RESUMO
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.
Assuntos
Predisposição Genética para Doença , Transtornos do Crescimento/genética , Histona-Lisina N-Metiltransferase/genética , Hipertricose/congênito , Deficiência Intelectual/genética , Proteína de Leucina Linfoide-Mieloide/genética , População Negra/genética , Constipação Intestinal/epidemiologia , Constipação Intestinal/genética , Constipação Intestinal/patologia , Insuficiência de Crescimento/epidemiologia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Estudos de Associação Genética , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/patologia , Humanos , Hipertricose/epidemiologia , Hipertricose/genética , Hipertricose/patologia , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Mutação com Perda de Função/genética , Estudos Retrospectivos , População Branca/genéticaRESUMO
Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
Assuntos
Anormalidades Múltiplas/genética , Canalopatias/genética , Anormalidades Craniofaciais/genética , Canais de Potássio Éter-A-Go-Go/genética , Fibromatose Gengival/genética , Mutação com Ganho de Função , Hallux/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Unhas Malformadas/genética , Canais de Potássio/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Polegar/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Canalopatias/patologia , Criança , Anormalidades Craniofaciais/patologia , Feminino , Fibromatose Gengival/patologia , Hallux/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Unhas Malformadas/patologia , Fenótipo , Polegar/patologiaRESUMO
Kallmann syndrome (KS) is defined by the association of idiopathic hypogonadotropic hypogonadism and anosmia/hyposmia. Diagnosis is frequently delayed, however, because hypogonadotropic hypogonadism is usually not apparent until puberty and individuals with anosmia/hyposmia are often unaware of this sensory deficit. Mutations in at least six genes have been associated with KS; however, the sensitivity of molecular testing is only about 30% and, therefore, the diagnosis is largely based on clinical findings. We describe the findings in six individuals with KS, which demonstrate the utility of associated anomalies in making this diagnosis. Analysis of our case series and literature review suggests the consideration of KS for males with microphallus and/or cryptorchidism and for any patient with hearing loss, renal agenesis, and/or synkinesis. Conversely, patients with features of KS should have an audiology evaluation and a renal ultrasound.