Association of generalized dystrophic epidermolysis bullosa with positive acetylcholinesterase and markedly elevated maternal serum and amniotic fluid alpha-fetoprotein

A case of fatal generalized dystrophic epidermolysis bullosa is described in a prematurely born female whose mother had strikingly elevated mid-trimester serum and amniotic fluid alpha-fetoprotein concentrations, a positive amniotic fluid acetylcholinesterase band, and negative serial ultrasound studies. This case lends further support to an association between autosomal recessive generalized dystrophic epidermolysis bullosa and increased levels of alpha-fetoprotein, positive amniotic fluid acetylcholines'terase, and normal ultrasound findings.     

Prenatal diagnosis for Epidermolysis bullosa: a study of 144 consecutive pregnancies at risk

Epidermolysis bullosa (EB) is a group of inherited disorders characterized by increased skin fragility, resulting in blisters and erosions after minor trauma. Mutations in 10 structural genes expressed in the cutaneous basement membrane zone have been reported. The DebRA Molecular Diagnostics Laboratory at Jefferson Medical College has performed 144 DNA-based prenatal diagnoses since 1993 in families at risk for recurrence of the most severe forms of EB, including the recessive dystrophic EB (RDEB), junctional EB (JEB), EB with pyloric atresia (EB-PA), and EB simplex (EBS). A mutation-detection strategy using either conformation-sensitive gel electrophoresis (CSGE) or denaturing high-performance liquid chromatography (dHPLC) scanning analysis, followed by nucleotide sequencing, was applied to most cases with DEB and to all JEB, EB-PA, and EBS families. For some RDEB families, linkage analysis was performed, either alone when the inheritance pattern was clear or in combination with one mutation. Among the 144 prenatal diagnoses, 63 were for RDEB, 69 for JEB, 6 for EB-PA, and 6 for EBS. Twenty-eight normal, 73 heterozygous carrier, and 28 affected RDEB, JEB, and EB-PA pregnancies were reported in these recessively inherited diseases. Two affected and four normal pregnancies were predicted in dominantly inherited EBS. Among the 144 pregnancies, 9 were terminated without confirmation, 13 cases were lost to follow-up, and 6 pregnancies are ongoing. There were 6 families with inconclusive results due either to recombination events between flanking markers, absence of informative markers for one allele, or lack of sample from the previously affected child. There were three discordant results, one that was explained by maternal contamination of the chorionic villus sample and two that were unresolved. Overall, the availability, relative ease, and over 98% success rate make molecular DNA-based prenatal diagnosis a viable option for EB families at risk. Copyright © 2003 John Wiley & Sons, Ltd.     

Aplasia cutis congenita associated with epidermolysis bullosa and pyloric atresia: The diagnostic role of prenatal ultrasonography

Aplasia cutis congenita associated with epidermolysis bullosa and pyloric atresia is a rare congenital disease in which localized or widespread areas of skin are absent at birth. Alpha- fetoprotein (AFP) and skin biopsy have been used for prenatal diagnosis of this condition. A patient in whom normal levels of amniotic AFP at 16 weeks' gestation presumably excluded the disease and who was at risk for aplasia cutis congenita associated with epidermolysis bullosa and pyloric atresia is described. However, 10 weeks later, ultrasonographic examination revealed hydramnios, a dilated stomach, a deformed external ear, and a contracted fisted hand. All signs were confirmed postnatally. The role of ultrasonography and the value of other diagnostic methods in this congenital disease are discussed.     

Applicability of 19–DEJ-l monoclonal antibody for the prenatal diagnosis or exclusion of junctional epidermolysis bullosa

Recently a monoclonal antibody (19–DEJ-l) was produced with binding specificity for the mid-lamina lucida of the skin dermoepidermal junction, in very close association with overlying hemidesmosomes. Since skin cleavage occurs within the lamina lucida in the inherited blistering disorder, junctional epidermolysis bullosa (EB), and is associated with aberrations in the morphology and/or number of hemidesmosomes in such tissue, we have sought to determine whether this monoclonal antibody could be used for prenatal diagnosis. Fetoscopy-directed skin biopsies were obtained from two fetuses at risk for junctional EB and post-mortem samples from two other fetuses with the Herlitz type of junctional EB, the latter after prenatal diagnosis by electron microscopy and termination of each pregnancy. Specimens were examined in part by light and electron microscopy for evidence of skin cleavage or other alterations in morphology, and in part by indirect immunofluorescence for altered basement membrane antigenicity. Three of four fetuses were shown to have intra-lamina lucida blister formation indicative of, and hemidesmosome hypoplasia proving, junctional EB. Each was also shown to lack expression of GB3 and 19–DEJ-l antigens, consistent with findings noted postnatally in junctional EB; diagnosis was confirmed in each at the time of therapeutic abortion. A fourth fetus had no abnormalities detected; lack of disease involvement was confirmed at the time of delivery, and subsequently over 8 months of careful serial evaluation. We conclude that 19–DEJ-l monoclonal antibody is an accurate and sensitive irnmunohistochemical probe for junctional EB, and may be employed in the prenatal diagnostic evaluation of fetuses at risk for this disorder.     

卡马西平片致严重药疹2例

2例男性患者（年龄35、33岁）,分别因面神经性麻木、睡眠型癫痫给予卡马西平片对症治疗,服药后均出现了严重药疹.例1服药后出现口腔大面积溃疡伴脓血分泌物,眼结膜稍红,无渗出,躯干及四肢可见多形性红色斑疹;例2服药后出现面颈部及躯干四肢弥漫的紫红色斑疹,面颈部有不规则松弛性水疱,表皮松弛,眼角、口唇、口腔糜烂,伴有肝功能、胰腺受损.均予以停用卡马西平片,予甲强龙、左西替利嗪抗过敏等对症治疗后药疹症状好转.参5.     

The association of congenital skin disorders with acetylcholinesterase in amniotic fluid

We describe a fetus with epidermolysis bullosa dystrophica and a fetus with aplasia cutis congenita who were normal by careful ultrasound examination but whose midtrimester amniotic fluids exhibited elevated concentrations of alpha-fetoprotein and presence of acetyl-cholinesterase. These cases show that serious fetal skin pathology can be a source of amniotic fluid acetylcholinesterase and elevated alpha-fetoprotein concentration and should be considered as part of the differential diagnosis of these amniotic fluid findings.     

Genetic basis of lethal junctional epidermolysis bullosa in an affected fetus: Implications for prenatal diagnosis in one family

Fetal skin biopsy at 20 weeks' gestation in a woman at risk for a child with the lethal skin-blistering disorder junctional epidermolysis bullosa (Herlitz) confirmed an affected fetus. Genomic DNA from the aborted fetus was examined for mutations in laminin 5, a macromolecule involved in adhesion at the dermal-epidermal junction, and a candidate protein in this condition. Polymerase chain reaction (PCR) amplification of exon 10 and parts of the flanking introns of the gene encoding the β3 chain of laminin 5 (LAMB3) and subsequent analysis by agarose gel electrophoresis showed a more slowly migrating band in the affected fetus compared with the normal control. Nucleotide sequencing of the abnormal PCR product revealed a homozygous 77 bp duplication within the exon, resulting in a premature termination codon 250 bp downstream from the 3′ end of the duplication. Maternal DNA was heterozygous for the mutant and wild-type alleles. These findings illustrate the genetic basis of the skin disease in this case and also offer the prospects of a simple, rapid, and reliable first-trimester DNA-based prenatal, or even preimplantation, diagnostic test for future pregnancies in this family.     

Alpha-fetoprotein and acetylcholinesterase are not predictive of fetal junctional epidermolysis bullosa,Herlitz variant

Junctional epidermolysis bullosa, Herlitz variant (junctional EB-Herlitz) is a lethal autosomal recessive skin disorder currently amenable to prenatal diagnosis only by direct analysis of fetal skin. However, elevated levels of alpha-fetoprotein, as well as the presence of acetylcholinesterase in amniotic fluid, have been associated with other severe fetal genodermatoses. Fetal skin samplings were performed in ten pregnancies at risk for fetal junctional EB-Herlitz, with three fetuses affected on the basis of electron microscopic detection of blisters within the lamina lucida and abnormal hemidesmosomes. In neither affected nor unaffected pregnancies were maternal serum or amniotic fluid alpha-fetoprotein levels elevated. Moreover, alphafetoprotein levels in both maternal serum and amniotic fluid were not statistically different comparing affected and unaffected fetuses. Acetylcholinesterase was not present in the amniotic fluid samples of the three affected pregnancies. Unlike other severe fetal genodermatoses, neither alpha-fetoprotein nor acetylcholinesterase was predictive of junctional EB-Herlitz.