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).
