Liran Horev

Monilethrix: a keratin hHb6 mutation is co‐dominant with variable expression

Monilethrix is a rare autosomal dominant disease characterized by hair fragility and hyperkeratotic papules. Mutations in type‐II hair specific keratins hHb6 and hHb1 have recently been reported. We describe a large family with a E410D mutation in the evolutionary conserved helix termination motif of keratin hHb6 that was variably expressed among 12 heterozygous members, and severely expressed among 3 homozygous members. These 3 patients had essentially complete lack of scalp hair since the age of 2 months with no improvement over time as well as follicular keratotic involvement extensively expressed over the scalp and large body areas. The variability seen in heterozygous patients, along with seasonal and pregnancy‐related improvement suggest that other genetic or environmental factors may modify keratin gene expression. This represents the first report of a co‐dominant keratin hHb6 mutation resulting in severe disease.

A novel splice-site mutation in ECM-1 gene in a consanguineous family with lipoid proteinosis

Abstract:  Lipoid proteinosis (LP) (OMIM 247100) is a rare, autosomal recessive disorder. Recent studies have shown that LP is the result of reduced expression of the extracellular matrix protein gene (ECM‐1), in which loss‐of‐function mutations have been described. In the present report, we describe a large consanguineous family with LP. We identified a homozygous splice‐site mutation in intron 1 (IVS1 + 1G→C) in three clinically affected patients. This is the first splice‐site mutation reported in LP and is the most 5′ of all ECM‐1 mutations described thus far. It is predicted to result in the removal of the translation initiation site, thus ablating all three known ECM‐1 isoforms (ECM‐1a, ECM‐1b, and ECM‐1c). In addition, we found a novel splicing variant that is not associated with the disease (DQ010946) and results in the generation of a short, prematurely terminating transcript. This case further emphasizes the role of ECM‐1 in LP and highlights the unresolved genotype–phenotype correlation in this disease.

Mutations in lipase H cause autosomal recessive hypotrichosis simplex with woolly hair

BACKGROUND Mutations in lipase H (LIPH) are a rare cause of autosomal recessive hypotrichosis (HT) simplex. OBJECTIVE In this study, we investigated the clinical and molecular basis of HT simplex with woolly hair in 3 nonrelated families. METHODS Three families of Jewish, Arab Muslim, and Italian origin that presented with HT with woolly hair were studied. The phenotype was confirmed by clinical, microscopic, and histologic examination. Polymorphic microsatellite genotyping and direct automated DNA sequencing of the LIPH gene were used to identify the mutations in our probands. RESULTS All patients had woolly hair since birth. At presentation, scalp hair density was reduced or normal. Sequencing of the LIPH gene revealed two homozygous mutations: a large recurrent 90-base pair duplication mutation in exon 2 in the Jewish and Arab families, and a novel deletion/insertion mutation in exon 4 in the Italian family. LIMITATIONS Only 3 families were studied. CONCLUSION Mutations in LIPH result in variable degrees of HT. Woolly hair is an essential component of the clinical spectrum. A hot spot in the LIPH gene may be c.280_369dup in exon 2.

Marie Unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript

Please cite this paper as: Marie Unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript. Experimental Dermatology 2010; 19: e320–e322.

A novel deletion mutation in P2RY5/LPA6 gene cause autosomal recessive woolly hair with hypotrichosis

only once a day for 1 month because of pain after application and cutaneous improvement was moderate. After another month of treatment and a twice daily application regimen, the acne disappeared. She continued treatment for 5 months and then stopped, inducing a relapse of acne and pain. It is interesting that this acne occurred solely within an area of neuropathic pain, disappeared after capsaicin treatment and recurred when capsaicin was withdrawn. We speculate that nerve injury induced neurogenic inflammation through the release of substance P. Substance P is a neuropeptide that plays a role in vomiting, stress, respiratory frequency and pain. Neuropathic pain is associated with the release of substance P at the peripheral terminals of sensory nerve fibres. Substance P has an important role in neurogenic inflammation. It is possible that cutaneous neurogenic factors could contribute to the onset and ⁄ or exacerbation of acne. It has been shown by immunohistochemistry that there is an increase in the number of substance P-immunoreactive nerve fibres in close proximity to sebaceous glands in the skin of acne patients relative to healthy subjects. In support, supplementation of substance P to organ-cultured skin induced the development of cytoplasmic organelles in sebaceous cells, stimulated sebaceous stem cells and induced significant increases in size of sebaceous glands and the number of sebum vacuoles for each differentiated sebaceous cell. These findings suggest that substance P may stimulate lipogenesis of the sebaceous glands, which may be followed by proliferation of Propionibacterium-related acne. Hence, the neuropathy of our patient clearly appeared to be responsible for her acne. Capsaicin is used in topical preparations to treat localized itching and pain. First applications may induce burning sensations, but continued application abolishes the itching and pain. Capsaicin binds to the transient receptor potential vanilloid type 1 (TRPV1), which is expressed in peripheral primary afferent neurons (and also in dorsal root ganglia in the brain). This activation leads to cellular degranulation by neuropeptides such as substance P. Repeated application of capsaicin inhibits release of substance P, which explains the analgesic effect. In our case report, we propose that the inhibition of substance P release induced by capsaicin plays a role in the disappearance of acne. The importance of this observation is twofold: it underscores the role of neurogenic inflammation in acne development and suggests possible the effectiveness of capsaicin treatment for such conditions. Moreover, recent data suggest that capsaicin may also control acne by directly affecting TRPV1 expression by sebocytes.

IL36RN mutation causing generalized pustular psoriasis in a Palestinian patient

Deficiency of interleukin‐36 (IL‐36) receptor antagonist (DITRA; OMIM 614204) is a rare autoinflammatory disorder characterized by periodic fever associated with a generalized erythematous and pustular skin rash. A 6‐year‐old Arab‐Palestinian boy presented with a history of periodic fever and unremitting, erythematous, scaly skin rash accompanied by widespread pustules that had been present since the age of one month. The patients skin lesions were compatible with generalized pustular psoriasis. Sequence analysis revealed a homozygous nonsense mutation, c.28C>T (p.Arg10X) in the IL36RN gene. The patient improved with oral methotrexate in combination with oral and topical corticosteroids. The molecular basis for DITRA has only recently been identified, and the mutation spectrum for this disorder in many populations is still obscure. This paper reports the presence of the c.28C>T mutation in an Arab‐Palestinian patient and thus represents the first description of this mutation in a non‐Japanese subject.

A novel XPD mutation in a compound heterozygote; the mutation in the second allele is present in three homozygous patients with mild sun sensitivity.

The XPD protein plays a pivotal role in basal transcription and in nucleotide excision repair (NER) as one of the ten known components of the transcription factor TFIIH. Mutations in XPD can result in the DNA repair‐deficient diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD), cerebro‐oculo‐facial‐skeletal syndrome, and in combined phenotypes such as XP/Cockayne syndrome and XP/TTD. We describe here an 18‐year‐old individual with mild sun sensitivity, no neurological abnormalities and no tumors, who carries a p.R683Q mutation in one allele, and the novel p.R616Q mutation in the other allele of the XPD gene. We also describe four patients from one family, homozygous for the identical p.R683Q mutation in XPD, who exhibit mild skin pigmentation and loss of tendon reflexes. Three homozygous patients presented with late‐onset skin tumors, and two with features of premature aging and moderate cognitive decline. Cells from the compound heterozygous individual and from one of the patients homozygous for p.R683Q exhibited similar responses to UV irradiation: reduced viability and defective overall removal of UV‐induced cyclobutane pyrimidine dimers, implying deficient global genomic NER. Cells from the compound heterozygous subject also failed to recover RNA synthesis after UV, indicating defective transcription‐coupled NER. Mutations affecting codon 616 in XPD generally result in functionally null proteins; we hypothesize that the phenotype of the heterozygous patient results solely from expression of the p.R683Q allele. This study illustrates the importance of detailed follow up with sun sensitive individuals, to ensure appropriate prophylaxis and to understand the mechanistic basis of the implicated hereditary disease. Environ. Mol. Mutagen., 2012.

Oculoectodermal syndrome with coarctation of the aorta and moyamoya disease: expanding the phenotype to include vascular anomalies.

Oculoectodermal syndrome (OES, OMIM 600268) is characterized by discrete areas of alopecia of the scalp and epibulbar dermoids which are present from birth, with additional variable anomalies. We describe two patients, one of whom has been reported [Lees et al. (2000); Am J Med Genet 91:391–395], who both had coarctation of the descending aorta and moyamoya disease, and developed epilepsy, recurrent transient ischemic attacks, and cerebrovascular accidents during early childhood. We suspect that the vascular findings are an integral part of the syndrome.

AISI 316L Stainless-Steel Ear Piercing Post Assembly Does Not Cause Dermatitis in Nickel-Sensitive Subjects

Twenty-three female and 2 male subjects, documented to be sensitive to nickel by history and diagnostic patch testing, were pierced with American Iron Steel Institute (AISI) 316L stainless-steel ear piercing post assemblies (The Ear Piercing Manufacturers of Europe, UK), AISI 316L having a specification that includes a nickel content of between 10 and 14%. After piercing, the subjects were examined on days 7, 14, 30 and 42. Seven of the ear piercing post assemblies collected at random from the subjects at the end of the study and 10 unused post assemblies selected at random were analysed for nickel content and release. None of the nickel-sensitive patients showed signs of nickel dermatitis during the study. The nickel content of the ear piercing post assemblies collected from patients was reported as being between 11.5 and 12.9%, and the calculated rate of nickel release was below the detection limit of the method, thus recorded at <0.05 µg/cm2/week. By comparison, the nickel content of the unused post assemblies was reported to be between 9.93 and 10.5%, and the calculated rate of nickel release was between 0.11 and 0.21 (mean: 0.15) µg/cm2/week. These results suggest that the AISI 316L stainless-steel ear piercing post assemblies do not elicit adverse reactions to nickel in previously sensitized subjects.

Metformin-Induced Leukocytoclastic Vasculitis

To the Editor: Leukocytoclastic vasculitis (LCV) is often caused by exposure to drugs. There are a large number of medications that have been reported to be associatedwith LCV; however, development of LCV after exposure to metformin has only been sparsely reported. We present a case of LCV due to metformin administration. Since this drug is being used extensively in the treatment of diabetes mellitus, it is essential to also report its rare adverse effects. A 60-year-old woman was admitted to the HadassahHebrewUniversityMedical Center dermatology department in December 2009, exhibiting week-old hemorrhagic papules, vesicles, and bullae, bilaterally spread on her shins, thighs, and buttocks. No systemic complaints such as fever, arthralgia, abdominal pain, hematochezia, hemoptysis, or hematuria were reported. The patient’s past medical history included hyperlipidemia and diabetes. A month prior to her admission the patient was started on metformin hydrochloride 850mg, which she did not take on a daily basis due to low compliance. Despite meticulous questioning, the patient denied the use of any other drug, prior infectious symptoms, or any change in her life or food habits. Physical examination revealed a mildly obese woman in good condition. A general medical check-up was unremarkable. On both her legs and buttocks there were numerous erythematous papules, petechiae, hemorrhagic vesicles and bullae, and erosions of different sizes and crusts (figure 1). Laboratory tests showed a white blood cell count of 13 400/mm, increased C-reactive protein of 6.8mg/mL (normal <0.5mg/mL), and an erythrocyte sedimentation rate of 78mm/hour. The patient had normal liver and kidney function tests. Serum complement (C) 3, anti-streptolysin O antibody, cytoplasmic anti-neutrophilic cytoplasmic antibodies, perinuclear anti-neutrophilic cytoplasmic antibodies, hepatitis B surface antigen, hepatitis C virus antibody, throat swab, blood and urine cultures, and fecal occult blood were all negative or within normal limits. Antinuclear antibody was very weakly positive (1/4). Chest x-ray, abdominal ultrasound, and bilateral Doppler ultrasound of the legs did not reveal any pathology. Histopathologic examination of involved skin showed an intraand subepidermal blister, filled with polymorphonuclear cells and erythrocytes. In addition, small dermal blood vessels were occupied by fibrin thrombi (fibrinoid necrosis) accompanied by a neutrophilic infiltrate. A cellular infiltrate, composed mainly of neutrophils, was present around the dermal blood vessels and within the vascular walls. Extravasation of erythrocytes was also seen (figure 2). These findings were diagnosed as bullous LCV. Direct immunofluorescence was negative for IgG, IgA, IgM, and serum C3. Since no other identifiable cause other than the drug was recognized, metformin was withdrawn immediately and the patient was treated with topical corticosteroids and topical antibacterials, and oral prednisone 0.5mg/kg/day, which was tapered rapidly. The patient experienced no new lesions