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Early assessment of ambiguous genitalia


A L Ogilvy-Stuart and C E Brain

Arch. Dis. Child. 2004;89;401-407


doi:10.1136/adc.2002.011312

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LEADING ARTICLE 401

Determination of sex (through duplication of Xp21) and


....................................................................................... Wnt4 (through duplication of 1p35),
have been associated with impaired

Early assessment of ambiguous


gonadal development and undervirilisa-
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).

T
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 Müllerian ducts and in the absence of
baby is devastating and often determines the development of both anti-Müllerian hormone (AMH) (also
incomprehensible for most parents. It the internal genital tracts and the known as Müllerian inhibiting sub-
is paramount that clear explanations external genitalia and thus phenotypic stance) and testosterone, Müllerian
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 Müllerian 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
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-
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-Müllerian 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,
dehydroepiandrosterone sulphate; DHT,
direct appropriate investigations and to genitalia.3 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

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402 LEADING ARTICLE

drugs (table 2) that may cause virilisa-


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 geni-
tal ambiguity in other family members
(for example, an X-linked recessive con-
dition such as androgen insensitivity).

Examination
The general physical examination
should determine whether there are
any dysmorphic features and the gen-
eral health of the baby. A number of
syndromes are associated with ambig-
uous genitalia, for example, Smith-
Lemli-Opitz syndrome (characterised
by hypocholesterolaemia and elevated
7-dehydrocholesterol levels, and result-
ing from mutations affecting 7-dehy-
drocholesterol 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)
testis determining factor; AMH, anti-Müllerian 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 Müllerian
location development Associated disorder ambiguity development

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 Sex reversal (=) Yes (=)
SF1 9q33 Dysgenesis (=) Adrenal failure Sex reversal (= Yes (=)
SRY Yp11.3 =R ovary Sex reversal or genital = (variable)
ambiguity (=)
DAX1 Xp21 = Dysgenesis Adrenal failure and No No
hypogonadotrophic
hypogonadism/impaired
spermatogenesis
SOX9 17q24.3–25.1 = Dysgenesis or Campomelic dysplasia Sex reversal or genital Variable
ovary/ovotestis ambiguity (=)
AMH 19p 13.3–13.2 Normal Yes (=)

Gene duplication or translocation (gain of function)


SRY Y fragment Yp11.3 RR testis Sex reversal or genital No
translocation ambiguity (R)
DAX1 duplication dupXp21 = Dysgenesis or Sex reversal or genital Variable
ovary/ovotestis ambiguity (=)
Wnt 4 duplication Dup 1p35 = Dysgenesis Genital ambiguity (=) Yes
SOX9 duplication dup17q24.3–25.1 RR Testis Genital ambiguity (R) No

WAGR, Wilms’ tumour, aniridia, genitourinary anomalies, mental retardation; Denys-Drash (exonic mutations) WT, diffuse mesangial sclerosis; Frasier (intronic
mutations) no WT, focal segmental glomerulosclerosis. Other abbreviations as for fig 1.

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LEADING ARTICLE 403

Table 2 Disorders of sex differentiation in babies with CAH. The gestation of the
baby can cause confusion—in preterm
Virilisation of XX females girls the clitoris and labia minora are
Increased fetal adrenal androgen production relatively prominent and in boys, the
Congenital adrenal hyperplasia (3b-hydroxysteroid dehydrogenase deficiency, 21-hydroxylase
testes are usually undescended until
deficiency, 11b-hydroxylase deficiency)
Androgen secreting tumour about 34 weeks gestation.
Placental aromatase deficiency
Fetal gonadal androgen production
True hermaphrodite with both testicular and ovarian tissue
INVESTIGATIONS
Transplacental passage of maternal androgens Initial investigations ascertain whether
Drugs administered during pregnancy: e.g. progesterone, danazol the child is an undervirilised male or a
Maternal androgen secreting tumour, luteoma of pregnancy virilised female and from these a differ-
Other causes ential diagnosis can be established and
Dysmorphic syndromes
Prematurity—prominent clitoris subsequent investigations planned
Bisexual gonads (fig 3). The principal aims of the initial
Hermaphroditism. Usual genotype 46XX investigations are to determine the most
appropriate sex of rearing and in a
Undervirilisation of XY males
Testicular dysgenesis/malfunction
genetic female, to exclude CAH and
Pure XY gonadal dysgenesis avert a salt losing crisis. Rarer forms of
Mixed gonadal dysgenesis–45X/46XY. May be associated with gene mutations on SRY, SOX9, or CAH (steroidogenic acute regulatory
WT1 genes protein (StAR) deficiency, 3b-hydroxys-
Dysgenetic testis
Testicular regression syndromes
teroid dehydrogenase deficiency) may
True agonadism, rudimentary testis syndrome also present with an adrenal crisis in
Biosynthetic defect—decreased fetal androgen biosynthesis undervirilised males.
Leydig cell hypoplasia (LH deficiency or LH receptor defect)
Testosterone biosynthesis (non-virilising CAH): (StAR, 3b-HSD, 17a-OHD/17–20 lyase, Smith-Lemli-
Opitz syndrome) Karyotype
5a-reductase deficiency As the differential diagnosis and a
Deficient synthesis or action of AMH—persistent Müllerian duct syndrome. May be due to mutations number of subsequent investigations
in AMH or AMH receptor gene or SF1 gene will depend on the genetic sex, an
End organ unresponsiveness
Androgen receptor and post-receptor defects (complete and incomplete androgen insensitivity urgent karyotype should be sent. Rapid
syndrome) FISH studies using probes specific for
Others the X (DX1) and Y (SRY) chromosomes
Urogenital malformations can provide useful information,
Dysmorphic syndromes
Exogenous maternal oestrogens
although a full karyotype is required
for confirmation and exclusion of
mosaicism. The latter may be tissue
specific and may not be apparent from
blood, but only from skin or gonadal
biopsies. In cases with a mosaic karyo-
or hypertension (table 3). Although the detect the presence of a gonad. They type, for example, XO/XY or XX/XY, the
cardiovascular collapse with salt loss may be situated high in the inguinal gonads are often different. This may
and hyperkalaemia in congenital adre- canal so careful examination is required. involve one being a streak gonad and
nal hyperplasia does not usually occur A unilateral palpable gonad may be a the other a testis or ovotestis, or two
until between the 4th to 15th day of life testis, ovotestis, or rarely an ovary ovotestes with different ovarian and
and so will not be apparent at birth in a within an inguinal hernia. Congenital testicular components.
well neonate, it should be anticipated adrenal hyperplasia must be excluded in
until CAH has been excluded. Jaundice a phenotypically male baby with bilat- Determination of internal anatomy
(both conjugated and unconjugated) eral undescended testes. As with the external genitalia, the
may be caused by concomitant thyroid The length of the phallus should be degree of virilisation of the internal
hormone or cortisol deficiency. The determined. The normal term newborn genital tracts is defined by Prader stages
urine should be checked for protein as penis is about 3 cm (stretched length I–V (fig 2). The anatomy of the vagina
a screen for any associated renal anom- from pubic tubercle to tip of penis) with or a urogenital sinus and uterus may be
aly (for example, Denys-Drash/Frasier micropenis less than 2.0–2.5 cm, determined by ultrasound, and if neces-
syndromes). although this does vary slightly depend- sary, further delineation by EUA/cysto-
ing on ethnic origin.5 Chordee should be scopy or urogenital sinogram.
Examination of external genitalia noted as this may decrease the apparent Ultrasound is also useful in excluding
and Prader staging length of the phallus and the penis may associated renal anomalies, particularly
Examination of the external genitalia be ‘‘buried’’ in some cases. The presence if Denys-Drash syndrome is suspected or
determines whether gonads are palpable of hypospadias and the position of the proven. It may also be used to visualise
and the degree of virilisation or Prader urethral meatus should be determined. the adrenal glands. Ultrasound may also
stage. Prader stages I–V describe The urine may be coming from more locate inguinal gonads, although it is
increasing virilisation from a phenotypic than one orifice. The degree of fusion not sensitive for intra-abdominal
female with mild cliteromegaly (stage I) and rugosity of the labioscrotal folds gonads. Ultrasound sensitivity and
to a phenotypic male with glandular should be noted and the presence or accuracy depend on probe resolution;
hypospadias (stage V) (fig 2). absence of a separate vaginal opening an experienced ultrasonographer is
If both gonads are palpable they are determined. required. Identification of the gonads
likely to be testes (or ovotestes) which Hyperpigmentation, especially of the may require magnetic resonance ima-
may be normal or dysgenetic. Flat finger genital skin and nipples occurs in the ging (MRI) or laparoscopy. These latter
palpation from the internal ring milking presence of excessive ACTH and pro- investigations are also useful for deter-
down into the labial scrotal folds may opiomelanocortin and may be apparent mining the anatomy of the internal

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404 LEADING ARTICLE

Table 3 Forms of CAH causing genital ambiguity in the newborn period, but AMH is undetectable in
female serum until the onset of puberty.
StAR protein AMH may prove to be a more sensitive
Type of CAH deficiency 3b-HSD 17a-OHD 11b-OHD 21-OHD marker for the presence of testicular
Genital = = = R R tissue than serum testosterone levels,
ambiguity both before and after the neonatal
Salt wasting Yes Yes Hypertension Hypertension Yes androgen surge, and, consequently,
Enzyme P-450cc 3b-HSD P-450c17 P-450c11 P-450c21
may obviate the need for hCG stimula-
Steroidsq None DHEA, DOC, DOC, 11- 17-OHP, A4
17-OH-preg corticosterone deoxycortisol tion in the evaluation of certain intersex
SteroidsQ All Aldosterone, Cortisol, Cortisol Cortisol, disorders.9 Similarly, basal inhibin B has
testosterone, testosterone aldosterone been shown to predict the testosterone
cortisol response to hCG in boys, and therefore
Defective gene StAR HSD3B2 CYP17 CYP11B1 CYP21
Chromosome 8p11.2 1p13.1 10q24.3 8q24.3 6p21.3
may give reliable information about
both the presence and function of the
StAR protein, steroidogenic acute regulatory protein deficiency, otherwise known as lipoid hyperplasia/ testes. Furthermore, inhibin B levels
cholesterol desmolase deficiency; 3b-HSD, 3b-hydroxysteroid dehydrogenase deficiency; 17a-OHD, have been shown to demonstrate spe-
17a-hydroxylase deficiency; 11b-OHD, 11b-hydroxylase deficiency; 21-OHD, 21-hydroxylase
cific alterations in patients with genital
deficiency; DOC, 11-deoxycorticosterone; DHEA, dehydroepiandrosterone; 17-OHP, 17-
hydroxyprogesterone; 17-OH-preg, 17-hydroxypregnenolone; A4, androstenedione. ambiguity which may aid the differen-
tial diagnosis of male undervirilisation.10
However, these assays are not routinely
available in the UK.
genitalia, and gonadal and genital skin (testosterone secretion normally rises
biopsies can be performed at the time of in the fourth week of life, peaking at Assessment of gonadotrophins
laparoscopy. 1–3 months6–8) and proceeding with the Assessment of the gonadotrophins may
investigations as promptly as possible. give useful information. Raised basal
Testosterone response to human While some would advocate that this gonadotrophins are consistent with pri-
chorionic gonadotrophin (hCG) test is deferred beyond 2 weeks of age, mary gonadal failure. The gonadotro-
To determine whether functioning this may not be necessary. In the new- phin response to GnRH is difficult to
Leydig cells are present (that is, capable born period an increase in testosterone, interpret in the prepubertal child unless
of producing testosterone in response to reaching adult male levels, would nor- exaggerated, which is consistent with
LH), an hCG stimulation test is under- mally be expected after hCG. gonadal failure but adds little to the
taken. This is also used to delineate a The hCG test can be extended to a basal levels alone. Pituitary failure
block in testosterone biosynthesis from three week test if the three day hCG would give a flat response but is not
androstenedione (17b-hydroxysteroid test is inconclusive. The same dose of diagnostic, and hypothalamic abnorm-
dehydrogenase deficiency) or conver- hCG is administered twice weekly for alities such as Kallmann’s syndrome are
sion of testosterone to DHT (5a-reduc- three weeks and testosterone, DHT, not excluded by a ‘‘normal’’ response
tase deficiency). There are a variety of and androstenedione samples taken The optimal time to assess this is within
protocols for the hCG test, but essen- 24 hours after the last hCG injection. the first six months of life when there is
tially it involves taking baseline samples The clinical response in terms of testi- a gonadal surge in both sexes (girls
for testosterone and its precursors dehy- cular descent and change in the size of greater than boys), and the axis is hence
droepiandrosterone (DHEA) (or DHEA the phallus and frequency of erections maximally responsive.
sulphate (DHEAS)) and androstene- should be documented. Photographs
dione and its metabolite (DHT). One to pre- and post-hCG, may be helpful.
Assessment of adrenal function
three intramuscular injections of high Urine steroid profile
dose hCG (500–1500 IU) are given at Anti-Müllerian hormone (AMH) and Output of adrenal steroids will be low in
24 hour intervals and repeat androgen inhibin B levels adrenal insufficiency. In CAH specific
samples are taken at 72 hours or While hCG stimulation tests the func- ratios of metabolites will be altered,
24 hours after the last injection. The tion of the Leydig cells, both AMH and depending on the level of the enzyme
neonatal gonad is more active than at inhibin B are secreted by the Sertoli block.
any time in childhood until puberty, cells. Inhibin B is detectable for the first
reaching a peak at about a 6–8 weeks of six months, rising again at puberty.
Synacthen test
age. A balance needs to be reached AMH levels are high in human male
A standard short Synacthen test is
between performing the hCG test when serum postnatally for several years
useful in the following situations:
the gonad is normally most active before declining during the peripubertal
N Suspected CAH where a peak 17-
hydroxyprogesterone (17-OHP) of
100–200 nmol/l is suggestive of 21-
hydroxylase deficiency. (Higher
reference ranges for preterm infants.)
N Suspected CAH to assess adrenal
cortical reserve (measurement of
cortisol levels).

The dose of Synacthen is dependent on


local protocol (example 36 mg/kg or a
standard dose of 62.5 mg intravenously
Figure 2 Differential virilisation of the external genitalia using the staging system of Prader, from or intramuscularly). Cortisol and 17-
normal female (left) to normal male (right). Sagittal (upper panel) and perineal (lower panel) views OHP levels are normally measured at 0
shown. and 30 minutes only as the 60 minute

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LEADING ARTICLE 405

CAH are DHEA, androstenedione, tes-


tosterone, ACTH, and plasma renin
activity, all of which may be increased.
From day 3 of life, the ratio of urinary
steroid metabolites will be altered
depending on the site of the block,
and is very helpful in the diagnosis of
21-OHD and the rarer forms of CAH. A
skilled ultrasound examination will
show normal internal genitalia, but an
EUA may be required to confirm the
presence of normal Müllerian struc-
tures, and to show the level of entry
of the vagina into the urogenital
sinus, in the case of a single perineal
opening.
The excessive androgen may be gona-
dal in origin—usually from an ovotestis
or testis in a true hermaphrodite. While
the commonest karyotype of the true
hermaphrodite is 46XX (70.6%), the
next commonest karyotype is a chromo-
somal mosaicism containing a Y chro-
mosome (usually 46XX/46XY) (20.2%).11
Figure 3 Investigation flow plan for assessment of ambiguous genitalia.
It is important to check fibroblast and/or
gonadal genotype in these babies, which
may contain a mosaic cell line.
Transplacental transfer of androgen
value does not usually contribute The androgens may be derived from the may rarely occur if the mother has an
further. A normal basal value, or even fetal adrenal gland (CAH and placental androgen secreting tumour (she may be
a normal stimulated response does not aromatase deficiency), fetal gonad (the virilised as a result) or from drugs given
exclude the evolution of adrenal insuf- testis or ovotestis in true hermaphrodit- during pregnancy. Placental aromatase
ficiency, and may need to be repeated ism), or rarely, exogenously via trans- deficiency, by inhibiting the conversion
depending on clinical suspicion. A basal placental passage from the mother of androgens to oestrogens, may cause
ACTH level may be helpful, but in most (adrenal or ovarian tumours). virilisation of a female fetus, and in
laboratories the turnaround time is Absence of palpable gonads in addition, maternal virilisation occurs
slower than for cortisol. association with otherwise apparently from placental transfer of the excessive
male genitalia should always alert one fetal androgens.12
Skin and gonadal biopsies to the possibility of a virilised female. By Table 2 lists conditions that cause
Genital skin biopsies (2–4 mm) per- far the commonest cause of this is virilisation of a female fetus.
formed at the time of examination CAH. Of the enzyme defects that
under anaesthesia (EUA) or genito- cause virilisation in female fetuses, 21- Genital ambiguity with a 46XY
plasty are useful to establish cell lines hydroxylase deficiency is the most fre- karyotype indicates an
for androgen receptor binding assays quent (accounting for 90–95%, UK undervirilised male
and analysis of 5a-reductase activity. incidence 1/15–20 000). Diagnosis is This is a genetically XY male with two
The cell line is also a source of genomic made on a raised serum 17-hydroxypro- testes, but whose genital tract fails to
DNA and RNA and/or subsequent mole- gesterone level. This level may be differentiate normally. There are numer-
cular and functional studies. Karyotype increased in the first 48 hours in nor- ous presentations of genital anomaly,
analysis for the presence of mosaicism mal babies, and may be significantly from apparently normal female (Prader
may be indicated. Gonadal biopsies are increased in sick and preterm babies in I) with a palpable gonad through to an
essential when considering diagnostic the absence of CAH. The other enzyme apparently normal male with hypospa-
categories such as dysgenesis and true defects that can cause virilisation of dias (Prader V).
hermaphroditism. A detailed histo- female fetuses are 11b-hydroxylase The three main diagnostic categories
pathological report is essential. As spe- deficiency (where the 11-deoxycortisol are: testicular dysgenesis/malfunction, a
cial treatment of the samples may be levels will be increased) and less com- biosynthetic defect, and end-organ
required, prior discussion with the monly 3b-hydroxysteroid dehydrogen- unresponsiveness (table 2).
pathologist or genetics laboratory ase deficiency (diagnosed by raised If the gonads are palpable, they are
should take place. 17-hydroxypregnenolone and dehydro- likely to be testes (or rarely ovotestes).
epiandrosterone) (table 3). Investigations are directed at determin-
INTERPRETATION OF RESULTS If CAH is confirmed, the electrolytes ing the anatomy of the internal genita-
Genital ambiguity with a 46XX need to be watched closely as salt lia, and establishing whether the
karyotype indicates a virilised wasting occurs in 70% of cases of 21- testicular tissue is capable of producing
female hydroxylase deficiency, usually between androgens. Investigations that may help
The female fetus with ovaries and days 4 and 15. Mineralocorticoid defi- with the former include pelvic ultra-
normal internal genitalia has been ciency induces a rise in serum potas- sound, examination under anaesthetic
exposed to excessive testosterone, and sium levels (usually the first sign of salt with cystoscopy and laparoscopy.
hence dihydrotestosterone (by conver- wasting) and sodium levels fall. Urinary Genital skin biopsy specimens can be
sion of testosterone by 5a-reductase) sodium levels will be inappropriately taken at the time of endoscopies.
which virilises the external genitalia. high. Further confirmatory tests for Occasionally urogenital sinogram or

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406 LEADING ARTICLE

MRI can be helpful. Laparoscopy/laparo- This condition is rare in the UK, but consistent with X linkage. The majority
tomy and gonadal biopsy may be recognised in the Dominican Republic, of XY infants with undervirilisation
required. where individuals are often raised as remain unexplained.
female and convert to male in puberty,
Testicular dysgenesis/malfunction when body habitus and psychosexual
DNA ANALYSIS
A 46 XY karyotype, with low basal and orientation becomes male. Virilisation
Many of the causes of genital ambiguity
hCG stimulated testosterone and low improves but is incomplete.
have a genetic basis, and in these cases
testosterone precursors suggests A biochemical diagnosis is made by
genetic counselling will be required. For
either gonadal dysgenesis (which may showing a ratio of T:DHT .30 after
example, androgen insensitivity syn-
require laparoscopy and testicular puberty or following hCG stimulation
biopsy) or lipoid CAH (caused by an drome is X-linked recessive, and CAH
before puberty, and the ratio of 5a:5b
abnormality in the steroidogenic acute is autosomal recessive. In addition,
metabolites in a urine steroid profile will
regulatory (StAR) protein) identification and characterisation of a
be increased after 6 months of age. The
In the latter condition total adrenal number of mutations of the genes
urinary 5a:5b metabolites can also be
failure is confirmed on Synacthen test, used if the gonads have been removed. involved in sexual differentiation has
electrolytes, and urinary steroids. The diagnosis is confirmed by screening resulted in DNA tests which can be
Because of the other associated gene for mutations in the 5a-reductase type II used in prenatal diagnosis. Iden-
defects (table 1), there may be other gene (5RD5A2). tification of carriers will facilitate
anomalies such as bony dysplasias or genetic counselling.
renal anomalies, which should be A 46XY karyotype, low basal and hCG
looked for. stimulated testosterone levels with Congenital adrenal hyperplasia
The poorly functioning testicular tis- increased testosterone precursors Several laboratories within the UK will
sue is likely to give a subnormal indicates a testosterone biosynthetic undertake DNA analysis for this condi-
testosterone response to hCG and basal defect tion. Once the diagnosis has been made,
gonadotrophins will usually be Those forms of CAH that cause under- a DNA sample from the proband should
increased, consistent with primary virilisation of male genitalia include be taken. If a gene mutation is identi-
gonadal failure. In addition, the dysge- 17a-hydroxylase/17,20-lyase deficiency fied, the carrier status of the parents
netic testes may secrete inadequate and 3b-hydroxysteroid dehydrogenase may be determined and the family
amounts of anti-Müllerian hormone, deficiency (table 3). should be counselled about the possibi-
and Müllerian structures may be present The conversion of androstenedione to lity of antenatal screening of subsequent
(although often hypoplastic) in children testosterone occurs predominantly in pregnancies, and of steroid treatment of
with gonadal dysgenesis and a 46XY the gonad and a post-hCG stimulated the mother in an attempt to reduce
karyotype. ratio of androstenedione to testosterone virilisation of a subsequent affected
A mosaic karyotype, for example 45X/ of .20:1 suggests 17b-hydroxysteroid female fetus. In the UK, antenatal
46XY suggests gonadal dysgenesis. dehydrogenase deficiency. A urine ster- diagnosis and treatment is offered as
There is a very variable phenotype both oid profile is generally not helpful in this part of a national British Society for
in terms of internal and external geni- diagnosis before puberty. Molecular Paediatric Endocrinology and Diabetes
talia, which is not dependent on the analysis of the HSD III gene supported study monitoring efficacy,
percentage of each karyotype as deter- (HSD17B3) is sought as confirmation short and long term side effects, and
mined by lymphocyte analysis. Over of the diagnosis. outcome measures.
90% of individuals with prenatally diag-
nosed 45X/46XY karyotype have a nor- End-organ unresponsiveness
mal male phenotype, suggesting most A 46XY karyotype with genital Androgen insensitivity
individuals with this karyotype escape ambiguity, normal or increased basal DNA analysis is now being undertaken
detection and that an ascertainment and peak testosterone on hCG test, in Cambridge as part of a molecular
bias exists towards those with clinically and a normal T:DHT ratio points to genetics service in collaboration with
evident abnormalities.13 14 partial androgen insensitivity Professor Ieuan Hughes. Samples are
There is a variable phenotype, and sex of only analysed following collection of
Biosynthetic defect rearing depends on the degree of phallic clinical, biochemical, and histological
A 46XY karyotype, low basal and peak development, and sometimes cultural data that are consistent with an andro-
testosterone level on hCG testing, considerations. The child may benefit gen insensitive pathophysiology.
often with increased gonadotrophins from a trial of topical DHT cream or
suggests a diagnosis of an inactivating intramuscular testosterone (for example
Suspected 5a-reductase deficiency
mutation of the LH receptor (Leydig using 12.5–25 mg, monthly for three
and 17b-hydroxysteroid
cell hypoplasia) months) on penile growth to help
dehydrogenase deficiency
This condition is associated with a anticipate response in puberty.
DNA samples in patients with suspected
variable phenotype from a completely The diagnosis is suggested by showing
5a-reductase deficiency and 17b-hydro-
phenotypic female to undervirilisation an abnormality in androgen binding in
xysteroid dehydrogenase deficiency can
of varying degrees.15 genital skin fibroblasts, or a mutation in
also be processed through the
the androgen receptor gene. This
Cambridge laboratory.
A 46XY karyotype with normal or requires DNA and a genital skin biopsy,
increased basal and peak testosterone taken at the time of EUA or genital
on hCG test, and an increased T:DHT surgery. Despite clear evidence of a Unusual cases of sexual ambiguity
ratio is seen in 5a-reductase phenotype consistent with partial Mutations of developmental genes such
deficiency androgen PAIS and normal production as DAX1, SOX9, and WT1 may account
DHT dependent virilisation of external and metabolism of androgens, only a for rarer cases of sexual ambiguity.
genitalia is deficient, resulting in a small minority of patients are found to have Samples should be taken and DNA
phallus and perineal hypospadias. an androgen receptor gene mutation. extracted and either stored or forwarded
Wolffian structures are normal but The likelihood of finding a mutation is to the relevant laboratories, depending
spermatogenesis is usually impaired.16 increased if there is a family history on clinical suspicion.

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LEADING ARTICLE 407

ASSIGNMENT OF SEX OF CONCLUSIONS 3 Ahmed SF, Hughes IA. The genetics of male
undermasulinization. Clin Endocrinol
REARING Genital ambiguity resulting in uncer- 2002;56:1–18.
A decision about the sex of rearing tainty of sex at birth is uncommon. The 4 Vainio S, Heikkila M, Kispert A, et al. Female
should be made as soon as is practic- most frequent cause in a genetic female development in mammals is regulated by Wnt-4
signalling. Nature 1999;379:707–10.
able, usually based on the internal and is CAH, which may be life threatening if 5 Cheng PK, Chanoine JP. Should the definition of
external genital phenotype and the there is a risk of a salt losing crisis. micropenis vary according to ethnicity? Horm Res
results of the various investigations. Reaching a diagnosis, particularly in 2001;55:278–81.
6 Winter JS, Hughes IA, Reyes FI, et al. Pituitary-
Cultural aspects may also be important undervirilised males, is currently not gonadal relations in infancy: 2. Patterns of serum
in cases of severe ambiguity. always possible, but many may have a gonadal steroid concentrations in man from birth
Assignment of sex of rearing can be to two years of age. J Clin Endocrinol Metab
partial androgen insensitivity syndrome 1976;42:679–86.
extremely difficult, particularly as there yet to be defined in molecular terms or 7 Ng KL, Ahmed SF, Hughes IA. Pituitary-gonadal
is a paucity of data on long term milder variants of testicular dysgenesis. axis in male undermasculinisation. Arch Dis Child
outcome in this area. 2000;82:54–8.
Prompt counselling and investigations 8 Davenport M, Brain C, Vandenberg C, et al. The
In the case of a virilised female (with the backup of recognised bio- use of the hCG stimulation test in the endocrine
(usually CAH), there is usually the chemical and genetic laboratories) is evaluation of cryptorchidism. Br J Urol
potential for fertility and these babies 1995;76:790–4.
essential. The decision of sex of rearing 9 Rey RA, Belville C, Nihoul-Fekete C, et al.
are usually raised as girls. This is much and the timing of surgery need careful Evaluation of gonadal function in 107 intersex
easier if the diagnosis of CAH is made consideration within a multidisciplinary patients by means of serum antimullerian
early. hormone measurement. J Clin Endocrinol Metab
environment with full informed consent 1999;84:627–31.
Decisions about nature and timing of of the family. 10 Kubini K, Zachmann M, Albers N, et al. Basal
any surgery are made with the family inhibin B and the testosterone response to
acknowledging the considerable psycho- human chorionic gonadotropin correlate in
logical impact of having a child with ACKNOWLEDGEMENTS prepubertal boys. J Clin Endocrinol Metab
We thank Professor Ieuan Hughes and Dr 2000;85:134–8.
genital ambiguity. There is considerable 11 Krob G, Braun A, Kuhnle. True hermaphroditism:
John Achermann for their helpful comments. geographical distribution, clinical findings,
debate as to the optimal timing of any
Email address for Professor Hughes for chromosomes and gonadal histology. Eur J Pediatr
genital surgery.17 In the presence of mutation analysis and discussion on the 1994;153:2–10.
marked clitoromegaly, clitoral reduction androgen receptor, 5a-reductase deficiency, 12 Shozu M, Akasofu K, Harada T, et al. A new
is usually undertaken in infancy. Lesser and 17b-hydroxysteroid dehydrogenase: cause of female pseudohermaphroditism:
degrees of clitoral enlargement may be placental aromatase deficiency. J Clin Endocrinol
iah1000@cam.ac.uk. Email address for Dr
Metab 1991;72:560–6.
left until puberty when the child can be Achermann for mutation analysis and dis- 13 Chang HJ, Clark RD, Bachman H. Chromosome
involved with the decision making. The cussion on early gonadal genes or cases mosaicism in 6,000 amniocenteses. Am J Med
timing of any vaginoplasty is dependent associated with adrenal failure: j.achermann Genet 1989;32:506–13.
@ich.ac.uk. 14 Wilson MG, Lin MS, Fujimoto A, et al. The
on the anatomy of the internal and phenotype of 45,X/46,XY mosaicism: an analysis
external genitalia and influenced by Web address for the British Society for
of 92 prenatally diagnosed cases. Am J Hum
Paediatric Endocrinology and Diabetes: Genet 1990;46:156–67.
local practice. However, there has been www.bsped.org.uk. 15 Laue L, Wu S-M, Kudo M, et al. A nonsense
a move away from early vaginoplasty in mutation of the human luteinizing hormone
all infants. It may be appropriate to Arch Dis Child 2004;89:401–407. receptor gene in Leydig cell hypoplasia. Hum Mol
delay surgery until puberty when a doi: 10.1136/adc.2003.011312 Genet 1995;4:1429–33.
16 Hochberg Z, Chayen R, Reiss N, et al. Clinical,
single stage reconstruction can be
...................... biochemical, and genetic findings in a large
undertaken. Recent outcome data on pedigree of male and female patients with 5
clitoral sensation18 and success of early Authors’ affiliations alpha-reductase 2 deficiency. J Clin Endocrinol
A L Ogilvy-Stuart, Neonatal Unit, Rosie Metab 1996;81:2821–7.
vaginoplasty19 20 in adult women who
Hospital, Addenbrooke’s NHS Trust, 17 Creighton S. Surgery for intersex. J R Soc Med
underwent genital surgery in infancy Cambridge CB2 2SW, UK 2001;94:218–20.
and childhood has induced a more C E Brain, Dept of Paediatric Endocrinology, 18 Minto CL, Liao LM, Woodhouse CRJ, et al. The
cautious surgical approach.21 22 effect of clitoral surgery on sexual outcomes in
Great Ormond Street Hospital, Great Ormond individuals who have intersex conditions with
The appropriate sex of rearing of a Street, London WC1N 3JH, UK ambiguous genitalia: a cross sectional study.
very undervirilised male requires as Lancet 2003;361:1252–7.
much information as possible, from the 19 Alizai NK, Thomas DF, Lilford RJ, et al.
Correspondence to: Dr A L Ogilvy-Stuart, Feminizing genitoplasty for congenital adrenal
investigations discussed, as well as Neonatal Unit, Rosie Hospital, Addenbrooke’s hyperplasia: what happens at puberty? J Urol
thorough, multidisciplinary discussions NHS Trust, Cambridge CB2 2SW, UK; 1999;161:1588–91.
involving the parents, urologist, endo- amanda.ogilvy-stuart@addenbrookes.nhs.uk 20 Creighton S, Minto C, Steele SJ. Feminizing
childhood surgery in ambiguous genitalia:
crinologist, geneticist, and a clinical objective cosmetic and anatomical outcomes in
psychologist. It may be appropriate to REFERENCES adolescence. Lancet 2001;358:124–5.
defer gender assignment until the 21 Creighton S, Minto C. Managing intersex. BMJ
1 Hamerton JL, Canning N, Ray M, et al. A 2001;323:1264–5.
results of relevant investigations are cytogenetic survey of 14,069 newborn infants. I. 22 Creighton S, et al. Regarding the consensus
reviewed and the effects of exogenous Incidence of chromosome abnormalities. Clin statement on 21-hydroxylase deficiency from the
androgens have been assessed. The birth Genet 1975;4:223–43. Lawson Wilkins Paediatric Endocrine Society and
2 Blackless M, Charuvastra A, Derryck A, et al. the European Society for Paediatric
registration should be delayed for as How sexually dimorphic are we? Am J Hum Biol Endocrinology [letter]. Hormone Res
long as it takes for the final decision to 2000;12:151–66. 2003;59:262; and J Clin Endocrinol Metab
be made. 2003;88:3455.

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Consensus statement on management of intersex


disorders
I A Hughes, C Houk, S F Ahmed, P A Lee and LWPES/ESPE Consensus Group

Arch. Dis. Child. 2006;91;554-563; originally published online 19 Apr 2006;


doi:10.1136/adc.2006.098319

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554 LEADING ARTICLE

LEADING ARTICLE clearly associated with other aspects of


....................................................................................... psychosexual development.8 9 There are
dose related effects on childhood play

Consensus statement on management behaviour in girls with congenital adre-


nal hyperplasia (CAH), whereby those

of intersex disorders
with the more severe mutations and
marked genital virilisation play more
with boys’ toys.10 Prenatal androgen
I A Hughes, C Houk, S F Ahmed, P A Lee, exposure is also associated with other
LWPES1/ESPE2 Consensus Group psychological characteristics such as
maternal interest and sexual orienta-
................................................................................... tion. It is important to emphasise the
separability of sex-typical behaviour,
Management of intersex disorders sexual orientation, and gender identity.
Thus homosexual orientation (relative

T
he birth of an intersex child individuals with DSD are limited, it is to sex of rearing) or strong cross-sex
prompts a long term management essential to employ precision when interest in an individual with DSD is not
strategy that involves a myriad of applying definitions and diagnostic an indication of incorrect gender assign-
professionals working with the family. labels.3 4 It is also appropriate to use ment. Understanding variations in psy-
It is estimated that genital anomalies terminology that is sensitive to the chosexual development in individuals
occur in 1 in 4500 births. There has been concerns of patients. The ideal nomen- with DSD requires reference to studies
progress in diagnosis, surgical techni- clature should be sufficiently flexible to in non-human species that show
ques, understanding psychosocial incorporate new information yet robust marked but complex effects of andro-
issues, and recognising and accepting enough to maintain a consistent frame- gens on sex differentiation of the brain
the place of patient advocacy. The work. Terms should be descriptive and and on behaviour. Outcomes can be
Lawson Wilkins Pediatric Endocrine reflect genetic aetiology when available, influenced by timing, dose, and type of
Society (LWPES) and the European and accommodate the spectrum of androgen exposure, receptor availability,
Society for Paediatric Endocrinology phenotypical variation. Clinicians and and modification by the social environ-
(ESPE) considered it timely to review scientists must value its use and it must ment.11–14
the management of intersex disorders be understandable to patients and their Data from rodent studies suggest that
from a broad perspective, to review data families. An example of how the pro- sex chromosome genes may also influ-
on longer term outcome, and to for- posed nomenclature could be applied in ence brain structure and behaviour
mulate proposals for future studies. The a classification of DSD is shown in directly.15 16 However, studies in indivi-
methodology comprised establishing table 2. duals with complete androgen insensi-
several working groups whose member- Psychosexual development is tradition- tivity syndrome (CAIS) do not indicate a
ship was drawn from 50 international ally conceptualised as three components. behavioural role for Y chromosome
experts in the field. The groups prepared Gender identity refers to a person’s self genes, although data are limited.17 Sex
prior written responses to a defined set representation as male or female (with differences in brain structures have
of questions resulting from an evidence the caveat that some individuals may not been identified across species, some of
based review of published reports. At a identify exclusively with either). Gender which coincide with pubertal onset,
subsequent gathering of participants, a role (sex-typical behaviours) describes perhaps suggesting hormonal responsiv-
framework for a consensus document the psychological characteristics that are ity.18–20 The limbic system and hypotha-
was agreed. This paper constitutes its sexually dimorphic within the general lamus, both playing a role in
final form. population, such as toy preferences and reproduction, show sex differences in
physical aggression. Sexual orientation specific nuclei but it is not clear when
NOMENCLATURE AND refers to the direction(s) of erotic interest these differences emerge. Interpretation
DEFINITIONS (heterosexual, bisexual, homosexual) of sex differences is complicated by the
Advances in identification of molecu- and includes behaviour, fantasies, and effect of cell death and synaptic pruning
lar genetic causes of abnormal sex with attractions. Psychosexual development is on normal maturation and by effects of
heightened awareness of ethical issues influenced by multiple factors such as experience on the brain. Structure of the
and patient advocacy concerns necessi- exposure to androgens, sex chromosome brain is not currently useful for gender
tate a re-examination of nomenclature.1 genes, and brain structure, as well as assignment.
Terms such as intersex, pseudoher- social circumstance and family dynamics.
maphroditism, hermaphroditism, sex Gender dissatisfaction denotes
reversal, and gender based diagnostic unhappiness with assigned sex. Causes INVESTIGATION AND
labels are particularly controversial. of gender dissatisfaction are poorly MANAGEMENT OF DSD
These terms are perceived as potentially understood, even among individuals General concepts of care
pejorative by patients,2 and can be without DSD. Gender dissatisfaction Optimal clinical management of indivi-
confusing to practitioners and parents occurs more frequently in individuals duals with DSD21 should comprise the
alike. The term ‘‘disorders of sex devel- with DSD than in the general popula- following:
opment’’ (DSD) is proposed, as defined tion, but is difficult to predict from
by congenital conditions in which devel-
opment of chromosomal, gonadal, or
karyotype, prenatal androgen exposure,
degree of genital virilisation, or assigned
N gender assignment must be avoided
before expert evaluation in new-
anatomical sex is atypical. gender.5–7 Prenatal androgen exposure is borns;
The proposed changes in terminology
are summarised in table 1. A modern Abbreviations: CAH, congenital adrenal hyperplasia; CAIS, complete androgen insensitivity
lexicon is needed to integrate progress syndrome; DSD, disorders of sex development; ESPE, European Society for Paediatric
in molecular genetic aspects of sex Endocrinology; LWPES, Lawson Wilkins Pediatric Endocrine Society; MGD, mixed gonadal
development. As outcome data in dysgenesis; PAIS, partial androgen insensitivity syndrome

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LEADING ARTICLE 555

N evaluation and long term manage-


ment must be carried out at a centre
Table 1 Proposed revised nomenclature
with an experienced multidisciplin- Previous Proposed
ary team; Intersex Disorders of sex development (DSD)
N all individuals should receive a gen-
der assignment; Male pseudohermaphrodite

N
Undervirilisation of an XY male 46,XY DSD
open communication with patients Undermasculinisation of an XY male
and families is essential and partici-
pation in decision making is encour- Female pseudohermaphrodite
Overvirilisation of an XX female 46,XX DSD
aged; Masculinisation of an XX female
N patient and family concerns should
be respected and addressed in strict True hermaphrodite Ovotesticular DSD

confidence. XX male or XX sex reversal 46,XX testicular DSD

The initial contact with the parents of XY sex reversal 46,XY complete gonadal dysgenesis
a child with a DSD is important, as first
impressions from these encounters
often persist. A key point to emphasise
is that the DSD child has the potential to
The multidisciplinary team Ideally, discussions with the family are
become a well adjusted, functional
Optimal care for children with DSD conducted by one professional with
member of society. While privacy needs
requires an experienced multidisciplin- appropriate communication skills.24
to be respected, DSD is not shameful. It
ary team which is generally found in Transitional care should be organised
should be explained to the parents that
tertiary care centres. Ideally, the team with the multidisciplinary team operat-
the best course of action may not includes paediatric subspecialists in ing in an environment comprising spe-
initially be clear, but the health care endocrinology, surgery or urology or cialists with experience in both
team will work with the family to reach both, psychology/psychiatry, gynaecol- paediatric and adult practice. Support
the best possible set of decisions in the ogy, genetics, neonatology, and, if avail- groups have an important role in the
circumstances. The health care team able, social work, nursing, and medical delivery of care to DSD patients and their
should discuss with the parents what ethics.22 Core composition will vary families25 (see appendix 1).
information to share in the early stages according to DSD type, local resources,
with family members and friends. developmental context, and location.
Parents need to be informed about Ongoing communication with the family Clinical evaluation
sexual development, and web based primary care physician is essential.23 A family and prenatal history, a general
information may be helpful, provided The team has a responsibility to physical examination with attention to
the content and focus of the informa- educate other health care staff in the any associated dysmorphic features, and
tion is balanced and sound (http:// appropriate initial management of an assessment of the genital anatomy in
www.sickkids.ca/childphysiology/cpwp/ affected newborn infants and their comparison with published norms needs
genital/genitalintro.html). families. For new DSD patients, the team to be recorded (table 3). Criteria that
Ample time and opportunity should should develop a plan for clinical man- suggest DSD include:
be made for continued discussion agement with respect to diagnosis, gen-
with review of information previously
provided.1
der assignment, and treatment options
before making any recommendations.
N overt genital ambiguity (for example,
cloacal exstrophy);

Table 2 An example of a DSD classification


Sex chromosome DSD 46,XY DSD 46,XX DSD

(A) 45,X (Turner syndrome and variants) (A) Disorders of gonadal (testicular) development (A) Disorders of gonadal (ovarian) development
1. Complete gonadal dysgenesis (Swyer syndrome) 1. Ovotesticular DSD
2. Testicular DSD (eg, SRY+, dup SOX9)
(B) 47,XXY (Klinefelter syndrome and 2. Partial gonadal dysgenesis 3. Gonadal dysgenesis
variants) 3. Gonadal regression
4. Ovotesticular DSD

(C) 45,X/46,XY (mixed gonadal (B) Disorders in androgen synthesis or action (B) Androgen excess
dysgenesis, ovotesticular DSD) 1. Androgen biosynthesis defect (eg, 17- 1. Fetal (eg, 21-hydroxylase deficiency, 11-hydroxylase
hydroxysteroid dehydrogenase deficiency, 5a deficiency)
reductase deficiency, StAR mutations 2. Fetoplacental (aromatase deficiency, POR)
(D) 46,XX/46,XY (chimeric, 2. Defect in androgen action (eg, CAIS, PAIS) 3. Maternal (luteoma, exogenous, etc)
ovotesticular DSD) 3. LH receptor defects (eg, Leydig cell
hypoplasia, aplasia)
4. Disorders of AMH and AMH receptor (persistent
mullerian duct syndrome)
(C) Other
(C) Other (eg, cloacal extrophy, vaginal atresia, MURCS, other
(eg, severe hypospadias, cloacal extrophy) syndromes)

While consideration of karyotype is useful for classification, unnecessary reference to karyotype should be avoided; ideally, a system based on descriptive terms
(for example, androgen insensitivity syndrome) should be used wherever possible.
AMH, anti-mullerian hormone; CAIS, complete androgen insensitivity syndrome; DSD, disorders of sex development; MURCS, mullerian, renal, cervicothoracic
somite abnormalities; PAIS, partial androgen insensitivity syndrome; POR, cytochrome P450 oxidoreductase.

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556 LEADING ARTICLE

Table 3 Anthropometric measurements of the external genitalia


Stretched penile length Penile width Mean testicular
Sex Population Age (PL) (cm) (cm) volume (ml) Reference

M USA 30 wks GA 2.5 26


M USA Full term 3.5 (0.4) 1.1 (0.1) 0.52 (median) 26, 27
M Japan Term to 14 years 2.9 (0.4) to 8.3 (0.8) 28
M Australia 24–36 weeks GA PL = 2.27 + (0.16 GA) 29
M China Term 3.1 (0.3) 1.07 (0.09) 30
M India Term 3.6 (0.4) 1.14 (0.07) 30
M N America Term 3.4 (0.3) 1.13 (0.08) 30
M Europe 10 years 6.4 (0.4) 0.95 to 1.20 27, 31
M Europe Adult 13.3 (1.6) 16.5 to 18.2 27, 31

Sex Population Age Clitoral length (mm) Clitoral width (mm) Perineal length* (mm) Reference

F USA Full term 4.0 (1.24) 3.32 (0.78) 32


F USA Adult nulliparous 15.4 (4.3) 33
F UK Adult 19.1 (8.7) 5.5 (1.7) 31.3 (8.5) 34

Values are mean (SD) unless specified.


*Distance from posterior fourchette to anterior anal margin.
GA, gestational age; PL, penile length.

N apparent female genitalia with an


enlarged clitoris, posterior labial
specific probe detection (even when
prenatal karyotype is available), ima-
assigned male) live as males.5 In
5aRD2 and possibly 17b-hydroxysteroid
fusion, or an inguinal/labial mass; ging (abdomino-pelvic ultrasound), dehydrogenase (17bHSD3) deficiencies,
N apparent male genitalia with bilateral
undescended testes, micropenis, iso-
measurement of 17-hydroxyprogester-
one, testosterone, gonadotropins, anti-
where the diagnosis is made in infancy,
the combination of a male gender
lated perineal hypospadias, or mild mullerian hormone, serum electrolytes, identity in the majority and the poten-
hypospadias with undescended tes- and urinanalysis. The results of these tial for fertility (documented in 5aRD2,
tis; investigations are generally available but unknown in 17bHSD3) should be
N a family history of DSD such as CAIS; within 48 hours and will be sufficient discussed when providing evidence for
N a discordance between genital
appearance and a prenatal karyotype.
for making a working diagnosis.
Decision making algorithms are avail-
gender assignment.5 44 45
patients with PAIS, androgen biosyn-
Among

able to guide further investigation.38 thetic defects, and incomplete gonadal


Most causes of DSD are recognised in These include hCG and ACTH stimula- dysgenesis, there is dissatisfaction with
the neonatal period; later presentations in tion tests to assess testicular and adre- the sex of rearing in about 25% of
older children and young adults include: nal steroid biosynthesis, urinary steroid individuals, whether raised male or
previously unrecognised genital ambigu- analysis by GC mass spectroscopy, ima- female.46 Available data support male
ity; inguinal hernia in a girl; delayed or ging studies, and biopsies of gonadal rearing in all patients with micropenis,
incomplete puberty; virilisation in a girl; material. Some gene analyses are carried taking into account equal satisfaction
primary amenorrhoea; breast develop- out in clinical service laboratories. with assigned gender in those raised
ment in a boy; and gross and occasionally However, current molecular diagnosis male or female, but no need for surgery,
cyclical haematuria in a boy. is limited by cost, accessibility, and and the potential for fertility in patients
quality control.39 Research laboratories reared male.42 The decision on sex of
provide genetic testing, including func- rearing in ovotesticular DSD should
Diagnostic evaluation
tional analysis, but may face restrictions consider the potential for fertility based
Considerable progress has been made
on communicating results.40 on gonadal differentiation and genital
over understanding the genetic basis of
development, and assuming the genita-
human sexual development,35 yet a
Gender assignment in newborn infants lia are, or can be made, consistent with
specific molecular diagnosis is identified
Initial gender uncertainty is unsettling the chosen sex. In the case of mixed
in only about 20% of cases of DSD. The
and stressful for families. Expediting a gonadal dysgenesis (MGD), factors to
majority of virilised 46,XX infants will
thorough assessment and decision is consider include prenatal androgen
have CAH. In contrast, only 50% of
required. Factors that influence gender exposure, testicular function at and
46,XY children with DSD will receive a
assignment include the diagnosis, geni- after puberty, phallic development, and
definitive diagnosis.36 37 Diagnostic algo-
tal appearance, surgical options, need gonadal location. Individuals with cloa-
rithms do exist, but with the spectrum
for life long replacement therapy, the cal exstrophy reared female show varia-
of findings and diagnoses, no single
potential for fertility, views of the bility in gender identity outcome, but
evaluation protocol can be recom-
family, and sometimes the circum- more than 65% appear to live as female.6
mended in all circumstances. Some
tests, such as imaging by ultrasound, stances relating to cultural practices.
are operator dependent. Hormone mea- More than 90% of 46,XX CAH patients41 Surgical management
surements need to be interpreted in and all 46,XY CAIS assigned females in The surgeon has a responsibility to
relation to the specific assay character- infancy42 identify as females. Evidence outline the surgical sequence and sub-
istics and to normal values for gesta- supports the current recommendation to sequent consequences from infancy to
tional and chronological age. In some raise markedly virilised 46,XX infants adulthood. Only surgeons with expertise
cases serial measurements may be with CAH as female.43 Approximately in the care of children and specific
needed. 60% of 5a-reductase (5aRD2) deficient training in the surgery of DSD should
First line testing in newborns patients assigned female in infancy undertake these procedures. Parents
includes: karyotyping with X and Y and virilising at puberty (and all now appear to be less inclined to choose

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LEADING ARTICLE 557

surgery for less severe clitoromegaly.47 mullerian remnants, is required testosterone esters are commonly used
Surgery should only be considered in although symptoms in future may indi- in males; other options include oral
cases of severe virilisation (Prader III, cate surgical removal. For the male who testosterone undecanoate, and transder-
IV, and V) and should be carried out in has a successful neophalloplasty in mal preparations are also available.63–65
conjunction, when appropriate, with adulthood, an erectile prosthesis may Patients with PAIS may require supra-
repair of the common urogenital sinus. be inserted but has a high morbidity. physiological doses of testosterone for
As orgasmic function and erectile sensa- The testes in patients with CAIS35 and optimal effect.66 Females with hypogo-
tion may be disturbed by clitoral sur- those with PAIS, raised female, should nadism require oestrogen supplementa-
gery, the surgical procedure should be be removed to prevent malignancy in tion to induce pubertal changes and
anatomically based to preserve erectile adulthood. The availability of oestrogen menses. A progestin is usually added
function and the innervation of the replacement therapy allows for the after breakthrough bleeding develops or
clitoris. Emphasis is on functional out- option of early removal at the time of within one to two years of continuous
come rather than a strictly cosmetic diagnosis which also takes care of the oestrogen. There is no evidence that the
appearance. It is generally felt that associated hernia, psychological pro- addition of cyclic progesterone is bene-
surgery that is carried out for cosmetic blems with the presence of testes, and ficial in women without a uterus.
reasons in the first year of life relieves the malignancy risk. Parental choice
parental distress and improves attach- allows deferment until adolescence, Psychosocial management
ment between the child and the par- recognising that the earliest reported Psychosocial care provided by mental
ents.48–51 The systematic evidence for this malignancy in CAIS is at 14 years of health staff with expertise in DSD
belief is lacking. age.59 The streak gonad in a patient with should be an integral part of manage-
There is inadequate evidence cur- MGD raised male should be removed ment in order to promote positive
rently in relation to establishment of laparoscopically (or by laparotomy) in adaptation. This expertise can facilitate
functional anatomy, to abandon the early childhood.35 Bilateral gonadectomy team decisions about gender assign-
practice of early separation of the vagina is performed in early childhood in ment/reassignment, timing of surgery,
and urethra.52 The rationale for early females (bilateral streak gonads) with and sex hormone replacement.
reconstruction is based on guidelines on gonadal dysgenesis and Y chromosome Psychosocial screening tools that iden-
the timing of genital surgery from the material. In patients with androgen tify families at risk for maladaptive
American Academy of Pediatrics biosynthetic defects raised female, gona- coping with a child’s medical condition
(AAP),53 the beneficial effects of oestro- dectomy should be undertaken before are available.67 Once the child is suffi-
gen on tissue in early infancy, and the puberty. A scrotal testis in patients with ciently developed for a psychological
avoidance of potential complications gonadal dysgenesis is at risk for malig- assessment of gender identity, such an
from the connection between the urin- nancy. Current recommendations are evaluation must be included in discus-
ary tract and peritoneum through the testicular biopsy at puberty seeking signs sions about gender reassignment.
Fallopian tubes. It is anticipated that of the premalignant lesion termed carci- Gender identity development begins
surgical reconstruction in infancy will noma in situ or undifferentiated intra- before the age of 3 years,68 but the
need to be refined at the time of tubular germ cell neoplasia. If positive, earliest age at which it can be reliably
puberty.54–56 Vaginal dilatation should the option is sperm banking before assessed remains unclear. The general-
not be undertaken before puberty. The treatment with local low dose radio- isation that the age of 18 months is the
surgeon must be familiar with several therapy which is curative.60 upper limit of imposed gender reassign-
operative techniques in order to recon- Surgical management in DSD should ment should be treated with caution
struct the spectrum of urogenital sinus also consider options that will facilitate and viewed conservatively. Atypical
disorders. An absent or inadequate the chances of fertility. In patients with gender role behaviour is more common
vagina (with rare exceptions) requires a symptomatic utriculus, removal is best in children with DSD than in the
a vaginoplasty performed in adolescence undertaken laparoscopically to increase general population but should not be
when the patient is psychologically the chance of preserving continuity of taken as an indicator for gender reas-
motivated and a full partner in the the vasa deferentia. Patients with bilat- signment. In affected children and
procedure. No one technique has been eral ovotestes are potentially fertile from adolescents who report significant gen-
universally successful; self dilatation, functional ovarian tissue.35 61 Separation der dysphoria, a comprehensive psycho-
skin substitution, and bowel vagino- of ovarian and testicular tissue can be logical evaluation69 and an opportunity
plasty each have specific advantages technically difficult and should be to explore feelings about gender with a
and disadvantages. undertaken, if possible, in early life. qualified clinician is required over a
In the case of a DSD associated with period of time. If the desire to change
hypospadias,57 standard techniques for Sex steroid replacement gender persists, the patient’s wish
surgical repair such as chordee correc- Hypogonadism is common in patients should be supported and may require
tion, urethral reconstruction, and the with dysgenetic gonads, defects in sex the input of a specialist skilled in the
judicious use of testosterone supple- steroid biosynthesis, and resistance to management of gender change.
mentation apply. The magnitude and androgens. The timing of initiation of The process of disclosure concerning
complexity of phalloplasty in adulthood puberty may vary but this is an occasion facts about karyotype, gonadal status,
should be taken into account during the that provides an opportunity to discuss and prospects for future fertility is a
initial counselling period if successful the condition and set a foundation for collaborative ongoing action which
gender assignment is dependent on this long term adherence to treatment. requires a flexible individual based
procedure.58 At times this may affect the Hormonal induction of puberty should approach. It should be planned with
balance of gender assignment. Patients attempt to replicate normal pubertal the parents from the time of diagnosis.70
must not be given unrealistic expecta- maturation to induce secondary sexual Studies in other chronic medical dis-
tions about penile reconstruction, characteristics, a pubertal growth spurt, orders and of adoptees indicate that
including the use of tissue engineering. and optimal bone mineral accumula- disclosure is associated with enhanced
There is no evidence that prophylactic tion, together with psychosocial psychosocial adaptation.71 Medical edu-
removal of asymptomatic discordant support for psychosexual maturation.62 cation and counselling for children is a
structures, such as a utriculus or Intramuscular depot injections of recurrent gradual process of increasing

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558 LEADING ARTICLE

sophistication which is commensurate those disorders where some evidence requires less surgery to achieve an
with changing cognitive and psycholo- base is available. They include CAH, acceptable outcome and results in fewer
gical development.72 CAIS and PAIS, disorders of androgen urological difficulties.46 Long term data
Quality of life encompasses falling in biosynthesis, gonadal dysgenesis on sexual function and quality of life
love, dating, attraction, ability to syndromes (complete and partial), and among those assigned female as well as
develop intimate relationships, sexual micropenis. Long term outcome in DSD male show great variability. There are no
functioning, and the opportunity to should include the following: external controlled clinical trials of the efficacy of
marry and to raise children, regardless and internal genital phenotype, physical early (less than 12 months of age)
of biological indicators of sex. The most health including fertility, sexual func- versus late surgery (in adolescence and
frequent problems encountered in DSD tion, social and psychosexual adjust- adulthood), or of the efficacy of differ-
patients are sexual aversion and lack of ment, mental health, quality of life, and ent techniques.
arousability, which are often misinter- social participation. There are additional
preted as low libido.73 Health care staff health problems in individuals with
Risk of gonadal tumours
should offer adolescent patients oppor- DSD. These include the consequences
tunities to talk confidentially without of associated problems such as other Interpretation of published reports is
their parents and encourage the partici- malformations, developmental delay hampered by unclear terminology and
pation in condition specific support and intellectual impairment, delayed by effects of normal cell maturation
groups which enhance the ability of growth and development, and delay.82–84 The highest tumour risk is
the patient to discuss their concerns unwanted effects of hormones on libido found in TSPY (testis-specific protein Y
comfortably. Some patients avoid inti- and body image.76 encoded) positive gonadal dysgenesis
mate relationships and it is important to and PAIS with intra-abdominal gonads,
address fears of rejection and advise on while the lowest risk (,5%) is found in
Surgical outcome ovotestis85 and CAIS.83 86 Table 4 pro-
the process of building a relationship Some studies suggest satisfactory out-
with a partner. The focus should be on vides a summary of the risk of tumour
comes from early surgery.43 46 47 77 development according to diagnosis and
interpersonal relationships and not Nevertheless, outcomes from clitoro-
solely on sexual function and activity. recommendations for management.
plasty identify problems related to
Referral for sex therapy may be needed. decreased sexual sensitivity, loss of
Repeated examination of the genitalia, clitoral tissue, and cosmetic issues.78 Cultural and social factors
including medical photography, may be Techniques for vaginoplasty carry the DSD may carry a stigma. Social and
experienced as deeply shaming.74 potential for scarring at the introitus, cultural factors, as well as hormonal
Medical photography has its place for necessitating repeated modification effects, appear to influence gender role
record keeping and education, but before sexual function can be reliable. in 5a-reductase deficiency. Gender role
should be undertaken whenever possi- Surgery to construct a neo-vagina car- change occurs at different rates in
ble if the patient is under anaesthesia ries a risk of neoplasia.79 The risks from different societies, suggesting that social
for a procedure and with appropriate vaginoplasty are different for high and factors may also be important modifiers
consent. Medical interventions and low confluence of the urethra and of gender role change.
negative sexual experiences may have vagina. Analysis of long term outcomes In some societies, female infertility
fostered symptoms of post-traumatic is complicated by a mixture of surgical precludes marriage, which also affects
stress disorder and referral to a qualified techniques and diagnostic categories.80 employment prospects and creates eco-
mental health professional may be Few women with CAIS need surgery to nomic dependence. Religious and philo-
indicated.75 lengthen the vagina.81 sophical views may influence how
The outcome in undermasculinised parents respond to the birth of an infant
OUTCOME IN DSD males with a phallus is dependent with a medical condition. Fatalism and
As a general statement, information on the degree of hypospadias and the guilt feelings in relation to congenital
across a range of assessments is insuffi- amount of erectile tissue. Feminising as malformations or genetic conditions
cient in DSD. The following is based on opposed to masculinising genitoplasty have an influence, while poverty and

Table 4 Risk of germ cell malignancy according to diagnosis


Malignancy risk
Risk group Disorder (%) Recommended action Studies (n) Patients (n)

High GD* (+Y)! intra-abdominal 15–35 Gonadectomy` 12 .350


PAIS non-scrotal 50 Gonadectomy` 2 24
Frasier 60 Gonadectomy` 1 15
Denys-Drash (+Y) 40 Gonadectomy` 1 5
Intermediate Turner (+Y) 12 Gonadectomy` 11 43
17b-HSD 28 Monitor 2 7
GD (+Y)` scrotal Unknown Biopsy1 and irradiation? 0 0
PAIS scrotal gonad Unknown Biopsy1 and irradiation? 0 0
Low CAIS 2 Biopsy1 and ??? 2 55
Ovotestis DSD 3 Testis tissue removal? 3 426
Turner (–Y) 1 None 11 557
No (?) 5a-reductase 0 Unresolved 1 3
Leydig cell hypoplasia 0 Unresolved 2

*Gonadal dysgenesis (including not further specified, 46XY, 46X/46XY, mixed, partial, complete).
!GBY region positive, including the TSPY gene.
`At time of diagnosis.
1At puberty, allowing investigation of at least 30 seminiferous tubules, with diagnosis preferably based on OCT3/4 immunohistochemistry.
CAIS, complete androgen insensitivity syndrome; DSD, disorders of sex development; HSD, hydroxysteroid dehydrogenase deficiency; PAIS, partial androgen
insensitivity syndrome.

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LEADING ARTICLE 559

Table 5 Genes known to be involved in disorders of sex development: 46,XY


Mullerian External Associated features/variant
Gene Protein OMIM Locus Inheritance Gonad structures genitalia phenotypes

46,XY DSD
Disorders of gonadal (testicular) development: single gene disorders
WT1 TF 607102 11p13 AD Dysgenetic +/2 Female or Wilms tumour, renal abnormalities,
testis ambiguous gonadal tumours (WAGR, Denys-
Drash, and Frasier syndromes)
SF1 Nuclear receptor TF 184757 9q33 AD/AR Dysgenetic +/2 Female or More severe phenotypes include
(NR5A1) testis ambiguous primary adrenal failure; milder
phenotypes have isolated partial
gonadal dysgenesis
SRY TF 480000 Yp11.3 Y Dysgenetic +/2 Female or
testis or ambiguous
ovotestis
SOX9 TF 608160 17q24-25 AD Dysgenetic +/2 Female or Campomelic dysplasia (17q24
testis or ambiguous rearrangements milder phenotype than
ovotestis point mutations)
DHH Signalling molecule 605423 12q13.1 AR Dysgenetic + Female The severe phenotype of one patient
testis included minifascicular neuropathy,
other patients have isolated gonadal
dysgenesis
ATRX Helicase (?chromatin 300032 Xq13.3 X Dysgenetic – Female, a-Thalassaemia, mental retardation
remodelling) testis ambiguous or
male
ARX TF 300382 Xp22.13 X Dysgenetic – Ambiguous X-linked lissencephaly, epilepsy,
testis temperature instability

Disorders of gonadal (testicular) development: chromosomal changes involving key candidate genes
DMRT1 TF 602424 9p24.3 Monosomic Dysgenetic +/2 Female or Mental retardation
deletion testis ambiguous
DAX1 Nuclear receptor TF 300018 Xp21.3 dupXp21 Dysgenetic +/2 Female or
(NR0B1) testis or ovary ambiguous
WNT4 Signalling molecule 603490 1p35 dup1p35 Dysgenetic + Ambiguous Mental retardation
testis

Disorders of hormone synthesis or action


LHGCR G protein receptor 152790 2p21 AR Testis – Female, Leydig cell hypoplasia
ambiguous or
micropenis
DHCR7 Enzyme 602858 11q12-13 AR Testis – Variable Smith-Lemli-Opitz syndrome: coarse
facies, second-third toe syndactyly,
failure to thrive, developmental delay,
cardiac and visceral abnormalities
STAR Mitochondrial 600617 8p11.2 AR Testis – Female Congenital lipoid adrenal hyperplasia
membrane protein (primary adrenal failure), pubertal
failure
CYP11A1 Enzyme 118485 15q23-24 AR Testis – Female or Congenital adrenal hyperplasia
Ambiguous (primary adrenal failure), pubertal
failure
HSD3B2 Enzyme 201810 1p13.1 AR Testis – Ambiguous CAH, primary adrenal failure, partial
androgenisation due to qDHEA
CYP17 Enzyme 202110 10q24.3 AR Testis – Female, CAH, hypertension due to
ambiguous or qcorticosterone & 11-
micropenis deoxycorticosterone (except in isolated
17,20-lyase deficiency)
POR (P450 CYP enzyme electron 124015 7q11.2 AR Testis – Male or Mixed features of 21-hydroxylase
oxido- donor ambiguous deficiency, 17a-hydroxylase/17,20-
reductase) lyase deficiency, and aromatase
deficiency; sometimes associated with
Antley Bixler craniosynostosis
HSD17B3 Enzyme 605573 9q22 AR Testis – Female or Partial androgenisation at puberty,
ambiguous qandrostenedione:testosterone ratio
SRD5A2 Enzyme 607306 2p23 AR Testis – Ambiguous or Partial androgenisation at puberty,
micropenis qtestosterone:DHT ratio,
AMH Signalling molecule 600957 19p13.3-13.2AR Testis + Normal male Persistent mullerian duct syndrome
AMH- Serine-threonine 600956 12q13 AR Testis + Normal male (PMDS). Male external genitalia,
Receptor kinase transmembrane bilateral cryptorchidism
receptor
Androgen Nuclear receptor TF 313700 Xq11-12 X Testis – Female, Phenotypic spectrum from complete
receptor ambiguous, androgen insensitivity syndrome
micropenis or (female external genitalia) and partial
normal male androgen insensitivity (ambiguous) to
normal male genitalia/infertility

AD, autosomal dominant; AR, autosomal recessive; CAH, congenital adrenal hyperplasia; TF, transcription factor; X, X-linked recessive; Y, Y-linked recessive.
Copyright 2002, The Endocrine Society.

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560 LEADING ARTICLE

Table 6 Genes known to be involved in disorders of sex development: 46,XX


Mullerian External Associated features/variant
Gene Protein OMIM Locus Inheritance Gonad structures genitalia phenotypes

Disorders of
gonadal (ovarian)
development
SRY TF 480000 Yp11.3 Translocation Testis or – Male or
ovotestis ambiguous
SOX9 TF 608160 17q24 dup17q24 ND – Male or
ambiguous

Androgen excess
HSD3B2 Enzyme 201810 1p13 AR Ovary + Clitoromegaly CAH, primary adrenal failure, partial
androgenisation due to qDHEA
CYP21A2 Enzyme 201910 6p21-23 AR Ovary + Ambiguous CAH, phenotypic spectrum from
severe salt losing forms associated
with adrenal failure to simple
virilising forms with compensated
adrenal function, q17-
hydroxyprogesterone
CYP11B1 Enzyme 202010 8q21-22 AR Ovary + Ambiguous CAH, hypertension due to q11-
deoxycortisol and 11-
deoxycorticosterone
POR (P450 oxido- CYP enzyme 124015 7q11.2 AR Ovary + Ambiguous Mixed features of 21-hydroxylase
reductase) electron donor deficiency, 17a-hydroxylase/17,20-
lyase deficiency and aromatase
deficiency; associated with Antley
Bixler craniosynostosis
CYP19 Enzyme 107910 15q21 AR Ovary + Ambiguous Maternal androgenisation during
pregnancy, absent breast
development at puberty, except in
partial cases
Glucocorticoid Nuclear 138040 5q31 AR Ovary + Ambiguous qACTH, 17-hydroxyprogesterone
receptor receptor TF and cortisol; failure of
dexamethasone suppression
(NB patient heterozygous for a
mutation in CYP21)

ACTH, adrenocorticotropin; AD, autosomal dominant; AR, autosomal recessive; CAH, congenital adrenal hyperplasia; ND, not determined; TF, transcription
factor; X, X chrosomal; Y, Y chromosomal.
88
Chromosomal rearrangements likely to include key genes are included. Modified from Achermann et al , with permission from the Endocrine Society.

illiteracy negatively affect access to timing and content. The pattern of ACKNOWLEDGEMENTS
health care.87 surgical practice in DSD is changing The LWPES and ESPE gratefully acknowl-
with respect to the timing of surgery edge unrestricted educational grant support
and the techniques employed. It is for the consensus meeting from Pfizer
FUTURE STUDIES Endocrine Care, Novo Nordisk, Ferring, and
Establishing a precise diagnosis in DSD essential to evaluate the effects of early
Organon. The work of Alan Rogol, Joanne
is just as important as in other chronic versus later surgery in an holistic Rogol, Pauline Bertrand, and Pam Stockham
medical conditions with lifelong con- manner, recognising the difficulties in organising the meeting is gratefully appre-
sequences. Considerable progress has posed by an ever evolving clinical ciated.
been achieved with molecular studies, practice.
as illustrated in tables 5 and 6, which The consensus has clearly identified a CONSENSUS GROUP
summarise the genes known to be major shortfall in information about The following participants contributed to the
long term outcome. Future studies production of the Consensus document: John
involved in DSD. Use of tissue specific
should use appropriate instruments that Achermann (London, UK), Faisal Ahmed
animal knock out models, comparative (Glasgow, UK), Laurence Baskin (San
genomic hybridisation, and microarray assess outcomes in a standard man-
Francisco, USA), Sheri Berenbaum
screens of the mouse urogenital ridge ner68 69 and take cognisance of guide- (University Park, USA), Sylvano Bertelloni
will provide benefits in identifying new lines relevant to all chronic conditions (Pisa, Italy), John Brock (Nashville, USA),
genes causing DSD.89 It is essential that (http://www.who.int/classifications/icf/ Polly Carmichael (London, UK), Cheryl Chase
the momentum for an international en/). These should preferably be pro- (Rohnert Park, USA), Peggy Cohen-Kettenis
collaborative approach to this task is spective in nature and designed to avoid (Amsterdam, Netherlands), Felix Conte (San
selection bias. Several countries already Francisco, USA), Patricia Donohoue (Iowa
maintained. City, USA), Chris Driver (Aberdeen, UK),
Much remains to be clarified about have registers of DSD cases but there Stenvert Drop (Rotterdam, Netherlands),
the determinants of gender identity in could be added benefit from pooling Erica Eugster (Indianapolis, USA), Kenji
DSD. Future studies require representa- such resources to enable prospective Fujieda (Asahikawa, Japan), Jay Giedd
tive sampling to carefully conceptualise multicentre studies to be undertaken (Bethesda, USA), Richard Green (London,
and measure gender identity, recognis- on a larger number of cases that are UK), Melvin Grumbach (San Francisco,
ing that there are multiple determinants clearly defined. Allied to this should be USA), Vincent Harley (Victoria, Australia),
an educational programme to ensure Melissa Hines (London, UK), Olaf Hiort
to consider and gender identity may
( L ü b e c k , G e r m a n y ) , I e u a n H u g h e s
change into adulthood. In terms of that professionals tasked with providing (Cambridge, UK), Peter Lee (Hershey, USA),
psychological management, studies are care for DSD families are suitably Leendert Looijenga (Rotterdam,
needed to evaluate the effectiveness of trained to discharge their responsibil- Netherlands), Berenice Mendonça (Sao
information management with regard to ities. Paulo, Brazil), Heino Meyer-Bahlburg (New

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LEADING ARTICLE 561

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Academy of Pediatrics. Disclosure of illness status
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to children and adolescents with HIV infection. ROLE OF SUPPORT GROUPS
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are more salient issues for many in the Children Act 1989, in which
82 Honecker F, Stoop H, de Krijger RR, et al. affected people. parental rights were replaced by paren-
Pathobiological implications of the expression of Support groups complement the tal responsibilities.91 UK courts can
markers of testicular carcinoma in situ by fetal work of the health care team and, intervene with orders made requiring
germ cells. J Pathol 2004;203:849–57.
83 Cools M, Van Aerde K, Kersemaekers AM, et al. together, can help improve services. or preventing a specific action related to
Morphological and immunohistochemical Initiatives by support groups have led the child. Age is not a barrier to

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LEADING ARTICLE 563

informed consent, providing that a was formulated for parental and physi- who did and those who did not want
minor demonstrates an understanding cian intervention. The process of con- early surgery for their child, until there
of the issues sufficient to have the sent requires ‘‘qualified and persistent was clear evidence of harm in deferring
capacity to consent. informed consent’’ over an extended surgery until the child was competent to
period of time. Authorisation is given decide. Parents cannot consent for
Colombia in stages to allow time for the parents to children over 5 years of age, as by then
Colombian law is noted for a reasoned come to terms with their child’s condi- children are deemed to have identified
set of guidelines advanced by the high- tion. The court aimed to strike a balance with a gender and so are considered to
est court in cases of DSD.92 A protocol between parental autonomy for those be autonomous.

IMAGES IN PAEDIATRICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
doi: 10.1136/adc.2006.093682
Intraoral graphite tattoo

G
raphite pencils, in addition to
their usual role as teaching tools,
may cause traumatic injury and
foreign body reaction, especially during
early childhood.
A 5 year old healthy female patient
was referred from the paediatric clinic
because of her father’s concern about a
blue lesion on the upper gum which has
been increasing in size over four Figure 1 Intraoral view showing the macule Figure 2 Destruction of alveolar labial bone
months. Intraoral examination showed labial to maxillary left primary central and and presence of black granules.
an asymptomatic, firm, well defined, lateral incisors.
F B Rihani
scalloped, blue–black macule measuring Prince Rashid Bin AL-Hassan Hospital, Royal
15 mm65 mm involving the attached Medical Services, Jordan
gingiva and extending apically to the D M Da’ameh
mucogingival junction in the area labial incisor, and residues of solid black Queen Alia Hospital, Royal Medical Services,
to the maxillary left primary central and granules (fig 2). Histopathology showed Jordan
lateral incisors (fig 1). There was no mild chronic inflammatory cell infiltrate
Correspondence to: Dr F B Rihani, Irbid, AL-
associated inflammation and the lesion with multinucleated giant cells. There Huson, PO Box 434, Irbid 21510, Jordan;
failed to respond to the blanching test. A was no evidence of cellular atypia and fbrihani@yahoo.com
periapical radiograph of the anterior solid granules were consistent with
Competing interests: none
maxillary region did not show any pencil graphite.
Consent was obtained for publication of the
pathological changes. Differential diag- The most common causes of exogen- figures
noses of foreign body pigmentation, ous localised oral pigmentation are
References
melanocytic nevi, and malignant mela- amalgam tattoo, followed by graphite.1 2 1 Witman PM, Rogers RS 3rd. Pediatric oral
noma were considered. A full mucoperi- Intraoral graphite implantation is com- medicine. Dermatol Clin 2003;21:157–70.
osteal flap was raised, revealing abun- mon in the anterior palates of younger 2 Kauzman A, Pavone M, Blanas N, et al.
Pigmented lesions of the oral cavity: review,
dance of granulation tissue, destruction children; biopsy is mandatory to rule out differential diagnosis, and case presentations.
of labial cortical bone to the central malignancy.2 J Can Dent Assoc 2004;70:682–3.

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