A previously unrecognized Ankyrin-1 mutation associated with Hereditary Spherocytosis in an Italian family.

Hereditary spherocytosis is the most common inherited hemolytic anemia characterized by the presence of spherical-shaped erythrocytes on peripheral blood smear. The clinical manifestations of HS are highly variable, from severe forms to asymptomatic forms. HS is caused by defects in red blood cell membrane proteins, encoded by the ANK1, EPB42, SLC4A1, SPTA1 and SPTB genes. Mutation of the ANK 1 gene is the most common and inheritance is autosomal dominant in 75% of cases. In our case, heterozygous an ANK1 c.4123C > T mutation was identified in a 4-year-old girl, using targeted next-generation sequencing and Sanger sequencing.

Epidermolysis Bullosa (EB) Acquisita in an Adult Patient with Previously Unrecognized Mild Dystrophic EB and Biallelic COL7A1 Mutations.

Circulating anti-type VII collagen autoantibodies are frequently detected in patients with recessive dystrophic epidermolysis bullosa (RDEB). However, evidence supporting their pathogenic role in inducing epidermolysis bullosa acquisita (EBA) has been provided for only one individual with dominant dystrophic epidermolysis bullosa (DDEB). We describe here a patient who presented with dystrophic toenails since early childhood and developed trauma-induced skin blisters and oral erosions at age 26 years. Direct immunofluorescence showed IgG deposits with a u-serrated pattern along the cutaneous basement membrane zone, while no change in the expression of collagen VII could be detected by antigen mapping. High-titre anti-collagen VII antibodies were detected by enzyme-linked immunoassay (ELISA). In parallel, sequencing of epidermolysis bullosa (EB) genes identified compound heterozygous COL7A1 missense c.410G>A (p.Arg137Gln) and splicing c.3674C>T (p.Ala1225_Gln1241del) mutations, previously unrecognized in dystrophic epidermolysis bullosa (DEB). Thus, our patient had RDEB "nails-only" and developed mechanobullous EBA in adulthood. These data support a pathogenic role of circulating autoantibodies to collagen VII in inducing EBA in selected patients with DEB. Unforeseen worsening of skin symptoms in DEB should prompt laboratory investigations for EBA.

Ichthyosis Linearis Circumflexa as the Only Clinical Manifestation of Netherton Syndrome.

Ichthyosis linearis circumflexa (ILC) presents as serpiginous and migratory erythematous patches with double-edged scales. ILC is rarely an isolated skin manifestation, but most commonly a part of Netherton syndrome (NS). NS is caused by SPINK5 mutations, which lead to absent or sometimes reduced expression of the serine protease inhibitor LEKTI. NS is characterised by congenital ichthyosiform erytroderma, trichorrhexis invaginata (TI) and atopy. We report 2 children who presented since the first months of life cheek erythema followed by the appearance of sparse ILC lesions on the face, trunk and proximal extremities. Erythroderma at birth, TI and atopy were absent. LEKTI immunoreactivity was reduced in patient epidermis, and serine protease activity was modestly increased, while desmoglein-1 expression remained unaffected. SPINK5 mutation and expression analysis in patient keratinocytes revealed compound heterozygous splicing variants, which allowed residual LEKTI secretion. Our results show that ILC can be the only clinical manifestation of NS.

Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune bullous disease, associated with autoantibodies directed against the hemidesmosomal components BP180 and BP230. In this study for the first time different laboratories have analyzed the autoantibody profile in the same group of 49 prospectively recruited BP patients. The results show that: 1) disease severity and activity correlated with levels of IgG against the BP180-NC16A domain, but also against a COOH-terminal epitope of BP180, 2) distinct epitopes of the BP180 ectodomain other than BP180-NC16A were recognized by 96% of the BP sera; and 3) the combined use of BP180 and BP230 ELISA led to the detection of IgG autoantibodies in all the BP sera. These results demonstrate the usefulness of the combined ELISAs based on various BP180 and BP230 fragments in establishing the diagnosis of BP and support the concept that BP180 is the major autoantigen of BP.

Dermatitis artefacta in a child.

The high visibility of dermatologic diseases and their easy accessibility make the skin a primary and direct target for dysfunctional behaviors. Self-harm tendencies can frequently be expressed through dermatologic lesions, and dermatitis artefacta falls within this clinical frame. The occurrence of this cutaneous manifestation in children is very rare, with a peak of greater frequency in adolescence. We describe the characteristics of a multidisciplinary intervention-dermatologic and psychologic. Our pediatric patient displays a dermatologic picture that has no etiologic confirmation. The source of this disorder must therefore be found in socio-relational difficulties within the family and school environments, which lead the patient to self-harm behaviors that have a high communication value.

Molecular basis of Kindler syndrome in Italy: novel and recurrent Alu/Alu recombination, splice site, nonsense, and frameshift mutations in the KIND1 gene.

Kindler syndrome (KS) is a rare autosomal recessive disorder characterized by skin blistering in childhood followed by photosensitivity and progressive poikiloderma. Most cases of KS result from mutations in the KIND1 gene encoding kindlin-1, a component of focal adhesions in keratinocytes. Here, we report novel and recurrent KIND1 gene mutations in nine unrelated Italian KS individuals. A novel genomic deletion of approximately 3.9 kb was identified in four patients originating from the same Italian region. This mutation deletes exons 10 and 11 from the KIND1 mRNA leading to a truncated kindlin-1. The deletion breakpoint was embedded in AluSx repeats, specifically in identical 30-bp sequences, suggesting Alu-mediated homologous recombination as the pathogenic mechanism. KIND1 haplotype analysis demonstrated that patients with this large deletion were ancestrally related. Five additional mutations were disclosed, two of which were novel. To date, four recurrent mutations have been identified in Italian patients accounting for approximately approximately 75% of KS alleles in this population. The abundance of repetitive elements in intronic regions of KIND1, together with the identification of a large deletion, suggests that genomic rearrangements could be responsible for a significant proportion of KS cases. This finding has implications for optimal KIND1 mutational screening in KS individuals.

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.

Identification of a novel splice site mutation in the human hairless gene underlying atrichia with papular lesions.

Atrichia with Papular Lesions (APL) is a rare autosomal recessive disorder characterized by complete hair loss that begins shortly after birth with the development of papular lesions on various regions of the body. Since the establishment of hairless (HR) gene mutations as the cause of this disorder, several patients previously assumed to suffer from alopecia universalis have been subsequently diagnosed with APL. In this study we have identified a novel splicing mutation, IVS8+2T-->G, in the hairless gene. This mutation most likely abolishes normal splicing of exon 8 and potentially leads to out-of-frame skipping of this exon and a downstream premature termination codon (PTC). Our findings contribute to the growing body of HR mutations implicated in APL and provide further evidence for the differentiation of APL from alopecia universalis.

Novel and recurrent ALDH3A2 mutations in Italian patients with Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS; MIM#270200) is an autosomal recessive neurocutaneous disease caused by mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that catalyzes the oxidation of medium- and long- chain aliphatic aldehydes fatty acids. We studied two unrelated Italian SLS patients with ichthyosis, developmental delay, spastic diplegia and brain white matter disease. One patient was homozygous for a novel ALDH3A2 insertion mutation (c.767insA) in exon 5. The other SLS patient was a compound heterozygote for two previously reported mutations: a slice site mutation (c.1094C > T; S365L) in exon 7. Analysis of fibroblast RNA by RT-PCR indicated that the spice-site mutation caused skipping of exons 2 and 3. The c.1094C > T mutation, previously associated with two ALDH3A2 haplotypes, was found on a third distinct haplotype in our patient, which indicates that arose independently in this kindred. These results add to understanding of the genetic basis of SLS and will be useful for DNA diagnosis of this disease.