RESUMO
Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.
Assuntos
Dermatan Sulfato/biossíntese , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Heterogeneidade Genética , Fenótipo , Adolescente , Adulto , Sequência de Aminoácidos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biópsia , Criança , Colágeno/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Síndrome de Ehlers-Danlos/diagnóstico , Éxons , Matriz Extracelular/metabolismo , Fácies , Feminino , Fibronectinas/metabolismo , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Alinhamento de Sequência , Pele/patologia , Pele/ultraestrutura , Sulfotransferases/química , Sulfotransferases/genética , Sulfotransferases/metabolismo , Adulto JovemAssuntos
Anemia Aplástica/diagnóstico por imagem , Doenças da Medula Óssea/diagnóstico por imagem , Hemoglobinúria Paroxística/diagnóstico por imagem , Proteína do Locus do Complexo MDS1 e EVI1/genética , Anormalidades Múltiplas , Sequência de Aminoácidos , Transtornos da Insuficiência da Medula Óssea , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Deleção de Sequência , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: At the start of the implementation of TESE-ICSI for Klinefelter men in the Netherlands, we aimed to evaluate their wish to father children and their attitudes towards this artificial reproduction technique. METHODS: Questionnaires were distributed to members of the Dutch Klinefelter Association (n = 365) and to Klinefelter cases known at our Department (n = 58). Questions addressed several aspects: socio-demographic characteristics, ascertainment of diagnosis, children and child wish, and TESE-ICSI. Data were characterized using descriptive statistics. RESULTS: A total of 260 questionnaires (corresponding to 194 cases, 46%) were returned. A possible wish to father children was reported by 90% of Klinefelter men. 70% of Klinefelter men and 74% of their partners would (probably) opt for TESE-ICSI. CONCLUSION: The majority of Dutch Klinefelter men and their partners desire to have children and have a positive attitude towards TESE-ICSI. Concerns include the risk of congenital malformations/developmental delay of the child and the limited success rate of TESE-ICSI.
Assuntos
Família/psicologia , Síndrome de Klinefelter/psicologia , Injeções de Esperma Intracitoplásmicas/psicologia , Recuperação Espermática/psicologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Gravidez , Injeções de Esperma Intracitoplásmicas/métodosRESUMO
BACKGROUND: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers. METHODS: Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated. RESULTS: No significant association with pancreatic cancer was found for any of the seven SNPs. CONCLUSIONS: Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Síndrome do Nevo Displásico/genética , Mutação em Linhagem Germinativa , Melanoma/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Síndrome do Nevo Displásico/complicações , Síndrome do Nevo Displásico/patologia , Feminino , Heterozigoto , Humanos , Masculino , Melanoma/complicações , Melanoma/patologia , Pessoa de Meia-Idade , Países Baixos , Razão de Chances , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Linhagem , Fatores de Risco , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologiaRESUMO
Klinefelter syndrome is the most common chromosome abnormality in humans. The estimated prevalence is one in 500 to one in 1000 males but due to the widely variable and often aspecific features, only one in four cases are recognized. The most specific clinical features which can be observed at adult age are small testes, gynecomastia, female distribution of fat and body hair, slightly increased body length due to an increased leg length and azoospermia. Cognition is characterized by verbal deficits and psychosocial features include autistiform behavior. Structural brain abnormalities have been observed by MRI, such as decreased brain volumes and a decrease of asymmetry in areas corresponding to language performance. In the vast majority of cases a non-mosaic 47,XXY karyotype is observed. Parental imprinting of the extra X chromosome, variable inactivation of some X-chromosomal genes and CAG repeat length polymorphism of the androgen receptor may all be related to the variability of the phenotype. Surgical procedures of obtaining sperm in combination with repeated intracytoplasmic sperm injection/in vitro fertilization treatment may allow up to one in four men with Klinefelter syndrome to father children.