RESUMO
The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.
Assuntos
Deleção Cromossômica , Anormalidades Craniofaciais/genética , Endoglina/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas com Homeodomínio LIM/genética , Proteínas Munc18/genética , Fatores de Transcrição/genética , Adolescente , Criança , Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/diagnóstico , Epilepsia/diagnóstico , Feminino , Haploinsuficiência , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , SíndromeRESUMO
OBJECTIVE: To determine the frequency and types of renal malformations, and to evaluate renal function in a cohort of patients with Kabuki syndrome (KS). STUDY DESIGN: Renal ultrasound scans and plasma creatinine measurements were collected from a French cohort of 94 patients with genotyped KS. Renal function was evaluated based on the estimated glomerular filtration rate. A genotype-phenotype study was conducted for renal and urinary tract malformations. RESULTS: Renal malformations were present in 22% of cases, and urinary tract anomalies were present in 15%. Renal malformations were observed in 28% of the MLL2 mutation-positive group and in 0% of the MLL2 mutation-negative group (P = .015). No correlation was found between the presence or absence of renal or urinary tract malformations and the location or type of MLL2 mutation. Renal function was normal except for 1 patient with a MLL2 mutation diagnosed in the first days of life and severe renal disease due to unilateral renal agenesia and controlateral severe hypoplasia that progressed to the terminal stage at age 2 years. CONCLUSION: Our study emphasizes the need for ultrasound and renal function screening in children diagnosed with KS.
Assuntos
Anormalidades Múltiplas/diagnóstico , Doenças Hematológicas/diagnóstico , Rim/anormalidades , Doenças Vestibulares/diagnóstico , Anormalidades Múltiplas/sangue , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Estudos de Coortes , Creatinina/sangue , Proteínas de Ligação a DNA/genética , Face/anormalidades , Face/fisiopatologia , Feminino , França , Estudos de Associação Genética , Marcadores Genéticos , Técnicas de Genotipagem , Taxa de Filtração Glomerular , Doenças Hematológicas/sangue , Doenças Hematológicas/genética , Doenças Hematológicas/fisiopatologia , Histona Desmetilases/genética , Humanos , Lactente , Rim/diagnóstico por imagem , Rim/metabolismo , Rim/fisiopatologia , Masculino , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Estudos Retrospectivos , Ultrassonografia , Doenças Vestibulares/sangue , Doenças Vestibulares/genética , Doenças Vestibulares/fisiopatologia , Adulto JovemRESUMO
Out of a series of 30 French patients with Pearson syndrome, we report on two patients with an atypical presentation, which include growth deficiency, pancytopaenia, tubulopathy and absence of exocrine pancreas dysfunction. Patient 1, a 4-year-old boy with a past history of pancytopaenia and transient metabolic acidosis at 13 months of age, presented at 2(1/2) years of age with severe tubulopathy of de Toni-Debré-Fanconi type, growth retardation, metabolic lactic acidosis and mild cytolysis. Despite normal exocrine pancreatic function, study of mitochondrial DNA revealed a 3.5 kb deletion. Patient 2 had a personal history of pancytopaenia requiring blood transfusions at 11 months of age and presented with severe intractable proximal and distal tubulopathy at 2 years of age. Exocrine pancreatic deficiency could not be evidenced and post-mortem studies revealed a 4.9 kb deletion of the mitochondrial DNA. A review of the literature revealed three patients presenting with Pearson syndrome and tubulopathy with normal pancreatic function and highlights delay in diagnosis in those three patients. The series of 30 French patients with Pearson syndrome also revealed that tubulopathy was present in 7/30 cases (23%), with variable outcome. In conclusion, Pearson syndrome should be screened for in children presenting with the association of growth retardation, anaemia/pancytopaenia, lactic acidosis and tubulopathy, even in the absence of exocrine pancreatic deficiency.