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Paediatric Biochemistry > Disorders of Sex Development (DSD) > Flashcards

Disorders of Sex Development (DSD) Flashcards

1
Q

What are Intersex Disorders?

A

A partial or complete variance of genotype from sexual phenotype

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2
Q

What are Ambiguous genitalia?

A

When external phenotype is sufficiently abnormal to cause uncertainty with regards to gender

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3
Q

What are Disorders of sex development (DSD)?

A

Defines congenital conditions involving atypical chromosomal, gonadal or anatomical sex.

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4
Q

What is Gender identity disorder (GID)?

A

Unhappiness with assigned sex.

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5
Q

Describe the Embryology of Sexual Development?

A
  • Development of bipotential gonad
  • 6 - 8weeks: Formation of the urogenital ridge, double system (Wolffian and Mullerian)
  • 8weeks: Mid-line genital tubercle
  • 9weeks: Testicular differentiation and testosterone production
  • 11weeks: Ovarian differentiation
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6
Q

Describe Internal Genital Development?

A

If there is no Y chromosome, there is absence of testis determining genes so no AMH. The default mechanism to female

  • Mullerian system forms Fallopian tubes, uterus, upper 1/3 of vagina. In presence of testis, there is involution of Mullerian structures.
  • Wolffian ducts form epididymis, vas deferens, seminal vesicles and ejaculatory ducts
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7
Q

What embryological structures that form parts of the external genital?

A
  • Genital tubercle: Formed at clitoris or glans penis
  • Genital fold: Labia minora or corpus spongiosum
  • Genital swelling: Separate to form labia majora or fuse to form scrotum and ventral penis
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8
Q

What is the Genetic pathophysiology of human sex determination?

A
  • Gene transcription occurs through cellular signalling pathways (WNT4–RSPO1 in ovary determination, Map- kinase in testis determination).
  • In 46, XY individuals, Map- kinase signalling through MAP3K1 may alter chromatin and histone conformation, activates GATA4 binds directly to SRY promoter which turns on SOX9, initiating testis gene expression
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9
Q

What are clinical presentation of pathologies associated with disorders of sexual development?

A
  • At birth: Ambiguous genitalia
  • In childhood: Virilisation of female
  • In adolescence: Virilisation of female, Lack of virilisation in male, Pubertal delay and primary amenorrhoea in female
  • In Adulthood: Primary amenorrhoea in female - Infertility in male and female
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10
Q

What are the responsibilities of Health care professional for neonates?

A
  • Gender assignment & decision as to sex of rearing as soon as possible through involving MDT and investigations
  • To promote attachment & acceptance
  • To define condition & avoid illness (CAH)
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11
Q

What are causes of Virilised Girls/Undervirilised boys?

A

Virilised Female

  • Fetal Androgens - CAH
  • Maternal Androgens – Ovarian & Adrenal Tumours

Undervirilised Male

  • Abnormal Testis Determination – Partial (XY) & Mixed (X/XY) gonadal dysgenesis

Androgen Biosynthetic defects

  • LH receptor-inactivation mutations
  • 17βOH-dehydrogenase deficiency
  • 5α-reductase deficiency

Resistance to Androgen

  • Androgen insensitivity

True Hermaphroditism (Karyotype XX, XY, XX/XY)

  • Presence of testicular and overian tissue
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12
Q

What is the Clinical Examination of Virilised Girl/Undervirilised boy?

A

Clinical Examination

  • Presence of palpable gonads-likely to be tested

Initial investigation

  • Karyotype
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13
Q

What is the Prader Scale of Virilisation?

A

Apparently females but

  • Clitoromegaly
  • Posterior Labial Fusion
  • Labial/Inguinal Mass

Apparently male BUT

  • Non-Palpable Testes
  • Perineal Hypospadias
  • Micropenis
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14
Q

What are features examined in a Genital Examination?

A
  • Gonads: absent, scrotal, inguinal, abdominal
  • Phallic structure: length, width
  • Chordee
  • Urethral meatus position
  • Labioscrotal fusion / scrotum: bifid, shawl, underdeveloped
  • Vaginal opening
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15
Q

What causes ambiguous genitalia in gonadal dysgenesis?

A

Karyotypes include 46,XY, 46,XY/45Xothers

  • Complete - Pure streak gonads
  • Partial gonads - usually asymmetric. Streak + dysplastic testis (or ovotestis)

Testis can produce testosterone but little AMH. External and internal phenotype dependant on testicular dysgenesis

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16
Q

What are features of congenital adrenal hyperplasia?

A
  • 21-Hydroxylase deficiency is the most common cause of CAH
  • Presentation - neonatal period till early adolescence
  • Salt wasting only in early onset cases with severe androgenisation
  • Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition, resulting in glucocorticoid and mineralocorticoid deficiency and androgen excess, with >90% of cases caused by mutations in CYP21.
  • The condition is associated with considerable morbidity and mortality (male neonates).
17
Q

What are functional tests used in the assessement of an infant with DSD?

A
  • Urination
  • Adrenocortical function – Cortisol levels to Synacthen
  • Salt and water balance – Daily Urine Na, plasma U&E, renin
  • Gonad anatomy and endocrine function – US, MRI, EUA HCG test; GnRH test
  • Sexual function – Urology opinion, EUA phallic response to testosterone
  • Reproductive function – gonad biopsies, uterus
18
Q

What are definitive tests used in the assessement of an infant with 21-OHD in DSD?

A
  • Karyotype – 46XX
  • 17OHP and Raised Angrogens
  • Synacthen test
  • Renin, Na, Urea, K, Testosterone, Androstenedione, DHEA, ACTH
19
Q

What are features of 3β-HSD?

A
  • Undervirilization in males
  • Clitoromegaly in females
  • Salt wasting in 75%
  • Elevated DHEAS
20
Q

What are investigations for 3β-HSD?

A
  • Karyotype
  • Synacthen test with measurement of cortisol, 11-deoxycortisol Urine steroid profile
  • Genetic testing
21
Q

What are features of 11 β-Hydroxylase?

A

Severe virilization ±Hypertension

22
Q

What are investigations for 11 β-Hydroxylase?

A
  • Karyotype
  • Synacthen test with measurement of cortisol, 11-deoxycortisol Urine steroid profile
  • Genetic testing
23
Q

How is Salt Wasting CAH managed?

A
  • Hydrocortisone 10-15mg/m2/day, TDS,PO Typical dose in neonates- 1.5-2mg, TDS, PO
  • Fludrocortisone 150μg/m2/day in neonates, 50- 100μg/m2/day in older children and adults
  • Salt during infancy 5-20mmol/kg/day
24
Q

How is management of Salt Wasting CAH monitored?

A
  • Regular height measurement
  • Adjustment of the dosage based on body size
  • 4 mo measurement of 17OHP profile
  • 24hr Cortisol profile
25
Q

What is the surgical management of CAH?

A
  • Correction of anatomy of external genitalia in females
  • Examination of all females with CAH with examination under anaesthesia for cystovaginoscopy
  • Re-examination during adolescent for further correction and possible vaginal dilatation.
26
Q

What are features of 17β-HSD & 5α-reductase defects?

A
  • Spectrum- undervirilisation with varying phenotype
  • Marked virilisation during puberty
  • Most will be infertile

Early gender assignment is essential to avoid disorder of gender identity

27
Q

What are investigations for 17β-HSD & 5α-reductase defects?

A

Human chorionic gonadotropin (HCG) stimulation test

  • High doses of HCG which acts on the LH receptor of the testes and stimulates testosterone production
28
Q

What are clinical features of 5 alpha reductase deficiency?

A
  • 46XY, Autosomal recessive
  • Genitalia: usually ambiguous with small hypospadic phallus and blind vaginal pouch
  • Wolffian ducts normal
  • Mullerian ducts absent
  • Normal testes
  • Partial virilisation at puberty with gynaecomastia
29
Q

What are the presentations of Complete Androgen Insensitivity syndrome?

A

Complete androgen insensitivity syndrome

  • Complete female phenotype
  • Karyotype 46, XY
  • X linked
  • Bilateral inguinal hernia’s
  • Sex of rearing- female with or without gonadal removal
  • Genitalia female with blind vaginal pouch
  • Wolffian duct derivatives absent or rudimentary, intra abdominal testes
  • Mullerian duct derivatives absent or vestigial (AMH production normal)
  • Low or undetectable amount of androgen receptor
30
Q
A
31
Q

How is Androgen Insentitivity Syndrome investigated?

A
  • Karyotype
  • Ultrasound pelvis
  • HCG stimulation test
  • Genetic testing
32
Q

What are the presentations of Partial Androgen Insensitivity Syndrome?

A

Varying degree of virilization

  • 46XY
  • X Linked
  • External genitalia: ambiguous/ hypoplastic male/ normal male (fertile/ infertile)
  • Testes
  • Androgen receptor mutations lead to qualitative abnormalities
  • Only 20% have detectable mutations
33
Q

What are the physical features of AIS?

A
  • Female body shape
  • Enlarged breast with juvenile nipples Absent or scanty axillary or pubic hair Female external genitalia with small labia Blind-ending vagina
  • Absent or rudimentary internal genitalia Cryptorchid (undescended testicles) Normal male blood levels of testosterone
  • No male pattern baldness
  • Flawless complexion - no hormone-driven acne at puberty
  • Long, well-developed legs
  • Greater than average height for a female
  • Physique often more angular and “athletic” than average female
34
Q

What are biochemical features of AIS?

A
  • Normal male blood levels of testosterone
  • Testes produce androgens and estrogen
  • Elevated production of gonadotrophins
35
Q

What is True Hermaphroditism?

A
  • Gonads contain combination of testicular and ovarian tissues
  • Varying degree of virilization
  • Karyotype and USS pelvis helps in differential diagnosis
  • Karyotype mosaic 46,XX/XY;46,X/46,Y/46,XX;

Paediatric Biochemistry (31 decks)

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