The portal for rare diseases and orphan drugs

The estimated prevalence, based on germline mutation rates, is 1/25,000 -40,000; although this may be an underestimate due to clinical misdiagnosis with other disorders such as Kabuki syndrome and Rubinstein-Taybi syndrome as well as a subgroup of patients that have only slight or even no apparent developmental delay and therefore often do not undergo genetic evaluation.

Wiedemann-Steiner syndrome (WSS) has a variable clinical phenotype presenting rarely in the prenatal period and more commonly neonatally or in infancy or childhood. Many infants with WSS have hypotonia and some degree of feeding problems, which may require tube feeding. Constipation also often starts from a young age and early eruption of teeth is typical. Hypertrichosis (often on the back and/or cubiti) can be already present in infancy, but can also develop in childhood. Children often have telecanthus, long/dense eyelashes and vertically narrow palpebral fissures, as well as other dysmorphic features. Short stature or relative short stature compared to target height is often present and most commonly develops during the first year of life. Some degree of developmental delay/intellectual disability, usually mild to moderate, is often present, although it can range from very mild to severe. Behavioral problems are common and include features of autism and attention deficit and hyperactivity disorder. Anxiety issues seem to play an increased role with advancing age. Less common features include congenital cardiac abnormalities (usually minor, such as persistent ductus arteriosus), urogenital abnormalities, skeletal abnormalities (mostly of the cervical vertebrae), dental abnormalities and small puffy hands and feet. A minority of individuals have seizures, which are more commonly observed in combination with severe developmental delay/intellectual disability. Also tethered cord, chiari malformation, and dysmotility of the gut are sometimes present. Growth hormone deficiency and immune deficiency (hypogammaglobulinemia) have been reported in some patients.

WSS is caused by variants in the KMT2A gene (11q23.3). This gene is involved in the regulation of many other genes in the genome.

Diagnostic criteria for WSS have not been established. The diagnosis is usually made by DNA-testing. If a mutation is not identified a diagnosis can be suspected by a combination of clinical symptoms and methylation profile (episignature).

The differential diagnosis includes Kabuki syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, and non-syndromic intellectual disability.

Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.

The disorder is autosomal dominant; whilst the large majority of cases occur de novo, genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.

Ultrasound of the urinary tract and heart and immunologic screening (immunoglobulins) should be considered in all pediatric patients. Upon indication, cervical X-rays and imaging of the cerebrum or spinal cord can be considered. Growth hormone therapy is indicated for patients with a growth hormone deficiency and is considered in some countries in WSS patients with short stature, although based on very limited evidence.

There is currently no evidence that life expectancy of individuals with WSS is shortened for the majority of individuals with the disorder. Most individuals have mild to moderate intellectual disability.