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. 2024;240(3):397-413.
doi: 10.1159/000536366. Epub 2024 Apr 8.

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

Andrea Diociaiuti  1 , Marialuisa Corbeddu  1   2 , Sabrina Rossi  3 , Elisa Pisaneschi  4 , Claudia Cesario  4 , Angelo Giuseppe Condorelli  5 , Tonia Samela  6 , Simona Giancristoforo  1 , Adriano Angioni  4 , Giovanna Zambruno  5 , Antonio Novelli  4 , Rita Alaggio  3 , Damiano Abeni  6 , May El Hachem  1
Affiliations

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

Andrea Diociaiuti et al. Dermatology. 2024.

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.

Conclusion: 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.

Keywords: Collodion baby; Congenital ichthyosiform erythroderma; Electron microscopy; Lamellar ichthyosis; Next-generation sequencing.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1.
Fig. 1.
Frequency distribution of patients presenting with alopecia (a), ectropion (b), and eclabium (c), by each mutated gene. Alopecia was significantly more frequent in TGM1-mutated patients as compared to ALOX12B (p < 0.001), ALOXE3 (p < 0.006), CYP4F22 (p < 0.004), and NIPAL4 (p < 0.006). ABCA12-mutated patients had alopecia more frequently than patients carrying ALOX12B (p < 0.004), ALOXE3 (p < 0.035), CYP4F22 (p < 0.0036), and NIPAL4 (p < 0.0035) mutations. Ectropion was more frequently present in TGM1-mutated patients as compared to ALOX12B and CYP4F22 (p < 0.001), NIPAL4 and ALOXE3 (p = 0.019). Eclabium was overall rarer, and with one exception (in ALOXE3) all cases were concentrated in ABCA12- and TGM1-mutated patients. The frequencies observed for these two genes were statistically significantly different when each was compared to the frequency in all other genes combined (p = 0.011, and p = 0.016, respectively).
Fig. 2.
Fig. 2.
Ear deformities in ARCI patients. Three infants carrying mutations in TGM1 (a), ABCA12 (c) and ALOXE3 (d) genes, and an ALOX12B-mutated child (b) are shown. Note anterior overfolding in all cases.
Fig. 3.
Fig. 3.
Clinical appearance of lower limbs lesions in a 4-year-old child (a) and an adult patient (b), both carrying NIPAL4 mutations. The insets show details of patchy psoriasiform lesions in the child at 2 years of age and in the adult patient.
Fig. 4.
Fig. 4.
Clinical features of SDR9C7- and CERS3-mutated patients. The SDR9C7-mutated adult patient shows large thin adherent light-brown scales on the leg (a), and small whitish scales on the arms with elbow hyperkeratosis and follicular keratosis (b). The infant carrying CERS3 homozygous mutation presents generalized mild erythema with thin whitish scales (c, d).
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A.D., A.G.C., S.G., G.Z., and M.E.H. as well as T.S. and D.A. were supported, in part, by the “Progetto Ricerca Corrente” of the Italian Ministry of Health, Rome, Italy.