Hypertrichosis cubiti is a rare form of unusual hair growth in the arms around the elbow area. Here, we report a case of hypertrichosis cubiti in a six-year-old female child with a sacral cleft, otherwise of normal health. Specifically, terminal hair growth was observed in this case. The excessive hair growth often poses aesthetic concerns for patients and can be treated to avoid emotional distress regarding physical appearance. Management of the condition typically involves common hair removal techniques, and over-the-counter depilatory creams and shaving were used to treat this case. 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. The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2A identified by molecular genetic testing. 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. 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.

Wiedemann-Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.

Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder characterized by dysmorphic features, neurodevelopmental delay, growth retardation, and hypertrichosis cubiti. It is caused by pathogenic variants in the KMT2A gene. Here, we report a child with WSS presented with neurodevelopmental delay. Genetic analysis revealed a heterozygous c.2312dupC (p.Ser774Valfs*11) variant at the KMT2A gene that was classified as pathogenic in dbSNP (rs1057518649). To the best of our knowledge, this is the first patient of WSS from Turkey. This case draws attention to the diagnosis of WSS in children with neurodevelopmental delay.

Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder. Patients with WSS have characteristics of growth retardation, facial dysmorphism, hypertrichosis cubiti (HC), and neurodevelopmental delays. WSS is in an autosomal dominant inherited pattern caused by a mutation of the KMT2A gene (NM_001197104.2). In this article, we discuss a 5-year-old boy who has mild intellectual disability (ID), hypotonia, HC, hypertrichosis on the back, dysmorphic facies, psychomotor retardation, and growth delay. Trio-based whole-exome sequencing (trio-WES) was carried out on this patient and his parents, confirming the variants with Sanger sequencing. Trio-WES showed a de novo mutation of the KMT2A gene (NM_001197104.2: c.4696G>A, p.Gly1566Arg). On the basis of the clinical features and the results of the WES, WSS was diagnosed. Therefore, medical professionals should consider a diagnosis of WSS if patients have growth retardation and development delay as well as hirsutism, particularly HC.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.