RESUMO
Pyloric atresia (PA) is a rare gastrointestinal anomaly that occurs either as an isolated lesion or in association with other congenital or hereditary anomalies. Familial occurrence of PA with epidermolysis bullosa (EB) has been well documented and variants in ITGA6, ITGB4, and PLEC are known to cause EB with PA. However, no gene variants have been defined in familial isolated PA. Five siblings with familial isolated PA are presented that suggest biallelic ITGB4 variants may underlie the development of PA without EB. Five siblings from two unrelated families with isolated PA were studied with exome sequencing (ES) to identify the genetic etiology in isolated familial cases. Exome sequencing was performed in one affected patient from each family. Validation and segregation studies were done by Sanger sequencing. Parents were first cousins in one family but there was no consanguinity in the other family. Type-2 PA was detected in both families and none of the probands had associated anomalies. All patients underwent successful gastroduodenostomy and have been under follow-up uneventfully. All patients had biallelic ITGB4 variants, c.2032G > T p.(Asp678Tyr) being a novel one. Biallelic ITGB4 variants may underlie the development of PA without associated EB. Further detection of variants in this gene may establish any possible genotype-phenotype correlations.
Assuntos
Epidermólise Bolhosa/genética , Obstrução da Saída Gástrica/genética , Predisposição Genética para Doença , Integrina beta4/genética , Piloro/anormalidades , Adulto , Alelos , Criança , Pré-Escolar , Epidermólise Bolhosa/patologia , Feminino , Obstrução da Saída Gástrica/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Piloro/patologia , Irmãos , Sequenciamento do ExomaRESUMO
Congenital absence of skin (CAS) is a clinical sign associated with the main types of epidermolysis bullosa (EB). Very few studies have investigated the genetic background that may influence the occurrence of this condition. Our objective was to investigate genotype-phenotype correlations on EB with CAS through a literature revision on the pathogenic variants previously reported. A total of 171 cases (49 EB simplex, EBS; 23 junctional EB, JEB; and 99 dystrophic EB, DEB), associated with 132 pathogenic variants in eight genes, were included in the genotype-phenotype analysis. In EBS, CAS showed to be a recurrent clinical sign in EBS with pyloric atresia (PA) and EBS associated with kelch-like protein 24; CAS was also described in patients with keratins 5/14 alterations, particularly involving severe phenotypes. In JEB, this is a common clinical sign in JEB with PA associated with premature termination codon variants and/or amino acid substitutions located in the extracellular domain of integrin α6ß4 genes. In DEB with CAS, missense variants occurring close to non-collagenous interruptions of the triple-helix domain of collagen VII appear to influence this condition. This study is the largest review of patients with EB and CAS and expands the spectrum of known variants on this phenomenon.
Assuntos
Atresia das Cóanas/genética , Displasia Ectodérmica/genética , Epidermólise Bolhosa Distrófica/genética , Obstrução da Saída Gástrica/genética , Piloro/anormalidades , Anormalidades da Pele/genética , Substituição de Aminoácidos/genética , Atresia das Cóanas/fisiopatologia , Displasia Ectodérmica/fisiopatologia , Epidermólise Bolhosa Distrófica/fisiopatologia , Obstrução da Saída Gástrica/patologia , Estudos de Associação Genética , Genótipo , Humanos , Mutação/genética , Piloro/patologia , Pele/patologia , Anormalidades da Pele/patologiaAssuntos
Epidermólise Bolhosa Simples/genética , Obstrução da Saída Gástrica/genética , Predisposição Genética para Doença , Distrofias Musculares/genética , Plectina/genética , Piloro/anormalidades , Doenças Urológicas , Epidermólise Bolhosa Simples/complicações , Epidermólise Bolhosa Simples/diagnóstico , Seguimentos , Obstrução da Saída Gástrica/complicações , Obstrução da Saída Gástrica/diagnóstico por imagem , Humanos , Recém-Nascido , Masculino , Monitorização Fisiológica , Distrofias Musculares/complicações , Distrofias Musculares/diagnóstico , Mutação , Piloro/diagnóstico por imagem , Doenças RarasRESUMO
We report a case of nonfatal junctional epidermolysis bullosa and pyloric atresia in a newborn. We identified a substitution (c.914C>T) for the integrin ß4 gene that has been associated with favorable outcome. A novel mutation (c.2011T>G) of unknown significance was also found in this patient who is now thriving.
Assuntos
Epidermólise Bolhosa Juncional/genética , Obstrução da Saída Gástrica/genética , Integrina beta4/genética , Piloro/anormalidades , Epidermólise Bolhosa Juncional/complicações , Epidermólise Bolhosa Juncional/diagnóstico , Feminino , Obstrução da Saída Gástrica/complicações , Obstrução da Saída Gástrica/cirurgia , Heterozigoto , Humanos , Recém-Nascido , Laparotomia/métodos , Mutação , Piloro/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Pele/patologiaRESUMO
Plectin has been characterized as a linker protein that is expressed in many cell types and is distinctive in various isoforms in the N-terminus and around the rod domain due to complicated alternative splicing of PLEC, the gene encoding plectin. Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs, such as muscle and gastrointestinal tract, depending on the expression pattern of the defective protein. In addition, a point mutation in the rod domain of plectin leads to autosomal dominant EBS, called as EBS-Ogna. Plectin can be targeted by circulating autoantibodies in subepidermal autoimmune blistering diseases. This review summarizes plectin-related skin diseases, from congenital to autoimmune disorders.
Assuntos
Doenças Autoimunes/genética , Epidermólise Bolhosa Simples/genética , Plectina/genética , Plectina/imunologia , Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Epidermólise Bolhosa Simples/complicações , Obstrução da Saída Gástrica/complicações , Obstrução da Saída Gástrica/genética , Humanos , Distrofias Musculares/complicações , Distrofias Musculares/genética , Plectina/deficiência , Mutação Puntual , Piloro/anormalidades , Dermatopatias Vesiculobolhosas/genética , Dermatopatias Vesiculobolhosas/imunologiaRESUMO
The signaling molecule nitric oxide (NO), first described as endothelium-derived relaxing factor (EDRF), acts as physiological activator of NO-sensitive guanylyl cyclase (NO-GC) in the cardiovascular, gastrointestinal, and nervous systems. Besides NO-GC, other NO targets have been proposed; however, their particular contribution still remains unclear. Here, we generated mice deficient for the beta1 subunit of NO-GC, which resulted in complete loss of the enzyme. GC-KO mice have a life span of 3-4 weeks but then die because of intestinal dysmotility; however, they can be rescued by feeding them a fiber-free diet. Apparently, NO-GC is absolutely vital for the maintenance of normal peristalsis of the gut. GC-KO mice show a pronounced increase in blood pressure, underlining the importance of NO in the regulation of smooth muscle tone in vivo. The lack of an NO effect on aortic relaxation and platelet aggregation confirms NO-GC as the only NO target regulating these two functions, excluding cGMP-independent mechanisms. Our knockout model completely disrupts the NO/cGMP signaling cascade and provides evidence for the unique role of NO-GC as NO receptor.
Assuntos
Obstrução da Saída Gástrica/enzimologia , Guanilato Ciclase/deficiência , Guanilato Ciclase/metabolismo , Hipertensão/enzimologia , Obstrução Intestinal/enzimologia , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Obstrução da Saída Gástrica/genética , Obstrução da Saída Gástrica/mortalidade , Obstrução da Saída Gástrica/patologia , Guanilato Ciclase/genética , Frequência Cardíaca , Hipertensão/genética , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Obstrução Intestinal/genética , Obstrução Intestinal/mortalidade , Obstrução Intestinal/patologia , Camundongos , Camundongos Knockout , Óxido Nítrico/metabolismo , Agregação Plaquetária , Receptores Citoplasmáticos e Nucleares/genética , Guanilil Ciclase SolúvelRESUMO
Pyloric atresia occurs in one in a million births and usually occurs sporadically. We report a family with nine affected members and review the literature for all reported familial cases. The article stresses the possibility of recurrence of pyloric atresia in the progeny of consanguinous parents, with an emphasis on prenatal diagnosis and counseling, diagnosis of the entity in neonates, associated conditions, and prognosis in sporadic and familial cases. A high index of suspicion in affected families contributes to the early diagnosis and treatment with a great impact on outcome.