Chromosomal Abnormalities

Question 1

What is Turner’s Syndrome?

Answer 1

females with an absent/nonfunctional X sex chromosome

1 in every 2500 female newborns

Question 2

What are the hallmarks of Turner Syndrome?

Answer 2

HALLMARKS:

hypogonadism ⇒

_primary amenorrhea or early ovarian failure*_, delayed secondary sex characteristics (absence of breasts), infertility, short stature (with normal growth hormone levels), webbed neck, edema, low hairline, low set ears, widely spaced nipples

renal and cardiovascular abnormalities

Question 3

Pathophysiology of Turner Syndrome

Answer 3

Mosaicism: (67 - 90%). some cells have a combination of X monosomy (45, XO – missing X chromosome), some cells that are normal (46, XX), cells with partial monosomies (X/abnormal X), or cells that have a Y chromosome (46, XY)

45, XO = absence/nonfunction of 1 of the X chromosome ⇒ gonadal dysgenesis

Question 4

Clinical Manifestations of Turner Syndrome

Answer 4

1. Hypogonadism: absent/nonfunctional sex chromosome (45XO) ⇒ gonadal dysgenesis ⇒ rudimentary, fibrosed ovaries ⇒ primary amenorrhea** in 80% (menopause before menarche) or early ovarian failure with secondary amenorrhea (20%), delayed secondary sex characteristics (absence of breasts), infertility in the majority of patients

2. Physical Exam: short stature, webbed neck, prominent ears, low posterior hairline, broad chest with hypoplastic widely-spaced nipples, (congenital lymphedema seen in neonates), short 4th metacarpalls, high-arched palate, nail dysplasia, may have hearing loss

3. Cardiovascular: coarctation of the aorta (30%), mitral valve prolapse, bicuspid aortic valves, aortic dissection, HTN

4. Renal: congenital abnormalities (ex horseshoe kidney), hydronephrosis

5. Endocrine: osteoporosis, hypothyroidism, Diabetes Mellitus, dyslipidemias

6. GI: telangectasias (may present with GI bleeding), IBD, colon cancer, liver disease

Question 5

Diagnosis of Turner Syndrome

Answer 5

1. Karyotyping - definite diagnosis. 45, XO, mosaicism, or X chromosome abnormalities
2. High serum FSH and LH levels

Question 6

Management of Turner Syndrome

Answer 6

1. Growth hormone replacement (may increase final height)
2. Estrogen/Progesterone replacement to cause pubertal development

Question 7

What is Klinefelter’s Syndrome?

Answer 7

Males with extra X chromosome = 47, XXY karyotype 80% (extra sex chromosome due to failure of separation of sex chromosoe or translocation) ⇒

males with hypogonadism & small testes

1:800 births

MC chromosomal abnormality with hypogonadism

Question 8

Clinical Manifestations of Klinefelter’s Syndrome

Answer 8

• normal appearance before puberty onset ⇒ tall stature (thin & long-limbed with Eunochoid features. In adulthood, they become obese. + scoliosis, ataxia, mild developmental delays, expressive language disorders. Increased risk of testicular cancer
• Hypogonadism: small testicles & infertility (azoospermia), gynecomastia, scarce pubic hair

Question 9

Diagnosis of Klinefelter’s Syndrome

Answer 9

47, XXY kayotype, low serum testosterone. Testosterone may help with secondary sex characteristics

Question 10

What is Fragile X Syndrome?

Answer 10

X-linked genetic disorder that is the MC gene related cause of autism. The loss of funcion of the fragile X mental retardation 1 gene ⇒ lack of the production of the Fragile X mental retardation protein

Question 11

Clinical Manifestations of Fragile X Syndrome

Answer 11

Younger males: mitral valve prolapse, hyperextensible joints, hypotonia, soft skin, flexible flat feet, macrocephaly

Older males: long and narrow face, prominent forehead & chin, large ears, macroorchidism** (enlarged testicles)

Behavioral: wide range of manifestations expressive language deficits > receptive

Question 12

What is Down Syndrome? (trisomy 21)

Answer 12

three copies of chromosome 21 or 3 copies of a region of the long arm of chromosome 21

Question 13

Clinical Manifestations of Down Syndrome

Answer 13

• Head & neck: low-set, small ears, flat facial profile/flat nasal bridge, open mouth protruding tongue, upslanting palpebral fissures, folded or dysplastic ears, brachycephalic (short head), epicanthic folds (fold of upper skin over the eyelid), excessive skin at the nape of the neck, short neck, Brushfield spots: white/gray/brown spots on the iris
• Extremities: transverse, single, palmar (simian) crease*, hyperflexibility of the joints, short broad hands, increased space between 1st & 2nd toes (sandal gap)
• neonates: poor moro reflex, dysplasia of the pelvis, hypotonia, anomalous ears. may develop transient neonatal leukemia
• intellectual impairment: wide range
• Congenital heart disease: atrioventricular septal defects, ventricular septal defect, atrial septal defect, Tetralogy of Fallot, PDA
• GI: duodenal atresia or stenosis, Hirschsprung disease