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Abstract：
BACKGROUND: Autosomal recessive congenital ichthyoses (ARCIs) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes. The aim of our study was to assess disease severity, phenotypic, and ultrastructural features and to evaluate their association with genetic findings in ARCI patients.
METHODS: Clinical signs and symptoms, and disease severity were scored in a single-center series of patients with a genetic diagnosis of ARCI. Skin ultrastructural findings were reviewed.
RESULTS: Seventy-four consecutive patients (mean age 11.0 years, range 0.1-48.8) affected with lamellar ichthyosis (50/74, 67.5%), congenital ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74, 2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled. Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%). Twenty-five previously undescribed mutations in the different ARCI causative genes, as well as two microduplications in TGM1, and two microdeletions in CYP4F22 and NIPAL4 were identified. The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients. Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick, and brownish scales with TGM1 mutations. Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients. Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients.
CONCLUSIONS: Our study expands the phenotypic and genetic characterization of ARCI by the description of statistically significant associations between disease severity, specific clinical signs, and different mutated genes. Finally, we highlighted the presence of psoriasis-like lesions in NIPAL4-ARCI patients as a novel phenotypic feature with diagnostic and possible therapeutic implications.
METHODS: Clinical signs and symptoms, and disease severity were scored in a single-center series of patients with a genetic diagnosis of ARCI. Skin ultrastructural findings were reviewed.
RESULTS: Seventy-four consecutive patients (mean age 11.0 years, range 0.1-48.8) affected with lamellar ichthyosis (50/74, 67.5%), congenital ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74, 2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled. Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%). Twenty-five previously undescribed mutations in the different ARCI causative genes, as well as two microduplications in TGM1, and two microdeletions in CYP4F22 and NIPAL4 were identified. The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients. Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick, and brownish scales with TGM1 mutations. Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients. Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients.
CONCLUSIONS: Our study expands the phenotypic and genetic characterization of ARCI by the description of statistically significant associations between disease severity, specific clinical signs, and different mutated genes. Finally, we highlighted the presence of psoriasis-like lesions in NIPAL4-ARCI patients as a novel phenotypic feature with diagnostic and possible therapeutic implications.
摘要：
背景：常染色体隐性遗传先天性鱼鳞病（ARCI）是一组临床异质性的角质化疾病，其特征是由于至少12个基因的突变而导致的全身性皮肤鳞屑。我们研究的目的是评估疾病的严重程度，ARCI患者的表型和超微结构特征，并评估其与遗传发现的关联。
方法：临床体征和症状，在单中心系列的ARCI基因诊断患者中对疾病严重程度进行评分.对皮肤超微结构的发现进行了综述。
结果：连续74例患者（平均年龄11.0岁，范围0.1-48.8）受层状鱼鳞病影响（50/74，67.5％），先天性鱼鳞状红皮病(18/74,24.3%),丑角鱼鳞病（2/74，2.7％），和其他次要ARCI亚型(4/74,5.4%)入组.突变基因为：18/74（24.3％）患者中的TGM1，ALOX12B在18/74（24.3%），CYP4F22在12/74（16.2%），ABCA12在9/74（12.2%），ALOXE3在7/74（9.5%），NIPAL4在7/74（9.5%），CERS3、PNPLA1和SDR9C7各1例(1.4%)。在不同的ARCI致病基因中，有25个以前未描述的突变，以及TGM1中的两个微重复，以及CYP4F22和NIPAL4中的两个微缺失。TGM1和ABCA12突变患者的鱼鳞病严重程度平均评分明显高于所有其他突变基因，而在CYP4F22突变的患者中观察到最低评分。脱发,外翻,和eclabium与TGM1和ABCA12突变显著相关，而且很大，有TGM1突变的厚褐色鳞片。在特定的表型特征中，在NIPAL4突变的患者中存在牛皮癣样病变以及躯干网状鳞屑模式和横纹角化病。56例患者的超微结构数据显示，TGM1突变病例的胆固醇裂口具有100％的特异性，并在SDR9C7和CERS3患者中发现异常的层状体。
结论：我们的研究通过描述疾病严重程度之间的统计学显着关联来扩展ARCI的表型和遗传特征。具体的临床体征，和不同的变异基因.最后,我们强调NIPAL4-ARCI患者中存在银屑病样病变是一种新的表型特征,具有诊断和可能的治疗意义.
方法：临床体征和症状，在单中心系列的ARCI基因诊断患者中对疾病严重程度进行评分.对皮肤超微结构的发现进行了综述。
结果：连续74例患者（平均年龄11.0岁，范围0.1-48.8）受层状鱼鳞病影响（50/74，67.5％），先天性鱼鳞状红皮病(18/74,24.3%),丑角鱼鳞病（2/74，2.7％），和其他次要ARCI亚型(4/74,5.4%)入组.突变基因为：18/74（24.3％）患者中的TGM1，ALOX12B在18/74（24.3%），CYP4F22在12/74（16.2%），ABCA12在9/74（12.2%），ALOXE3在7/74（9.5%），NIPAL4在7/74（9.5%），CERS3、PNPLA1和SDR9C7各1例(1.4%)。在不同的ARCI致病基因中，有25个以前未描述的突变，以及TGM1中的两个微重复，以及CYP4F22和NIPAL4中的两个微缺失。TGM1和ABCA12突变患者的鱼鳞病严重程度平均评分明显高于所有其他突变基因，而在CYP4F22突变的患者中观察到最低评分。脱发,外翻,和eclabium与TGM1和ABCA12突变显著相关，而且很大，有TGM1突变的厚褐色鳞片。在特定的表型特征中，在NIPAL4突变的患者中存在牛皮癣样病变以及躯干网状鳞屑模式和横纹角化病。56例患者的超微结构数据显示，TGM1突变病例的胆固醇裂口具有100％的特异性，并在SDR9C7和CERS3患者中发现异常的层状体。
结论：我们的研究通过描述疾病严重程度之间的统计学显着关联来扩展ARCI的表型和遗传特征。具体的临床体征，和不同的变异基因.最后,我们强调NIPAL4-ARCI患者中存在银屑病样病变是一种新的表型特征,具有诊断和可能的治疗意义.
