1. Welcome To Seminar
Dr. Fatema Begum Sadia,Year-5
Dr. Faria Yasmin,Year-3
Resident , Department Of Neonatology
2. Case scenario- 1
B/O Mousumi, outborn ,2nd issue of non
consanguineous parents presented with:
• Atypical pattern of external genitalia more female
pattern, clitoromegaly (1.6 cm), urethral opening at
the base of clitoris ,partial fusion of labioscrotal fold
with a vaginal opening present ,skin hyperpigmented.
• Hypertension & hyperpigmentation around nipple &
umbilicus. Other wise the Child was normal.
3. Case scenario-2
Abu sufiyan, 15 days old, 1st issue of non-
consanguinous parents presented with the
complaints of atypical pattern of external
genitalia [ more male pattern, phallus size about
2.2 cm, hypospadias’s present, both testes are in
the scrotum, scrotum is bifid, scrotal skin is more
pigmented. Otherwise the baby was normal.
4. What are the abnormalities of these babies?
What may be the cause of these abnormalities?
What should be the approach?
6. Outline:
• Introduction
• Development & Function of Gonads
• Definition of DSD & Nomenclature
• Etiological classification of DSD
• Evaluation of DSD Patient
• Investigations
• Treatment of DSD
• Counseling
7. Introduction
• The Birth of a baby is an exiting event.
• If a baby born with Genitalia that cannot be readily identified as
either male or female inevitably precipitates a crisis for the parents.
8. Disorders of Sex Development (DSD):
• DSD is a condition “in which development of chromosomal, gonadal or
anatomical sex is atypical.”
• Discrepancy between external genitalia & internal gonad.
• Atypical genitalia are present when the sex of an infant is not readily
apparent after examination of the external genitalia.
• It is increasingly preferable to use the term “atypical genitalia” rather
than “ambiguous genitalia”
9. Development of the Gonads
• Genetic sex (XX or XY) is determined at fertilization .
• Gonadal sex- is determined by 7th weeks of gestation from
undifferentiated, bipotential fetal gonad that arises from a thickening of
the urogenital ridge & develops into either ovary or testis.
• Phenotypic sex is established at the end of first trimester.
11. Figure: Indifferent stages of the external genitalia.
A. Approximately 4 weeks. B. Approximately 6 weeks.
Figure: Development of external genitalia in the male at 10
weeks.
Figure: Development of the external genitalia in the
female at 5 months A and in the newborn B.
Ref: Langman’s Medical Embryology, 12th Edition
12. Figure: Genes responsible for Gonadal differentiation
Ref: Langman’s Medical Embryology, 12th Edition
13. Proposed Revised Nomenclature:
PREVIOUS PROPOSED
Intersex Disorders of sex development
(DSD)
Male pseudohermaphrodite 46, XY DSD
Female pseudohermaphrodite 46, XX DSD
True hermaphrodite Ovotesticular DSD
XX male or XX sex reversal 46,XX testicular DSD
XY sex reversal
46,XY complete gonadal
dysgenesis
European Society for Paediatric Endocrinology (ESPE) : 2006
14. INCIDENCE:
• 1 in 5000
• CAH is the most frequent cause of atypical genitalia in
the newborn, constituting approximately 60% of all
DSDs.
• BSMMU ENDOCRINOLOGY CLINIC (2020)
Total New case DSD CAH
3454 347 23 13(56%)
15. NICU, BSMMU
Year Total admitted patient DSD
2019 1848 (1789 +59) 3 (0.2%)
2020 1241 (1219+22) 5 (0.4%)
16. Etiologic Classification of Disorders of Sex Development (DSD):
Disorder of sexual development (DSD)
46,XX DSD 46,XY DSD Ovo-testicular DSD
Sex chromosome
DSD
17. 46,XX DSD
1. Androgen Exposure
Congenital adrenal hyperplasia(CAH): 21-OH, 11β-OH, 3β- HSD
Tumor: Virilizing maternal adrenal or ovarian tumor.
Maternal drugs: e.g. Danazol, Progestins etc.
2. Disorder of Ovarian Development
XX gonadal dysgenesis
Testicular DSD
3. Undetermined Origin
Associated with genitourinary and gastrointestinal tract defects
18. 46,XY DSD
1) Deficiency of Testicular Hormones
• Leydig cell aplasia
• 3β-HSD II deficiency
• 17-Hydroxylase/17, 20-lyase deficiency
2) Defect in Androgen Action
• Androgen Insensitivity Syndromes
• DHT Deficiency (5 –α- reductase deficiency)
3) Defects in Testicular Development
• Denys-Drash syndrome
• WAGR syndrome
• Mutation in SRY gene
• XY Gonadal agenesis
19. • In ovotesticular DSD, both ovarian and testicular tissues are present, either
in the same or in opposite gonad.
• Genotype :
• 46XX - 70% ,
• 46XY - 10%
• Mosaics 46XX/45XO/46XY/multiple X/multiple Y - 20%
• Affected patients have ambiguous genitals, varying from normal female with
only slight enlargement of the clitoris to almost normal male external
genitals.
• Palpable Gonad: Ovotestis which may be bilateral. If unilateral, the
contralateral gonad is usually an ovary but may be a testis.
Ovotesticular DSD
20. • 45,X (Turner syndrome and variants)
• 47,XXY (Klinefelter syndrome and variants)
• 45,X/46,XY (mixed gonadal dysgenesis, sometimes a cause of
ovotesticular DSD)
Sex chromosome DSD
21. CONGENITAL ADRENAL HYPERPLASIA
It is a group of AR disorders of cortisol biosynthesis characterized by
a deficiency of one of the adrenal enzymes.
Enzyme deficiency results in-
• Reduction in end-products such as cortisol deficiency
• Accumulation of hormone precursors
• Increased ACTH production.
22. Figure: Adrenal metabolic pathways related to normal sex development
Ref: Gomella’s Neonatology, 8th Edition
23. Pathophysiology
• Congenital Adrenal Hyperplasia
1. 46 XX DSD
a) 21α –Hydroxylase (21α –OH) deficiency
b) 11β –Hydroxylase (11β –OH) deficiency
c) 3β –hydroxysteroid dehydrogenase II (3β –HSD II) deficiciency
2. 46 XY DSD
a) 3β-HSD II deficiency
b) 17-Hydroxylase (17α-OH)/17,20-lyase deficiency
25. 21- hydroxylase deficiency most common 90%
• Three forms of 21- hydroxylase deficiency.
1. Classic-
salt wasting-75%
Simple virilizing-25%
2. Non-classic or late onset-
26. Clinical features of 21-hydroxylase deficiency:
•Female- born with ambiguous genitalia (clitoromegaly, labial fusion)
with normal development of ovary and female internal genital
structure.
•Male- external genital normal.
•Common for both male & female:
•Symptoms of salt wasting- anorexia, vomiting, wt loss,
dehydration, shock.
•Hyponatremia , hyperkalemia, acidosis and often hypoglycaemia
present
29. 17 α-hydroxylase def./ associate with 17-20-lyase def
•Decreased/absent- Androgen & cortisol.
•Increased DOC- ↑↑ BP, Hypokalemia and Suppression of renin.
•Affected male incompletely virilized; present as Female phenotype.
30. Defect in androgen action:
• Results in failure of the external genitalia to undergo male
differentiation because of the lack of DHT.
• The outcome is a neonate with female or atypical genitalia but
with a 46XY karyotype, normally developed testes, and male
internal duct.
5α-REDUCTASE DEFICIENCY:
31. • Also called testicular feminization
• The AISs are the most common forms of male DSD.
• Can be caused by defect in androgen receptor or an unknown defect with
normal receptor.
• Two Types :
• Complete AIS : Genetic male(XY) appears with labial testes &
otherwise normal female external genitalia.
• Partial AIS : incomplete virilization of a male, more common.
Androgen Insensitivity Syndromes (AIS):
32. Gonadal dysgenesis:
Pure gonadal dysgenesis:
• Presence of a streak gonad bilaterally (complete gonadal dysgenesis)
or unilaterally (partial gonadal dysgenesis).
• Streak gonads in Y-positive patients carry a significant risk for tumor
development.
Mixed gonadal dysgenesis:
• Presence of a unilateral functioning testis and a contralateral streak
gonad.
• All patients have a Y chromosome and some degree of virilization of
the external genitalia;
• High risk of gonadal malignancy in mid to late childhood.
33. Defects in testicular development:
DENYS-DRASH SYNDROME :
Nephropathy with ambiguous genitals and bilateral
Wilms tumor.
WAGR SYNDROME :
• Consists of Wilms tumor, aniridia, genitourinary
malformations, and mental retardation.
35. .
1. Family history of
- Familial genital ambiguity
- CAH
- Cryptorchidism
- Hypospedias
- Pubertal delay,Amenorrhea,Infertility
- Consanguinity
2. History of maternal drug exposure ( Particularly androgen)
3. H/O maternal virilization in pregnancy
4. History of Neonatal/early infancy death
5. Vomiting/ dehydration of sibling(possibility of CAH)
6. H/O any corrective genital surgery
7. Genetic syndrome
History
36. Physical examination
General examination
• Any dismorphic features ( Syndromes & chromosomal anomaly)
• Vitals, to see any evidence of salt wasting ( CAH) – Low BP, F/O
dehydration , shock
• Hyperpigmentation of skin and areola
Per abdomen : Any abdominal mass
37. Physical examination
Genitalia examination
Phallus length: Stretched phallic length (Normal should be
>= 2cm)
Clitoral length ( < 1cm)
Urethral meatus: hypospadiasis, chordee
Presence of vaginal opening
Labioscrotal fold: Pigmentation and symmetry of the
scrotum or labioscrotal fold.
Labia majora – normally unfused but may show variable
degree of post fusion.
Scrotum – Fused or bifid, rugosity suggest androgen effect
Gonadal size, position and descent
Inguinal hernia
39. Investigations
For chromosome analysis
• Karyotyping
To find-out etiology:
Hormone analysis
• S. Cortisol
• S. ACTH
• Rapid ACTH stimulation test
• 17 Hydroxyprogesterone
• Dehydroepiandosterone sulfate ( DHEA-S)
• S. Testosterone
• S. Testosterone & S. Dihydrosterone ( DHT) ratio at basal and after 24 hour of successive 3 days
injection of ꞵ-hcg.
40. Investigations
Imaging
1. USG of whole abdomen
• To find out presence,localization and characteristics of gonad
• To see internal female genital organ- uterus,fallopian tube
• To see the hyperplasia of adrenal gland
2. CT/MRI of pelvic organ
3. Genitourethrography / Urogenital sinogram: Before surgery
4. Diagnostic laparoscopy: To Identify testis and to take tissue for biopsy
41. Investigations
To find out association
Serum electrolytes
Hyperkalemia and Hyponatremia
(21-hydroxylase deficiency)
Hypoglycemia (21-hydroxylase deficiency)
Hypokalemia (11β-hydroxylase deficiency)
Molecular genetic analysis
• FISH for SRY gene analysis
• CYP 21
• DNA analysis
42. Virilization of a genetic female (by excessive maternal or fetal androgen
in CAH)
Hormone assay
17-OHP (Increase in CAH)
S. Cortisol (Decrease in CAH)
S. ACTH (Increase in CAH)
Testosterone, DHT, androstenedione (Increase in CAH)
If Karyotyping is 46XX
43. If Karyotyping is 46XY
Testosterone, DHT, androstenedione (A high Testosterone to
DHT ratio suggests 5 α reductase deficiency)
Testosterone , LH & FSH
Increased- Androgen insensitivity syndrome
Decreased in Gonadal Dysgenesis
HCG stimulation test
44. Interpretation:
Rise in testosterone- Normal
Absent response with elevated LH/FSH- Primary gonadal failure
Rise in testosterone with no rise in Di-hydrotestosterone-
5 α reductase deficiency
An absent testosterone with elevation of androstenedione
suggests- block in testosterone synthesis
Other Endocrine screening
Anti-mullerian hormone and inhibin B levels
HCG stimulation test
45. Prenatal diagnosis of CAH
• Done by chorionic villus sampling and amniocentesis
• DNA analysis to for sex determination & CYP21 gene analysis from
chorionic villus sampling
• 17-OH-progesterone & androstenedione in amniotic fluid is used for
antenatal diagnosis
Ref:New et al,Inborn errors of adrenal steroidogenesis. Molecular and Cellular
Endocrinology2003;211(12):75-84
47. B/O Mousumi, Atypical pattern of external genitalia ,
hyperpigmentation around nipple & genitalia. Other
wise the Child was normal.
O/E- stable vitals, no signs of dehydration
hyperpigmented nipple,
skin pigmentation present
Genitalia exam-
-Clitoromegaly measuring about 1.6 cm
-partial fusion of labioscrotal fold
-urethral opening was at the base of clitoris, vaginal
orifice present,
-hyperpigmented
-gonad was not palpable
Case scenario 1
48. 17-OHP- ↑26.50 ng/ml
S. ACTH-↑ 132.40 pg/ml
S. Cortisol- ↓140.50 nmol/L
DHEA- –↑ 651µg/dl
S electrolyte : Na -125 mmol/l
K -9.5 mmol/l
Cl - 93 mmol/l
TCO2 -16.4 mmol/l
USG of pelvic organ- There is a small structure
measuring about 1.31 cm in length and 0.50 cm in
AP diameter simulating a uterus behind urinary
bladder.
None of the ovaries could be well identified
No testis could be visualized.
Karyotyping- 46XX
Diagnosed as 46 due to
Congenital Adrenal
Hyperplasia ( 21 alpha
hydroxylase deficiency).
Baby was discharged with
oral Hydrocortisone 10
mg/sqm/day
49. Abu sufiyan, 15 days old, 1st issue of non-
consanguinous parents presented with the complaints
of atypical pattern of external genitalia , more male
pattern
O/E- stable vitals, no signs of dehydration
Genitalia exam-
Atypical genitalia more in male pattern, phallus present
length was measuring about 2.2 cm, urethral opening
was single and present under surface of phallus, both
testes were in the scrotum, scrotum was bifid, scrotal
skin was more pigmented.
Case scenario 2
50. S. Cortisol – 126.30 nmol/L
S. ACTH – 26.30 pg/ml
17 OHP – 0.31 ng/ml
DHEA-S – 13.50 µg/dlS.
Testosterone – 68.84 ng/dl
S electrolyte: Na -140 meq/l
Cl -103 meq/l
K – 4.3 meq/l
TCO2 -22 meq/l
USG of pelvic organ-
USG of pelvic organ- No mullerian structure
was found.
Karyotyping- 46XY
Diagnosed as 46XYDSD due
to Androgen insensitivity
syndrome or
Dihydrotestosterone
deficiency
Baby was discharged with
advice of EBF.
51. Early diagnosis of classic CAH is critical to save lives, and
diagnosing nonclassic CAH is important to prevent unnecessary
suffering. Molecular genetic analysis of CYP21A2 is useful in
confirming the diagnosis, providing genetic counseling, and
predicting prognoses. Genotype is well correlated with the clinical
severity of 21OHD. However, further research is needed to identify
modifier genes in 21OHD, which could explain the phenotypic
variability of androgen effects.
54. Treatment Principles of CAH
• Treatment is life-long
• Treatment goals are
To normalize electrolytes & hormone levels by
using glucocorticoids & mineralocorticoids
replacement.
To maintain growth velocity & skeletal
maturation.
55. Acute Medical Management
• Fluid therapy in babies with salt losing crisis : 0.9% sodium chloride 10
ml/kg as IV bolus, followed by a continuous IV infusion of 0.9% or 0.45%
saline 1.5-2 times of maintanence fluid.
• If the patient is hypoglycemic, 2ml/Kg of 10% dextrose.
• Correction of electrolyte imbalance (Hyperkalaemia, Hyponatremia)
• I.V Hydrocortisone
• If HTN : Start Anti hypertensive
56. Long Term Therapy
Glucocorticoids
Replacement
Hydrocortisone 15-20
mg/m2/day divided in 3
oral doses.
Dose should doubled
during crisis & stressful
conditions.
Mineralocorticoids
Treatment
Fludrocortisone acetate 0.05-
0.1 mg once daily orally
It will restore the sodium-
potassium balance
Hormone replacement therapy: for induction of puberty
57. Surgical Management
• Some female infants with adrenal hyperplasia are only mildly virilized and
may not require corrective surgery if they receive adequate medical
therapy to prevent further virilization
• Traditional approach is clitoris is embeded under the skin
• Vaginoplasty : If there is urogenital sinus.
• Removal of gonads : Dysgenesis
58. Newer Treatment Options
• Continuous Subcutaneous Hydrocortisone Infusions (CSHI)
• Inhibitors of Adrenal Androgen Synthesis (ketoconazole)
• Androgen Receptor Antagonists (Flutamide)
• Aromatase Inhibitors (AIs) (Testolactone)
• 5-α Reductase Inhibitors (Finasteride and Dutasteride)
• Gene Therapy
• Stem Cell Transplantation
• Bilateral Adrenalectomy
Ref: New et al,Inborn errors of adrenal steroidogenesis. Molecular and Cellular
Endocrinology.2003;211(12):75-84
59. Combination treatment
At the National Institutes of Health, a long-term randomized clinical
trial investigated a new treatment regimen combining a reduced
hydrocortisone dose, an anti-androgen, and an aromatase
inhibitor.
Ref: White and Speiser et al,Updates on Congenital Adrenal Hyperplasia.New
England Journal of Medicine.2003;349(8):776-88
60. New treatment approaches currently under investigation include
combination therapy to block androgen action and inhibit estrogen
production, and bilateral adrenalectomy in the most severely affected
patients
Ref: Gunther et al.‘Prophylactic Adrenalectomy of a Three-Year-Old Girl with
Congenital Adrenal Hyperplasia:Pre- and Postoperative Studies’.The Journal
of Clinical Endocrinology & Metabolism.2015.82(10).3324–3327
61. Follow Up
• Too little glucocorticoid : Results in symptoms of adrenal
insufficiency (e.g., anorexia, nausea, vomiting, abdominal pain,
asthenia) and will result in progressive virilization
• Excess glucocorticoid : excess weight gain, cushingoid features,
hypertension, hyperglycemia, cataracts, and growth failure
62. Prognosis
Early adequate therapy : Short stature, sexual precocity & metabolic
effects are not seen .
Late diagnosis & inadequate therapy may cause:
• Death of newborns with salt-losing types & if patients are not provided
with stress doses of glucocorticoid in times of illness, trauma, or
surgery.
• Psychological problems in girls with ambiguous genitalia.
• Short stature and infertility
65. To determine the sex, physicians should consider….
• Genetic and phenotypic sex
• Fertility potential
• Capacity for normal sexual function
• Endocrine function
• Potential for malignant change
• Parental opinion / preference (Full informed consent)
66. REVIEW ARTICLE| VOLUME 12, ISSUE 6, P418-425, DECEMBER 01, 2016
Fertility in disorders of sex development: A review
J.P. Van Batavia,T.F. Kolon
Journal of Pediatric Urology
Patients with some CAH may have functioning gonads with viable germ cells
but an inability to achieve natural fertility secondary to incongruent internal
or external genitalia,
other patients may have phenotypically normal genitalia but infertility due
to abnormal gonad development.
Infertility is seen in complete AIS .
Fertility is rare in pure or mixed gonadal dysgenesis, ovotesticular disorder,
Klinefelter syndrome.
67. Tony Briffa has PAIS.
Briffa is worlds first
intersex mayor.
Independent councillor,
mayor, deputy mayor in
the city of Hobsons
bay, Victoria.
Lady Colin
Campbell – Jamaican
born British writer.
Best seller books in
1992.
Sarah Gronert-
retired german tennis
player
Got award of best
world ranking of 164
on May 2012.
Not the end of life
68. ULTIMATE GOAL
To provide the framework for a child to develop into well
adjusted, psychosocially stable individual who identified with
and is happy in the chosen sex.
69. KEY MESSAGES
• Always think , Could this neonate have salt wasting CAH?
• Remember the risk of testicular cancer.
• Take the possible step to avoid assigning the neonate to the
wrong sex.
