (including gene mutations and chromo- outcome of some of the investigations tion, WT1 is expressed in the kidney and somal abnormalities (for example, may take some weeks, and registration gonad, hence the association of Wilms’ 46XY/46XX, 45X/46XY), inappropriate of the child’s birth should be deferred tumour and gonadal dysgenesis in hormone levels, or end-organ unrespon- until gender has been assigned. This Denys-Drash syndrome, for example. siveness) may result in genital ambi- on September 26, 2021 by guest. Protected copyright. may require communication with the The undifferentiated gonad is capable guity, with undervirilisation of an XY Registrar of Births, and a skilled clinical of developing into either an ovary or a individual, virilisation of an XX indivi- psychologist will help the parents in testis. The theory that the ‘‘default’’ dual, or the very rare true hermaphro- deciding what to tell family and friends programme generates an ovary is prob- dite (an individual with both ovarian in the interim. It is also helpful (if ably not correct, although the exact role tissue with primary follicles and testi- appropriate) to reassure the parents that of ‘‘ovarian determining’’ genes in cular tissue with seminiferous tubules their child is otherwise healthy. humans is unclear at present. In con- which may be in separate gonads or While not all intersex conditions are trast, testicular development is an active ovotestes). apparent at birth (for example, complete process, requiring expression of the androgen insensitivity may only become primary testis determining gene SRY, CLINICAL ASSESSMENT OF apparent in a child with a testis within and other testis forming genes such as AMBIGUOUS GENITALIA an inguinal hernia, or at puberty with SOX9. Transcription factors such as SF1 History primary amenorrhoea and lack of and WT1 are also required for develop- The history should include details of the androgen hair), only those presenting ment of the undifferentiated gonad, as pregnancy, in particular the use of any with genital ambiguity at birth will be well as for the activation of the other considered in this article. male pathway genes required for testis Abbreviations: AMH, anti-Mu¨llerian hormone; An understanding of sex determina- development and the consequent devel- CAH, congenital adrenal hyperplasia; DHEA, tion and differentiation is essential to opment of male internal and external dehydroepiandrosterone; DHEAS, direct appropriate investigations and to genitalia.3 dehydroepiandrosterone sulphate; DHT, dihydrotestosterone; EUA, examination under establish a diagnosis. DAX1 and Wnt 4 are two genes that anaesthesia; hCG, human chorionic Genetic sex is determined from the may act to ‘‘antagonise’’ testis develop- gonadotrophin; StAR, steroidogenic acute moment of conception and determines ment. Over-expression of DAX1 regulatory protein www.archdischild.com 402 LEADING ARTICLE drugs (table 2) that may cause virilisa- Arch Dis Child: first published as 10.1136/adc.2002.011312 on 21 April 2004. Downloaded from tion of a female fetus and details of any previous neonatal deaths (which might point to an undiagnosed adrenal crisis). A history of maternal virilisation may suggest a maternal androgen secreting tumour or aromatase deficiency. A detailed family history should be taken, including whether the parents are con- sanguineous (which would increase the probability of an autosomal recessive condition) or if there is a history of genital ambiguity in other family members (for example, an X-linked recessive condition such as androgen insensitivity). Examination The general physical examination should determine whether there are any dysmorphic features and the general health of the baby. A number of syndromes are associated with ambiguous genitalia, for example, Smith- Lemli-Opitz syndrome (characterised by hypocholesterolaemia and elevated 7-dehydrocholesterol levels, and result- ing from mutations affecting 7-dehydrocholesterol reductase), Robinow syndrome, Denys-Drash syndrome, and Beckwith-Wiedemann syndrome. Mid- line defects may point towards a hypothalamic-pituitary cause for micro- penis and cryptorchidism. Hypoglycaemia may indicate cortisol deficiency secondary to hypothalamic- pituitary or adrenocortical insufficiency. The state of hydration and blood pres- sure should be assessed as various forms Figure 1 Normal sexual differentiation. SRY, sex determining region on Y chromosome; TDF, of congenital adrenal hyperplasia (CAH) http://adc.bmj.com/ testis determining factor; AMH, anti-Mu¨llerian hormone; T, testosterone; DHT, dihydrotestosterone; WT1, Wilms’ tumour suppressor gene; SF1, steroidogenic factor 1; SOX9, SRY-like HMG-box; can be associated with differing degrees Wnt4, Wnt = a group of secreted signalling molecules that regulate cell to cell interactions during of salt loss, varying degrees of virilisa- embryogenesis; DAX1, DSS-AHC critical region on the X chromosome. tion in girls or undervirilisation in boys, Table 1 Consequences of mutations/deletions and duplications/translocations of genes involved in gonadal differentiation Chromosome Gonadal Sex reversal/genital Mu¨llerian location development Associated disorder ambiguity development on September 26, 2021 by guest. Protected copyright. Gene mutation or deletion (loss of function) WT1 11p13 Dysgenesis (R and =) WAGR syndrome Genital ambiguity (=) Variable (=) Denys-Drash syndrome Sex reversal or genital Variable (=) ambiguity (=) Frasier syndrome

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