Common Genetic syndromes

Dr. E.M. Honey

Department Genetics

Division Human Genetics

University of Pretoria

Definitions

• Deformation

• Malformation

• Disruption

• Dysplasia

• Syndrome

• Associations

• Complex

• Sequences

• Major and minor anomalies

Introduction

• Developing countries has a higher burden

• Genetic disorders not rare

• 2-3% of all births

• 12% of Paediatric admissions

• 50% of adult disorders have a genetic

component

• 11% of neonatal deaths

• More than 6000 syndromes described

Classification(Causes) • Genetic:

Chromosomal 6%

Single gene 7,5%

Multifactorial 20-30%

Subtotal 30-40%

• Environmental: Drugs and chemicals 2%

Infections 2%

Maternal illness 2%

Physical agents 1%

Subtotal 5-10%

• Unknown: 50%

Neurofibromatosis type 1

• Autosomal dominant

• 1 in 3000

• NF 1 locus on

chromosome 17 and

the gene has been

clones

• Recurrence risk 50%

Clinical features:

• Café au lait patches

• Neurofibroma

• Lisch nodules

• Intellectual disability

• Seizures

• Malignant changes

(5-10%)

• Learning disorders

(40%)

Oculocutaneous albinism

• Autosomal recessive

• Hereditary defect in the

metabolism of melanin

resulting in the

decrease or absence of

this pigment in the skin,

mucosa, hair or eyes

• 1 in 3900 (African

population)

• Recurrence risk 25%

Clinical features:

• Depigmented skin

• Skinsensitivity

• Nystagmus

• Visual problems

• Increased

susceptibility to skin

cancer

Management

• Limit skin exposure

• Protective clothing

• Protective sunscreen lotion

• Wear sunglasses

• School of the blind

• Attention to suspicious skin lesions

• Visit Dermatologist and Ophthalmologist on a yearly basis

Duchenne muscular dystrophy

• X-linked recessive

• 1 in 3500 males with no

ethnic variation

• DMD gene on Xp21 -

dystrophin product

• Carrrier testing in affected

females possible

• Becker muscular

dystrophy: milder degree

Clinical features

• Muscle weakness from 3-5

years

• Positive Gower’s sign

• Delay in walking

• Wheelchair bound by 11 years

• Death at a mean age of 18

years

• Pseudohypertrophy of calf

muscles and wasting of the

proximal muscles

• Mild to moderate intellectual

impairment

• Cardiac muscle involvement

Down syndrome

• Commonest cause of

congenital mental

disability in developed

countries

• 1 in 700 pregnancies

• 3 types:

1. Non-dysjunction

(92-95%)

2. Translocation(5%)

3. Mosaic(3%)

Clinical features

• Small brachicephalic

head, third fontanel

• Facial dysmorphism,

open mouth, protuberant

tongue, epicantic folds

and upslanting palpebral

features

• Short stature

• Prominent hypotonia

Clinical features • Short stubby fingers,

single palmar crease and clinodactily

• Increased distance between first and second toes (“sandal gap”)

• Cardiac, skeletal and gastro-intestinal defects

• Mental retardation (IQ 20-50)

• Increased risk for haematological and endocrine diseases

Management

• Mental retardation:

Stimulation

programmes,

special schooling(?)

and sheltered

employment

• Cardiac defects

• Recurrent infections

Recurrence risk

• Non-disjunction - 1% and increase with AMA

• Translocation - 10% if from the mother and 2% if from

the father

• Mosaic - less than 1%

• Antenatal testing possible:

Maternal screening

Ultrasound: Nuchal translucency

Chorionic villi sampling or amniocentesis

Trisomy 18 (Edward syndrome)

• Incidence of approximately 0,3 per 100

• More than 130 different abnormalities noted

• Non-disjunction(full), translocation, mosiac, partial trisomy 18

Monosomy X/ 45X0 (Turner syndrome)

• Described in 1938

• Incidence of 1 in 2500 females

• Most 45X0 conceptuses die early

• Paternal X chromosome most likely missing

• No significant older maternal age and usually sporadic

• Approximately 6% of females with Turner syndrome have 45X/46XY mosaïcism

• If mentally deficient look for another chromosomal defect

47XXY/ Klinefelter syndrome

• Most common single

cause for

hypogonadism and

infertility

• Affects approximately

1 in 500 males

Neural tube defects

• Multifactorial

• Three conditions:

1. Anencephaly

2. Encephalocoele

3. Spina bifida

• Failure of the neural tube to

close by the end of the forth

postconceptual week

• Aethiology: Genetic

predisposition and

environmental factors e.a. folic

acid deficiency

Neural tube defects

• Recurrence risk:

1 affected child 5%

2 affected children 10%

1 affected parent 4%

• Folic acid periconceptually reduces the risk by 72%

• Prenatal diagnosis: AFP(maternal and amniotic fluid) and maternal ultrasound

Teratogenesis

• Teratogen: A drug, chemical, infectious or physical agent, maternal disease or metabolic agent that by acting on the developing fetus causes a structural or functional abnormality(congenital malformation or birth defect) present at birth

• Susceptible stages of development:

1st trimester: 0-17 days: not susceptible

18-30 days: highly susceptible

31-60 days: susceptibility continue

2nd trimester: decreasing susceptibility

3rd trimester: minimal susceptibility

Fetal alcohol syndrome

• Most common teratogen

• Growth deficiency:

1. Small stature

2. Microcephaly

Mental deficiency

Poor fine motor

Hyperactivity

3. Facial dysmorphisms

Short nose

Inner epicantic folds

Smooth philtrum

Thin upper lip

Small midface

4. Other defects

Cardiac, skeletal

Fetal alcohol syndrome(cont.)

• Etiology:

Heavy alcohol exposure

Unsure about “safe” level during pregnancy

Bingeing more harmful

All women should abstain from taking alcohol during pregnancy

Genetic predisposition

Other Human teratogens

• Maternal disease: Diabetes mellitis, phenylketonuria,

epilepsy, hyperthermia, hypothyroidism, starvation

• Maternal infections: Toxoplamosis, Rubella, CMV,

Herpes simplex, syphilis, varicella zoster, parvovirus, HIV

• Environmental chemicals

• Radiation

• Drugs: Anticoagulants(Warfarin), anti-

convulsants(Phenytoin), anti-cancer drugs,

antibiotics(Tetracycline), hormones(androgens and

diethylstilbestrol), psychiatric drugs(Lithium), Vitamin A

congeners(Ruaccutane) and salicylates(Aspirin)

Ambiguous genitalia

• Medical emergency!

• Differential diagnosis:

Chromosomal abnormalities

CAH

Testicular feminization

Hermaphrodite

Effect of androgens or estrogens in utero

Hypothalamic and pituitary defects