Ambiguous Genitalia
This is the subcategory of
Disorders of Sex Development (DSD)
which presents with abnormalities of the external genitalia. The incidence of genital anomalies at
birth is as high as 1 in 300 births, but the prevalence of complex
anomalies
with true sexual ambiguity is lower, approximately 1 in 5000. A newborn with ambiguous genitalia is a
diagnostic challenge. The
announcement of the probable sex or use of personal pronouns should be
avoided. The parents should be
informed that the child is healthy, but that more tests need to be run
before
the sex can accurately be determined.
Critical in the sex determination is the
ability of the genitalia to function
sexually in adulthood. Therefore
assignment of sex and decisions concerning rearing should be postponed
until
all test results are known.
Continuous psychosocial support for the
parents is necessary throughout
the process and may be necessary for the family and the child during
the
child’s development.
Chicago Consensus
In 2005 a consensus was
reached at a meeting in Chicago
regarding the terminology and classification of intersex disorders. The use of ‘intersex’ would be replaced
by ‘disorders of sex development’, defined as ‘a congenital condition
in which
development of chromosomal, gonadal or anatomical sex is atypical’. The
use of ‘hermaphrodite’
and ‘pseudohermaphrodite’ would be replaced by the karyotype and an
accurate
description of the abnormality.
The karyotype is first identified and then
based on the other test
results, the diagnoses have been divided into the following categories:
disorders of gonadal development, disorders of androgen synthesis,
disorders of
androgen action, disorders of androgen excess, leydig cell defect,
persistent
mullerian duct syndrome, defects of mullerian development, non-specific
disorder of undermasculinisation, and other.
Sex Chromosome DSD
47,XXY (Klinefelter)
45,X (Turner)
45,X/46,XY
46,XX/46,XY
46,XY DSD
Disorders of gonadal
development
Disorders in androgen
synthesis or action
Other
46,XX DSD
Disorders of gonadal
development
Androgen Excess
Other
Which infants should be
evaluated?
·
Overt genital ambiguity.
·
Family history of DSD such
as complete androgen
insensitivity syndrome.
·
Discordance between genital
appearance and a prenatal
karyotype.
·
Apparent female genitalia
with an enlarged
clitoris and posterior labial fusion, an inguinal/labial mass.
·
Apparent male genitalia with
bilateral
undescended testes, a microphallus, proximal hypospadias or distal or
mid-shaft
hypospadias with undescended testis.
Why is an evaluation
necessary?
·
To determine the sex of
rearing
·
To evaluate for concern of
CAH and adrenal insufficiency
·
To determine the etiology
and the best long term
management
·
To address questions of
future fertility, sexual
function and tumor development
History
·
Family History – parental
consanguinity and relatives
with ambiguous genitalia, primary amenorrhea, early death, medical
issues. Autosomal recessive pattern may
suggest
altered steroidogenesis. X-linked
recessive pattern may suggest androgen insensitivity syndrome.
·
Maternal history –
medications
(androgens-progesterones, danazol, testosterone or endocrine
disrupters-
phenytoin, aminoglutethimide), virilization before or during pregnancy,
prenatal test results.
Physical Exam
·
General Exam
o
General
health
o
Dysmorphic
features
o
Midline
defects
o
Hydration
o
Blood
pressure
·
Genital Exam
o
Penile/Clitoral
length and diameter
o
Gonads
– present/absent, size, location
§
‘Federman’s rule – a gonad
felt below the
inguinal ligament is a testes until proven otherwise’
o
Urethral
opening – hypospadias, epispadias, virilized urogenital sinus
o
Rectal
inspection
o
Labiosacral
fusion – anogenital ratio (distance between anus and posterior
fourchette
divided by the distance between the anus and the base of the clitoris)
of
>0.5 suggests virilization with some posterior labial fusion.
o
External
Masculinisation Score – scores scrotal fusion, microphallus, location
of
urethral meatus and location of each gonad.
Initial Laboratory Studies
·
Karyotype
o
Including
FISH with SRY probe
·
Serum electrolytes
·
Serum 17 alpha
hydroxyprogesterone (17-OHP)
o
Elevated
in most common cause of CAH, 21-hydroxylase deficiency
·
Ultrasound of the
pelvis/abdomen for mullerian
structures
·
Serum anti-mullerian hormone
(AMH)
·
Further testing may be
necessary depending on
karyotype and other laboratory results.
This may include 11-deoxycortisol,
cortisol, DHEA, ACTH stimulation
test, hCG stimulation test.
Sex Chromosome DSD
·
Less likely to present with
ambiguous genitalia,
mosaic presentations must be considered.
46,XY DSD, Undervirilized Boy
·
Environmental chemicals
leading to hypospadias,
undescended testes that may not meet full criteria for DSD
·
Congenital adrenal
hyperplasia
o
Multiple
enzyme deficiencies may cause this.
21 hydroxylase deficiency does not result
in genital ambiguity in males,
but can lead to death from salt wasting if unrecognized.
·
5 alpha reductase deficiency
·
Androgen insensitivity
syndrome or receptor
defects (testicular feminization)
·
Gonadal dysgenesis
·
Testicular regression
syndromes
46,XX
DSD, Virilized
Girl
·
Congenital adrenal
hyperplasia
o
21
alpha hydroxylase deficiency is the most severe and presents at about
two weeks
of age with salt wasting and are at risk for adrenal crisis. 21 alpha hydroxylase deficiency and 11
beta hydroxylase deficiency can be excluded with serum 17
hydroxyprogesterone.
·
Gestational androgen excess
states such as
maternal androgen use, oral contraceptives, polycystic ovarian
syndrome, tamoxifen
use and androgen secreting tumors
·
Aromatase deficiency leading
to estrogen
deficiency and androgen excess – may see double virilizing effect – on
both
mother and child during pregnancy
References
·
Ahmed SF, and Rodie M. Investigation and initial management of
ambiguous
genitalia. Best Practice &
Research Clinical Endocrinology & Metabolism. 2010;
24 (197-218).
·
Anhalt H, and Hintz R. Ambiguous Genitalia. Pediatrics in Review.
June 1996.
·
Houk C, Levitsky L. Evaluation of the infant with ambiguous
genitalia. Uptodate. Updated April 2010
·
Huges I.
Disorders of sex development: a new
definition and classification. Best
Practice & Research Clinical
Endocrinology & Metabolism. 2008; 22 (119-134).
·
McDermott, Frank. Ambiguous
Genitalia. PedClerk
website.
·
Rosenfield RJ, Lucky AW,
Allen TD. The diagnosis and management of
intersex. Current Problems in
Pediatrics. 1980; 10(7).
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