Klinefelter Syndrome (47,XXY)

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Klinefelter syndrome is seen in 1 in 1,000 births. Diagnosis is seldom made before puberty. Physical findings include tall stature, testicular atrophy, azoospermia, gynecomastia, and trun-cal obesity. Learning disorders, autoimmune diseases, and low IQ are common.

Down Syndrome

Trisomy 21 is seen in 1 in 800 births and accounts for 50% of all cytogenetic diseases at term.IUGR and polyhydramnios are common. T21 incidence increases with advancing maternal age. The syndrome is characterized by mental retardation, short stature, muscular hypotonia, brachycephaly, and short neck. The typical facial appearance is oblique orbital fissures, flat nasal bridge, small ears, nystagmus, and protruding tongue. Congenital heart disease (endocardial cushion defects) is more common along with duodenal atresia.

of Down Syndrome

1:25

125

Rate (per 1,000)

1:100

100

1:500

1:1,00

Rate

Birth

1:5,00

–

Maternal age

Figure I-1-5. Birth Rate and Rate of Down Syndrome versus Maternal Age

Edward syndrome

Trisomy 18 is seen in 1 in 5,000 births and is more frequent with advancing maternal age. IUGRis common. It is associated with profound mental retardation. Unique findings are rocker-bottom feet and clenched fists. Eighty percent of cases occur in females. Survival to 1 year of age is <10%. Mean survival is 14 days.

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Chapter 1 l Reproductive Basics

Patau syndrome

Trisomy 13 is also seen more frequently with advancing maternal age. It is associated withprofound mental retardation. Associated findings include IUGR, cyclopia, proboscis, holopros-encephaly, and severe cleft lip with palate. Survival to 1 year of age is rare, with mean survival 2 days.

Table 1-8. Genetic Syndromes

Name

Karyotype

Stature IQ

Unique finding

Kline

47,XXY

TALL

↓ IQ

Microgenitals,

infertility

Turner

45,X

Normal

Web neck,

coarctation aorta

Down

T21, T18,

Functional

Duodenal atresia,

(Trisomy)

T13

AV canal defect

SHORT

↓

Edward

T18

Abnormal feet, fist

Severe MR

Patau

T13

↓

Holoprosencephaly

Profound

Cyclops

mental

retardation

Mendelian Genetics

A 23-year-old black primigravida is seen at 12 weeks’ gestation. She has been diagnosed with sickle cell trait (AS). Her husband and father of the baby is also AS. She inquires as to the risk of her baby having sickle cell disease (SS).

Prevalence. About 1% of liveborn infants have a congenital Mendelian disorder. 15% of allbirth defects are attributable to Mendelian disorders. Of these, 70% are autosomal dominant. The remainder are autosomal recessive or X-linked.

Autosomal dominant genetics

Transmission occurs equally to males and females, and serial generations are affected. Gross anatomic abnormalities are the most common findings. Age of onset is usually delayed, withvariability in clinical expression. Each affected individual has an affected parent (unless this is a new mutation). Affected individuals will transmit the disease to 50% of their offspring. Unaffected individuals will bear unaffected children (if penetrance is complete). There are no carrier states.

Autosomal dominant examples:

Polydactyly	Marfan syndrome	Polycystic kidneys
Huntington chorea	Myotonic dystrophy	Neurofibromatosis
Achondroplasia		Osteogenesis imperfecta

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OB Triad

Autosomal Dominant

• Transmitted by both sexes

• All generations affected

• No carrier states

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USMLE Step 2 l Obstetrics

OB Triad

Autosomal Recessive

• Transmitted by both sexes

• Often skips generations

• Male and female carriers

OB Triad

X-Linked Recessive

• No male–male transmission

• Expressed only in males

• Female carriers

Autosomal recessive

Transmission occurs equally to males and females, but the disease often skips generations. Enzyme deficiencies are most common findings. Age of onset is usually earlier with consistency in clinical expression. If both parents are heterozygous for the gene, 25% of offspring are affect-ed, 50% are carriers, and 25% are normal. If one parent is homozygous and one is heterozygous, 50% of offspring will be affected, and 50% will be carriers. If both parents are homozygous, 100% of children will be affected. Carrier states are common.

Autosomal recessive examples:

Deafness	Albinism	Phenylketonuria (PKU)
Cystic fibrosis (CF)	Sickle cell anemia	Congenital adrenal hyperplasia (CAH)
Thalassemia	Tay-Sachs (TS) disease	Wilson disease

X-linked recessive

These conditions are functionally dominant in men, but may be dominant or recessive in women. There is no male-to-male transmission (because the father gives only his Y chromo-some to his son), but transmission is 100% male to female. The usual transmission is from heterozygous females to male offspring in an autosomally dominant pattern. The disease is expressed in all males who carry the gene. Family history reveals the disorder is only found in male relatives, and commonly in maternal uncles.

X-linked recessive examples:

Hemophilia A

Diabetes insipidus

G-6-PD deficiency

Color blindness

Hydrocephalus

Duchenne muscular dystrophy

Complete androgen insensitivity

Every generation?

No carrier states?

Yes

Dominant

Recessive

(anatomic disorders)

(enzyme disorders)

Father gives it to son?

Lethal in males?

Yes

Autosomal

X-linked

Autosomal

X-linked

achondroplasia

hypophosphotemic,

CF, TS, SC,

hemophilia

rickets

PKU, CAH

Figure I-1-6. Mendelian Genetics

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Chapter 1 l Reproductive Basics

X-linked dominant

These conditions may show up as two types of disorders: (1) manifested in female heterozygotes as well as carrier males (hemizygotes). Example is hypophosphatemic rickets. (2) manifested in female heterozygotes but lethal in males. The increased spontaneous abortion rate represents male fetuses. Examples are incontinentia pigmenti, focal dermal hypoplasia, and orofaciodigital syndrome.

Calculations of Autosomal Recessive Risk

X X^H

Figure I-1-7. Calculations of X-linked Risk (Hemophilia)

Autosomal Dominant

X-linked Dominant

Autosomal Recessive
	Males
	Females
X-linked Recessive	Affected
	Unaffected but
	heterozygous
	Consanguineous

Figure 1-8. Familial Transmission Patterns of Inheritance

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USMLE Step 2 l Obstetrics

Multifactorial Inheritance

A 32-year-old woman with corrected tetralogy of Fallot is pregnant at 18 weeks’ gestation with a male fetus. She inquires as to the chance that her son has congenital heart disease.

Prevalence. The majority of birth defects (70%) are multifactorial or polygenic in origin, whichmeans there is an interaction of multiple genes with environmental factors. Characteristic Mendelian patterns are not found, but there is an increased frequency of the disorder or phe-notype in families. The overall recurrence rate is 2–3%.

• As the number of genes for a multifactorial trait increases, the liability for the disease increases.

• The more severe the malformation, the higher the risk for recurrence.

• Examples of multifactorial inheritance include neural tube defects, congenital heart disease, cleft lip and palate, and pyloric stenosis.

Neural tube defects (NTD)

The incidence of NTD is 1–2 per 1,000 births. These anomalies result from failure of neural tube closure by days 26–28 of embryonic life. The spectrum ranges from anencephaly to very slight vertebral defects. Anencephaly and spina bifida occur with equal frequency. Polyhydramnios is frequently seen. Preconception folic acid supplementation may decrease incidence of NTD. Women with high risk for NTD should take 4 mg of folic acid. All women should take 0.4 mg of folic acid.

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