Chapter 1:


Student Author: Kira Düsterwald

Specialist Advisors:

Prof. Karen Fieggen and Gillian Düsterwald

Illustration showing doctor thinking hard

This chapter covers the following topics:


Occasionally, one will encounter a neonate or child who looks “different”. These children may have a single dysmorphic feature, or a group of features, suggestive of a syndrome, many of which are caused by genetic abnormalities and others by teratogens. Many of these children will also have one or more structural abnormalities and developmental delay, while others may have structural abnormalities without unusual characteristics.

It is important to know how to approach these children and what should be done at a primary care level, as well as when to refer to a secondary or tertiary unit. As in all clinical practice, a good history and thorough clinical examination should always be the first step. Particular attention should be paid to the family history and perinatal history. The child’s growth measurements should be charted and a full systematic examination conducted.

Unique Features in the Child with a Genetic Disorder

Multi-system involvement is common. A variant (genetic difference which is present at conception) will usually be present in every cell of the body. This is especially true if the variance is due to teratogenicity (teratogens can act on various systems).

Specialist care and treatment may be needed and the child is often best managed by a multidisciplinary team. For example, the child may need to be referred to a medical geneticist or other specialist to assist in diagnosis and management.

Additionally, the patient and his/her family may need specialised health care and psychosocial support for the rest of their lives, especially with conditions where there is a risk of recurrence of the disease in the affected child, future sibling and extended family members.

Aetiology of Dysmorphic Syndromes and Congenital Anomalies

There are different causes for dysmorphic syndromes and congenital anomalies, not all of which are hereditary. However, all causes affect cellular function in some way.

When to Suspect an Underlying Genetic or Syndromic Disorder

The features listed below should prompt you to look closely for additional features and, if appropriate, to refer for further evaluation. The clinician’s suspicion should increase if any of the below occur together:


Down syndrome (also known as Trisomy 21) is the most common genetic syndrome, occurring in approximately 1 in 600 live births. Although an individual woman’s risk of having a child with Down syndrome increases with age (particularly after 35), anyone at any age can have a child with Down syndrome. There are several screening tests, including blood tests and ultrasound scans, that are available to determine the risk of aneuploidy (an abnormal chromosome number) in a pregnancy. How these are applied depends partly on local resources. Women with a child with Down syndrome are at greater risk of having another child with aneuploidy and should be offered referral for appropriate counselling before they become pregnant again.


Down syndrome is caused by the presence of three copies of chromosome 21, usually due to an additional chromosome 21 not joined to any other chromosome (non-disjunction).

3–4% of cases are caused by a translocation (14/21 or 21/21). Parents of these children may carry a balanced translocation, which is why their family members are at higher risk for having more children with Down syndrome. The risk in these families is independent of maternal age and is the reason why chromosome analysis is important.

About 2% of people with Down syndrome have mosaicism (there are two cell lines in the same zygote – some somatic cells contain the extra chromosome, with visual examples accessible on this link, and some do not).

Clinical Features

There are no distinct diagnostic dysmorphic features, but the overall pattern of recognisable features in the setting of hypotonia and developmental delay assists with diagnosis. On physical examination, one should look for:

See related image here.

Systemic involvement is common, and the child may have:

Initial Evaluation and Management

The initial evaluation of the child clinically diagnosed with Down syndrome often includes karyotyping, so that the diagnosis is certain and causes other than nondisjunction can be excluded for family counselling reasons. Surveillance for the commonly associated health complications and early developmental stimulation can substantially improve the long-term outcome for children with Down syndrome.

Early assessment for congenital cardiac abnormalities clinically by chest X-ray and by ECG should be done in all children with Down syndrome, bearing in mind that a large AVSD will not always cause a heart murmur. An echocardiogram is recommended where available. If there is a serious cardiac abnormality, the baby will not thrive and will generally have other clinical signs of concern. Long-term monitoring of growth, vision, hearing and speech are important, as are periodic checks of thyroid function. Other care can be directed by clinical need.


Down syndrome (T21), Edward syndrome (T18) and Patau syndrome (T13) are the only trisomies compatible with life. T18 and T13 frequently result in death shortly after birth or in utero, but a small group of children (<5%) will survive to childhood. This is important to know when counselling expectant parents. These trisomies are also commonly due to nondisjunction, but can be caused by mosaicism or balanced translocation in a parent. Therefore, karyotyping is important to determine recurrence risk and implications for other family members.

Edward Syndrome (Trisomy 18)

Edward Syndrome occurs in ~1 in 6 000–8 000 births. Clinical features of T18 include:

Some visuals associated with T18 features are accessible online via this link.

Patau Syndrome (Trisomy 13)

It occurs in ~1 in 8 000-12 000 live births. Clinical features of T13 include:

Visuals related to some facial features in T13 are available here.


Klinefelter Syndrome

Klinefelter syndrome (47XXY) occurs in phenotypic males and has an incidence of ~1 in 600 (see examples of 47XXY features here). Affected individuals are tall and have hypogonadism (are usually infertile). They may also have learning difficulties, gynaecomastia, hypotonia and low muscle mass. It is difficult to detect in childhood although 1/3 of patients may have undescended testes. There are other health associations of which one should be aware.

Turner Syndrome

Turner syndrome is most often associated with a 45X0 karyotype and these children often have high rates of mosaicism. These children are phenotypically female but should have a PCR test done to look for Y chromosomal material, as its presence can indicate a higher risk of gonadoblastoma. See an example of preoperative webbed neck in Turner syndrome available here.

Prenatally, hydrops fetalis is common. Children may present early with puffy feet and webbing of the neck or at preschool age with short stature. Ovarian dysgenesis can present as delayed puberty or infertility.

There are some associated health complications, including congenital cardiac diseases (e.g. coarctation of the aorta, ASD, VSD, bicuspid aortic valve), renal abnormalities, mild learning difficulties (especially spatial/perceptual skills), hearing loss and hypothyroidism. However, intellect is usually normal.


FASD is a spectrum of disorders, including alcohol-related birth defects (ARBDs), alcohol-related neurodevelopmental disorders (ARNDs), foetal alcohol syndrome (FAS) and partial foetal alcohol syndrome (PFAS). No amount of alcohol at any stage of pregnancy is safe.

Between 1 in 5 and 1 in 100 children in some parts of South Africa are affected, depending on the social setting. It is more common in communities where there is poverty, low maternal education, high unemployment rates and heavy or binge drinking.


Alcohol is a teratogen that crosses the placenta and interferes with the normal growth and development of the foetus. As with all teratogens, the outcome is related to the timing of exposure in gestation, the quantity of exposure and the duration of exposure. The outcome will be influenced by additional environmental factors. The most damage occurs in the embryogenic period, during the first 10 weeks after conception. However, alcohol can cause adverse neurological effects throughout pregnancy.

Clinical Features

Clinical manifestations depend, in part, on the stage of pregnancy in which the embryo or foetus was exposed to alcohol. For example, the characteristic facial appearance is due to drinking between weeks 4 and 10 of gestation. A visual of a baby with alcohol syndrome is available here.

One should suspect FASD in children with combinations of the following:


For children with short stature (remember to calculate a mid-parental height), one should determine whether they have normal body proportions. Those that are disproportionately short in the trunk or limbs have a high likelihood of skeletal dysplasia and skeletal radiography can be helpful. A short trunk usually implies spinal involvement and is seen in conditions like spondyloepiphyseal dysplasia and mucopolysaccharidoses. The most common skeletal dysplasia is achondroplasia, in which children present with disproportionately short limbs. Height abnormalities will be more extensively covered in the endocrine section.


Achondroplasia occurs in ~1 in 15 000–40 000 neonates. It is an autosomal dominant condition, although most cases are the result of a new mutation. Individuals who inherit two copies of the mutation have such severe achondroplasia that they are stillborn or die soon after birth. Phenotypically, individuals with achondroplasia are short (average male = 131 cm and female = 124 cm) with rhizomelic shortening of arms and legs (the proximal limb segments are most affected – humerus and femur – see also image here), relative macrocephaly with prominent foreheads and short fingers with a gap between the 2nd and 3rd digits (trident hands).

Children with achondroplasia have low tone and joint laxity. They are prone to:

Macrocephaly is inevitable but true hydrocephalus is rare. There is always a narrow craniocervical junction and infants in particular should be closely monitored for any neurological abnormalities and referral for imaging should be considered. Growth should be plotted on an achondroplasia growth chart. Careful attention should be given to supporting the relatively heavy head in infancy and avoiding overextension or flexion of the neck.


Neurocutaneous Disorders

They include:

Neuromuscular Disorders

They include:

Additional Autosomal Recessive Disorders

These disorders may not be apparent in family history because they are recessive (both copies of the gene must be abnormal for disease to manifest). Most metabolic conditions and many causes of hearing and vision loss are autosomal recessive.

Sickle Cell Disease/Anaemia

In this condition, red blood cells have a sickle shape and haemoglobin has abnormal oxygen-carrying capacity of haemoglobin. Patients may present with pain crises, stroke or severe anaemia. Sickle cell anaemia is common in sub-Saharan Africa and other areas where malaria is prevalent.

Cystic Fibrosis

It is the result of a defect in the cystic fibrosis transmembrane conductance regulator (CFTR), resulting in thick secretions. This multisystemic disorder causes:

It is more common in those of European ancestry but occurs in all ethnicities. Examples of red blood cells and sickle cells are accessible here.

Conditions Presenting with Developmental Delay and Intellectual Disability

Fragile X Syndrome

It is an X-linked condition, thus males are more severely affected. Females are protected by skewed inactivation and usually have milder symptoms. Children present with delayed milestones (particularly delayed speech at 2 years), hyperactive behaviour, mild-to-moderate intellectual disability and ASD. Physical features may include a long and narrow face, prominent forehead, large jaw, large ears and joint laxity.

Velocardiofacial Syndrome/DiGeorge Syndrome (22q11.2 Deletion Syndrome)

It is caused by a microdeletion of chromosome 22. Clinical features include:

Psychiatric comorbidities (schizophrenia, bipolar mood disorder) may develop later on in some.

Prader-Willi Syndrome

It is an imprinting disorder that usually occurs in the absence of a family history. Patients often present in infancy with hypotonia and low birth weight or later on with insatiable hunger and obesity. Thus, food control is essential.

Prader-Willi syndrome is associated with delayed milestones, hypotonia, narrow forehead, small hands and feet. These children are prone to endocrine abnormalities including hypogonadism, hypocortisolism and hypothyroidism.

Pierre-Robin Sequence

A sequence is a series of sequential developmental effects. In this case, the primary abnormality is underdevelopment of the jaw which leads to displacement of the tongue posteriorly and can cause a cleft palate. This results in problems in early life including upper airway obstruction, feeding difficulties and failure to thrive (FTT). It may be isolated or part of a genetic syndrome.

Other Syndromes to Recognise

Alagille Syndrome

It is an autosomal syndrome condition in which there is intrahepatic bile duct paucity. The child will present with prolonged neonatal jaundice, cholestasis and pale stools. Other features include cardiac disease (VSD, pulmonary valve stenosis), skeletal abnormalities (butterfly vertebrae), ocular abnormalities and typical facies (deep set eyes, pointed chin).

Peutz-Jeghers Syndrome

It is an autosomal dominant syndrome in which children have gastrointestinal polyps (may present with intussusception), hyper-pigmented mucosae and freckles on the face, hands, feet and digits. It is associated with early-onset cancers in adulthood especially GI, breast and pancreatic cancers.

Beckwith-Wiedemann Syndrome

It is an overgrowth syndrome with clinical features of macrosomia at birth, neonatal hypoglycaemia, macroglossia, midline abdominal defects and ear creases/pits. It is associated with an increased risk of embryonal tumours, including Wilms tumour and hepatoblastoma.


Genetic testing can be done for different reasons and the technique chosen will depend on the question being asked and the disorder in question. It is important to liaise with a geneticist and the laboratory to ensure you choose the best test for the situation and that you are aware of the limitations of that test.

Types of Genetic Tests

The genetic test may be:

See related image here.

Genetic Test Results

As there is so much interindividual variability, it can be difficult to know if a genetic variant found on a test is the cause of a problem or not. This means there are three possible results from a genetic test:

As more genes are tested (what with testing of the whole exome or whole genome), VUS is becoming a more frequent result (particularly in African populations, which are not well represented in datasets). Thus it is important to understand the concept of VUS. One must remember that information is rapidly being produced and variants may be reclassified in time. A genetic counsellor can help with the interpretation of test results and with communicating genetic information to patients.