Wiedemann-Steiner Syndrome - Symptoms, Causes, Treatment | NORD (2024)

Disease Overview

Summary

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).

Introduction

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.

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Signs & Symptoms

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).

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Causes

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.

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Affected populations

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.

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Disorders with Similar Symptoms

Some features of Coffin-Siris syndrome, Kabuki syndrome, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, Noonan syndrome, and Suleiman-El-Hattab syndrome may be similar to those of Wiedemann-Steiner syndrome. These conditions are described below. Comparisons may be useful for a differential diagnosis.

Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth (congenital). The disorder may be characterized by abnormalities of the head and facial (craniofacial) area, resulting in a coarse facial appearance. Craniofacial changes may include an abnormally small head (microcephaly) or large head (macrocephaly), a wide and flat nose, a wide mouth with thick, prominent lips, thick eyebrows and eyelashes or excess hair growth in unusual places such as the back (hypertrichosis) and sparse scalp hair. In addition, affected infants and children may have short pinkies and toes with underdeveloped (hypoplastic) or absent nails, other differences of the fingers and toes, and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, diminished muscle tone (hypotonia), abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Changes in seven different genes, ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1 and SOX11 have been found to cause CSS. CSS can be inherited in an autosomal dominant pattern, but most cases appear to be the result of a new genetic change that is not inherited. (For more information on this disorder, choose “Coffin-Siris Syndrome” as your search term in the Rare Disease Database.)

Kabuki syndrome is a rare genetic disorder that involves many organ systems and may be evident at birth (congenital). Individuals have certain facial features, including long eye openings (long palpebral fissures), arched, broad, and sparse eyebrows, large, prominent or cupped ears and a flat nose. Many patients will have delayed growth after birth, skeletal differences and some degree of intellectual disability. Other features include persistent fingertip pads, increased susceptibility to infections, autoimmune disorders, feeding problems, hormonal (endocrine) abnormalities, seizures, hearing loss, heart problems present at birth (congenital heart defects), cleft lip and/or palate and digestive system (gastrointestinal) differences. The presentation of the disease can vary between individuals. Most individuals with Kabuki syndrome have a change in the KMT2D gene, while fewer individuals will have a change in the KDM6A gene. The condition can be inherited in an autosomal dominant or X-linked manner. (For more information on this disorder, choose “Kabuki Syndrome” as your search term in the Rare Disease Database.)

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is generally apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth retardation), abnormalities of the head and facial (craniofacial) area, a distinctive facial appearance, differences of the hands and arms (upper limbs) and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly), a prominent vertical groove between the upper lip and nose (philtrum), a flat nose, upturned nostrils (anteverted nares) and a small chin (micrognathia). Additional facial abnormalities may include thin, downturned lips, low-set ears, arched, well-defined eyebrows that grow together across the base of the nose (synophrys), an unusually low hairline on the forehead and the back of the neck and curly, unusually long eyelashes. Affected individuals may also have distinctive changes to the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers and webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands and fingers. Infants with CdLS may also have feeding and breathing difficulties, an increased susceptibility to respiratory infections, a low-pitched “growling” cry and a low voice, heart problems, delayed skeletal maturation, hearing loss or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from person to person. CdLS can be inherited as an autosomal dominant condition or an X-linked condition. Seven genes have been found to be associated with CdLS including NIPBL, SMC1A, SMC3, Rad21, HDAC8, ANKRD11, and BRD4. Most affected individuals have a new genetic change that is not inherited from a parent. Other genes may be found to be associated with CdLS in the future. (For more information on this disorder, choose “Cornelia de Lange Syndrome” as your search term in the Rare Disease Database.)

Rubinstein-Taybi is a rare genetic condition that can be apparent at birth (congenital). Patients with the condition have distinctive facial features, including downward slanting eyes (down slanted palpebral fissures), low-hanging nasal septum (columella), high roof of the mouth (palate), a grimacing smile and a rare dental anomaly called tallen cusps. In addition to facial features, the condition is characterized by the presence of intellectual disability to varying degrees, short stature, hand differences and growth delays after birth. Other features of the condition may include heart problems, kidney (renal) abnormalities, undescended testes (cryptorchidism), sight and hearing difficulties, respiratory difficulties, feeding problems, recurrent infections, and constipation. Patients may have genetic changes in the CREBBP gene or EP300 gene. Rubinstein-Taybi is inherited in an autosomal dominant manner, but most cases appear to be the result of a new genetic change that is not inherited. (For more information on this disorder, choose “Rubinstein-Taybi” as your search term in the Rare Disease Database.)

Noonan syndrome is a genetic disorder that is typically evident at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. Many affected individuals have abnormalities that can include a distinctive facial appearance, a broad or webbed neck, a low posterior hairline, a typical chest deformity and short stature. Characteristic features of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism), skin folds that may cover the eyes’ inner corners (epicanthal folds), drooping of the upper eyelids (ptosis), a small jaw (micrognathia), a short nose with broad base and low-set, posteriorly rotated ears. Distinctive skeletal changes are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis) and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart problems. Additional abnormalities may include problems with the blood vessels or blood clotting, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males and/or other symptoms and findings. Noonan syndrome can be caused by changes in more than eight genes. Changes in PTNP11 are found in 50% of cases. Other genes that can cause Noonan syndrome include: SOS1, LZTR1, RAF1, RIT1, KRAS, BRAF, MAP2K1, MRAS, NRAS, RASA2, RRAS2 and SOS2. Most of the time, the condition is inherited in an autosomal dominant manner. Noonan syndrome caused by genetic changes in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner. (For more information on this disorder, choose “Noonan Syndrome” as your search term in the Rare Disease Database.)

Suleiman-El-Hattab syndrome is an autosomal recessive genetic disorder that may be evident at birth (congenital). It is characterized by distinct facial features, hypotonia, feeding difficulties, developmental delay, intellectual disability and a generally happy demeanor. Features of the head and facial (craniofacial) area may include a small head (microcephaly), thick arched eyebrows that grow together at the base of the nose (synophrys), increased distance between the eyes (hypertelorism), skin folds that may cover the eyes’ inner corners (epicanthal folds), low-set ears, wide nose (broad nasal bridge) and a thin upper lip. Additional, more variable features may include recurrent infections, heart problems, undescended testes (cryptorchidism), seizures and hand and feet differences. Suleiman-El-Hattab syndrome is caused by changes in the TASP1 gene.

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Diagnosis

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.

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Standard Therapies

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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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Sheppard SE, Campbell IM, Harr MH, et al. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome [published correction appears in Am J Med Genet A. 2022 Mar;188(3):1015]. Am J Med Genet A. 2021;185(6):1649-1665. doi:10.1002/ajmg.a.62124

Yu H, Zhang G, Yu S, Wu W. Wiedemann-Steiner Syndrome: Case Report and Review of Literature. Children (Basel). 2022;9(10):1545. Published 2022 Oct 12. doi:10.3390/children9101545

Sun Y, Hu G, Liu H, et al. Further delineation of the phenotype of truncating KMT2A mutations: The extended Wiedemann-Steiner syndrome. Am J Med Genet A. 2017;173(2):510-514. doi:10.1002/ajmg.a.38025

Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am J Hum Genet. 2012 Aug 10;91(2):358-64. doi: 10.1016/j.ajhg.2012.06.008. Epub 2012 Jul 12. PMID: 22795537; PMCID: PMC3415539.

INTERNET
Sheppard SE, Quintero-Rivera F. Wiedemann-Steiner Syndrome. 2022 May 26. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK580718/
Accessed January 25, 2023.

Wiedemann Steiner syndrome. Orphanet: Wiedemann Steiner syndrome. 2021. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=21621&Disease_Disease_Search_diseaseGroup=Wiedemann-Steiner-Syndrome&Disease_Disease_Search_diseaseType=Pat&Disease%28s%29%2Fgroup+of+diseases=Wiedemann-Steiner-syndrome&title=Wiedemann-Steiner+syndrome&search=Disease_Search_Simple Accessed January 25, 2023.

Deardorff MA, Noon SE, Krantz ID. Cornelia de Lange Syndrome. 2005 Sep 16 [Updated 2020 Oct 15]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1104/
Accessed January 25, 2023.

Suleiman-el-Hattab syndrome. Online Mendelian Inheritance of Man (OMIM). Last updated 07/28/2020. https://omim.org/entry/618950 Accessed January 25, 2023.

Roberts AE. Noonan Syndrome. 2001 Nov 15 [Updated 2022 Feb 17]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1124/ Accessed January 25, 2023.

Stevens CA. Rubinstein-Taybi Syndrome. 2002 Aug 30 [Updated 2019 Aug 22]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1526/
Accessed January 25, 2023.

Schrier Vergano S, Santen G, Wieczorek D, et al. Coffin-Siris Syndrome. 2013 Apr 4 [Updated 2021 Aug 12]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK131811/
Accessed January 25, 2023.

Wiedemann-Steiner Syndrome. WSS Foundation. https://www.wssfoundation.org/wiedemann-steiner-syndrome/. Accessed January 25, 2023.

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