Birth Defects was written for healthcare workers who look after individuals with birth defects, their families, and women who are at increased risk of giving birth to an infant with a birth defect. This book is being used in the Genetics Education Programme which trains healthcare workers in genetic counselling in South Africa. It covers: modes of inheritance, medical genetic counselling, birth defects due to chromosomal abnormalities, single gene defects, teratogens, multifactorial inheritance

1. Addendum A: Clinical features, diagnosis,
treatment, genetic counselling and
prevention of common birth defects
SINGLE GENE DEFECTS
Common Autosomal Recessive Disorders
Oculocutaneous albinism
(Autosomal recessive – 1 in 5000 in sub-Saharan Africa)
Clinical features: Treatment and Counselling:
• Skin, hair and retina lack pigment • Treat skin infections*
• Skin and eye hypersensitivity to sunlight • Sunscreen*
• Increased risk of skin cancer • Surgery for skin cancer
• Reduced visual acuity and nystagmus • Glasses for reduced vision
• Genetic counselling*
Diagnosis: • Advice on skin and eye care and coverage
• Clinical diagnosis with clothes and wide-brimmed hats*
• DNA diagnosis available**
Prevention:
• 1o – Family planning, family history* and
preconception DNA carrier screening**
• 2o – Prenatal carrier screening and
prenatal DNA diagnosis**
• 3o – Early detection* and treatment of
skin cancer

2. ADDENDUM A 115
SINGLE GENE DEFECTS
Common Autosomal Recessive Disorders
Cystic fibrosis
(Autosomal recessive – 1 in 2000 European and 1 in 2500 in Middle Eastern countries)
Clinical features: Treatment and Counselling:
• Recurrent chest infections and wheeze • Aggressive treatment of respiratory
• Clubbing of fingers infections (antibiotics, bronchodilators,
• Chronic diarrhoea physiotherapy)
• Malabsorption • Pancreatic enzyme replacement
• Failure to thrive • Gene therapy in the future
• Genetic counseling**
Diagnosis:
Prevention:
• Sweat test**
• 1o – Family planning, family history* and
• DNA diagnosis**
preconception carrier screening**
• 2o – Prenatal carrier screening and
prenatal diagnosis**
• 3o – Newborn screen
Sickle cell anaemia
(Autosomal recessive. Birth prevalence varies in different countries – 1 in 50 newborns in Nigeria)
)
Clinical features: Treatment and Counselling:
• Moderate to severe haemolytic anaemia • Prevention or early treatment of
• Haemolytic or aplastic crises infections (vaccines, antibiotics, anti-
• Jaundice malarials)*
• Initially splenomegaly but later this • Maintain hydration to prevent crises
disappears • Manage crises and acute complications
• Hyposplenism • Genetic counselling*
• Increased susceptibility to infection
(especially Streptococcus pneumoniae, Prevention:
Haemophilus influenzae, Salmonella, • 1o – Family planning, family history*
malaria) and preconception population carrier
• Vaso-occlusive episodes (abdominal screening**
including kidneys and spleen, dactylitis, • 2o – Prenatal carrier screening and
priapism, stroke) prenatal diagnosis**
• Leg ulcers, aseptic necrosis of bone • 3o – Newborn screening
• Cholelithiasis (gallstones)
Diagnosis:
• Full Blood Count-normocytic/mildly
macrocytic anaemia, reticulocytosis, target
cells
• Haemoglobin electrophoresis-increased
haemoglobin F and S
• Positive sickling test
• Increased serum bilirubin
• DNA diagnosis**
• X-rays – increased medullary spaces and
cortical thinning, avascular necrosis of bone

3. 116 BIR TH DEFECTS
SINGLE GENE DEFECTS
Rarer Single Gene Defects
Neurofibromatosis I
(Autosomal dominant – 1 in 3000)
Clinical features: Treatment and Counselling:
• Café-au-lait patches • Surgery when indicated and if available
• Neurofibroma • Neurodevelopmental therapy/
• Axillary freckling community-based rehabilitation including
• Macrocephaly (head circumference psychosocial support
above 97th centile) • Genetic counselling**
• Scoliosis
• Learning difficulties Prevention:
• Complication from compression by • 2o – Prenatal diagnosis (DNA diagnosis)
neurofibroma
• Increased risk of malignancy in
neurofibroma
Diagnosis:
• Clinical diagnosis
• DNA diagnosis available
• Neurodevelopmental/psychometric
assessment
Tuberous sclerosis
(Autosomal dominant – 1 in 15 000)
Clinical features: Treatment and Counselling:
• Variable expressivity • Surgery if indicated
• Adenoma sebaceum and café-au-lait
afé-au-lait • Neurodevelopmental therapy/
patches community-based rehabilitation including
• Ash leaf patches and shagreen patches
hagreen psychosocial support
• CNS (cortical) tubers on CT scan • Seizure control
• Renal angiomyolipoma • Genetic counselling**
• Ungual fibroma
• Intellectual disability and epilepsy Prevention:
• 2o – Prenatal diagnosis (DNA diagnosis)
Diagnosis:
• Clinical diagnosis
• DNA diagnosis available
• Neurodevelopmental/psychometric
assessment

4. ADDENDUM A 117
SINGLE GENE DEFECTS
Rarer Single Gene Defects
Huntington disease
(Autosomal dominant – 1 in 10 000)
Clinical features: Treatment and Counselling:
• Adult onset (Average age 35 years) • No effective treatment. Diagnosis to
• Progressive involuntary movements death averages 15 years
(chorea) • Psychosocial support
• Progressive dementia and psychiatric • Genetic counselling
symptoms
• Weight loss Prevention:
• 1o – Family history*, presymptomatic and
Diagnosis: pre-pregnancy (DNA) diagnosis** and family
• DNA diagnosis*** Presymptomatic planning*
testing possible** • 2o – Prenatal diagnosis (DNA diagnosis)**
• Brain scan**
Achondroplasia
(Autosomal dominant 1 in 26 000)
Clinical features: Treatment and Counselling
• Skeletal dysplasia with asymmetric short • Surgery when indicated and if available
stature (short limbs) • Avoid contact sports
• Macrocephaly (head circumference • Genetic counseling
above 97th centile)
• Trident hand. May develop Prevention:
hydrocephalus and spinal cord compression • Genetic counselling**
• 2o – Prenatal diagnosis (ultrasound**
Diagnosis: /DNA diagnosis)
• Clinical diagnosis
• DNA diagnosis available
Myotonic dystrophy
(Autosomal dominant 1 in 9000)
Clinical features: Treatment and Counselling:
• Presents usually in young adults. • Supportive
Progressive muscular weakness • Genetic counselling**
• Myotonia and frontal baldness
• Cataracts Prevention:
• Cardiac conduction defects • 1o – Family history* and DNA diagnosis**
• Hypogonadism • Family planning*
• Congenital form (gene inherited from • 2o – Prenatal diagnosis (DNA diagnosis)**
mother) severe hypotonia, facial diplegia,
ptosis, arthrogryposis, cataracts
Diagnosis:
• Electromyography (EMG)**
• DNA diagnosis**

5. 118 BIR TH DEFECTS
SINGLE GENE DEFECTS
Rarer Single Gene Defects
Waardenburg syndrome
(Autosomal dominant – 1 in 30 000)
Clinical features: Treatment and Counselling:
• Sensorineural deafness • Hearing aid
• Poliosis (White forelock/early greying) • Neurodevelopmental therapy/
• Sapphire blue eyes or eyes of different community-based rehabilitation including
colours (heterochromia) psychosocial support
• Partial albinism • Genetic counselling**
• Telecanthus and medial eyebrow flare
Prevention:
Diagnosis: • Nil
• Clinical diagnosis
• Audiology**
• DNA diagnosis**
Congenital hypothyroidism
(Autosomal recessive 1 in 4000)
Clinical features: Treatment and Counselling:
• Feeding problems • Growth monitoring*
• Decreased activity • Thyroxine
• Constipation • Neurodevelopmental therapy/
• Macroglossia (Large tongue) community-based rehabilitation including
• Hypothermia and dry skin psychosocial support
• Umbilical hernia • Genetic counselling**
• Intellectual disability/deafness
Prevention:
Diagnosis: • 3o – Newborn screening (Not currently
• Thyroid function tests – Thyroid done universally in South Africa)
stimulating hormone (TSH)
• Free thyroxine (T3 and T4)**
• Neurodevelopmental/psychometric
assessment**
• Audiological testing (Pendred syndrome
– have deafness)**

6. ADDENDUM A 119
SINGLE GENE DEFECTS
Rarer Single Gene Defects
Fragile X syndrome
(X-linked recessive 1 in 2000 males)
Clinical features: Treatment and Counselling:
• Intellectual disability • Genetic counselling**
• Speech disability
• Autistic-like behaviour Prevention:
• Macrocephaly • 1o – Family history* and carrier
• Long narrow faces with large ears screening**
• Testicular enlargement • Family planning*
• 2o – Prenatal diagnosis (DNA diagnosis)**
Diagnosis:
• DNA diagnosis**
• Neurodevelopmental/psychometric
assessment**
• Neurodevelopmental therapy/
community-based rehabilitation including
psychosocial support
Haemophilia A and B
(X-linked recessive – Haemophilia A 1 in 2000 males/Haemophilia B 1 in 20 000 males)
Clinical features: Treatment and Counselling:
• Spontaneous bleeding disorder • Replace factor VIII (A) or IX (B)*
• Variable clinical expression • Pain relief*
• Haemarthrosis • Splinting*
• Physiotherapy/CBR*
Diagnosis: • Genetic counselling*
• Prolonged partial thromboplastin time
• Decreased factor VIII (A) or IX (B) in Prevention:
blood** • 1o – Family history* and DNA carrier
• DNA diagnosis available** screening**
• Family planning*
• 2o – Prenatal diagnosis (DNA diagnosis)**
• 3o – Avoid injury

7. 120 BIR TH DEFECTS
SINGLE GENE DEFECTS
Rarer Single Gene Defects
Duchene Muscular Dystrophy
(X-linked recessive 1 in 3700 males)
Clinical features: Treatment and Counselling:
• Clinical onset 3–5 years of age • Physiotherapy
• Gait abnormalities • Surgery if indicated**
• Weakness of the pelvic girdle • Cardiac failure treatment*
• Gower sign • Treatment of respiratory infection*
• Pseudohypertrophy of the calves • Wheel chair
• Tightening of the Achilles tendons • Genetic counselling**
• Lumbar lordosis
• Progressive muscle weakness and Prevention:
atrophy of muscles • 1o – Family history* and DNA carrier
• Loss of ability to walk by 9-16 years screening**
• Cardiomyopathy/heart failure • Family planning* and 2o – prenatal
• Respiratory failure diagnosis (DNA diagnosis)**
• Death by 25 years
Diagnosis:
• High creatine phosphokinase (CPK)
• DNA diagnosis**
CHROMOSOMAL DISORDERS
Down syndrome
Currently 1 in 500 live births in South Africa
Clinical features: Treatment and Counselling:
• Hypotonia • Growth monitoring
• Intellectual disability • Surgery when indicated and available
• Craniofacial: brachycephaly, flat face, up- • Treatment for cardiac failure*
slanting palpebral fissures, epicanthic folds, • Treatment of infections*
flat nasal bridge, small, low set ears, squint, • Thyroxine if indicated
relative macroglossia, Brushfield spots • Neurodevelopmental therapy/
(Caucasians) community-based rehabilitation including
• Short stature psychosocial support
• Brachydactyly, single palmar creases, • Genetic counselling*
5th finger clinodactyly and hypoplasia
midphalanx
• Sandal gap between first and second
toes, plantar creases
• Small penis/hypogonadism
• Congenital heart disease
• Duodenal atresia
• Recurrent infection, especially of the
respiratory tract

8. ADDENDUM A 121
CHROMOSOMAL DISORDERS
Down syndrome
Currently 1 in 500 live births in South Africa
Diagnosis: Prevention:
• Chromosomal/ FISH analysis/QR-PCR** • 1o – Family planning and preconception care*
• Trisomy 21 – 95% • 2o – Prenatal (AMA) screening*
• Mosaicism – 2.5% Ultrasound and maternal serum screening
• Translocation – 2.5% for Down syndrome
• Thyroid function tests • Prenatal chromosome/QR-PCR
• Neurodevelopmental/psychometric diagnosis**
assessment
• Cardiac assessment
• Audiology
Trisomy 18
(1 in 1500 live births)
Clinical features: Treatment and Counselling:
• Decreased fetal movement. Prenatal • Supportive/Palliative care*
growth deficiency • Genetic counselling*
• Severe developmental delay • Supportive
• Hypertonia with weak cry, poor sucking
• Craniofacial: bifrontal narrowing, Prevention:
prominent occiput, microcephaly, low set
malformed ears, short palpebral fissures, • 1o – Family planning and preconception
small chin and mouth, cleft lip/palate care*
• Clenched hands, overriding fingers • 2o – Prenatal screening for chromosomal
• Rocker-bottom feet, clubfeet disorders
• Congenital heart disease • Ultrasound scanning for birth defects
• Genital hypoplasia • Prenatal diagnosis. Chromosomal/ FISH
• Neonatal or early infant death analysis/QR-PCR**
Diagnosis:
• Chromosomal/FISH analysis/QR-PCR**
Trisomy 13
(1 in 4500 live births)
Clinical features: Treatment and Counselling:
• Prenatal growth deficiency • Supportive/Palliative care*
• CNS malformations • Genetic counselling*
• Hypertonia/hypotonia with severe
developmental delay Prevention:
• Craniofacial: Microcephaly/sloping • 1o – Family planning and preconception
forehead, microphthalmia, anophthalmia, care*
abnormal ears, cleft lip/palate, micrognathia • 2o – Prenatal screening for chromosomal
• Polydactly, camptodactyly, convex disorders
hypolastic finger nails, cryptorchidism • Ultrasound scanning for birth defects
• Congenital heart disease • Prenatal chromosome diagnosis**
• Neonatal or early infant death
Diagnosis:
• Chromosomal/FISH analysis/QR-PCR.**

9. 122 BIR TH DEFECTS
CHROMOSOMAL DISORDERS
Turner syndrome
(1 in 1000 female live births)
Clinical features: Treatment and Counselling:
• Female phenotype • Growth monitoring*
• Short stature • Surgery when indicated and if available**
• Congenital heart disease (aortic stenosis/ • Ovarian hormone replacement therapy**
coarctation of aorta) • Neurodevelopmental therapy/
• Renal anomalies community-based rehabilitation including
• Ovarian dysgenesis/infertility psychosocial support
• Learning difficulties • Genetic counselling**
Prevention:
Diagnosis:
• 1o – Family planning and preconception
• Chromosomal/FISH analysis/QF-PCR**
care*
• Monosomy XO/Turner mosaics
• 2o – Prenatal screening for chromosomal
• Neurodevelopmental/psychometric
disorders
assessment
• Ultrasound scanning for birth defects
• Cardiac assessment
• Prenatal diagnosis. Chromosomal/FISH
analysis/QR-PCR**
MULTIFACTORIAL DISORDERS
Spina bifida
Clinical features: Treatment and Counselling:
• Spinal lesion with paraplegia/ • Surgery when indicated and if available
incontinence • Incontinence care
• Hydrocephalus and developmental delay • Neurodevelopmental therapy/
communitybased rehabilitation including
Diagnosis: psychosocial support
• Clinical diagnosis • Palliative care*
• Brain ultrasound/CAT scan
Prevention:
• Urological assessment
• Genetic counselling*
• Neurodevelopmental/psychometric
• 1o – Optimising women’s diet. Folic acid
assessment
supplementation*
• 2o – Maternal serum alpha feto-protein
screening
• Ultrasound scanning for birth defects
Anencephaly
Clinical features: Treatment and Counselling:
• Incomplete development and closure of • Palliative care*
the skull and development of the brain
Prevention:
• Incompatible with life
• Genetic counselling*
• 1o – Optimising women’s diet. Folic acid
Diagnosis:
supplementation*
• Clinical diagnosis
• 2o – Maternal serum alpha feto-protein
screening
• Ultrasound scanning for birth defects

10. ADDENDUM A 123
MULTIFACTORIAL DISORDERS
Encephalocele
Clinical features: Treatment and Counselling:
• Incomplete closure of the skull with out- • Surgery when indicated and if possible
pouching containing neural tissue • Neurodevelopmental therapy/
• Microcephaly community-based rehabilitation including
• Developmental delay psychosocial support
• Seizures • Seizure control
• Genetic counselling*
Diagnosis:
• Clinical diagnosis Prevention:
• Brain scan • 1o – Optimising women’s diet. Folic acid
• Neurodevelopmental/psychometric supplementation*
assessment • 2o – Ultrasound scanning for birth defects
Cleft lip/palate
Clinical features: Treatment and Counselling:
• Cleft lip and/or palate • Surgery
• Feeding problems • Feeding plate in infancy
• Speech difficulties • Neurodevelopmental therapy/
community-based rehabilitation including
Diagnosis: psychosocial support
• Clinical diagnosis • Genetic counselling*
• Audiology
Prevention:
• Nil
Talipes equinovarus
(Clubfoot)
Clinical features: Treatment and Counselling:
• Fixed equinovarus deformation of the • Manipulation and plaster of Paris casts
foot (feet) • Surgery when indicated
• Genetic counselling*
Diagnosis:
• Clinical diagnosis Prevention:
• X-rays • Nil

11. 124 BIR TH DEFECTS
TERATOGENS
Fetal alcohol syndrome
(Prevalence varies between communities. Estimated more than 1% of South African infants are
born with FAS)
Clinical features: Treatment and Counselling:
• Pre- and postnatal growth deficiency • Neurodevelopmental/psychometric
• Microcephaly assessment
• Intellectual disability • Cardiac assessment
• Behaviour disorder • Growth monitoring*
• Craniofacial: short palpebral fissures, • Surgery when indicated and if available.
short upturned nose, smooth philtrum, thin • Neurodevelopmental therapy/
vermillion border community-based rehabilitation including
• Joint anomalies psychosocial support
• Congenital heart defects • Neuro-behavioural management
• Genetic counselling*
Diagnosis:
• Clinical diagnosis Prevention:
• 1o – Optimising women’s diet
• Public education on the bad effects of
alcohol use and abuse in pregnancy*
Fetal rubella syndrome
Clinical features: Treatment and Counselling:
• Growth deficiency • Growth monitoring*
• Microcephaly • Surgery when indicated and if available
• Intellectual disability • Auditory and vision management
• Sensori-neural deafness • Neurodevelopmental therapy/
• Cataracts, chorioretinitis, community-based rehabilitation including
microphthalmia, squint psychosocial support
• Congenital heart disease (PDA, septal • Genetic counselling*
defects, peripheral pulmonary stenosis)
• Hepatosplenomegaly Prevention:
• Thrombcytopenia, anaemia • 1o – Preventing maternal infection by
mass rubella immunisation
Diagnosis: • 2o – Prenatal screening for sero-
• Clinical diagnosis negativity and immunisation prior to
• Serum IgG and IgM for rubella. Identify subsequent pregnancy*
virus in urine • Detection of congenital malformations
• Neurodevelopmental/psychometric with ultrasound screening
assessment • Avoid contact between pregnant women
• Visual assessment and ill children
• Audiology
• Cardiac assessment
• Full Blood Count

12. ADDENDUM A 125
Abbreviations:
* Possible in primary health care.
** Available in South Africa
1o – Primary prevention (Preconception and early postconception period).
2o – Secondary prevention (Antenatal period).
3o – Tertiary prevention (Postnatal period).
CBR. Community-based rehabilitation
FISH. Fluorescent in situ hybridisation
(Adapted from Christianson A L and Modell B. Medical Genetics in Developing Countries, Ann.
Rev. Genomics Hum Genetics. 2004;5: 219–265).