Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction. OBJECTIVES: To characterize patients with PC with symptomatic mucosal involvement. METHODS: We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction. CONCLUSIONS: It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.

Grover disease and bullous pemphigoid: a clinicopathological study of six cases.

Grover disease (GD) is an idiopathic dermatosis that typically manifests as itchy papules over the trunk in middle-aged men. Bullous pemphigoid (BP) is an autoimmune bullous disease that affects older people. Not only are the two diseases easily distinguishable on clinical grounds, they are also characterized by differences in histopathology, pathogenesis and response to treatment Thus, the co-occurrence of these two conditions in the same patient is usually considered coincidental. In this report, we present a multicentre retrospective analysis of six patients who developed both GD and BP over a short period of time, and in all cases but one, GD preceded BP. We discuss the clinical and histopathological features of these patients, and the suggested mechanisms of the diseases. We conclude that GD might predispose to the development of BP.

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.

Topical pimecrolimus for paediatric cutaneous mastocytosis.

BACKGROUND: Most cases of paediatric cutaneous mastocytosis (CM) occur before the age of 2 years, and regression occurs in only 67% of children. Given the absence of any specific therapy, CM is usually treated symptomatically. A few publications have reported the beneficial effect of calcineurin inhibitors for CM. AIM: We sought to evaluate the clinical effectiveness and safety profile of topical pimecrolimus cream for the treatment of CM. METHODS: We performed a retrospective study of all diagnosed cases of CM treated with topical pimecrolimus 1% cream between 2013 and 2015. All patients were evaluated in a paediatric dermatology unit of a tertiary medical centre. Epidemiological, clinical and treatment data, including effectiveness and safety, were reviewed. RESULTS: In total, 18 children (11 male, 7 female; age range 3-42 months) with CM were evaluated. Of the 146 treated lesions, 39 (26.7%) disappeared and 98 (67%) faded or developed postinflammatory hyperpigmentation. Of the 119 papular lesions, 24 (16.4%) showed partial flattening and 56 (47%) became macular. Darier sign became negative in 14 (82%) of 17 patients. No topical or systemic complications were observed. CONCLUSIONS: Topical therapy with pimecrolimus 1% cream should be considered in the treatment of CM.

B-FAHF-2 plus oral immunotherapy (OIT) is safer and more effective than OIT alone in a murine model of concurrent peanut/tree nut allergy.

BACKGROUND: Concurrent sensitization to peanut (PN) and tree nuts (TN), the most dangerous food allergies, is common. Current oral immunotherapy (OIT) is not fully satisfactory. OBJECTIVE: To determine whether the herbal formula B-FAHF-2 (BF2) ameliorates PN/TN OIT adverse reactions and enhances persistence of a tolerant state. METHODS: Concurrently sensitized PN-, walnut- (WN) and cashew (CSH)-allergic mice received 1-day PN/WN/CSH rush OIT plus 3 weeks of maintenance dosing, with or without 3 weeks prior and 3 weeks BF2 co-treatment. Anaphylactic symptom scores, core body temperatures, plasma histamine levels, basophil numbers, antigen-specific IgE, cytokine levels, and IL-4, INF-γ and Foxp3 gene promoter DNA methylation status, and their correlation with final challenge symptom scores were determined. RESULTS: BF2+OIT-treated mice experienced significantly fewer and less severe adverse reactions than OIT-only-treated mice (P<.01) during the 1-day rush OIT build-up dose phase. Both OIT-only and BF2+OIT mice showed significant desensitization (P<.01 and .001, respectively) at 1 week post-therapy challenge, being greater in BF2+OIT mice. All sham-treated and 91% of OIT-treated mice experienced anaphylaxis whereas only 21% of BF2+OIT-treated mice exhibited reactions during 5-6 weeks of dose escalation single PN and TN challenges. Greater and more persistent protection in BF2+OIT mice was associated with significantly lower plasma histamine and IgE levels, increased IFN-γ/IL-4 and IL-10/IL-4 ratios, DNA remethylation at the IL-4 promoter and demethylation at IFN-γ and Foxp3 promoters. Final challenge symptom scores were inversely correlated with IL-4 DNA methylation levels (P<.0002) and positively correlated with IFN-γ and Foxp3 gene promoter methylation levels (P<.0011) (P<.0165). CONCLUSIONS AND CLINICAL RELEVANCE: Combined BF2/OIT therapy was safer and produced longer post-treatment protection and more tolerance-prone immunological and epigenetic modifications than OIT alone. BF2/OIT may provide an additional OIT option for patients with concurrent PN/TN and other food allergies.

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.

Machine learning classification of OARSI-scored human articular cartilage using magnetic resonance imaging.

OBJECTIVE: The purpose of this study is to evaluate the ability of machine learning to discriminate between magnetic resonance images (MRI) of normal and pathological human articular cartilage obtained under standard clinical conditions. METHOD: An approach to MRI classification of cartilage degradation is proposed using pattern recognition and multivariable regression in which image features from MRIs of histologically scored human articular cartilage plugs were computed using weighted neighbor distance using compound hierarchy of algorithms representing morphology (WND-CHRM). The WND-CHRM method was first applied to several clinically available MRI scan types to perform binary classification of normal and osteoarthritic osteochondral plugs based on the Osteoarthritis Research Society International (OARSI) histological system. In addition, the image features computed from WND-CHRM were used to develop a multiple linear least-squares regression model for classification and prediction of an OARSI score for each cartilage plug. RESULTS: The binary classification of normal and osteoarthritic plugs yielded results of limited quality with accuracies between 36% and 70%. However, multiple linear least-squares regression successfully predicted OARSI scores and classified plugs with accuracies as high as 86%. The present results improve upon the previously-reported accuracy of classification using average MRI signal intensities and parameter values. CONCLUSION: MRI features detected by WND-CHRM reflect cartilage degradation status as assessed by OARSI histologic grading. WND-CHRM is therefore of potential use in the clinical detection and grading of osteoarthritis.

Best treatment practices for pachyonychia congenita.

BACKGROUND: Numerous therapeutic modalities have been proposed to treat the manifestations of pachyonychia congenita (PC). While research hopes lie with molecular therapies, patients are in need of answers regarding the efficacy of conventional treatments. AIM OF THE STUDY: To determine patients' experience and preferences regarding conventional treatments for PC. METHODS: The study population included 120 PC patients from 20 countries. The study was based on a patient survey developed by physicians and researchers from the International Pachyonychia Congenita Consortium and conducted via the internet. Using an effectiveness scale of 1 to 5, the patients were asked to grade treatments for different manifestations, including keratoderma, cysts, follicular hyperkeratosis, fingernail and toenail involvement. RESULTS: Patients reported surgical treatments being most effective for cysts and mechanical treatments the most effective conventional therapeutic approach for all other investigated manifestations. The other conventional medical treatments were found to be non-effective to only slightly effective. Among patients with keratoderma, older people were more likely to report beneficial effect from mechanical treatments (P = 0.04), topical retinoids (P = 0.04) and topical steroids (P = 0.02). Likewise, females were more inclined to report filing and grinding beneficial than males (P = 0.02). Finally, carriers of KRT16 and KRT6a were more likely to benefit from keratolytics than carriers of mutations in KRT17 (P = 0.04). CONCLUSIONS: None of the currently available therapeutic options for PC are ideal, although they provide some relief, with mechanical/surgical options being preferred over medical therapies. These results emphasize the need for more efficient and targeted therapies.

Utility of hospitalization following a first unprovoked seizure.

OBJECTIVES: Hospital admission in otherwise healthy patients following a first unprovoked seizure is controversial. We aimed to evaluate the influence of admission in a neurology department on the identification of risk factors for seizure recurrence in patients with a first unprovoked seizure. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients with a first unprovoked seizure, who were admitted to the neurology departments at two medical centers between 2007 and 2009. Risk factors for seizure recurrence included the following: abnormal neurological examination, abnormal brain CT scan, and epileptiform discharges on the EEG. RESULTS: The study group included 97 patients (52 men) aged 18-85 years (mean 42). Eighty-seven (90%) patients were admitted following a generalized tonic-clonic seizure. Risk factors were identified in the emergency room (ER) in 36 (37%) patients, mainly including abnormalities of the neurological examination and brain CT scan. Nineteen (20%) patients had a risk factor which was not apparent during ER evaluation, consisting of epileptiform activity on the EEG. Five (5%) patients had recurrent seizures during admission, three of them without risk factors during the ER evaluation. CONCLUSIONS: Risk factors for seizure recurrence were detected during admission in nearly a quarter of the patients who presented to the emergency room with a first unprovoked seizure. Because the main advantage of admission is the EEG recording, we suggest that an early EEG should be obtained in these patients either during admission or through a special accelerated outpatient arrangement.

Comparative study of high-resolution multifrequency ultrasound of the plantar skin in patients with various types of hereditary palmoplantar keratoderma.

BACKGROUND: High-variable-frequency ultrasound is used as an imaging tool for various cutaneous disorders. We utilized this tool in pachyonychia congenita (PC) patients, who typically present with plantar hyperkeratosis and often severely debilitating pain, compared to patients with epidermolytic palmoplantar keratoderma (EPPK) and mal de Meleda (MDM). OBJECTIVE: To ascertain the feasibility of ultrasound technology for the diagnosis of PC. METHODS: The study included a total of 16 patients, 7 with PC, 5 with EPPK and 4 with MDM, who underwent ultrasound examination of the plantar skin with high-resolution multifrequency ultrasound equipment. RESULTS: Ultrasound scans performed over the proximal and distal plantar foot calluses in PC patients demonstrated hyperechoic dots and lines within the epidermis compatible with hyperkeratosis, engorged varicose veins in the dermis and an anechoic layer interposed between the epidermis and the dermis, corresponding to blister fluid below the calluses. In contrast to PC patients, patients with MDM and EPPK demonstrated no blisters. CONCLUSION: PC patients, as opposed to a group of patients with MDM and EPPK, displayed subepidermal blistering beneath their calluses. This finding may help in the diagnosis of PC and in partially explaining plantar pain as part of PC symptomatology.

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.

Oesophageal involvement in bullous pemphigoid.

Bullous pemphigoid (BP) is an acquired autoimmune disease that predominantly affects older people. Mucosal involvement is rare in BP. We report an unusual case of an elderly patient with BP with involvement of the oesophagus presenting as gastrointestinal (GI) bleeding. Although mucosal involvement is typically rare in BP, it should be considered in the differential diagnosis of GI bleeding in patients affected with the disease.

Non-syndromic autosomal recessive congenital ichthyosis in the Israeli population.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is the term given to a complex and heterogeneous group of cornification disorders associated with mutations in at least eight distinct genes. Mutation distribution and prevalence rates are instrumental for the design of diagnostic strategies in ARCI but have not yet been systematically explored in the Israeli population. Previous data suggest that the demographic features specific to Middle Eastern populations, such as a high frequency of consanguineous marriages, may have an effect on the molecular epidemiology of genodermatoses. METHODS: We systematically assessed all families with ARCI presenting at our clinics over a period of 9 years, using a combination of homozygosity mapping, direct sequencing and PCR-restriction fragment length polymorphism assays. RESULTS: In total, 20 families with ARCI were assessed, and causative mutations were identified in 7 genes: TGM1 (30% of patients), ALOX12B (20%), ABCA12 (5%), CYP4F22 (10%), ALOXE3 (10%), LIPN (5%) and NIPAL4 (5%) Two families (10%) had mutations mapped to an ARCI-associated locus on 12p11.2-q13, while no mutation was found for one additional kindred. In the subgroup of families of Arab Muslim origin, mutations were identified most frequently in ALOX12B and TGM1 (31%), whereas the other subgroups displayed a subtype distribution very similar to that previously reported in western populations. CONCLUSIONS: The present data point to the need for population-tailored mutation screening strategies in genetically heterogeneous genodermatoses, based on the relative prevalence of the disease subsets.

[Revascularization? Only as the last resort!].

Revascularization has been suggested for treatment of necrotic immature permanent teeth. The desirable outcome of the treatment is continuous growth of the root, maturation of the dentin walls underneath the cervical seal and apical closure. Despite of increasing numbers of case reports, a uniform treatment protocol has not been set. This procedure has many shortcomings of which tooth discoloration is the most prevalent and easy to observe. The severe discoloration is attributed to the use of Mincocycline in the antibiotic dressing, or to the use of MTA for the seal. The maturation of the root is not predictable and does not always occur. The outcome should be evaluated radiographically and clinically. Sensibility testing may not be possible due to the large MTA plug in the root canal. It is recommended only when alternative procedures such as apexificaiton, pulpotomy or pulp capping are impossible. The patient and his parents should be aware of the potential discoloration and must be committed to routine follow ups. Currently, this procedure should be limited to incisor or premolar teeth in which the crown is longer than the root, or the canal's width is larger than that of the dentinal wall.

Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels.

Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containing FAs, CD36 and ceramide that are secreted basolaterally as small (80-100 nm) exosome-like extracellular vesicles (sEVs). We visualize in transwells EC transfer of FAs in sEVs to underlying myotubes. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulate circulating FAs in emGFP-labeled puncta. The FA-sEV pathway is mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduces muscle FA uptake, raises circulating FAs, which remain in blood vessels, and lowers glucose, mimicking prominent Cd36-/- mice phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells.

Beneficial effect of acitretin in Chanarin-Dorfman syndrome.

Chanarin-Dorfman syndrome (CDS) is an autosomal recessive metabolic disorder characterized by congenital ichthyosis and visceral complications due to accumulation of neutral lipids. CDS is caused by mutations in the ABHD5 (previously termed CGI-58) gene. In the present study, we assessed a young child presenting with ichthyosis and hepatomegaly, suggesting a diagnosis of CDS. We identified an intronic mutation, c.960 + 5G>A, which was found to result in skipping of exon 6. Abnormal results on liver function tests led us to treat the child with acitretin, which resulted in satisfactory clinical and laboratory responses. The present case illustrates the beneficial effect of acitretin treatment in CDS even in the presence of compromised liver function.

Successful hip arthroplasty in an adult male with severe factor XI deficiency using Hemoleven®, a factor XI concentrate.

Severe factor XI (sFXI) deficiency is a rare bleeding disorder (RBD). FXI replacement is most often required for surgical hemostasis. Plasma, the sole US treatment option, is often complicated by life-threatening allergic reactions. In such circumstances, the FDA offers a mechanism for institution-industry collaboration to facilitate limited use of replacement products licensed abroad. A 58 years old man with sFXI deficiency, required hip replacement. In the past, he received prophylactic plasma for thyroidectomy and experienced a severe allergic reaction. A single use institutional IND FDA application was initiated in collaboration with LFB (Les Ulis, France) to access Hemoleven®, a plasma-derived FXI concentrate. The application required an investigator-initiated IRB-approved protocol for treatment and safety/efficacy monitoring that included: preoperative thrombophilia, FXI inhibitor and pharmacokinetic (PK) evaluations; peri- postoperative administration of ≤ 4 doses of 10-15 U/kg Hemoleven® ; DIC monitoring; postoperative thromboprophylaxis; observation for product efficacy and potential complications. PK study demonstrated the expected 1.8% FXI recovery per U/kg with half-life of 62 hours. Mild D-Dimer elevation was noted 6-9 hours post-infusion. The initial dose (15 U/kg) was administered 15 hours before surgery; subsequently, 3 doses (10 U/kg) were infused every 72 hours. Hemostasis was excellent. No complications were observed. Collaboration allowed for successful patient access to Hemoleven® with excellent PK, safety, and efficacy. This case underscores the need for additional efforts to ensure safe and effective licensed replacement therapies for RBD patients.