Nested case-control study investigating the diagnostic role of tissue eosinophilia in adverse cutaneous drug reactions.

BACKGROUND: Although tissue eosinophilia has traditionally been considered diagnostically supportive of adverse cutaneous drug reactions (ACDRs), studies have suggested it is neither a sensitive nor a specific finding in drug eruptions (DEs). OBJECTIVES: Determining whether skin tissue eosinophilia is a reliable indicator of ACDR. METHODS: A nested case-control retrospective study conducted in a cohort of 170 patients at a single institution. Tissue eosinophilia (number of eosinophils per high-power field (HPF)) was investigated in skin biopsies obtained from the following groups of patients who demonstrated: (i) in vitro assay and telephone interview-validated cutaneous drug reactions (true DE); (ii) initial clinical diagnosis of ACDR but drug aetiology was excluded by in vitro assay and telephone interview (false DE); and (iii) non-drug-associated cutaneous eruptions, skin tumours and nevi, randomly selected for evaluation (control). RESULTS: Significantly higher number of eosinophils per HPF was observed in the false DE compared to the true DE group (P = 0.02). The false DE group demonstrated a higher number of eosinophils (P < 0.001) while the true DE group eosinophils' number was not significantly higher as compared to control (P = 0.2032). CONCLUSIONS: Tissue eosinophilia is not a reliable indicator of ACDRs.

A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN.

BACKGROUND: Dowling-Degos disease (DDD), featuring reticulate pigmentation, and familial hidradenitis suppurativa (HS) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN, encoding the γ-secretase subunit protein presenilin enhancer. OBJECTIVES: To investigate PSENEN mutations in a series of four unrelated patients who presented with combined DDD and HS. METHODS: Mutation and haplotype analysis of PSENEN by polymerase chain reaction, and cellular assays investigating the Notch signalling pathway. RESULTS: Here we report four families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Genes associated with DDD, as well as HS, have been shown to encode important regulators of Notch signalling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in a patient's keratinocytes. CONCLUSIONS: The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.

Paraneoplastic pityriasis rubra pilaris: case report and literature review.

Pityriasis rubra pilaris (PRP; MIM 173200) is an uncommon papulosquamous inflammatory dermatosis. Only a few cases of PRP associated with an underlying malignancy have been documented. We investigated a 59-year-old patient presenting with a fulminant form of PRP recalcitrant to systemic retinoid therapy, in whom the skin disease heralded a diagnosis of cholangiocarcinoma. We searched the MEDLINE database to find articles reporting on similar associations of PRP with malignancies. We identified 10 studies linking PRP and malignancies, but an association between PRP and cholangiocarcinoma has not yet been reported.

A novel homozygous deletion in EXPH5 causes a skin fragility phenotype.

Epidermolysis bullosa simplex (EBS) is the most common form of EB. Eight different genes have been implicated in the pathogenesis of different types of EBS, but a substantial portion of the cases cannot be attributed to mutations in known genes. Recently, recessive mutations in the gene EXPH5 (encoding exophilin-5, also known as Slac2-b) were identified in patients affected with a mild form of EBS. We used immunohistochemistry, Sanger sequencing and PCR-restriction fragment length polymorphism analysis to identify the cause of mild congenital skin fragility in a 3-year-old girl. No mutations were detected in KRT5 or KRT14, but we identified a novel homozygous deletion in EXPH5, which was found to cosegregate with the disease phenotype in the family. Our results further expand the spectrum of mutations in EXPH5. Appraisal of the present case against previously reported patients indicate that EXPH5 mutations result in a distinctive skin fragility phenotype, with minimal blistering compared with other forms of basal EBS.

Circulating Cell-free miRNA Expression and its Association with Clinicopathologic Features in Inflammatory and Non- Inflammatory Breast Cancer.

Recent discovery showing the presence of microRNAs (miRNAs) in the circulation sparked interest in their use as potential biomarkers. Our previous studies showed the diagnostic potential of miR-451 as a serological marker for inflammatory breast cancer (IBC), miR-337- 5p and miR-30b for non-inflammatory breast cancer (non-IBC). The aim of this study is to investigate the prognostic values of circulating miRNAs by comparing the amounts of 12 circulating miRNAs in the serum of IBC and non-IBC from Tunisian breast cancer patients, and by determinating whether correlated pairs of miRNAs could provide useful information in the diagnosis of IBC and non-IBC patients. TaqMan qPCR was performed to detect circulating expression of miRNAs in serum of 20 IBC, 20 non-IBC and 20 healthy controls. Nonparametric rank Spearman rho correlation coefficient was used to examine the prognostic value of miRNAs and to assess the correlation profile between miRNAs expression. Further, a large number of miRNAs were highly correlated (rho>0.5) in both patients groups and controls. Also, the correlations profiles were different between IBC, non-IBC and healthy controls indicating important changes in molecular pathways in cancer cells. Our results showed that miR-335 was significantly overexpressed in premenopausal non-IBC patients; miR-24 was significantly overexpressed in non-IBC postmenopausal patients. Patients with previous parity had higher serum of miR-342-5p levels than those without. Furthermore, patients with HER2+ IBC present lower serum levels of miR-15a than patients with HER2- disease. Together, these results underline the potential of miRNAs to function as diagnostic and prognostic markers for IBC and non-IBC, with links to the menopausal state, Her2 status and parity.

Isotretinoin treatment of autosomal recessive congenital ichthyosis complicated by coexisting dysferlinopathy.

Consanguinity is known to be associated with an increase in the prevalence of autosomal recessive disorders such as autosomal recessive congenital ichthyosis (ARCI). ARCI often responds well to retinoid treatment. We describe a patient with ARCI who improved under isotretinoin treatment. The patient subsequently developed elevated levels of serum creatinine phosphokinase (CPK), which led to the diagnosis of a second autosomal recessive disorder, dysferlinopathy, a rare myopathy characterized by muscle weakness, decreased tendon reflexes and marked elevation of CPK levels. This report demonstrates the need for physicians to remain alert to the possible coexistence of rare and mutually relevant disorders in populations with a high rate of consanguinity.

Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene.

BACKGROUND: Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare hereditary, autosomal dominant, auto-inflammatory disease caused by mutations in the PSTPIP1 gene, which encodes proline-serine-threonine phosphatase interacting protein 1. The fact that PSTPIP1 is involved in immune regulation provides a rationale for treatment of this rare disease with interleukin (IL)-1 signalling blocking agents. AIM: We investigated a 33-year-old man with a long-standing history of ulcerative colitis, severe acne and recurrent skin ulcerations, and a 3-year history of a recalcitrant pustular rash. METHODS: We used direct sequencing to search for mutations in the PSTPIP1 gene. RESULTS: Examination of biopsies obtained from pustules and skin ulcers revealed folliculitis and ulceration with a diffuse neutrophilic dermal infiltrate, consistent with a diagnosis of pyoderma gangrenosum. Because of the known association of acne and pyoderma gangrenosum in PAPA syndrome, we determined the entire coding sequence of the PSTPIP1 gene, and identified a hitherto unreported heterozygous mutation predicted to alter a highly conserved residue (p.G403R) and to be damaging to the protein function. Based on this finding, we initiated treatment with a human IL-1 receptor antagonist, anakinra, which led to a dramatic improvement in the patient's condition. CONCLUSIONS: We describe a novel mutation in PSTPIP1 resulting in pyoderma gangrenosum, acne and ulcerative colitis. This novel constellation of clinical manifestations, which we term 'PAC syndrome', suggests the need to regroup all PSTPIP1-associated phenotypes under one aetiological group.

The expanding spectrum of IgA pemphigus: a case report and review of the literature.

IgA pemphigus (IGAP) is a rare, distinct variant of pemphigus, currently classified, depending upon the histological features, immunofluorescence staining pattern and autoantibody profile, into two types: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis. In a patient with a widespread blistering disease of the skin resembling SPD-type IGAP, we demonstrate the coexistence of IgA reactivity to both epidermal (desmocollins 2 and 3) and basement membrane-associated (BP180) proteins, suggesting the coexistence of atypical IGAP and linear IgA bullous dermatosis, respectively. This case, together with 20 previous reports of atypical IGAP, underscores the limitations of current classification schemes. Therefore, we suggest reclassifying these cases under the general term 'IGAP spectrum'.

Reactive angioendotheliomatosis presenting as cellulitis.

Reactive angioendotheliomatosis (RAE) is a diagnostically challenging condition characterized by multiple possible clinical presentations, which makes diagnosis challenging. We present a rare case of RAE mimicking cellulitis in a 74-year-old woman with a valvular disease and also end-stage renal disease, for which she was being treated with haemodialysis.

Chronic granulomatous disease of childhood: an unusual cause of recurrent uncommon infections in a 61-year-old man.

Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency that affects 1 : 250,000 of the population, which is characterized by recurrent bacterial and fungal infections and by granuloma formation. We investigated a 61-year-old man presented with a 20-year history of a relapsing skin rash appearing as mildly pruritic and erythematous plaques affecting various body regions. Cutaneous biopsies were taken and sent for histology and tissue culture. Leucocyte function was assessed by determining the generation of reactive oxygen species. Bactericidal activity was assessed in the presence of autologous and homologous sera. Western blotting was performed for protein analysis of the reduced nicotinamide adenine dinucleotide phosphate oxidase system, and mutation screening was carried out using PCR amplification and sequence analysis. Examination of biopsies obtained from lesional skin indicated a suppurative granulomatous process. Tissue cultures grew Aspergillus nidulans and Aspergillus fumigatus (confirmed by PCR). A. nidulans has often been associated with CGD, and the leucocyte function tests supported this diagnosis. Direct DNA sequencing led to the identification of a hemizygous missense novel mutation in CYBB (c.907C>T), which predicts a p.His303Tyr amino-acid substitution in gp91-phox, thus confirming the diagnosis of CGD. In conclusion, we report a case of a rare inherited immunodeficiency, CGD, in a 61-year-old man, and describe the novel hemizygous missense mutation underlying the condition. Mild forms of usually fatal immunodeficiencies should be considered when assessing the occurrence of unusual infectious diseases in apparently healthy people.

CEDNIK syndrome results from loss-of-function mutations in SNAP29.

BACKGROUND: CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. OBJECTIVES: To delineate the molecular consequences of disease-causing mutations in SNAP29. METHODS: We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. RESULTS: We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. CONCLUSIONS: The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery.