Addendum A: Clinical features, diagnosis, treatment, genetic counselling and prevention of common congenital disorders

Single gene defects
Common Autosomal Recessive Disorders
Oculocutaneous albinism (Autosomal recessive – 1 in 5000 in sub Saharan Africa)
Clinical features:
Skin, hair and retina lack of pigmented
Skin and eye hypersensitivity to sunlight
Increased risk of skin cancer
Reduced visual acuity and nystagmus

Diagnosis:
Clinical diagnosis
DNA diagnosis available**
Treatment and Counselling:
Treat skin infections*
Sunscreen*
Surgery for skin cancer
Glasses for reduced vision
Genetic counselling*
Advice on skin and eye care and coverage with clothes and wide brimmed hats*

Prevention:
1° – Family planning, family history* and preconception DNA carrier screening**
2° – Prenatal carrier screening and prenatal DNA diagnosis**
3° – Early detection* and treatment of skin cancer
Common Autosomal Recessive Disorders
Cystic fibrosis
(Autosomal recessive – 1 in 2000 European and 1 in 2500 in Middle Eastern countries)
Clinical features: Recurrent chest infections and wheeze
Clubbing of fingers
Chronic diarrhoea
Malabsorption
Failure to thrive

Diagnosis:
Sweat test**
DNA diagnosis**
Treatment and Counselling:
Aggressive treatment of respiratory infections (antibiotics, bronchodilators, physiotherapy)
Pancreatic enzyme replacement
Gene therapy in the future
Genetic counseling**

Prevention:
1° – Family planning, family history* and preconception carrier screening**
2° – Prenatal carrier screening and prenatal diagnosis**
3° – Newborn screen
Sickle cell anaemia
(Autosomal recessive. Birth prevalence varies in different countries – 1 in 50 newborns in Nigeria)
Clinical features:Moderate to severe haemolytic anaemia
Haemolytic or aplastic crises
Jaundice
Initially splenomegaly but later this disappears
Hyposplenism
Increased susceptibility to infection (especially Streptococcus pneumoniae, Haemophilus influenzae, Salmonella, malaria)
Vaso-occlusive episodes (abdominal including kidneys and spleen, dactylitis, priapism, stroke)
Leg ulcers, aseptic necrosis of bone
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
Treatment and Counselling:
Prevention or early treatment of infections (vaccines, antibiotics, anti-malarials)*
Maintain hydration to prevent crises
Manage crises and acute complications
Genetic counselling*

Prevention:
1° – Family planning, family history* and preconception population carrier screening**
2° – Prenatal carrier screening and prenatal diagnosis**
3° – Newborn screening
Rarer Single Gene Defects
Neurofibromatosis I
(Autosomal dominant – 1 in 3000)
Clinical features:
Café-au-lait patches
Neurofibroma
Axillary freckling
Macrocephaly (head circumference above 97th centile)
Scoliosis
Learning difficulties
Complication from compression by neurofibromaIncreased risk of malignancy in neurofibroma

Diagnosis:
Clinical diagnosis
DNA diagnosis available
Neurodevelopmental/psychometric assessment
Treatment and Counselling:
Surgery when indicated and if available
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support
Genetic counselling**

Prevention:
2° – Prenatal diagnosis (DNA diagnosis)
Tuberous sclerosis
Autosomal dominant – 1 in 15 000)
Clinical features:
Variable expressivity
Adenoma sebaceum and café-au-lait patches
Ash leaf patches and shagreen patches
CNS (cortical) tubers on CT scan
Renal angiomyolipoma
Ungual fibroma
Intellectual disability and epilepsy

Diagnosis:
Clinical diagnosis
DNA diagnosis available
Neurodevelopmental/psychometric assessment
Treatment and Counselling:
Surgery if indicated
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support
Seizure control
Genetic counselling**

Prevention:
2° – Prenatal diagnosis (DNA diagnosis)
Huntington disease
(Autosomal dominant – 1 in 10 000)
Clinical features:
Adult onset (Average age 35 years)
Progressive involuntary movements (chorea)
Progressive dementia and psychiatric symptoms
Weight loss

Diagnosis:
DNA diagnosis***
Presymptomatic testing possible**
Brain scan**
Treatment and Counselling:
No effective treatment. Diagnosis to death averages 15 years
Psychosocial support
Genetic counselling

Prevention:
1° – Family history*, presymptomatic and pre-pregnancy (DNA) diagnosis** and family planning*
2° – Prenatal diagnosis (DNA diagnosis)**
Achondroplasia
(Autosomal dominant 1 in 26 000)
Clinical features:
Skeletal dysplasia with asymmetric short stature (short limbs)
Macrocephaly (head circumference above 97th centile)
Trident hand. May develop hydrocephalus and spinal cord compression

Diagnosis:
Clinical diagnosis
DNA diagnosis available
Treatment and Counselling:
Surgery when indicated and if available
Avoid contact sports
Genetic counselling

Prevention:
Genetic counselling**
2° – Prenatal diagnosis (ultrasound** /DNA diagnosis)
Myotonic dystrophy
(Autosomal dominant 1 in 9000)
Clinical features:
Presents usually in young adults. Progressive muscular weakness
Myotonia and frontal baldness
Cataracts
Cardiac conduction defects
Hypogonadismongenital form (gene inherited from mother) severe hypotonia, facial diplegia, ptosis, arthrogryposis,cataracts

Diagnosis:
Electromyography (EMG)**
DNA diagnosis**
Treatment and Counselling:
Supportive
Genetic counselling**

Prevention:
1° – Family history* and DNA diagnosis**
Family planning*
2° – Prenatal diagnosis (DNA diagnosis)**
Waardenburg syndrome
(Autosomal dominant – 1 in 30 000)
Clinical features:
Sensorineural deafness
Poliosis (White forelock/early greying)
Sapphire blue eyes or eyes of different colours (heterochromia)
Partial albinism
Telecanthus and medial eyebrow flare

Diagnosis:
Clinical diagnosis
Audiology**
DNA diagnosis**
Treatment and Counselling:
Hearing aid
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support
Genetic counselling**

Prevention: Nil
Congenital hypothyroidism
(Autosomal recessive 1 in 4000)
Clinical features:
Feeding problems
Decreased activity
Constipation
Macroglossia (Large tongue)
Hypothermia and dry skin
Umbilical hernia
Intellectual disability/deafness

Diagnosis:
Thyroid function tests – Thyroid stimulating hormone (TSH)
Free thyroxine (T3 and T4)**
Neurodevelopmental/psychometric assessment**
Audiological testing (Pendred syndrome – have deafness)**
Treatment and Counselling:
Growth monitoring*
Thyroxine
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support
Genetic counselling**

Prevention:
3° – Newborn screening (Not presently done universally in South Africa)
Fragile X syndrome
(X-linked recessive 1 in 2000 males)
Clinical features:
Intellectual disability
Speech disability
Autistic-like behaviour
Macrocephaly
Long narrow faces with large ears
Testicular enlargement

Diagnosis:
DNA diagnosis**
Neurodevelopmental/psychometric assessment**
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support.
Treatment and Counselling:
Genetic counselling**

Prevention:
1° – Family history* and carrier screening**
Family planning*
2° – Prenatal diagnosis (DNA diagnosis)**
Haemophilia A and B
(X-linked recessive – Haemophilia A 1 in 2000 males/Haemophilia B 1 in 20 000 males)
Clinical features:
Spontaneous bleeding disorder
Variable clinical expression
Haemarthrosis

Diagnosis:
Prolonged partial thromboplastin time
Decreased factor VIII (A) or IX (B) in blood**
DNA diagnosis available**
Treatment and Counselling:
Replace factor VIII (A) or IX (B)*
Pain relief*Splinting*
Physiotherapy/CBR*
Genetic counselling*

Prevention:
1° – Family history* and DNA carrier screening**
Family planning*
2° – Prenatal diagnosis (DNA diagnosis)**
3° – Avoid injury
Duchenne Muscular Dystrophy
(X-linked recessive 1 in 3700 males)
Clinical features:
Clinical onset 3–5 years of age
Gait abnormalities
Weakness of the pelvic girdle
Gower sign
Pseudohypertrophy of the calves
Tightening of the Achilles tendons
Lumbar lordosis
Progressive muscle weakness and atrophy of muscles
Loss of ability to walk by 9-16 years
Cardiomyopathy/heart failure
Respiratory failure
Death by 25 years

Diagnosis:
High creatine phosphokinase (CPK)
DNA diagnosis**
Treatment and Counselling:
Physiotherapy
Surgery if indicated**
Cardiac failure treatment*
Treatment of respiratory infection*
Wheel chai
Genetic counselling**

Prevention:
1° – Family history* and DNA carrier screening**
Family planning* and 2° – prenatal diagnosis (DNA diagnosis)**
Chromosomal disorders
Down syndrome
Currently 1 in 500 live births in South Africa
Clinical features:
Hypotonia
Intellectual disability
Craniofacial: brachycephaly, flat face, up-slanting palpebral fissures, epicanthic folds, flat nasal bridge, small, low set ears, squint, relative macroglossia, Brushfield spots (Caucasians)
Short stature
Brachydactyly, single palmar creases, 5th finger clinodactyly and hypoplasia mid-phalanx
Sandal gap between first and second toes, plantar creases
Small penis/hypogonadism
Congenital heart disease
Duodenal atresia
Recurrent infection, especially of the respiratory tract

Diagnosis:
Chromosomal/ FISH analysis/QR-PCR**
Trisomy 21 – 95%
Mosaicism – 2.5%
Translocation – 2.5%
Thyroid function tests
Neurodevelopmental/psychometric assessment
Cardiac assessment
Audiology
Treatment and Counselling:
Growth monitoring
Surgery when indicated and available
Treatment for cardiac failure*
Treatment of infections*
Thyroxine if indicated
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support
Genetic counselling*

Prevention:
1° – Family planning and preconception care*
2° – Prenatal (AMA) screening*
Ultrasound and maternal serum screening for Down syndrome
Prenatal chromosome/QR-PCR diagnosis**
Trisomy 18
(1 in 1500 live births)
Clinical features:
Decreased fetal movement. Prenatal growth deficiency
Severe developmental delay
Hypertonia with weak cry, poor sucking
Craniofacial: bifrontal narrowing, prominent occiput, microcephaly, low set malformed ears, short palpebral fissures, small chin and mouth, cleft lip/palate
Clenched hands, overriding fingers
Rocker-bottom feet, clubfeet
Congenital heart disease
Genital hypoplasia
Neonatal or early infant death

Diagnosis:
Chromosomal/ FISH analysis/QR-PCR**
Treatment and Counselling:
Supportive/ Palliative care*
Genetic counselling*
Supportive

Prevention:
1° – Family planning and preconception care*
2° – Prenatal screening for chromosomal disorders
Ultrasound scanning for congenital disorders.
Prenatal diagnosis. Chromosomal/ FISH analysis/QR-PCR.**
Trisomy 13
(1 in 4500 live births)
Clinical features:
Prenatal growth deficiency
CNS malformations
Hypertonia/hypotonia with severe developmental delay
Craniofacial: Microcephaly/ sloping forehead, microphthalmia, anophthalmia, abnormal ears, cleft lip/palate, micrognathiaPolydactyly, camptodactyly, convex hypoplastic finger nails, cryptorchidism
Congenital heart disease
Neonatal or early infant death

Diagnosis:
Chromosomal/ FISH analysis/QR-PCR.**
Treatment and Counselling:
Supportive/ Palliative care*
Genetic counselling*

Prevention:
1° – Family planning and preconception care*
2° – Prenatal screening for chromosomal disorders
Ultrasound scanning for congenital disorders
Prenatal chromosome diagnosis**
Turner syndrome
(1 in 1000 female live births)
Clinical features:
Female phenotype
Short stature
Congenital heart disease (aortic stenosis/ coarctation of aorta)
Renal anomalies
Ovarian dysgenesis/infertility
Learning difficulties

Diagnosis:
Chromosomal/ FISH analysis/QF-PCR**
Monosomy XO/ Turner mosaics
Neurodevelopmental/psychometric assessment
Cardiac assessment
Treatment and Counselling:
Growth monitoring*
Surgery when indicated and if available**
Ovarian hormone replacement therapy**
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support
Genetic counselling**

Prevention:
1° – Family planning and preconception care*
2° – Prenatal screening for chromosomal disorders
Ultrasound scanning for congenital disorders
Prenatal diagnosis. Chromosomal/ FISH analysis/QR-PCR**
Multifactorial disorders
Spina bifida
Clinical features:
Spinal lesion with paraplegia/ incontinence
Hydrocephalus and developmental delay

Diagnosis:
Clinical diagnosis
Brain ultrasound/ CAT scan
Urological assessment
Neurodevelopmental/psychometric assessment
Treatment and Counselling:
Surgery when indicated and if available
Incontinence care
Neurodevelopmental therapy/ community based rehabilitation including psychosocial supportalliative care*

Prevention:
Genetic counselling*
1° – Optimising women’s diet. Folic acid supplementation*
2° – Maternal serum alpha feto-protein screening
Ultrasound scanning for congenital disorders
Anencephaly
Clinical features:
Incomplete development and closure of the skull and development of the brain.
Incompatible with life.

Diagnosis:
Clinical diagnosis.
Treatment and Counselling:
Palliative care*

Prevention:
Genetic counselling.*
1° – Optimising women’s diet. Folic acid supplementation.*
2° – Maternal serum alpha feto-protein screening.
Ultrasound scanning for congenital disorders.
Encephalocele
Clinical features:
Incomplete closure of the skull with out-pouching containing neural tissue.
Microcephaly.
Developmental delay.
Seizures.

Diagnosis:
Clinical diagnosis.
Brain scan.
Neurodevelopmental/psychometric assessment.
Treatment and Counselling:
Surgery when indicated and if possible.
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support.
Seizure control.
Genetic counselling*

Prevention:
1° – Optimising women’s diet. Folic acid supplementation.*
2° – Ultrasound scanning for congenital disorders.
Cleft lip/palate
Clinical features:
Cleft lip and/or palate.
Feeding problems.
Speech difficulties.

Diagnosis:
Clinical diagnosis.
Audiology.
Treatment and Counselling:
Surgery.
Feeding plate in infancy.
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support.
Genetic counselling.*

Prevention:
Nil.
Talipes equinovarus
(Clubfoot)
Clinical features:
Fixed equinovarus deformation of the foot (feet).
X-rays.

Diagnosis:
Clinical diagnosis.
Treatment and Counselling:
Manipulation and plaster of Paris casts.
Surgery when indicated.
Genetic counselling.*

Prevention:
Nil.
Teratogens
Fetal alcohol syndrome
(Prevalence varies between communities. Estimated more than 1% of South African infants are born with FAS)
Clinical features:
Pre- and post natal growth deficiency.
Microcephaly.
Intellectual disability.
Behaviour disorder.
Craniofacial: short palpebral fissures, short upturned nose, smooth philtrum, thin vermillion border.
Joint anomalies.
Congenital heart defects.

Diagnosis:
Clinical diagnosis.
Treatment and Counselling:
Neurodevelopmental/psychometric assessment.
Cardiac assessment.
Growth monitoring.*
Surgery when indicated and if available.
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support.
Neuro-behavioural management.
Genetic counseling.*

Prevention:
1° – Optimising women’s diet.
Public education on the bad effects of alcohol use and abuse in pregnancy.*
Fetal rubella syndrome
Clinical features:
Growth deficiency.
Microcephaly.
Intellectual disability.
Sensori-neural deafness.
Cataracts, chorioretinitis, microphthalmia, squint.
Congenital heart disease (PDA, septal defects, peripheral pulmonary stenosis).
Hepatosplenomegaly.
Thrombocytopenia, anaemia.

Diagnosis:
Clinical diagnosis.
Serum IgG and IgM for rubella. Identify virus in urine.
Neurodevelopmental/psychometric assessment.
Visual assessment.
Audiology.
Cardiac assessment.
Full Blood Count.
Treatment and Counselling:
Growth monitoring.*
Surgery when indicated and if available.Auditory and vision management.
Neurodevelopmental therapy/ community based rehabilitation including psychosocial support.
Genetic counselling.*

Prevention:
1° – Preventing maternal infection by mass rubella immunisation.
2° – Prenatal screening for sero-negativity and immunisation prior to subsequent pregnancy.*
Detection of congenital malformations with ultrasound screening.
Avoid contact between pregnant women and ill children

Abbreviations:

* Possible in primary health care.
** Available in South Africa
1° – Primary prevention (Preconception and early postconception period).
2° – Secondary prevention (Antenatal period).
3° – 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).