Epidermolysis bullosa simplex associated with muscular dystrophy: Phenotype-genotype correlations and review of the literature
Epidermolysis bullosa simplex associated with muscular dystrophy: Phenotype-genotype correlations and review of the literature
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DOI：
10.1016/s0190-9622(99)70252-5
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发表时间：
1999-12-01
影响因子：
13.8
通讯作者：
Nishikawa, T
中科院分区：
文献类型：
--
作者：
Shimizu, H;Takizawa, Y;Nishikawa, T
背景资料：与肌营养不良相关的单纯性大疱性表皮病（EBS-MD; OMIM# 226670）是一种常染色体隐性遗传疾病，由plectin基因的遗传缺陷引起。由于EBS-MD相对罕见，且基因缺陷仅在有限数量的患者中被阐明，因此精确的表型-基因型相关性尚未完全阐明。目的：本研究的目的是定义EBS-MD的临床特征并阐明其表型-基因型相关性。我们记录了4例不相关的日本EBS-MD患者的临床、超微结构、免疫组化和分子特征。结果：EBS-MD患者的皮肤水疱形成多发生在半桥粒的正上方，所有病例的plectin表达均缺失或明显减少。所有10例患者（包括文献中的6例）在出生时或出生后不久均表现出全身性水疱，并出现指甲畸形。此外，龋齿（5例），尿道狭窄（3例），轻度掌跖角化过度（2例），婴儿呼吸道并发症（2例），脱发（1例）和喉蹼（1例）。所有8名年龄超过9岁的患者都表现出相当大的肌肉无力，其中大多数最终被轮椅束缚。10例患者中7例为近亲婚姻产物，9例在plectin基因的两个等位基因中都有提前终止密码子（PTC）突变，7例为突变纯合子。1例2719 de 19读框内缺失突变纯合子导致3个氨基酸缺失（QEA）的患者，46岁时仍能行走，临床症状较轻。结论：EBS-MD不仅具有EBS和MD的特征性临床表现，还具有尿道、牙齿和呼吸系统并发症等临床表现。大多数患者是近亲结婚的产物，具有纯合的plectin基因突变。尽管两个等位基因中具有PTC突变的患者通常表现出严重的EBS-MB临床特征并最终被轮椅束缚，但框内缺失突变的纯合子患者表现出阳性但减弱的凝集素表达和较轻的临床表型。因此，结合对潜在的plectin突变的鉴定，plectin免疫荧光在预测EBS-MD患者以后生活中发生的肌肉受累的严重程度方面具有价值。
Background: Epidermolysis bullosa simplex associated with muscular dystrophy (EBS-MD; OMIM# 226670) is an autosomal recessive disorder caused by genetic defects in the plectin gene. Because EBS-MD is relatively rare, and gene defects have been elucidated only in a limited number of patients, the precise phenotype-genotype correlations have not yet been fully elucidated.Objective: The purpose of this study was to define clinical features of EBS-MD and to clarify its phenotype-genotype correlations.Methods: Clinical, ultrastructural, immunohistochemical, and molecular features of 4 unrelated Japanese patients with EBS-MD were recorded. In addition, 6 cases with defined plectin gene mutations reported in the literature were reviewed.Results: In skin of the EBS-MD patients, the blister formation always occurs just above the hemidesmosomes, and expression of plectin is absent or markedly reduced in all cases examined. All 10 patients, including 6 cases in the literature, showed generalized blistering at birth or soon thereafter, and experienced nail deformities. In addition, decayed teeth (5 cases), urethral strictures (3), mild palmoplantar hyperkeratosis (2), infantile respiratory complications (2), alopecia (1), and laryngeal webs (1) were present. All 8 patients who were older than 9 years demonstrated considerable muscle weakness, and the majority of them ended up being wheelchair bound. Among the 10 patients, 7 were products of consanguineous marriage, 9 have premature termination codon (PTC) mutations in both alleles of the plectin gene, and 7 cases were homozygous for the mutation. One patient who is homozygous for a 2719de19 in-frame deletion mutation that resulted in elimination of 3 amino acids, QEA, could still walk at the age of 46 and showed milder clinical severityConclusion: EBS-MD reveals clinical features not only characteristic of EBS and MD, but also other manifestations including urethral, dental, and respiratory complications. The majority of patients are products of consanguineous marriage and have homozygous plectin gene mutations. Whereas patients with PTC mutations in both alleles typically showed severe clinical features of EBS-MB and ended up being wheelchair bound, a homozygous patient for an in-frame deletion mutation showed positive, yet attenuated plectin expression and milder clinical phenotype. Thus plectin immunofluorescence, combined with identification of the underlying plectin mutations, is of value in predicting the severity of the muscle involvement that occurs later in life of patients with EBS-MD.