Disorder of Sexual Differentiation

Kegawatan yang perlu diwaspadai

Harjoedi Adji Tjahjono

RSUD Dr. Saiful Anwar
Fak. Kedokteran Universitas Brawijaya
MALANG

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Case:
Adi, 15 tahun, ambigus genitalis
Hobby memasak, memiliki pacar perempun

A1 M1 P3, phallus 6 cm
Vagina +, testis -, uterus +, ovaries +
Coklat gelap, testosterone = 110 ng/mL,
17 OHP 115.6 (<2,83 ng/mL)
Kromosom 46 XX, Bone age 18 yo

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 Introduction
• Bayi baru lahir: kejadian dramatis dalam keluarga,
pertanyaan pertama? Laki / perempuan

• Jika ambigus genetalia – surprise dokter dan

keluarga

• Nomenclature for 'intersex', 'hermaphrodite',

'pseudohermaphrodite’ = out of date.
• Rekomendasi Chicago Consensus 2005 : disorders of
sex differentiation (DSDs)

Hughes, 2017 4
 Definisi
• Disorder of sexual differentiation (DSD) :
Perkembanganatipikal: chromosomal, gonadal atau
anatomis sex

• Atypical/Ambiguous genitalia:
Atypical genitalia : perkembangan tidak khas, tidak
lengkap laki atau perempuan

Hughes, 2017 5
Buku Ajar Endokrinologi Anak, 2016 6
Buku Ajar Endokrinologi Anak, 2016 7
 KEGAWATAN DSD
• Kegawatan medis ?

• Kegawatan sosial

Berglund, 2016 8
Patogenesis

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 10
Buku Ajar Endokrinologi Anak, 2016 9
11
Cholesterole
17,20
17α-OH lyase

Pregnenolone 17-OH Pregnenolone DHEA

3β-HSD

Progesterone 17-OH Progesterone Androstenedione

21α-OH
Deoxycorticosterone Deoxycortisol Testosterone

11β-OH

Corticosterone

Aldosterone Cortisol Estradiole DHT

BIOSINTESA STEROID 12
Gravkolt, 2016
 Congenital Adrenal Hyperplasia
1. 46 XXDSD
a) 21α-Hydroxylase (21 α-OH) deficiency
b) 11β-Hydroxylase (11β-OH) deficiency
c) 3β-Hydroxysteroid dehydrogenase II (3β- HSD II)
deficiency
2. 46 XYDSD
a) 3β-HSD II deficiency
b) 17-Hydroxylase (17α-OH) /17,20-lyase
deficiency

Lee PA, 2016 13

 21α-HYDROXYLASE DEFICIENCY
Cholesterole

Pregnenolone 17-OH Pregnenolone DHEA

Progesterone 17-OH Progesterone Androstenedione

21α-OH
Deoxycorticosterone Deoxycortisol Testosterone

No No
Aldosterone Cortisol Estradiole DHT

Na- ↓ Hypo-
K- ↑ Ambiguous
Glycaemia
Cl- ↓ Genitalia
Renin-↑ &
in girls
ACTH-↑ Gravholt, 2016 14
5α-reductase deficiency(SRD)
17β-HSD 5α-Reductase
Androstenedione Testosterone DHT

• So, boys born with ambiguous genitalia due to

impaired musculinization of male external genitalia.
• At puberty, testosterone dependent pubertal change
occurs such as
– Phallus enlargement
– Descent of inguinal testis
– Spermatogenesis
Gravholt, 2016 15
 Ovotesticular DSD
(true hermaphrodite)
• In ovotesticular DSD, both ovarian and testicular
tissues are present, either in same or in opposite
gonad.
• Genotype
• 46XX - 70%
• 46XY - 10%
• 46XX/46XY- 20%
• Affected patients have ambiguous genitalia, varying
form of normal female with only slight enlargement of
the clitories to almost normal male external genitalia.
• Most frequently gonads are bilaterally ovotestis, if
unilateral contralateral gonad usually ovary but may be
a testis,
Ono M, 2017 16
Pendekatan anak dengan DSD

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 Bayi baru lahir
1. Ambiguous genitalia
a) In genotypic (XX) female
• Cliteromegaly
• Labial fusion- complete/ partial
• Labioscrotal fold
• concealed vagina
• Some affected female mistakenly presumed to
be male with hypospadiasis and cryptorchidism
b) In genotypic (XY) male:
• Small phallus
• Bifid scrotum
• Hypospadiasis
• pigmentation
• Unilateral/bilateral cryptorchidism D€ohnert U, 2016 18
2. Salt wasting crisis:
a) Anorexia
b) Vomiting
c) Dehydration
d) Weakness
3. Increased skin pigmentation
4. Syndromic features
a) Turner syndrome
b) Klinefelter syndrome
c) Antley-Bixler syndrome

D€ohnert U, 2016 19
 Bayi / anak

• Nephrotic syndrome - Denys-Drash syndrome

• Unexplained obesity - WAGRsyndrome

D€ohnert U, 2016 20
 Pubertas
 Further Virilization at puberty and failed to go
into puberty- Aromatasedeficiency
 Normal female phenotype failed menarche and
breast development at puberty- XY puregonadal
dysgenesis, leydig cell aplasia,
 Breast development normal but nomenstruation
and no sex hair- AIS
 No secondary sexual changes but pubic hair may
be normal- Leydig cell aplasia, partialAIS
 Virilization occurs at puberty, phallusenlarges
and testis decend- 5α-Reductase deficiency.
 Breast development in boys
D€ohnert U, 2016 21
 Anamnesis

• Riwayat keluarga:
– Consanguinity-- ↑↑the risk of autosomal recessive
disorders like CAH
– Sibling affected--- CAH (autosomal recessive)
– H/o of neonatal death with ambiguity-- may suggest a
missed diagnosis of CAH
– H/o infertility or amenorrhea– 46 XX DSD
• Riwayat kehamilan
– Androgen secreting tumors
– maternal H/o of of taking Progestins, Androgens etc.

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 Pemeriksaan Fisis

• Dysmorphic features .
• Evidence of salt wasting, skin turgor, poor tone,
dehydration, low/high BP, increased HR
• Hyper pigmentation of the skin due ↑↑ ACTH
• Hypertension: glucocorticoid receptor genemutation,
CAH
• Abdominal masses
• Palpable gonad in groin or scrotal or labial fold
• Rectal examination: May reveal the cervix and uterus,
confirming internal Müllerian structures
Mouriquand PD, 2016 23
Pigmentasi

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Pemeriksaan genetalia eksterna

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Investigasi

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 For critically ill patient
Investigation 21α-OH 11β-OH 3β-HSD 17α OH
deficiency deficiency deficiency deficiency
S. S. Na- ↓↓ S. Na-↑↑ S. Na- ↓↓ S. Na-↑↑
Electrolyte
S. K - ↑↑ S. K- ↓↓ S. K - ↑↑ S. K- ↓↓

Blood Sugar ↓↓ ↓↓ ↓↓ ↓↓

Wilson JD, 2012 27

 Sex determinan
Anatomi genetalia interna
• Abdominal & pelvic USG to see
– Uterus
– Gonadal location
– Ovarian mass
– Kidney (wilms tumor)
– Adrenal gland - hyperplasia.
• Pelvic CT/ MRI
Wilson JD, 2012 28
For determination of sex chromosome –

• Karyotyping
• FISH (florescent in situ hybridization) for Y
chromosome material
• PCR analysis of the SRY gene on the Y
chromosome

Wilson JD, 2012 29

 Deteksi Etiologi

• Screen for CAH

a) 17 OHP- ↑ ↑
b) ACTH - ↑ ↑
c) S. cortisol- ↓↓
d) Androstenedione
• Screen for androgens and their biosynthetic
precursors

Wilson JD, 2012 30

• Gonadotropin level (LH, FSH)
• Testosterone level
• Screen for gonadal response to gonadotropin
(testosterone response to HCG)
• to differentiate leydig cellaplasia
with AIS
• 5-α reductase deficiency(SRD)
• Ovotesticular DSD

• Testosterone:DHT ratio : >17 in SRD

Wilson JD, 2012 31
 DIAGNOSIS PRENATAL

1) In 1st trimester : Chorionic villus sampling

(DNA analysis)

2) In 2nd trimester : Amniocentesis (by DNA

analysis & 17- OHP).
Guercio G, 2015 32
NEWBORN SCREENING

By detection of 17-OHP in dried

blood spot.

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Management

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Tata laksana diperlukan tim multi disiplin:
Endocrinologist
Gynecologist
Surgeon
Pediatric urologist
Psychologist
Geneticist
Radiologist

Peran utama tim oleh dokter Anak

Ahmed SF, 2012 35

Tahap pengobatan:
a. Initial management of shock and electrolyte
imbalance if required.
b. Counseling
c. Psycho-social and emotional support
d. Sex assignment
e. Medical management
f. Surgery
g. Follow up

Ahmed SF, 2012 36

 Konseling
1) Kegawatan sosial , segera didiagnosis dan
tatalaksana

2) Konseling harus segera dimulai

3) Genetic counseling:
i. Kehamilan berikutnya
ii. Antenatal diagnosis
iii. Antenatal management
iv. Terapi steroid seumur hidup jika krn CAH
v. Kartu steroid

Ahmed SF, 2012 37

 Tatalaksana medis
Disease Management
CAH Steroid replacement therapy
a) Glucocorticoid replacement by
hydrocortisone
b) Mineralocorticoid replacement by
Fludrocortisone
c) For 3β-HSD deficiency I/M testosterone in
early infancy to increase the size of phallus
d) For female with 17-α OH deficiency require
estrogen replacement therapy & for male
require androgen or estrogen based on sex
of raring.
e) Anti-hypertensive therapy for 11β-OH
deficiency and 17-α OH deficiency
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Ahmed SF, 2012
Tatalaksana medis .
Disease Management
Aromatase Low dose estradiole replacement
deficiency
CAIS Replacement with estrogen after removalof
testis
PAIS Testosterone enanthate/Androgen therapy
Ovotesticul I/M testosterone for 3 month for both
ar DSD diagnostic and as well as treatment
Newer 4 drug regimen
treatment for -Hydrocortisone
CAH -Fludrocortisone
-Testolactone
-Flutamide Ahmed SF, 2012 39
 Tatalaksana pembedahan
Stelah diagnosis ditegakkan:

1) Feminizing genitoplasty (to be raised asfemale)

a) Clitoral resection
b) Labioplasty
c) Vaginoplasty
d) Gonadectomy
2) Masculine reconstruction (to be raised as male)
a) Orchiopexy,
b) hypospadias repair
c) Removal of retained müllerian ductstructures.

* Ref: American academy of pediatrics

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 Komplikasi
• Infertility
• Ovarian cyst
• Gonadoblastoma
• Nephrotic syndrome
• Growth retardation
• Mental retardation
• Psychosocial stress

Mouriquand PD, 2016 41

Take home massage:
• Kegawatan DSD
• Kegawatan medis
• Kegawatan social

• Tatalaksana DSD harus segera dilakukan

oleh tim multi disiplin

• Konseling harus segera dimulai

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TERMA KASIH

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