Pathology Of Disorders Of Sexual Development

Question 1

What are the classifications of disorders of sexual development?

Answer 1

1. DSDs due to chromosomal aneuploidies
2. DSDs due to gonadal dysgenesis
3. DSDs of sex differentiation

Question 2

What are the DSD due to chromosomal aneuploidies?

Answer 2

1. Klienfilter syndrome XXY

2. Turner syndrome XO

Question 3

What are the disorders due to gonadal dysgenesis?

Answer 3

1. 46,XY dysgenesis (sweet syndrome)
2. 46, XX gonadal dysgenesis
3. 46, XX sex reversal (de la Chapelle syndrome)
4. Ovo-testicular DSDs (true hermaphroditism)

Question 4

What are examples of DSDs of sex differentiation?

Answer 4

1. Androgen insensitivity syndrome
2. Kallman syndrome
3. Congenital adrenal hyperplasia
4. 5-alpha reductive deficiency

Question 5

An 31 year old male with gynecomastia complains of problems with conceiving in the past 5 years. His intelligence quotient (IQ) is normal (104), however he has deficits in language development and speech. He has deficits in language development and speech. He has outburst of aggressive behavior and poor temper control especially under stressful situations.
His past psychiatric history was significant for diagnosis of attention deficit hyperactivity activity disorder ADHD and conduct disorder

On physical examination:
1. He is a tall 210 cm and overweight 120 kg with long arms and legs (BMI 27.2)
Bilateral gynecomastia
Testicular development is tanner stage 3

We have low testosterone total and free
LH high
FSH high

Sperm analysis —> absent spermatogensis (Azospermia)

A.What is your provisional diagnosis?
B. What are the differentials will u consider?
C. For additional confirmatory cytogenetic analysis what will u do?
D. How is what u do done?
E. They did the karyotype and it was —> 47,XXY what is the diagnosis?

Answer 5

A. Primary hypogonadism
B. Differentials:
Klinefelter syndrome 
Testicular atrophy 
Gonadal dysgenesis (streak)
Noon an syndrome
46, XX male syndrome (Ytranslocation)

C. Karytopying

D.
Requires a blood sample to grow WBCs in culture
Induction of mitosis at metaphase by mitotic inhibitor
Breaking cells open to disperse chromosome onto a glass slide using a hypotonic solution
Staining of chromosome with Giemsa stain

E. Klinefelter syndrome

Question 6

So, if the patient comes with psychological problems and infilterity think of?

Answer 6

Klinfiter syndrome

Question 7

What is the cause of klinfilter syndrome?

Answer 7

Abnormal meiosis non-disjunction events that occur sporadic and are not hereditary, however they are associated with increased maternal and paternal age

Question 8

What are features of klinfilter syndrome?

Answer 8

1. Tall stature (with long legs)
2. Small, firm testes
3. Signs of hypogonadism
4. Psychological problems

Question 9

What are signs of hypogonadism seen in patients with klinfiter syndrome ?

Answer 9

1. Sparse beard growth
2. Loss of libido
3. Erectile dysfunction
4. Mild anemia
5. Infertility

Question 10

What do u see in the biopsy of an adult klinfilter patient?

Answer 10

Testicular biopsy showing —> small hyalinized seminiferous tubules and pseudo-hyperplasia leydig cells

Question 11

How we treat Klinefelter syndrome?

Answer 11

1. Testosterone replacement therapy
2. Breast tissue removal if desired
3. Speech and physical therapy (for muscle weakness)
4. While this patient is infertile, for patients with minimal sperm production intracytoplasmic sperm injection (ICSI) into an egg is an option

Question 12

An otherwise healthy 18 year old female was admitted for amenorrhea. She was the healthy product of an uncomplicated term pregnancy, born to a 25-year-old mother and 29 year old father.
Her academic performance ranked in the middle of her class. She has a brother aged 23, who was of normal development. She also had rapid weight gain, with rate of more than 5 kg/ semester that was notes when she was a junior high school student

Note: —> there was no family history of anosmia and delayed sexual development

Physical exam:
Her vital signs were normal
Her weight was 75.8 kg
Height 139.7 BMI 38.8

Breasts and external genitalia were consistent with tanner stage 3 development

She has a short neck and acanthosis nigricans

Pelvic ultrasound —> streak ovaries and streak uterus
MRI was requested —> the same thing

Hormonal profile:
FSH was high
LH was high
Estradiol —> low

What is the provisional diagnosis?

What differentials would u consider?
Whatare the causes of acanothosis nigricans?
What is the diagnosis if the karyotype is 45,X
What additional test will u do?

Answer 12

A. Female primary hypogonadism with syndrome features
B. Swyer syndrome / 46, xx gonadal dysgenesis / Turner syndrome
C. Obesity / type 2 DM / Cushing syndrome
D. Chromosomal karyotyping
E. Turner syndrome

Question 13

What is the cause of turner syndrome?

Answer 13

It is not a hereditary disorder, but it occurs by mitotic/meiotitic non-disjunction

Question 14

What do u see in microscopy of Turner syndrome?

Answer 14

Primordial follicles with collapsed oocytes and empty follicle

Question 15

What are features of Turner syndrome?

Answer 15

1. Webbed neck
2. Short stature
3. Low hairline
4. Constriction of aorta
5. Poor breast development
6. Brown spots nevi
7. No menstruation
8. Small fingers
9. Shortened metacarpal

Question 16

A 19-year-old male was referred to the clinic due to absence of male secondary sexual characteristics and Anosmia.
At birth, he had bilateral cryptorchidism (undesended testes)
Anosmia
Deafness in left ear
Bilateral orchids-exhibit was performed at age five
His parents noted delayed pubertal growth spurt in comparison to his peers

Family history:
Consanguineous marriage
Negative for a similar phenotype

Physical examination:
An arm span at least 5 cm greater than his height
He had poorly developed secondary sexual characteristics
Infantile testes, infantile penis
Sparse axillary and pubic hair

Low testosterone 
Low FSH 
Low LH 
A. What tests will u request?
Patients MRI —> where the olfactory sulcus and bulb are absent 
What is your provisional diagnosis?

What differential will u consider?
Why is The cause of suspected diagnosis?
What do the syndrome features, MRI, and hormonal profile suggests?
What additional tests will u request?
There was identified KAL1 mutation identification ;
The case had: homozygous fir a nonsense mutation resulting in truncated protein
Mother had: heterozygous for nonsense mutation resulting in truncated protein
What is the diagnosis?

Answer 16

A.
Magnetic resonance imaging MRI of the hypothalamus, pituitary gland, and nose to look for anstomical abnormalities
Blood test for sex hormonal profile
B. Secondary hypogonadism
C. What differentials will u consider?
Idiopathic hypogonadotropic hypogonadism
Kallman syndrome
Idiopathic hypogonadotropic hypogonadism

D. Kallman syndrome is the only ascertain able differential, it is caused by mutations in FGF8, FGFR1, KAL1, PROK2,CHD7
E. A syndrome involving hypothalamus-pituitary-gonadal axis
F. Genetic analysis of syndrome associated genes by Sanger gene sequencing
Alternatively a gene panel is sequenced by next generation sequencing

Kallman syndrome —> x-linked recessive

Question 17

What is true about Kallmann syndrome?

Answer 17

May occur in both sexes
All 6 genes associated with kallmann syndrome function in the differentiation or migration of neurons that arise embryo logically in the olfactory mucosa to take up residence in the hypothalamus serving as gonadotropin releasing hormone (GNRH) neuron

Question 18

How we treat kallman syndrome?

Answer 18

Treatment is by testosterone replacement therapy and management of multi-systemic symptoms (renal a genesis, dental and eye abnormalities, low bone mineral density)

Question 19

What gene mutations associated with KS ?

What is the inheritance of those genes?

Answer 19

FGF8 
FGFR1 
KAL1 
PROK2 
PROK2 
CHD 7 

All play a role in the differentiation and migration of neurons that arise embryologically in the olfactory mucosa to take up residence in the hypothalamus serving as gonadotropin releasing hormone

They are inherited autosomal dominant, except KAL1 it is x-linked recessive

Question 20

What is the phenotype of kallman syndrome?

Answer 20

Variable by gene
Common features:
1. Anosmia / hypotonia
2. Decreased sex steroids / lack of sexual maturity and absence of secondary sexual characteristics
3. Amenorrhea in females
4. Lack of testicular development in males
Less common features?
1. Micro penis
2. Cryptorchidism
3. Unilateral hearing loss —due to—> FGFR1
4. Facial defects —due to —> FGFR1
5. Mirror movements of upper extremities —> Bimanual synkinesis)
6, having one kidney
MRI —shows—> loss of olfactory sulcus and olfactory bulb

Question 21

A 21-year-old patient was referred to adult endocrine team for gender assignment required for her official national identification papers.
Patients was diagnosed with ambiguous genitalia at birth but was lost to follow-up. antenatal period was uneventful and she remained relatively well thereafter.
In primary school, she was the tallest in class.
But in secondary school she is the shortest
Academic performance was average

Family history:
Consanguineous parents / brother died suddenly at w months of age

Physical exam:
She is 143 cm tall
External male body habits and has high-pitched voice

Pubic hair was tanner 4 with marked clitoromegalu measuring 3.5 cm
Prominent labia majors
No palpable testes

Never experienced vahinal bleeding

Karyotype 46xx, a normal female karyotype

Hormone profile:
Progesterone high
Testosterone high
Cortisol low

1. What disorder can cause low cortisol level?
2. What is the significance of consanguinity and no family history of disease in this case?
3. What confirmatory tests may be used to confirm the diagnosis?
4. Mutations in which genes can cause congenital adrenal hyperplasia?
5. Mutations in which of those genes can cause increased testosterone and progesterone?
6. CT scan shows increase size of adrenal what is the diagnosis

Answer 21

1. Addison’s disease ‘ congenital adrenal hyperplasia
2. Suggests the possibility of an autosomal recessive disorder
3. Abdominal CT scan of the adrenal
   ACTH level
   Gene sequencing for CAH related mutations
4. 21 hydroxylase
   11B hydroxylase
   17 alpha hydroxylase
   3B hydroysteriod dehdrogease
5. 21 hydroxylase / 11B hydroxylase
   Congenital adrenal hyperplasia due to 21 hydroxylase def.

Question 22

A 13-year-old Caucasian patient,reared as female, presented initially to the clinic for primary amenorrhea evaluation
Medical history included bilateral inguinal hernias surgically repaired at the age of 2 years
The patient is an only child, whose parents are divorced.
She top at school and a professional dancer

Physical examination?
Weight 50 KG, height 171 cm
Feminine habitual with development of both breasts and pubic hair growth at tanner stage 3

Gynecological examination revealed well-developed labia, small clitoris, and a short vagina (4cm) with blind ended pouch; thus, the cervix could not be visualized on speculum examination of

Hormone profile:
Decrease estradiol
Increase testosterone
Increase AMH

What other tests would u consider?

Pelvic MRI reveled absence of uterus and ovaries, hypoplastic vagina, and intrabdominal gonads, like testes

What karyotype u expect based on hormonal profile and MRI finding?
What are the conditions where 46, XY male chromosomal sex presents as female external gonadal sex?
Which differential is the likely cause and why?
What test will u perform to confirm provisional diagnosis?

Answer 22

1. Pelvic MRI to determine internal genital karytoyping
2. 46, XXY
3. 46, XY gonadal dysgenesis (sweyr syndrome )
   Androgen insensitivity syndrome
   5 alpha reductase def.
4. In sweyr syndrome AMH is low , and gonads are absent and in 5 alpha reductase deficiency AMH is normal and only testosterone is high

While in androgen insensitivity syndrome both are high
5. Sequencing the androgen receptor AR gene on chromosome X