Years published: 2023
NORD gratefully acknowledges Diego Quintero, BS, Caitlin Harrington, BS, Lamrot Tulu, BS, Jay Vaunado II, BS, and MaryAnn Campion, EdD, MS, Stanford University MS Program in Human Genetics and Genetic Counseling, and Sarah E. Sheppard, MD, PhD, Eunice Kennedy Shriver National Institute of Child Health and Human Development, for the preparation of this report.
Wiedemann-Steiner syndrome (WSS) is a rare genetic condition that can affect multiple organ systems. Many patients with this condition have symptoms including developmental delay, intellectual disability or autism and excessive hair growth in unusual places on the body (hypertrichosis). Characteristic facial features include a short distance between the upper and lower eyelid or down-slanting eyes (narrow or down-slanting palpebral fissures), a drooping upper eyelid over the eye (ptosis), wide-set eyes (hypertelorism), long eyelashes, thick eyebrows, wide nose (wide nasal bridge), deep-set nose (depressed nasal bridge), long vertical groove under the nose, low hairline, high palate, and dental/oral abnormalities. Additional findings can also be associated with the condition but are not always present. These anomalies may include growth delays, neurological abnormalities, muscular and skeletal differences, gastrointestinal differences, cardiac abnormalities, genitourinary anomalies, and endocrine problems. WSS is caused by a change in the KMT2A gene (previously known as the MLL gene).
Each patient with Wiedemann-Steiner syndrome can have very different symptoms making it difficult for physicians to accurately identify and diagnose patients. There are many conditions with similar symptoms, and there are no set diagnostic criteria for WSS. Therefore, WSS is much less likely to be diagnosed in patients without access to genetics providers or testing.
People with Wiedemann-Steiner syndrome can have a broad range of symptoms that affect many body systems. Not everyone will have all the symptoms mentioned below, and the body systems affected can differ from person to person. The symptoms may be present at birth but can also begin later during infancy or childhood.
Signs of delayed growth and development can be low birthweight and failure to meet milestones in childhood, such as sitting, standing, walking and speech. Other symptoms can include feeding difficulties, short stature and early eruption of teeth. Some of the symptoms affecting the brain can include intellectual disability, abnormal brain MRI findings, low muscle tone (hypotonia) and more rarely, seizures. Many people with WSS have excessive hair growth on different parts of the body such as face, chest, back, elbows, thick eyebrows, unibrow and long eyelashes. Characteristic facial features include a short distance between the upper and lower eyelid or down-slanting eyes (narrow or down-slanting palpebral fissures), a drooping upper eyelid over the eye (ptosis), wide-set eyes (hypertelorism), wide nose (wide nasal bridge), deep-set nose (depressed nasal bridge), long vertical groove under the nose, low hairline, high palate and dental/oral abnormalities.
Additional findings can also be associated with the condition but are not always present. These anomalies may include growth delays, muscular and skeletal differences, gastrointestinal differences, cardiac abnormalities, genitourinary anomalies and endocrine problems. Constipation is another symptom that can be seen commonly in individuals with this condition. Skeletal issues including a dimple on the lower back (sacral dimple), short fingers or toes, abnormally curved fingers, puffy hands or feet and issues with the spine (vertebrae) are also common in individuals with Wiedemann-Steiner syndrome.
More rarely seen symptoms include issues affecting the eyes, heart, immune system, kidney, ear nose and throat (ENT), cleft palate, endocrine system (hormones) and autism spectrum disorder (ASD).
Wiedemann-Steiner syndrome is caused by changes (pathogenic variants or mutations) in the KMT2A gene (previously known as the MLL gene). This gene plays a role in the regulation of early development and blood production.
WSS follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to child is 50% for each pregnancy. The risk is the same for males and females.
In most people with WSS, the change in the KMT2A gene that caused the disorder was not inherited from a parent but occurred spontaneously (de novo) in the individual with WSS. However, in a small number of patients reported in the medical literature, WSS was passed down from an affected parent to a child in an autosomal dominant manner.
The estimated prevalence of WSS in the general population is approximately 1 in 1,000,000 live births. WSS has been diagnosed more often are in the United States, China, and countries in Europe. This is likely due to better availability of genetic testing in these countries.
Wiedemann-Steiner syndrome may be suspected in a child with certain facial features, developmental delay, intellectual disability and excessive body hair. Patients may or may not have organ problems. There are currently no established clinical diagnostic criteria for Wiedemann-Steiner syndrome. Therefore, a diagnosis cannot be established by clinical features alone.
Genetic testing for pathogenic variants in the KMT2A gene is required to confirm the diagnosis. A single gene test or a test on a group of genes (panel) may be recommended, depending on the patient’s symptoms. Almost all pathogenic variants can be detected using a technology called next-generation sequencing. If next-generation sequencing does not identify a relevant genetic change, analysis of missing or extra pieces of chromosomes (deletions and duplication analysis) may be performed.
Sometimes, a genetic test result will show a variant in the KMT2A gene that may or may not be related to the disease (variant of uncertain significance). When this is the case, another test may be recommended to evaluate how the KMT2A gene is working in the patient to help make a diagnosis.
Clinical Testing and Work-Up
The clinical work-up and testing for Wiedemann-Steiner syndrome should be tailored to each patient’s individual needs and medical history.
Endocrine evaluations including blood tests and X-rays may be done to help detect hormone deficiencies and differences in bone growth.
Neurological evaluations, including magnetic resonance imaging (MRI), are important for detecting structural brain abnormalities like abnormal corpus callosum or abnormal myelination, which are present in about half of affected individuals. An electroencephalogram (EEG) should be performed if seizures are a concern, which occur in about 1 in 5 affected individuals. Patients with KMT2A genetic changes require close monitoring of developmental milestones. A developmental assessment can identify any developmental delays or intellectual disabilities, which are usually mild to moderate. Assessments of speech/language, cognitive function, and motor function are helpful for early intervention and special education.
A neuropsychiatric evaluation should be conducted later in childhood as behavioral problems, including autism, attention deficit and hyperactivity and aggressive behavior, are common. Orthopedic, occupational therapy and physical therapy evaluations should be performed to assess gross and fine motor skills, as well as any signs or symptoms suggestive of vertebral anomalies and hip dysplasia. Gastroenterology and nutrition evaluations are important as infants and children can have feeding problems and poor weight gain, requiring tube feeding. Assessments for constipation or bowel dysfunction should be conducted.
Cardiovascular evaluations, including echocardiograms and electrocardiogram, are necessary to detect congenital cardiac abnormalities (usually minor, such as persistent ductus arteriosus and arrhythmia). Immunologic evaluations can identify an immune deficiency, which has been detected in some patients by monitoring for signs of frequent infection, abnormal immunoglobulin levels and insufficient response to pneumococcal vaccinations.
Patients with Wiedemann-Steiner syndrome may also experience ear, nose, and throat issues, including sleep apnea and hearing loss, which should be assessed and treated accordingly by an otolaryngologist. In addition, a comprehensive eye exam should be conducted by an ophthalmologist since eye abnormalities such as strabismus (crossed eye), astigmatism (imperfection in the curvature of the eye’s cornea or lens) and blepharoptosis (drooping of upper eyelid) are common.
Patients with Wiedemann-Steiner syndrome may also benefit from immunology evaluations to assess immunoglobulins, response to vaccines and recurrent infections (if applicable). In addition, gastrointestinal evaluation, through abdominal ultrasounds and monitoring of growth and feeding difficulties, may be warranted.
Patients with WSS are treated for the specific symptoms they have. May different medical specialists may be involved in their care.
Treatment for feeding difficulty may include feeding therapy and nasogastric or gastrostomy tube placement.
Seizures are treated with standard anti-seizure medications. Constipation or bowel dysfunction is treated with laxatives or stool softeners.
Endocrine abnormalities, including growth hormone deficiency and thyroid dysfunction, may require hormone replacement therapy. Obstructive sleep apnea may require the use of a continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) machine or surgical removal of tonsils and adenoids. Immune deficiency may be managed with intravenous immunoglobulin (IVIG) in those with low antibody levels and prophylactic antibiotics in those with frequent infections.
Heart abnormalities may require medication or surgery.
Other problems are treated by relevant specialists. Patients with global developmental delay or intellectual disability may require special education and appropriate assessments at school.
Physical therapy, occupational therapy, speech therapy and early intervention can help improve physical and cognitive development, quality of life and independence in daily activities.
Patients with global developmental delay or intellectual disability may require special education and appropriate assessments at school.
Genetic counseling is recommended for families with an affected child.
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