Smith-Magenis syndrome (17p11.2)

Overview

Smith-Magenis syndrome is one of a number of congenital anomaly syndromes affecting many parts of the body.

Key features include mild to moderate intellectual disability, delayed language skills, characteristic facial features, sleep disturbances and behavioural problems.

Epidemiology

It affects at least 1 in 25 000 people worldwide, but the actual prevalence may be closer to 1 in 15 000.

Cause

A small deletion of chromosome 17 in each cell results in Smith-Maginnis syndrome. This deletion occurs at a position called p11.2 on the short (p) arm of the chromosome.

Although the deleted region contains several genes, the loss of the RAI1 gene is thought to underlie many of the characteristic features of Smith-Maginnis syndrome, as the RAI1 gene provides instructions for the creation of proteins that help regulate the expression of other genes, and RAI1 gene deletion leads to a reduction in the amount of RAI1 protein in the cell. This has been suggested to disrupt the expression of genes that affect the rhythm of sleep and may cause sleep disorders.

Symptoms

Most people with Smith-Maginnis syndrome have a broad, square face with deeply set eyes, full cheeks and a prominent mandible. The centre of the face and the bridge of the nose often appear flat, the mouth turns downwards and the upper lip curves outwards. These facial differences may not be noticeable in early childhood, but usually become more pronounced in late childhood and adulthood. Dental abnormalities are also common.

Smith-Maginnis syndrome is characterised by disturbed sleep patterns, usually beginning early in life. The patient is very sleepy during the day but has difficulty falling asleep at night, waking repeatedly during the night and in the early morning.

Patients with this disorder generally have an affectionate and engaging personality, but most also have behavioural problems, manifested by frequent tantrums and outbursts, aggression, anxiety, impulsivity and lack of attention. Self-harming behaviours such as biting, hitting, head banging and skin picking are very common. Repetitive self-hugging is considered to be a behavioural trait specific to Smith-Maginnis syndrome. Others compulsively lick their fingers or turn the pages of books and magazines.

Other symptoms of Smith-Maginnis syndrome include short stature, abnormal curvature of the spine (scoliosis), reduced sensitivity to pain and temperature and a hoarse voice. Some people with the condition have ear abnormalities leading to hearing loss. Eye abnormalities can also lead to vision problems such as myopia. Heart and kidney abnormalities have also been reported in people with Smith-Maginnis syndrome, although less frequently.

Diagnosis

Diagnosis is confirmed by DNA analysis, such as array CGH, MLPA, FISH analysis or whole genome sequencing.

A postnatal diagnosis may also be suspected by typical external features in combination with intellectual disability, sleep disturbances and characteristic behaviour. However, symptoms may be barely noticeable in infancy or early childhood. Diagnosis by typical appearance may be very difficult to recognise at first, but becomes more prominent as the child grows older…. In practice, therefore, the correct diagnosis is often not made until school age, when the characteristic facial features and behavioural disorders become more apparent.

Treatment

There is no fundamental cure, so symptomatic treatment is aimed at relieving symptoms and compensating for the functional impairment caused by the syndrome. As different organ systems can be affected by this condition, it is important to work with several specialists to co-ordinate testing, treatment and rehabilitation.

Prognosis

Intractable epilepsy, and also associated cardiac disease, has an impact on life expectancy.