Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients

Abstract

<b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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: <i>TGM1</i> in 18/74 (24.3%) patients, <i>ALOX12B</i> in 18/74 (24.3%), <i>CYP4F22</i> in 12/74 (16.2%), <i>ABCA12</i> in nine/74 (12.2%), <i>ALOXE3</i> in seven/74 (9.5%), <i>NIPAL4</i> in seven/74 (9.5%), and <i>CERS3</i>, <i>PNPLA1</i>, and <i>SDR9C7</i> in 1 patient each (1.4%). Twenty-five previously undescribed mutations in the different ARCI causative genes, as well as two microduplications in <i>TGM1</i>, and two microdeletions in <i>CYP4F22</i> and <i>NIPAL4</i> were identified. The mean ichthyosis severity score in <i>TGM1</i>- and <i>ABCA12</i>-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in <i>CYP4F22</i>-mutated patients. Alopecia, ectropion, and eclabium were significantly associated with <i>TGM1</i> and <i>ABCA12</i> mutations, and large, thick, and brownish scales with <i>TGM1</i> mutations. Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in <i>NIPAL4</i>-mutated patients. Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for <i>TGM1</i>-mutated cases and revealed abnormal lamellar bodies in <i>SDR9C7</i> and <i>CERS3</i> patients. <b><i>Conclusion:</i></b> 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 <i>NIPAL4</i>-ARCI patients as a novel phenotypic feature with diagnostic and possible therapeutic implications.