This document provides an overview of disorders of sex development (DSD). It begins with a definition of DSD and outlines the normal process of sex development, including hormones, chromosomes, genes involved and embryonic development. It then classifies and describes various types of DSD, including disorders of gonadal differentiation, true hermaphroditism, masculinized females, and undermasculinized males. For each type, it discusses etiology, phenotypes, management considerations, and specific conditions like congenital adrenal hyperplasia. The goal is to understand the complex topic of DSD by outlining the normal processes, defining key terms, and classifying the various potential disorders.
5. Chromosomal Sex
Genes associated with sex determination
SRY (sex-determining region Y gene) is responsible for testis
formation and called TDF (testis-determining factor).
Mutation in SRY gene may occurs and result in sex reversal As
it absent in Y chromosome result in XY female And it’s
present in X chromosome result in XX male And this prove that
SRY gene is TDF.
Sinclair et al 1990
6. Chromosomal Sex
Presence of SRY gene Testis formation
Absence of SRY gene ovary formation
(Passive)
• During the first 6 weeks the gonadal ridge, germ
cells bipotential sex development.
• Ovarian differentiation needs at least two X
chromosome ( this explain dysgenetic ovary in 45
X0 turner). Haqq et al 1994
7. Gonadal development
1. In Males
• Differentiation of sertoli cell (7th week) MIS production
regression of Mullerian ducts.
• MIS acts unilaterally.
• Formation of leydige cell (9th week) testosterone
production proliferation of wolffian duct and descend of the
testis.
8. Gonadal development
• Testosterone dihydrotestosterone (higher affinity to
androgen receptors) by intracellular 5α-reductase.
• Disorders of androgen receptors or 5α-reductase lead
to a spectrum of phenotypic abnormalities in the
genetic male.
Andersson et al, 1991
9. Gonadal development
2. In Females
• Absent SRY Ovary differentiation
No MIS NO testosterone
Proliferation of Mullerian duct
• Uterus
• Fallopian tube
• Upper 4/5 of vagina
Reggresion of wolffian duct
• Epoophoron and
paroophoron
• Gartener’s duct
11. Phenotypic differentiation
Undifferentiated stage
• Before the 8th week of gestation the urogenital tract is
identical in the two sexes.
• Undifferentiated stage of external genitalia consists of
1. Genital tubericle
2. Genital (urethral ) folds
3. Genital swelling
12. Phenotypic differentiation
In males
• Androgen -masculinization of the external genitalia
(12th-13th week).
-penile growth and testicular descent
(3rd trimester) Doymer et al 1994.
13. Phenotypic differentiation
In Females
• In the female fetus the absence of circulating
testosterone maintains the appearance of the Female
external genitalia at the 6-week gestational stage.
Doymer et al 1994
14. Gender Identity
• Gender identity;- the identification of self as
either male or female.
• Is complex, poor understood and multifactorial.
• Androgen has major role in brain imprint.
• Postnatal environmental factors and learning
appear to have an important effect.
Reiner et al 2004
15. Outlines
• Normal sex development and Embryology
• Definition
• Classification
• Disorders
• Workup
16. Definition of DSD
Conditions involving the following elements
• Sex chromosome anomalies as Turner syndrome.
• Disorder of gonadal developments as ovitestes
• Disorders of internal reproductive organs
• Disorders of external genitalia ( ambigious)
It was called intersex but this term is not accurate
and showed be avoided.
Hughes et al 2006
17. Outlines
• Normal sex development and Embryology
• Definition
• Classification
• Disorders
• Workup
18. Classification
1. Disorders of Gonadal Differentiation
2. True Hermaphroditism (Ovotesticular DSD)
3. Female Pseudohermaphrodite (Masculinized
Female)
4. Male Pseudohermaphrodite (Under-masculinized
Male)
5. Unclassified Forms
19. Disorders of Gonadal Differentiation
• Seminiferous tubule dysgenesis
1. Klinefelter syndrome
2. 46,XX male
• Syndromes of gonadal dysgenesis
1. Turner syndrome
2. Pure gonadal dysgenesis
3. Mixed gonadal dysgenesis
4. Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
• Bilateral vanishing testis/testicular regression
syndromes
• Seminiferous tubule dysgenesis
20. Seminiferous tubule dysgenesis
1. Klinefelter syndrome
• The Most common DSD.
• Genotype;- Male with at least Y + at least 2 X
chromosomes (47XXY (classic), 48XXXY,48XXYY,…..
Mosaic 46XY/47XXY)
• Gonads;- Small firm atrophic testes with small number of
leydig cells Azospermic except in mosaic.
• Hormones;-low normal Testosterone , Increase FSH and
LH, Increase estrogen.
• Phenotype; normal male external genitalia Not ambiguous
21. • Special features
• Complications
1. High incidence of
breast cancer (8 times).
2. Predispose to sertoli
and leydig cell tumour
3. Infertility
• Management
1. Androgen replacement
2. Surveillance for
testicular tumor and
breast carcinoma.
Staessen et al 2003
Klinefelter syndrome
22. Cont…Seminiferous tubule dysgenesis
2. 46,XX male
Due to translocation of Y chromosomal material, including SRY
(TDF) to the X chromosome.
• Gonads;- Small firm atrophic testes with small number of
leydig cells Azospermic
• Hormones;-low normal Testosterone , Increase FSH and
LH, Increase estrogen.
• Phenotype; normal male external genitalia Not ambiguous
but 10 % hypospadias.
• Complication and Management as Klinefelter but shorter and
normal skeletal proportions.
Fechner et al 1993
23. Disorders of Gonadal Differentiation
• Seminiferous tubule dysgenesis
1. Klinefelter syndrome
2. 46,XX male
• Syndromes of gonadal dysgenesis
1. Turner syndrome
2. Pure gonadal dysgenesis
3. Mixed gonadal dysgenesis
4. Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
• Bilateral vanishing testis/testicular regression
syndromes
• Syndromes of gonadal dysgenesis
24. Turner syndrome
• Incidence of 1 in 2500 live births.
• Genotype 45XO , Mosaic (45XO/46XX
,45XO/46XY).
• Gonads fibrous streaks (no surviving germ cells)
• Hormones Decrease both androgen and estrogen, increase in
FSH and LH
• Phenotype; normal female external genitalia ( well-
differentiated external genitalia, vagina and müllerian
derivatives) Not ambiguous Epstein, et al 1990
• Renal anomlies 33% (structural or positional );
Horseshoe kidney or renal agenesis , and malrotation.
Hall et al , 1990
26. Disorders of Gonadal Differentiation
• Seminiferous tubule dysgenesis
1. Klinefelter syndrome
2. 46,XX male
• Syndromes of gonadal dysgenesis
1. Turner syndrome
2. Pure gonadal dysgenesis
3. Mixed gonadal dysgenesis
4. Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
• Bilateral vanishing testis/testicular regression
syndromes
• Syndromes of gonadal dysgenesis
27. Syndromes of gonadal dysgenesis
• Abnormality of SRY gene that affects SRY
function fundamental abnormality of gonadal
development.
• Karyotyping is variable XX or XY.
• Gonads can be ‘streak’ gonad or dysgenetic.
• failure of the Gonads to produce testosterone and
MIS results in an entirely female phenotype.
• Partial gonadal dysgenesis may be unilateral or
bilateral, and so gives rise to varying degrees of
sexual ambiguity.
29. Mixed gonadal dysgenesis
Testis
(Often Intra-abdominal)
MIS and testosterone
ipsilateral wolffian duct
differentiation and müllerian
ducts regression
Streak gonad
NO MIS and testosterone
Mullerian duct differentiation
Ipsilateral uterus fallopian tube
Davidoff and Federman, 1973
30. • Gender assignment depends on
function of the external genitalia and
gonads (anatomy not fertility).
Female
Orchidectomy and
hormonal replacement
Male
Orchiolysis and pexy plus
screaning for germ
tumour Or
gonadectomy and
androgen replacement
31. Disorders of Gonadal Differentiation
• Seminiferous tubule dysgenesis
1. Klinefelter syndrome
2. 46,XX male
• Syndromes of gonadal dysgenesis
1. Turner syndrome
2. Pure gonadal dysgenesis
3. Mixed gonadal dysgenesis
4. Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
• Bilateral vanishing testis/testicular regression
syndromes
Bilateral vanishing testis/testicular
regression syndromes
32. Bilateral vanishing testis/testicular
regression syndromes
• 46,XY
• Absent testes with clear evidence of testicular
function at some point during embryogenesis.
• Due to genetic mutation, a teratogen, or bilateral
torsion.
• Diagnosis: Elevated FSH/LH and castrate
testosterone levels; 46 XY
Migeon et al 1994
33. Most sever
Before60-70 days
gestation
MIS secreted but before
the elaboration of
androgen.
phenotypic female
with no internal genital
structures
testicular regression
syndrome
Intermediate
After liberation of
MIS and incomplete
eloberation of
androgen
ambiguous
genitalia,
absent gonads
and internal
ductal structures
Least sever
Late after complete
anatomic development
of the male external genitalia
phenotypic males with fully
developed wolffian
structures but an empty
scrotum, and microphallus.
bilateral vanishing
testes syndrome
3 phenotypes according to the time that vanishing
occur.
34. Classification
1. Disorders of Gonadal Differentiation
2. True Hermaphroditism (Ovotesticular)
3. Female Pseudohermaphrodite (Masculinized
Female)
4. Male Pseudohermaphrodite (Under-masculinized
Male)
5. Unclassified Forms
35. True Hermaphroditism (Ovotesticular)
• Both testicular and ovarian tissue, either in
separate gonads or coexisting in the same gonad
as an ovotestis.
• Karyotype variable Not helpful for diagnosis.
• Phenotype Ambiguous genitalia with tendency
to masculinization (75% are raised as male).
• Internal organs are variable and according to the
present gonad
• Pregnancy documented in female only.
(Berkovitz et al, 1991)
37. True Hermaphroditism (Ovotesticular)
Management
• Gender assignment based on the functional potential
of external genitalia, internal ducts, and gonads,
according to the findings at laparoscopy or
laparotomy.
• If the patient is to be raised as female, all testicular
and wolffian tissue should be removed.
• If a male gender is assigned, all ovarian and müllerian
tissue should be removed
• Gonadectomy at puberty with androgen replacement
due to the high risk of malignancy and no hope for
fertility.
Starceski et al, 1988
38. Classification
1. Disorders of Gonadal Differentiation
2. True Hermaphroditism (Ovotesticular)
3. Female Pseudohermaphrodite (Masculinized
Female)
4. Male Pseudohermaphrodite (Under-masculinized
Male)
5. Unclassified Forms
39. Masculinized Female
(Female Pseudohermaphrodite)
• 46,XX DSD phenotypic disorder
• CAH is the main etiology
• Most common cause of ambiguous genitalia.
• Autosomal recessive disorder
• Deficiency of an enzyme involved in
glucocorticoid synthesis increase ACTH shift
to androgen pathway and adrenal hyperplasia
Ambiguous gentalia.
New and Levine, 1984
41. Congenital Adrenal Hyperplasia
• Types:
(1) salt wasters (patients with virilization and
aldosterone deficiency) 75%.
(2) simple virilizers (patients with virilization, but
without salt wasting) 25%.
(3) Non classic patients (those without evidence of
virilization or salt wasting) rare.
Kohn et al, 1995.
44. Congenital Adrenal Hyperplasia
• Diagnosis
• Demonstration of inadequate production of
cortisol, aldosterone, or both
• Demonstration of excess concentrations of
precursor hormones;
serum 17-hydroxyprogesterone
Urinary 17-ketosteroid levels
serum 11-deoxycortisol and deoxycorticosterone
45. Congenital Adrenal Hyperplasia
• Salt-wasting forms of CAH: Low serum
aldosterone concentrations, hyponatremia ,
hyperkalemia, and elevated plasma renin activity
(PRA).
• A karyotype is essential in an infant with
ambiguous genitalia, to establish the
chromosomal sex
46. Classification
1. Disorders of Gonadal Differentiation
2. True Hermaphroditism (Ovotesticular)
3. Female Pseudohermaphrodite (Masculinized
Female)
4. Male Pseudohermaphrodite (Under-masculinized
Male)
5. Unclassified Forms
47. Male Pseudohermaphrodite
(Undermasculinized Male)
• 46,XY with differentiated testes.
• Varying degrees of feminization phenotypically.
• Secondary to:
inadequate secretion of testosterone by the testes.
inability of target tissue to respond to androgen
appropriately.
impaired production or action of MIS.
48. Male Pseudohermaphrodite
Undermasculinized Male ( 46,XY DSD)
Classifications
1. Leydig Cell Aplasia (Luteinizing
Hormone Receptor Abnormality)
2. Disorders of Testosterone Biosynthesis
3. 5α-Reductase Deficiency
4. Androgen Receptor and Postreceptor
Defects (testicular feminization)
5. Persistent Müllerian Duct Syndrome
(hernia uteri inguinale).
LH
T
DHT
Receptor
50. Male Pseudohermaphrodite
Undermasculinized Male ( 46,XY DSD)
5.Persistent Müllerian Duct Syndrome (hernia uteri
inguinale).
• 46,XY
• normal male external genitalia
• internal müllerian duct structures.
• unilateral or bilateral undescended testes
• commonly diagnosed after müllerian tissue is
encountered during inguinal herniorrhaphy or
orchidopexy.
51. Cont.. Persistent Müllerian Duct
Syndrome
• The treatment of persistent müllerian duct
syndrome is relatively straightforward, in that all
patients are phenotypic males who require
orchidopexy.
• The vasa deferentia are in close proximity to the
uterus and proximal vagina, and preservation of
the necessary müllerian structures to avoid injury
to the vasa is recommended to preserve fertility
Sloan and Walsh, 1976
52. Outlines
• Normal sex development and Embryology
• Definition
• Classification
• Disorders
• Workup
54. • Classic ambiguous genitalia
• Female with palpable gonads
• Male with nonpalpable gonads
• Hypospadias and cryptorchidism
• “Normal” Female or Male
Common Neonatal Presentations
56. Questions to be answered
• What is the diagnosis
• What is the anatomy
• What is the function of gonads and
reproductive tract
• Gender Assignment
57. Important principles
A. Palpable gonad = testis; as ovaries do not
descend , Rarely, an ovotestis descent to the
inguinal canal.
B. Bilaterally impalpable testes or unilaterally
impalpable testis and hypospadias should be
considered DSD until proven otherwise, whether
or not the genitalia appear ambiguous.
59. Work up
• Karyotyping
• Hormonal assay; serum electolyte, T, DHT, serum
17-hydroxyprogesterone,
• HCG stimulation test ruling out anorchia.
• Laparoscopy and gonadal biopsy.
• Genitogram and endoscopy to detect urogenital
sinus.
61. Role of surgery
• Feminising surgery
Clitororeduction; Reduction of an enlarged
clitoris should be done with preservation of the
neurovascular bundle.
Separation of the vagina and the urethra is
preserved for high confluence anomalies for
urogenital sinus repair.
Vaginoplasty should be performed during the
teenage years.
62. Role of surgery
• Masculinising surgery
• Hypospadias surgery.
• Excision of Mullerian structures.
• Orchiopexy.
• Phalloplasty; severe penile inadequacy in DSD
patients.
• correction of penoscrotal transposition,
scrotoplasty
• insertion of testicular prostheses.