DSD Disorders of Sex Development

1. Disorders of Sex Development
(DSD)
Dr Inayat Ullah
PG-IV Pediatrics
Shifa International Hospital
Islamabad

2. Definition
• A congenital discrepancy between external
genitalia, gonadal and chromosomal sex
are classified as having a disorder of sex
development.
• A 2006 consensus conference suggested
that the potentially pejorative terms
"pseudohermaphrodite," "hermaphrodite,"
and "intersex" be replaced by the
diagnostic category "disorders of sex
development" (DSD)

3. Novel Nomenclature

4. Physiology
• Sexual differentiation is a sequential process
in which chromosomal sex determines
whether the gonad will develop into an ovary
or testis. Testes secrete hormones that
convert the basic female (or default)
phenotype into a male Urogenital tract and
external genitalia.
• The mechanisms by which the SRY gene on
the Y chromosome dictates testicular
development and testicular hormones
promote male development are incompletely
understood

5. Normal physiology/Embryogenesis
Genes/Molecules
• A 46,XX complement of chromosomes
– genetic factors DAX-1 and the
– signaling molecule WNT-4 are necessary for the
development of normal ovaries.
– Ovarian development in 10-11th wk of gestation
• Male phenotype requires a
– Y chromosome
– intact SRY gene,
– other genes such as SOX9, SF1, and WT1
– AMH activation in the testes require SF1 gene for
activation

6. Genes/hormones involved in
phenotypic differentiation of genital
tracts

9. 46 XX DSD

10. Characteristics
• Genotype is XX
• Gonads are ovaries uterus, fallopian
tubes, and cervix develop
• Virilized external genitalia(clitoral
hypertrophy and labioscrotal fusion)

11. Causes
• CAH (most common)
• Aromatase deficiency
• Glucocorticoid receptor gene mutation
• Virilizing maternal tumors
• Androgenic drugs to women in pregnancy

12. CAH
• 21 hydroxylase deficiency
• 11 hydroxylase deficiency
• 3b hydroxysteroid dehydrogenase
deficiency(DHEA is a weak androgen)
minimal virilization
• Salt losers have greater degree for virilization
• Complete penile urethra (male with bilateral
cryptorchidism)

14. Aromatase deficiency
• Aromatase is an enzyme that converts male
to female hormones.(androgen to estrogen)
• At puberty shows hypergonadotropic
hypogonadism
– (ovarian failure to synthesize estrogen)
– USG large ovarian cyst
• Can also present at birth with AG with low
maternal serum and urinary levels of
estrogen and high androgen levels.

15. Glucocorticoid receptor gene
mutation
• Elevated cortisol levels at baseline and after dexa
supression, hypertension, and hypokalemia,
suggest generalized glucocorticoid resistance.
• Homozygous mutation in exon 5 of the
glucocorticoid receptor
• Girls born with ambiguous genitalia, no
progression postnatally
– androgen levels are normal or low.
• Boys may be born undervirilized.
• Both may exhibit bony abnormality (radiohumeral
synostosis, long bone fractures and femoral
bowing)

16. Virilizing maternal tumors
• Maternal androgen producing tumor can
virilize female fetus
• Benign adrenal adenoma,
• Ovarian tumors : Androblastoma,
luteomas, krukenburg tumors
• Both Maternal and fetal virilization
• MOM of Unexplained 46XX DSD should
be screened for plasma testosterone,
DHEA, and androstenedione

17. Virilizing maternal tumors cont’d
• Maternal virilization:
clitoral enlargement, acne,
deepening of voice, dec. lactation,
hirsutism, high androgen levels.
• Infant virilization:
clitoral enlargement of varying degrees
labial fusion

18. Androgen drugs in pregnancy
• Testosterone and 17methyltestosterone
• Use of progestational compounds for
treatment of threatened abortion.
• Urinary and GIT defects in fetus

19. 46 XY DSD

20. Characteristics
• Genotype is XY
• Phenotype:
• Completely virilized,
• Ambiguous,
• Completely female

21. Underlying Causes
• Defects in testicular differentiation
• Defects in testicular hormones
• Defects in androgen action
• Some un determined causes

22. Defects in testicular
differentiation
• Conversion of indifferent gonads into testis
(1st step)
• Deletion of short arm of Y chromosome or of
SRY gene
– Phenotype is female
– Mullerian duct well developed because of
absence of AMH.
• Deletions of long arm of Y chromosome
– Normally developed male
– Azospermic
– Short strature

23. • Testis fails to differentiate ,Y chromosomes
are morphologically normal
– Denys drash syndrome
– WAGR syndrome
– Campomelic syndrome
– Swyer syndrome
– XY gonadal agenesis syndrome

24. Denys-Drash syndrome
• Nephropathy with ambiguous genitals and bilateral
Wilms tumor
• 46,XY. Müllerian ducts present, indicating a global
deficiency of fetal testicular function.
• 46,XX karyotype have normal external genitals
• Nephrotic syndrome and end-stage renal failure by 3 yr
of age
• Wilms tumor usually develops in children younger than 2
yr of age
• Gonadoblastoma also reported

25. WAGR syndrome
• Wilms tumor, Aniridia, Genitourinary
malformations, and Mental Retardation .
• Deletion of one copy of chromosome 11p13.
• Cryptorchidism to severe deficiency of
virilization.
• Unexplained obesity, obesity-associated gene
in this region of chromosome 11 (WAGRO).
• Gonadoblastoma

26. CAMPOMELIC SYNDROME
• Short limb dysplasia characterized by anterior
bowing of the femur and tibia, small,
bladeless scapulae, small thoracic cavities
and 11 pairs of ribs
• It is usually lethal in early infancy.

27. CAMPOMELIC SYNDROME
• 75% 46XY are completely female
phenotype
• Ambiguous genitals.
• The gonads appear to be ovaries but
histologically may contain elements of
ovaries and testes.

28. CAMPOMELIC SYNDROME
• The gene responsible for the condition is SOX9
on 17q24–q25.
• The inheritance is autosomal dominant.
• Gonadoblastoma also reported
• SF1 gene mutation ….adrenal insufficency &
46XY gonadal dysgenesis

29. XY PURE GONADAL DYSGENESIS
(SWYER SYNDROME).
• Normal stature and a female phenotype,
including vagina, uterus, and fallopian
tubes, but at pubertal age, breast
development and menarche fail to occur.
• Patients present at puberty with
hypergonadotropic primary amenorrhea.
• Familial cases suggest an X-linked
dominant autosomal transmission.
• Mutations of the SRY gene.

30. (SWYER SYNDROME).
• The gonads consist of almost totally undifferentiated
streaks despite the presence of a cytogenetically
normal Y chromosome.
• PRIMITIVE GONAD do not have testicular function,
including suppression of müllerian ducts.
• Hilar cells in the gonad can produce androgens so
clitoral enlargement, may occur at the age of puberty.
• Neoplastic changes, such as gonadoblastomas and
dysgerminomas

31. DEFECTS IN TESTICULAR
HORMONES
• These defects produce 46,XY males with
inadequate masculinization

32. LEYDIG CELL APLASIA.
• Produce testosterone in the presence of
luteinizing hormone
• Female phenotypes, but there may be mild
virilization.
• Testes, epididymis, and vas are present; the
uterus and fallopian tubes are absent.
• No secondary sexual changes at puberty; pubic
hair may be normal.

33. LEYDIG CELL APLASIA.
• Testosterone levels are low and do not
respond to hCG; LH levels are elevated.
• Leydig cells of the testes are absent or
markedly deficient.
• The defect may involve a lack of receptors
for LH.
• Autosomal recessive inheritance

34. LIPOID ADRENAL
HYPERPLASIA
• Enlarged adrenal glands resulting from
accumulation of cholesterol and cholesterol esters
in gonads & adrenal cortex
• Cholesterol transport into mitochondria is
mediated by a (StAR)
• ALL serum steroids are low/undetectable
• ACTH & RENIN level elevated
• Phenotype is female in both genetic female and
males
• Infant presents with acute adrenal crises & salt
wasting

35. 3β-HYDROXYSTEROID
DEHYDROGENASE DEFICIENCY.
• Various degrees of hypospadias, with or
without bifid scrotum and cryptorchidism
rarely, a complete female phenotype.
• Affected infants acquire salt-losing
manifestations shortly after birth.
• Incomplete defects with premature pubarche,
and late-onset nonclassic forms
• Infertility is frequent.
• No correlation between degree of salt
wasting and degree of phenotypic
abnormality

37. DEFICIENCY OF 17-
HYDROXYLASE/17,20 LYASE.
• Genetic males have a complete female
phenotype
• Various degrees of undervirilization from
labioscrotal fusion to perineal hypospadias and
cryptorchidism.
• Pubertal development fails to occur in both
genetic sexes.

38. • In classical disorder, dec. synthesis of cortisol.
• Levels of (DOC) and corticosterone are markedly
increased and lead to the hypertension and
hypokalemia
• Cortisol is low, the elevated corticotropin and
corticosterone levels maintain a eucorticoid state.
• The renin-aldosterone axis is suppressed because of
the strong mineralocorticoid effect of elevated DOC.

39. • Virilization does not occur at puberty; levels of
testosterone are low, and those of
gonadotropins are increased.
• Because fetal production of AMH is normal, no
müllerian duct remnants are present.
• In phenotypic XY females, gonadectomy and
replacement therapy with hydrocortisone and
sex steroids are indicated

40. • autosomal recessive inheritance.
• Affected XX females do not have pubertal
changes and have hypertension and
hypokalemia.
• primary amenorrhea and hypertension.

41. DEFICIENCY OF 17-KETOSTEROID
REDUCTASE.
• 17β-HSD convert androstenedione to testosterone
and also dehydroepiandrosterone to androstenediol
and estrone to estradiol.
• Complete or near-complete female phenotype in
46,XY males.
• Müllerian ducts are absent, shallow vagina is
present.
• The diagnosis is based on the ratio of testosterone
to androstenedione; in prepubertal children, prior
stimulation with hCG is necessary

42. • Most patients are diagnosed at puberty
because of the failure to menstruate and
of virilization.
• Testosterone levels at puberty may
approach normal, presumably as a result
of peripheral conversion of
androstenedione to testosterone; at this
time, some patients spontaneously adopt
a male gender role

43. PERSISTENT MÜLLERIAN DUCT
SYNDROME.
• Persistence of müllerian duct derivatives in
completely virilized males.
• Cases have been reported in siblings and
identical twins.
• Cryptorchidism is present in 80% of affected
males
• Testicular function is normal
• Testicular tumors after puberty are common.

44. PERSISTENT MÜLLERIAN DUCT
SYNDROME.
• Defects in the AMH gene, low AMH levels.
• Defect in the AMH type II receptor gene
• Treatment consists of removal of as many of the
müllerian structures as possible without causing
damage to the testis, epididymis, or vas deferens

45. DEFECTS IN ANDROGEN
ACTION
• Fetal synthesis of testosterone is normal
• Defective virilization results from inherited
abnormalities in androgen action
• 5a reductase deficiency
• AIS

46. 5α-REDUCTASE DEFICIENCY.
• Dec. production of (DHT) in utero results in
severe ambiguity of the external genitals of
the affected male fetus.
• Biosynthesis and peripheral action of
testosterone are normal.
• phenotype in boys have small phallus, bifid
scrotum, urogenital sinus with perineal
hypospadias, and a blind vaginal pouch

47. DHT fuctions
• Masculinization of the urogenital sinus and
external genitals
• Penis and scrotal development
• Growth of facial hair and of the prostate

49. • Testes are in the inguinal canals or
labioscrotal folds and are normal
histologically.
• There are no müllerian structures.
•
• Wolffian structures—the vas deferens,
epididymis, and seminal vesicles—are
present.

50. • Most affected patients identified as females.
• At puberty, virilization occurs; the phallus enlarges,
the testes descend and grow normally, and
spermatogenesis occurs.
• There is no gynecomastia.
• Beard growth is scanty, acne is absent, the
prostate is small, and recession of the temporal
hairline fails to occur.
• .

51. • The adult height reached is close to that of the
father and other male siblings.
• Autosomal recessive trait but is limited to males
• Significant phenotypic heterogeneity 5 types of
steroid 5α-reductase deficiency (SRD)
• Complete female (type 5),
Partial female (type 4),
Ambiguous (type 3),
Predominantly male with micropenis (type 2),
Completely male phenotype (type 1)

52. • Normal serum testosterone levels,
• Normal or low DHT levels with markedly
increased basal and especially hCG-stimulated
testosterone : DHT ratios (>17),
• High ratios of urinary etiocholanolone to
androsterone and 5α to 5α metabolites.
• Treatment of male infants with DHT results in
phallic enlargement.

53. ANDROGEN INSENSITIVITY
SYNDROMES.
• Most common forms of male DSD,
• Frequency of 1/20,000 genetic males.
• X-linked disorders
• More than 150 different mutations in the
androgen receptor gene, located on Xq11–
12:

54. Features
• 46,XY chromosomes, range from
– phenotypic females (in complete AIS) to males
– ambiguous genitals and undervirilization (partial AIS,
or clinical syndromes such as Reifenstein syndrome)
hypogonadism, severe hypospadias, and
gynecomastia
– phenotypically normal-appearing males with infertility.

55. Complete AIS,
• The vagina ends blindly in a pouch, uterus is absent.
unilateral or bilateral fallopian tube remnants are found.
• The testes are usually intra-abdominal but may descend
• At puberty, normal development of breasts, and the
habitus is female,
• Menstruation does not occur and sexual hair is absent.
• Adult heights of these women are commensurate with
those of normal males

56. CAIS (Cont’d)
• Prepubertal children diagnosis during
herniorrhaphy in a phenotypic female.
• Infants, elevated gonadotropin levels
should suggest the diagnosis.
• In adults, amenorrhea is the usual
presenting symptom.
• Reifenstein syndrome, Gilbert-Dreyfus
and Lubs syndromes (partial AIS)

57. • Diagnosis.
• Postnatal surge in testosterone and LH is
diminished in complete AIS but not in those
with partial AIS.
• Sufficiently virilized in infancy, the diagnosis
is not suspected
• Until puberty when there is inadequate
virilization with lack of facial hair or voice
change and the appearance of
gynecomastia. Azoospermia and infertility are
common.
•

58. (Cont’d)
• Androgen receptor defects are being
recognized in adults who have a small
phallus and testes and infertility.
• IGF2 and IGFBP2 but not IGFBP3 production
by genital skin fibroblasts is decreased in
CAIS compared with normal genital skin
fibroblasts, suggesting a possible role for the
IGF system in modulating androgen action

59. (Cont’d)
• Surgery
• Removal of the testes
• Vaginal lengthening
• Genital plastic surgery
– Reconstructive surgery on the female genitalia if
masculinization occurs
– Phalloplasty
– Vaginoplasty
– Pressure dilation
– Clitorectomy

60. CAIS (Cont’d)
• Hormone Replacement Therapy (HRT)
with estrogen at puberty
• Prevents osteoporosis

62. OVOTESTICULAR DSD

63. Ovotesticular DSD
• Both ovarian and testicular tissues are present,
either in the same or in opposite gonads.
• Ambiguous genitals, normal female or normal
male external genitals
• About 70% of all patients have a 46,XX
karyotype;
• About 20% have 46,XX/46,XY mosaicism.
• Usually sporadic
• Cause of most cases of ovotesticular DSD is
unknown.

64. • Ovotestis, which may be bilateral; if unilateral, the
contralateral gonad is usually an ovary but may be a
testis.
• The ovarian tissue is normal, but the testicular tissue is
dysgenetic.
• The presence and function of testicular tissue can be
determined by measuring basal and hCG-stimulated
testosterone levels and AMH levels.
• Patients who are highly virilized, have good testicular
function, and have no uterus are usually reared as
males.

65. Ovotesticular DSD(Cont’d)
• If a uterus exists, virilization is mild, and
testicular function minimal; assignment of
female sex may be indicated
• About 5% of patients acquire
gonadoblastomas, dysgerminomas, or
seminomas

66. DIAGNOSTIC APPROACH
DSD

67. Red Flags for DSD
• Bilaterally nonpalpable testes.
• Microphallus (stretched penile length less than 2.5 cm
in a full-term infant); microphallus without associated
hypospadias is not "ambiguous," but may be a marker
of other disorders.
• Perineal hypospadias with bifid scrotum.
• Clitoromegaly (clitoral width >6 mm or clitoral length
>9 mm)
• Posterior labial fusion (anogenital ratio >0.5).
• Gonads palpable in the labioscrotal folds.
• Hypospadias and unilateral nonpalpable gonad .
• Discordant genitalia and sex chromosomes

68. Red Flags

69. • History
• Physical Examination
• Karyotype
• Screening for CAH
• Screening for androgens & precursors
• Screening for gonadal response to gonadotropins in
pts with testicular gonads
• Molecular genetic analysis for SRY gene
• Gonadotropin levels
• Pelvic and Abdominal USG
• Pelvic MRI or CT Scan
• VCUG
• ENDOSCOPIC exam of genitourinary tract

72. Categorization
• The information from the initial evaluation
can be used to categorize the infant into
one of three categories, as suggested by
an international consensus conference:
• Virilized XX
• Undervirilized XY
• Mixed sex chromosome pattern

73. Prader scale

74. History
• The history in a child with a (DSD) should include the
following info:
• Prenatal exposure to androgens (eg, progesterones,
danazol , testosterone) or endocrine disrupters (
phenytoin , aminoglutethimide).
• Maternal virilization in pregnancy (placental aromatase
deficiency, luteoma).
• Family history of females who are childless or have
amenorrhea (androgen insensitivity).
• Family history of unexplained infant deaths (congenital
adrenal hyperplasia).
• History of consanguinity (or homogeneous population)
(recessive disorders, eg, CAH or disorders of androgen
biosynthesis).

75. History

76. Management
• Neonatal ambiguity of the genitals requires
immediate attention
• The family of the infant needs to be informed
of the child's condition as early, completely,
compassionately, and honestly as possible.
• The initial care is best provided by a team of
professionals that include Neonatologists and
Pediatric specialists, Endocrinologists,
Radiologists, Urologists, Psychologists, and
Geneticists

77. Immediate management
• Issue of salt wasting crises in salt losing type
CAH.
• Obtain a sample for blood hormone
measurement esp 17 OH Progesterone and
serum and urine electrolytes should be
measured
• The first steps to determine the cause of the
DSD are typically performed at the same
time, and should include a karyotype and
fluorescence in-situ hybridization (FISH) for
the sex-determining region on the Y

78. Immediate management cont’d
• Hydrocortisone treatment if electrolytes
are abnormal
• If signs or symptoms of adrenal
insufficiency are present (hypoglycemia,
hypovolemia, hyponatremia, with or
without hyperkalemia, with or without
vomiting and diarrhea), fluids and
electrolytes should be replaced urgently,
using normal saline with supplemental
dextrose, if needed. (SSS)

79. Immediate management cont’d
• The birth of an infant with ambiguous genitalia is
often confusing and highly distressing for the
family, and prompt communication and
psychosocial support is imperative.
• An appropriate therapeutic plan can only be
developed with the full participation of the family,
after a careful and complete evaluation by an
experienced team of endocrinologists, geneticists,
and surgeons, aided by individuals capable of
sophisticated psychosocial support.
• Referral to a specialized center for children with
DSD is strongly encouraged

80. Gender assignment and surgery

81. Surgery for medical purposes
• To repair major birth defects (Exstrophy)
• To repair minor birth defects (Hypospadias)
• To prevent urinary tract infection or problems
• To prevent dysgenetic gonads to prevent cancer
• To do genital reconstruction or resection

82. Long term issues
• Individuals with DSDs and their families needs support to
assist in psychosexual adjustment and decision-making.
These adjustments and decisions change as the child
matures
• Because of malignant potential in abdominally positioned
gonads bearing Y chromosomal material, orhiopexy or
orchidectomy should be done. However, the malignant
potential and optimal age for surgery varies substantially
among DSDs.
• Ongoing medical concerns in children with DSDs include the
potential for malignancy in gonadal tissue or kidneys, the
effects of altered levels of sex steroid exposure, and

83. =

84. Questions?

88. Q
• What’s the commonest cause of
ambiguous genitalia in females?
• CAH
• What’s the commonest cause of
ambiguous genitalia in males?
• AIS

89. Support groups and Internet
Sites
• Intersex Society of North America) Now
called Accord
Alliance(www.accordalliance.org )
• ( www.dsdguidelines.org )
• www.bodieslikeours.org/forums )
• The Magic Foundation
(www.magicfoundation.org )
• www.caresfoundation.org/productcart/pc/in
dex.html )

90. REFERENCES
• Lee PA, Houk CP, Ahmed SF, et al. Consensus statement on management of intersex
disorders. International Consensus Conference on Intersex. Pediatrics 2006;
118:e488.
• Hughes IA, Nihoul-Fékété C, Thomas B, Cohen-Kettenis PT. Consequences of the
ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex
development. Best Pract Res Clin Endocrinol Metab 2007; 21:351.
• Ahmed SF, Hughes IA. The genetics of male undermasculinization. Clin Endocrinol
(Oxf) 2002; 56:1.
• Clarkson MJ, Harley VR. Sex with two SOX on: SRY and SOX9 in testis
development. Trends Endocrinol Metab 2002; 13:106.
• Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mutations in DAX-1
and SF-1. Mol Cell Endocrinol 2001; 185:17.
• Ozisik G, Achermann JC, Meeks JJ, Jameson JL. SF1 in the development of the
adrenal gland and gonads. Horm Res 2003; 59 Suppl 1:94.
• Wada Y, Okada M, Hasegawa T, Ogata T. Association of severe micropenis with
Gly146Ala polymorphism in the gene for steroidogenic factor-1. Endocr J 2005;
52:445.
• Wada Y, Okada M, Fukami M, et al. Association of cryptorchidism with Gly146Ala