Clinical heterogeneity in epidermolysis bullosa simplex with plectin (PLEC) mutations-A study of six unrelated families from India.

Epidermolysis bullosa simplex (EBS) with plectin mutations is a very rare subtype of EB usually associated with pyloric atresia (PA) or muscular dystrophy (MD). We report six unrelated children between ages 4 and 14 years from India with varied clinical manifestations. Only one had PA, and none has developed MD to date. All except the one with PA presented with early onset blistering along with laryngeal involvement in the form of hoarseness of voice and nail involvement. Patient with PA presented with aplasia cutis and died in the first week. Two patients had predominantly respiratory and gastrointestinal involvement with varying severity while two had features of myasthenic syndrome but no limb-girdle involvement and one patient phenocopied laryngo-onycho-cutaneous (LOC) syndrome. Using whole-exome sequencing, we identified novel mutations in PLEC. Histopathological analysis (Immunofluorescence antigen mapping) showed absence of staining to plectin antibodies. Our observations propose to append a phenotype of EBS, hoarseness of voice and nail dystrophy or LOC-like phenotype with plectin mutations. Long-term follow up is necessary to monitor for the development of muscular dystrophy.

Genotype-phenotype correlations on epidermolysis bullosa with congenital absence of skin: A comprehensive review.

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.

Biallelic ITGB4 variants in familial pyloric atresia without epidermolysis bullosa: Report of two families with five siblings.

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.

A Nonlethal Case of Junctional Epidermolysis Bullosa and Congenital Pyloric Atresia: Compound Heterozygosity in a Patient with a Novel Integrin Beta 4 Gene Mutation.

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.

Neonatal gastric outlet obstruction by isolated pyloric atresia, an often forgotten diagnosis.

BACKGROUND: Pyloric atresia (PA) is a rare condition, and may be misdiagnosed and especially confused for duodenal atresia pre-operatively. We looked for clues to avoiding pre-operative misdiagnosis and hence allow the best neonatal medical and surgical management. METHODS: A retrospective case-note review was carried out of the five patients managed in four centres with the diagnosis of isolated PA. We focused on antenatal ultrasound findings, postnatal clinical and radiological features, operative findings, surgical procedures and outcomes. RESULTS: Four patients had polyhydramnios and one double bubble sign on antenatal ultrasound. After birth, non-bilious vomiting and upper abdominal distension were the main symptoms. Gastric decompression showed non-bilious gastric fluid. Radiological findings were a large gastric air bubble with no gas beyond in all cases. The diagnosis of duodenal atresia was postulated at first in all cases. The diagnosis of PA was established peroperatively. One patient referred late, died 13-day post-operatively of cardiopulmonary failure secondary to a severe pneumonia that may be related to aspiration syndrome. Outcomes were otherwise satisfactory. CONCLUSIONS: Even though it is a rare diagnosis, PA has a specific clinical and radiological presentation underlined here that should be kept in mind when managing a neonate with a gastric outlet obstruction.

[Lungs "Hassalloid´s-like" bodies in children with epidermolysis bullosa junctionalis and bart´s syndrome]. / "Hassalloidné" telieska v plúcach u dietata s epidermolysis bullosa junctionalis a s Bartovým syndrómom.

Epidermolysis bullosa and Bart´s syndrome are fairly accurately documented diseases by histopathology. In the article the authors describe interesting and hitherto undescribed phenomenon in the lungs male infant with epidermolysis bullosa junctionalis and Barts syndrome, who died 17 days after birth and 13 days after surgery for pyloric atresia, on multiorgan failure within basic congenital diseases.Histologically in lung alveoli was found to the massive presence of foamy macrophages and numerous globoid formations resembling morphological and immunohistochemical "Hassall´s" bodies in a thymus of the newborn. It was a acidophillic spherical bodies concentric tracks in the connective tissue with focal presence of fibrin, as a unique proof CKAE1/AE3 and CKHMW positive epithelial cells and CD68-positive histiocytic elements. An interesting finding was the follicular skin structure in the center "hassalloid´s-like" body, which suggests an aspiration components of the skin during intrauterine life.Normal Apgar score at birth of the child (10/10/10 s.) and severe histological features on the death of the child testify for the first pathogenetic formation "hassalloid´s-like" bodies in the lungs during the 17-day life of a disabled child.

LIM homeodomain transcription factor Isl1 directs normal pyloric development by targeting Gata3.

BACKGROUND: Abnormalities in pyloric development or in contractile function of the pylorus cause reflux of duodenal contents into the stomach and increase the risk of gastric metaplasia and cancer. Abnormalities of the pyloric region are also linked to congenital defects such as the relatively common neonatal hypertrophic pyloric stenosis, and primary duodenogastric reflux. Therefore, understanding pyloric development is of great clinical relevance. Here, we investigated the role of the LIM homeodomain transcription factor Isl1 in pyloric development. RESULTS: Examination of Isl1 expression in developing mouse stomach by immunohistochemistry, whole mount in situ hybridization and real-time quantitative PCR demonstrated that Isl1 is highly expressed in developing mouse stomach, principally in the smooth muscle layer of the pylorus. Isl1 expression was also examined by immunofluorescence in human hypertrophic pyloric stenosis where the majority of smooth muscle cells were found to express Isl1. Isl1 function in embryonic stomach development was investigated utilizing a tamoxifen-inducible Isl1 knockout mouse model. Isl1 deficiency led to nearly complete absence of the pyloric outer longitudinal muscle layer at embryonic day 18.5, which is consistent with Gata3 null mouse phenotype. Chromatin immunoprecipitation, luciferase assays, and electrophoretic mobility shift assays revealed that Isl1 ensures normal pyloric development by directly targeting Gata3. CONCLUSIONS: This study demonstrates that the Isl1-Gata3 transcription regulatory axis is essential for normal pyloric development. These findings are highly clinically relevant and may help to better understand pathways leading to pyloric disease.

A case of congenital pyloric atresia with dystrophic epidermolysis bullosa.

Pyloric atresia with epidermolysis bullosa (EB) dystrophica is a rare entity that may not be immediately recognized. We describe the fourth confirmed case of pyloric atresia associated with the dystrophic subtype of EB diagnosed by standard pathologic measures, and discuss the clinical disease features and recent advances in the pathophysiology.

Pyloric atresia in the neonate.

Bowel obstruction is a common cause for admission into the NICU, but pyloric atresia (PA) is a very rare cause of bowel obstruction. This article illustrates the development of the fetal gastrointestinal tract, most specifically the stomach and pylorus. Pathophysiology, typing, and treatment of PA are also explored. Presented are two cases of PA that occurred in a Level III NICU one month apart. Management of this condition is surgical in nature. Long-term prognosis is usually excellent because this defect is often isolated.

Double pylorus in the era of proton pump inhibitors.

Double pylorus and gastroduodenal fistula are rare conditions and can be either congenital or acquired. We report a case of a 58-year-old man with epigastric pain and dyspepsia in which the upper gastrointestinal endoscopy revealed an acquired double pylorus, probably caused by a gastric ulcer.

[Bart´s syndrome associated with epidermolysis bullosa junctionalis and with pyloric atresia. An autopsy case report]. / Bartov syndróm asociovaný s epidermolysis bullosa junctionalis a s atréziou pyloru. Nekroptická kazuistika.

Barts syndrome, in literature also known under the name CLAS (Congenital Localised Absence of Skin), first described by Bart in 1966 as congenital localized absence of skin, epidermolysis bullosa congenita and nail abnormalities. The authors present a macroscopic and histological findings of a newborn with Barts syndrome, with epidermolysis bullosa junctionalis and atresia pylori, who died 17 days after birth and 13 days after surgery for pyloric stenosis.

Epidermolysis bullosa simplex with PLEC mutations: new phenotypes and new mutations.

BACKGROUND: Genetic mutations in the plectin gene (PLEC) cause autosomal recessive forms of epidermolysis bullosa simplex (EBS) associated with either muscular dystrophy (EBS-MD) or pyloric atresia (EBS-PA). Phenotype-genotype analysis has suggested that EBS-MD is due mostly to genetic mutations affecting the central rod domain of plectin, and EBS-PA to mutations outside this domain. OBJECTIVES: This study aimed to describe new phenotypes of patients with EBS-MD and EBS-PA, to identify novel PLEC mutations and to establish genotype-phenotype correlations. METHODS: Seven patients with a suspicion of EBS linked to PLEC mutations were included. A standardized clinical questionnaire was sent to the physicians in charge of each patient. Immunofluorescence studies of skin biopsies followed by molecular analysis of PLEC were performed in all patients. RESULTS: We report the first case of nonlethal EBS-PA improving with age, the first multisystemic involvement in a patient with lethal EBS-PA, and the first patients with EBS-MD with involvement of either the bladder or oesophagus. Eleven novel PLEC mutations are also reported. CONCLUSIONS: Our results confirm that EBS-PA is linked to mutations in the distal exons 1-30 and 32 of PLEC. Long-term survival is possible, with skin improvement, but a delayed onset of MD is probable. While EBS-MD is linked to PLEC mutations in all exons, in most cases one of the mutations affects exon 31. The precocity of MD seems to be linked to the type and localization of the PLEC mutation(s), but no correlation with mucosal involvement has been found.

Pyloric atresia with epidermolysis bullosa: fetal MRI diagnosis with postnatal correlation.

Pyloric atresia is an uncommon congenital gastric outlet obstruction, accounting for only 1% of gastrointestinal atresias. Up to 55% of cases have associated anomalies, the most common of which is epidermolysis bullosa. Fetal MRI findings of the epidermolysis bullosa-pyloric atresia association have not been previously reported. We present a case of this association diagnosed by prenatal MRI with corroborative postnatal imaging and surgical findings.