Marshall-Smith syndrome

Marshall-Smith syndrome (MRSHSS) is a genetic disorder in which individuals typically have advanced bone age, difficulties gaining weight (failure to thrive), unique facial features, and intellectual disability. Other signs and symptoms of this condition may include eye abnormalities, breathing difficulties, and neurological issues. Individuals may also have heart defects, an increased amount of body hair (hirsutism), and flat feet (pes planus).^[1][2][3]

MRSHSS is caused by mutations in the NFIX gene. Most individuals with MRSHSS are the first in their family with this condition and are said to have a spontaneous (de novo) mutation.^[3] Although there is no specific treatment or cure for MRSHSS, there may be ways to manage the symptoms. A team of doctors is often needed to figure out the treatment options based on each person’s symptoms. Aggressive management of the early breathing and feeding problems may improve survival in individuals affected by this condition.^[2]

The main features of MRSHSS include intellectual disability and developmental delay, severe breathing difficulties, distinctive facial features (a wide and prominent forehead, protruding and widely spaced eyes, a depressed nasal bridge, a small upturned nose, and a small jaw (micrognathia)), accelerated skeletal maturation, and issues with weight gain compared to height (relative failure to thrive).

The breathing difficulties individuals with this condition experience are due to a number of underlying airway issues, which may include upper airway obstruction related to a small and/or underdeveloped jaw, narrowing of the nasal airway (choanal stenosis), and/or an abnormal larynx. Additionally, aspiration pneumonia may be a factor, which is typically secondary to an underdeveloped epiglottis and pharyngeal incoordination. Sleep apnea may also be associated.^[4]

Other common signs and symptoms are:^[1][2][4]

• A blue tint to the whites of the eyes (blue sclera)
• An abnormal curve in the spine (scoliosis and kyphosis)
• Loss of tissue in the gums
• Heart defects, such as a hole in the heart between the different chambers (septal defects)
• Protrusion of part of the intestines through the umbilical opening in the abdominal muscles (umbilical hernia)
• An abnormal amount of hair growth over the body (hirsutism)
• Hearing loss

Individuals with MRSHSS may also have neurological problems, including low muscle tone (hypotonia) and brain structural anomalies, such as enlarged ventricles in the brain (ventriculomegaly), and an abnormal number of folds in the brain (pachygyria or polymicrogyria). A condition caused by underdevelopment of the optic nerves and structures along the midline of the brain (septo-optic dysplasia) may also occur. Rarely, individuals experience seizures.^[4]

Yes, the symptoms of MRSHSS vary widely between patients.^[2][5] It is thought that no two patients with MRSHSS have the exact same symptoms. The morbidity and mortality associated with this condition also varies. Some children with MRSHSS die early in infancy, others during the toddler years, and some later in childhood or adulthood. Mortality appears to be highly correlated with the severity of respiratory problems.^[2] However, even those who survive without major complications exhibit some degree of intellectual impairment.^[2][5]

While most of the literature available on MRSHSS is made up of case reports, we have not been able to locate any articles which specifically address the issue of speech and/or language development. We recommend that you check the medical literature by searching PubMed, a searchable database of medical literature periodically for new reports. You may also find it useful to contact one of the organizations supporting this condition, such as the MSS Research Foundation.