Wiedemann-Steiner syndrome: A case report.
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ABSTRACT:
SUBMITTER: Hirst L
PROVIDER: S-EPMC7981703 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
Publications
Wiedemann-Steiner syndrome: A case report.
Clinical case reports 20210105 3
Wiedemann-Steiner syndrome (WDSTS) is an exceptionally rare autosomal dominant syndrome with considerable phenotypical variation. Clinical features include dysmorphic facial and skeletal features, growth deficiency, developmental delay, hypertrichosis cubiti and various dental features. We present a 7-year-old female with premature exfoliation of primary teeth and premature eruption of permanent teeth. ...[more]
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Project description:Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder with a broad and variable phenotypic spectrum characterized by intellectual disability, prenatal and postnatal growth retardation, hypertrichosis, characteristic facial features, behavioral problems, and congenital anomalies involving different systems. Here, we report a five-year-old boy who was diagnosed with WDSTS based on the results of Trio-based whole-exome sequencing and an assessment of his clinical features. He had intellectual disability, short stature, hirsutism, and atypical facial features, including a low hairline, down-slanting palpebral fissures, hypertelorism, long eyelashes, broad and arching eyebrows, synophrys, a bulbous nose, a broad nasal tip, and dental/oral anomalies. However, not all individuals with WDSTS exhibit the classic phenotype, so the spectrum of the disorder can vary widely from relatively atypical facial features to multiple systemic symptoms. Here, we summarize the clinical and molecular spectrum, diagnosis and differential diagnosis, long-term management, and care planning of WDSTS to improve the awareness of both pediatricians and clinical geneticists and to promote the diagnosis and treatment of the disease.
| S-EPMC9600770 | biostudies-literature
Project description:Case descriptionWe report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features.Clinical findingsKMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features.Treatment and outcomeWhole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature.Clinical relevanceIn diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.
| S-EPMC6536042 | biostudies-literature
Project description:RationaleWiedemann-Steiner syndrome (WDSTS, online mendelian inheritance in man 605130) is a rare autosomal dominant disorder characterized by hypertrichosis cubiti. Here, we report a Chinese boy who do not show the characteristic of hypertrichosis cubiti, and was misdiagnosed as blepharophimosis-ptosis-epicanthus inversus syndrome at first. We found a de novo frameshift mutation (p.Glu390Lysfs*10) in the KMT2A gene, which was not reported before. Our study increases the cohort of Chinese WDSTS patients, and expand the WDSTS phenotypic and variation spectrum.Patient concernsThe patient demonstrated typical craniofacial features of blepharophimosis-ptosis-epicanthus inversus syndrome, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, besides he had congenital heart disease (ventricular septal defects), strabismus, hypotonia, amblyopia, delayed speech and language development, delayed psychomotor development, and amblyopia (HP:0000646) which was not reported before.DiagnosisFOXL2 gene was cloned and sequenced, however, there was no mutation detected in this patient. The result of Chromosomal microarray analysis was normal. The patient was diagnosed as WDSTS by whole exome sequencing.InterventionsThe patient received cardiac surgery, frontalis suspension and regular speech and occupational therapy. He also treated with growth hormone (GH).OutcomesThe patient's symptoms are improved after cardiac surgery and frontalis suspension, he can express himself well now and had a 10 cm gain in height.LessonsAs the relationship between genotype and phenotype becomes more and more clear, WES is incredibly powerful tool to diagnose the disease of WDSTS.
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Project description:This study examined anxiety in Wiedemann-Steiner syndrome (WSS). Eighteen caregivers and participants with WSS completed the parent- and self-report versions of the Screen for Child Anxiety Related Disorder or the adapted version of the Screen for Adult Anxiety Related Disorder. Approximately 33.33% of parents and 65% of participants with WSS rated in the clinical range for overall anxiety. Across anxiety subtypes, parents primarily indicated concerns with Separation Anxiety (72%), which was also endorsed by the majority of participants with WSS (82%). The emergent trend showed Total Anxiety increased with age based on parent-informant ratings. The behavioral phenotype of WSS includes elevated anxiety. Clinical management should include incorporating early behavioral interventions to bolster emotion regulation given the observed risk of anxiety with age.
| S-EPMC9907226 | biostudies-literature
Project description:Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant disorder with a variable clinical phenotype including synophrys, hypertelorism, thick eyebrows, long eyelashes, wide nasal bridge, long philtrum, hypertrichosis, growth retardation, and intellectual disability. Cornelia de Lange syndrome (CdLS) is a rare disease characterized by synophrys, long eyelashes, limb abnormalities, generalized hirsutism, growth retardation, and intellectual disability. In both WDSTS and CdLS, the malformations are due to transcriptome disturbance caused by defects in the genes encoding the components of chromatin regulation and transcription process. The overlapping features in these two syndromes may complicate the original diagnosis of a patient. Here, we report on a Wiedemann-Steiner patient found to have a de novo pathogenic KMT2A variation who had been clinically suspected as CdLS. We suggest that targeted next-generation sequencing is a feasible tool for the precise diagnosis of patients who have phenotypically and clinically overlapping features of CdLS and WDSTS.
| S-EPMC7983614 | biostudies-literature
Project description:Excessive growth of terminal hair around the elbows (hypertrichosis cubiti) has been reported both in isolation and in association with a variable spectrum of associated phenotypic features. We identified a cohort of six individuals with hypertrichosis cubiti associated with short stature, intellectual disability, and a distinctive facial appearance, consistent with a diagnosis of Wiedemann-Steiner syndrome (WSS). Utilizing a whole-exome sequencing approach, we identified de novo mutations in MLL in five of the six individuals. MLL encodes a histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4. Each of the five mutations is predicted to result in premature termination of the protein product. Furthermore, we demonstrate that transcripts arising from the mutant alleles are subject to nonsense-mediated decay. These findings define the genetic basis of WSS, provide additional evidence for the role of haploinsufficency of histone-modification enzymes in multiple-congenital-anomaly syndromes, and further illustrate the importance of the regulation of histone modification in development.
| S-EPMC3415539 | biostudies-literature
Project description:BackgroundWiedemann-Steiner Syndrome (WSS) is an autosomal dominant genetic condition caused by mutations in the KMT2A gene. Lysine methyltransferase, encoded by KMT2A, plays critical roles in the regulation of gene expression during early development.MethodsTrio-based whole exome sequencing (Trio-WES) was performed on a 15 months old Chinese girl and her two parents by MyGenostics (Beijing, China) using the Illumina HiSeq X ten system. Variants were confirmed with Sanger sequencing. She exhibited mild/moderate intellectual disability (ID), hypotonia, hypertrichosis cubiti, hypertrichosis on the back, dysmorphic facies, psychomotor retardation, growth delay, small and puffy hands, fat pads anterior to calcanei, and palmar/plantar grooves.ResultsTrio-WES revealed a novel de novo mutation of KMT2A gene (NM_001197104.1: c.3566G>T, p.Cys1189Phe). WSS was diagnosed based on WES and clinical features.ConclusionOur findings expand the phenotypic and mutation spectra of WSS.
| S-EPMC7963408 | biostudies-literature
Project description: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.
| S-EPMC8620998 | biostudies-literature
Project description:IntroductionWiedemann-Steiner syndrome (WSS) is a rare autosomal-dominant disorder caused by KMT2A variants. The aim of this study was to characterize a novel KMT2A variant in a child with WSS and demonstrate integrated diagnostic approaches.MethodsA 3-year-old female with developmental delay, distinctive facial features, and anal fistula underwent whole exome sequencing (WES). RNA analysis was performed to assess splicing effects caused by a novel variant.ResultsWES identified novel heterozygous KMT2A c.5664+6T>C variant initially classified as a variant of uncertain significance. RNA analysis provided evidence of aberrant splicing (exon 20 skipping), allowing reclassification to likely pathogenic. The patient exhibited typical WSS features along with a potential novel finding of anal fistula.ConclusionThis report describes a novel non-canonical splice site variant in KMT2A associated with WSS. RNA analysis was critical for variant reclassification. Detailed phenotypic evaluation revealed common and expanded WSS manifestations. This case highlights the importance of combining clinical assessment, DNA testing, and RNA functional assays for the diagnosis of rare genetic disorders.
| S-EPMC10941593 | biostudies-literature
Project description:Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2A variants are non-sense and frameshift variants causing a typical form of Wiedemann-Steiner syndrome. We studied KMT2A gene in a cohort of 200 patients with unexplained syndromic and non-syndromic ID and identified four novel variants, one splice and three missense variants, possibly deleterious. We used primary cells from the patients and molecular approaches to determine the deleterious effects of those variants on KMT2A expression and function. For the putative splice variant c.11322-1G>A, we showed that it led to only one nucleotide deletion and loss of the C-terminal part of the protein. For two studied KMT2A missense variants, c.3460C>T (p.(Arg1154Trp)) and c.8558T>G (p.(Met2853Arg)), located at the cysteine-rich CXXC domain and the transactivation domain of the protein, respectively, we found altered KMT2A target genes expression in patient's fibroblasts compared to controls. Furthermore, we found a disturbed subcellular distribution of KMT2A for the c.3460C>T mutant. Taken together, our results demonstrated the deleterious impact of the splice variant and of the missense variants located at two different functional domains and suggested reduction of KMT2A function as the disease-causing mechanism.
| S-EPMC5839021 | biostudies-literature