Comprehensive Molecular Analysis of Disease-Related Genes as First-Tier Test for Early Diagnosis, Classification, and Management of Patients Affected by Nonsyndromic Ichthyosis.

Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes. The clinical picture and family history are crucial to formulating the diagnostic hypothesis, but only the identification of the genetic defect allows the correct classification. In the attempt to molecularly classify 17 unrelated Italian patients referred with congenital nonsyndromic ichthyosis, we performed massively parallel sequencing of over 50 ichthyosis-related genes. Genetic data of 300 Italian unaffected subjects were also analyzed to evaluate frequencies of putative disease-causing alleles in our population. For all patients, we identified the molecular cause of the disease. Eight patients were affected by autosomal recessive congenital ichthyosis associated with ALOX12B, NIPAL4, and TGM1 mutations. Three patients had biallelic loss-of-function variants in FLG, whereas 6/11 males were affected by X-linked ichthyosis. Among the 24 different disease-causing alleles we identified, 8 carried novel variants, including a synonymous TGM1 variant that resulted in a splicing defect. Moreover, we generated a priority list of the ichthyosis-related genes that showed a significant number of rare and novel variants in our population. In conclusion, our comprehensive molecular analysis resulted in an effective first-tier test for the early classification of ichthyosis patients. It also expands the genetic, mutational, and phenotypic spectra of inherited ichthyosis and provides new insight into the current understanding of etiologies and epidemiology of this group of rare disorders.

Multi-Gene Next-Generation Sequencing for Molecular Diagnosis of Autosomal Recessive Congenital Ichthyosis: A Genotype-Phenotype Study of Four Italian Patients.

Autosomal recessive congenital ichthyoses (ARCI) are rare genodermatosis disorders characterized by phenotypic and genetic heterogeneity. At least fourteen genes so far have been related to ARCI; however, despite genetic heterogeneity, phenotypes associated with mutation of different ARCI genes may overlap, thereby making difficult their clinical and molecular classification. In addition, molecular tests for diagnosis of such an extremely rare heterogeneous inherited disease are not easily available in clinical settings. In the attempt of identifying the genetic cause of the disease in four Italian patients with ARCI, we performed next-generation sequencing (NGS) analysis targeting 4811 genes that have been previously linked to human genetic diseases; we focused our analysis on the 13 known ARCI genes comprised in the panel. Nine different variants including three novel small nucleotide changes and two novel large deletions have been identified and validated in the ABCA12, ALOX12B, CYP4F22, and SULT2B1 genes. Notably, two patients had variants in more than one gene. The identification and validation of new pathogenic ABCA12, ALOX12B, CYP4F22, and SULT2B1 variants through multi-gene NGS in four cases of ARCI further highlight the importance of these genes in proper skin function and development.

Epidermolysis bullosa simplex with mottled pigmentation due to de novo P25L mutation in keratin 5 in an Italian patient.

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is an autosomal dominant inherited disorder of the skin, which manifests as recurrent blistering, punctate palmo-plantar hyperkeratoses, and mottled pigmentation of the trunk and extremities. Previous reports have identified the P25L mutation within the non-helical V1 domain of keratin 5 as the unique cause of the disease. We found this mutation in the first Italian case of EBS-MP. The proband was heterozygous for the P25L mutation, which occurred de novo as this change was not detected in the peripheral blood DNA of the healthy parents. Our report extends the limited number of EBS-MP cases and gives further evidence that mutation P25L is responsible for this unusual phenotype.

Tungiasis: Case Report of a Traveller to Kenya.

Tungiasis is a neglected parasitic skin disease caused by the permanent penetration of the female sand flea Tunga penetrans (also called jigger flea) into the skin of its host. Growing urbanisation, improved housing and the use of appropriate footwear have presumably led to an overall reduction of the occurrence of this ectoparasitosis within the last few decades. However, it is still highly prevalent in regions where people live in extreme poverty, such as in many Latin American and African countries [1, 2]. We report the case of a 44-year-old woman who returned from an excursion trip to Kenya's savannah with an infection of T. penetrans located on her right big toe around the nail. The natural history, pathology, epidemiology, diagnosis, therapy and control of this parasitic skin disease are discussed [1].

Cutaneous manifestations as presenting sign of autoimmune lymphoproliferative syndrome in childhood.

Autoimmune lymphoproliferative syndrome is a disorder due to a defect of lymphocyte apoptosis, whose clinical manifestations consist of hyperplasia of lymphoid tissues and autoimmune diseases. We report on a 26-month-old child who presented with frequent eruptions of weals and angioedema without any apparent triggering factor, who subsequently developed an erythematopapular rash with a histological pattern of a lymphoplasmacellular infiltrate. Familial anamnesis revealed a history of lymphoadenomegaly and massive spleen and liver enlargement in her sister. Functional and molecular analysis led to a diagnosis of type 1a autoimmune lymphoproliferative syndrome. Immunophenotyping of the cutaneous lesion revealed the presence of an inflammatory infiltrate with a considerably high number of Langerhans cells. Cutaneous features such as urticaria, angioedema and vasculitis in children with a personal and familial history of hyperplasia of lymphoid tissues may be a presenting sign of a systemic disease, such as autoimmune lymphoproliferative syndrome.