Wiedemann-Steiner Syndrome

Clinical characteristics: Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies. The facial features include thick eyebrows with lateral flare, vertically narrow and downslanted palpebral fissures, widely spaced eyes, long eyelashes, wide nasal bridge, broad nasal tip, thin vermilion of the upper lip, and thick scalp hair. About 60% of affected individuals have hypertrichosis cubiti ("hairy elbows"), which was once thought to be pathognomic for the syndrome, with a majority having hypertrichosis of other body parts. Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical spine), renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies.

Diagnosis/testing: The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2A identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy with possible supplemental tube feeding for those with poor weight gain / failure to thrive; growth hormone therapy for those with growth hormone deficiency; thyroid replacement therapy for hypothyroidism; consideration of IVIG therapy in those with low antibody levels; consideration of prophylactic antibiotics in those with frequent infections; stool softeners or osmotic agents for bowel dysfunction; oculoplasty for blepharoptosis; CPAP, BiPAP, or surgical removal of the tonsils and adenoids for those with obstructive sleep apnea; behavioral therapy; standard treatment for epilepsy, developmental delay / intellectual disability, congenital hip dysplasia, cervical vertebral fusion, eye anomalies, congenital heart defects, renal anomalies, uterine anomalies, and metabolic bone disease (which may include vitamin D supplementation).

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status; assessment for constipation; evaluation for new neurologic features and seizure activity with EEG follow up as indicated; assessment of clinical signs of medullar compression; monitoring for signs/symptoms of arrhythmia; assessment of developmental progress, behavior, and physical skills; monitoring for frequent infections. Dental evaluation every six months after the eruption of primary teeth. Assessment for premature thelarche or primary amenorrhea in childhood until growth/menarche is complete. Ophthalmologic evaluation annually, or as clinically indicated.

Agents/circumstances to avoid: The authors are aware of one individual with WSS who developed hyperammonemia with the use of the anti-seizure medication valproate. While this is not specific to individuals with WSS, valproate should be used with caution.

Pregnancy management: In affected pregnant women who have a seizure disorder, discussion of the most appropriate anti-seizure medication regimen during pregnancy is recommended. Cervical spine anomalies may lead to immobility or instability, which may complicate airway management. Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia.

Genetic counseling: Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Rarely, individuals diagnosed with WSS have an affected parent. In this situation, WSS can be inherited in an autosomal dominant fashion. Each offspring of an individual with WSS is at a 50% risk of being affected. Once the KMT2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.