Palmoplantar keratoderma caused by a missense variant in CTSB encoding cathepsin B.

BACKGROUND: Palmoplantar keratoderma (PPK) refers to a large group of disorders characterized by extensive genetic and phenotypic heterogeneity. PPK diagnosis therefore increasingly relies upon genetic analysis. AIM: To delineate the genetic defect underlying a case of diffuse erythematous PPK associated with peeling of the skin. METHODS: Whole exome and direct sequencing, real-time quantitative PCR, protein modelling and a cathepsin B enzymatic assay were used. RESULTS: The patient studied had severe diffuse erythematous PPK transgrediens. Pedigree analysis suggested an autosomal dominant mode of inheritance. Whole exome sequencing revealed a heterozygous missense mutation in the CTSB gene, encoding the cysteine protease cathepsin B. Genomic duplications in a noncoding region, which regulates the expression of CTSB, were recently found to cause erythrokeratolysis hiemalis, a rare autosomal dominant disorder of cornification. This mutation affects a highly conserved residue, and is predicted to be pathogenic. Protein modelling indicated that the mutation is likely to lead to increased endopeptidase cathepsin B activity. Accordingly, the CTSB variant was found to result in increased cathepsin B proteolytic activity. CONCLUSION: In summary, we report the identification of the first gain-of-function missense mutation in CTSB, which was found to be associated in one individual with a dominant form of diffuse PPK.

[Cutaneous leishmaniasis following military deployment to Iraq]. / Leishmaniose cutanée au cours du déploiement militaire en Irak.

Cutaneous leishmaniasis (CL) is a parasitic disease of the tropics and subtropics, transmitted by bites of infected female phlebotonine sandflies. Although CL lesions are normally self-healing they may be disfiguring or potentially disabling, and in field conditions may become secondarily infected; clinical intervention is appropriate in these circumstances. We describe two soldiers normally stationed in British Forces Germany who following deployment to Iraq presented with Leishmania tropica infection. The primary prevention of CL is discussed, together with the epidemiology of the disease, and its treatment under deployed conditions. Old World CL rarely requires aggressive antimonial terapy. Antiiosis with or without curettage is a simple, safe and effective field treatment.

Compound heterozygosity for mutations in the hairless gene causes atrichia with papular lesions.

BACKGROUND: Congenital atrichias represent a complex and heterogeneous group of genodermatoses, which have been shown in several consanguineous families to result from homozygous mutations in the hairless gene (HR). OBJECTIVES: To identify the molecular basis of congenital atrichia in a non-consanguineous family. METHODS: Genetic analysis was carried out in a two-generation family with two children with congenital atrichia and one healthy child. RESULTS: We established a diagnosis of atrichia with papular lesions based on clinical and histopathological data. We identified a heterozygous 11-bp deletion (189-199del) in the two affected children and their mother. In addition, the two affected children and their father were shown to carry a non sense mutation (Q478X), which has previously been described in a Pakistani family. Haplotype analysis revealed that mutation Q478X occurred independently in the two families. CONCLUSIONS: We have identified the first case of compound heterozygosity for mutations in HR as well as the first instance of a recurrent mutation in this gene. These data further expand our understanding of the molecular pathomechanisms underlying congenital atrichias.

An analysis of skin prick test reactions in asthmatics in a hot climate and desert environment.

BACKGROUND: Studies have shown that allergens are very important sensitizing agents in patients with asthma. Respiratory disorders such as asthma and allergic rhinitis are common in the United Arab Emirates, (UAE). OBJECTIVES: The aim of this study was to investigate the relationship between allergen specific IgE antibodies and skin test reactivity in patients with asthma in hot climate and desert Arabian country. DESIGN: A hospital-based prospective study conducted. SETTING: Tawam Teaching Hospital, Al-Ain, UAE. PATIENTS: 327 adult patients recruited with respiratory, dermatologic and ophthalmologic diseases of suspected allergic origin who attended Tawam Teaching Hospital of Faculty of Medicine, Al Ain, UAE, during three years from 1996 to 1998. METHODS: Skin Prick Test (SPT) and radioallegosorbent tests (RAST) were performed on 327 patients for common allergens. The blood sample was taken for measuring specific IgE concentration. RESULTS: There were 327 UAE patients of whom 117 (35.8%) were males and 210 (64.2%) were females. The population sample had a higher prevalence of diagnosed asthma among females (48.1%) than in males (36.7%). Skin prick testing showed that 244 patients (74.6%) had positive results, and 83 patients (25.4%) were found to be skin test negative. 44% had a positive family history of asthma. The twelve most common reactions in the United Arab Emirates were: Mesquite (45.5%), Grass Mix (40.7%). Cottonwood (33.1%), Bermuda Grass (31.3%), Kochi (25.8%), Acacia (25.6%), Alfalfa (22.9%), Chenopodium (19.6%), Date palm (13.8%), Cockroach (14.7%), house dust (11.9) and Dust mite (9.5%). Total IgE level (> 100 kU/l) was strongly associated with history of wheeze (p = 0.019), asthma (p = 0.01) and allergic rhinitis (p < 0.0001), atopy (p < 0.0001) and the presence of specific IgE antibodies to grass pollen (p < 0.0001), mite (p = 0.008) and cockroaches (p = 0.025). CONCLUSION: The present study revealed that hypersensitivity to pollens, house dust, dust mite and cockroach was common. The family history, environment, and airborne allergens are identified to be risk factors for asthma and other allergic diseases in Arabian Gulf Countries.

X-linked dyskeratosis congenita: restrictive pulmonary disease and a novel mutation.

Dyskeratosis congenita (DC) is a rare inherited multisystem disorder characterised by lesions of the skin and appendages. Bone marrow failure occurs in 80% of patients. The gene for the X-linked form of DC has been identified on Xq28 and designated as DKC1. Pulmonary manifestations have rarely been reported. It is not known whether there is a respiratory disease peculiar to these patients and, if so, whether it is associated with a specific genetic mutation. A 40 year old Egyptian man with pulmonary disease and his symptom free 35 year old brother both presented with mucocutaneous lesions characteristic of DC. In the older brother chest imaging revealed generalised intralobular interstitial thickening and honeycombing. Pulmonary function tests showed a restrictive pattern. Open lung biopsy specimens of lung tissue showed various degrees of fibrosis consistent with usual interstitial pneumonia of chronic idiopathic pulmonary fibrosis. The younger brother was free of pulmonary lesions. Both had a novel missense mutation 5C-->T in exon 1 of the DKC1 gene. It is concluded that pulmonary disease in DC may be underestimated, possibly because most patients die at an early age of bone marrow failure. No relationship between genotype and phenotype could be established in the patients studied. The genetic diagnosis of DC is now available, which may enable it to be diagnosed in patients with restrictive pulmonary disease and minimal cutaneous signs.

Association of acanthosis nigricans with risk of diabetes mellitus, and hormonal disturbances in arabian females: case-control study.

OBJECTIVE: To aim of the present study is to determine the association of acanthosis nigricans(AN) with risk of diabetes mellitus, and hormonal levels in female subjects from the United Arab Emirates (UAE). DESIGN: Matched case-control study. SETTING: Tawam Teaching Hospital of Faculty of Medicine and Health Sciences. SUBJECTS: 184 female subjects (92 females with AN and 92 females without AN); (age range 16-65 years) were recruited. METHODS: Height, weight, and sitting blood pressure were recorded on 184 female subjects with AN and without AN. Fasting blood samples were obtained for measurement of uric acid, glucose, cholesterol, HDL-cholesterol, and triglyceride levels. MAIN OUTCOME MEASURE: Risk factors were investigated. Analysis was based on univariate and multivariate analysis. RESULTS: The present study showed that BMI, family history of DM, fasting glucose, HDL-cholesterol (mmol/l), triglycerides (mmol/l) and uric acid (mmol/l) levels were statistically significantly higher in obese women in acanthosis and non acanthosis groups. The results revealed that BMI, family history of DM, total cholesterol (mmol/l), triglycerides (mmol/l) and uric acid (mmol/l) levels were statistically significant higher in diabetic women in non-acanthosis. Furthermore, systolic blood pressure, total cholesterol (mmol/l), triglycerides (mmol/l) and uric acid (mmol/l) levels were statistically significantly higher in diabetic women in acanthosis groups. Overall, DM subjects had significantly higher values for hormone levels of TSH, FSH, LH, progesterone, testosterone, cortisol, prolactin, GH, and ferritin. CONCLUSION: The conclusion has been stated as follows: patients in the UAE who have AN have a high prevalence of DM and insulin resistance. Since AN is rather prevalent in the UAE, identifying this skin lesion can help detect those subjects with a higher risk of DM and hormonal disturbances.

Congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis is an autosomal-recessive disorder resulting from defective neural crest differentiation with loss of the first-order afferent system, which is responsible for pain and temperature sensation. There is also a neuronal loss in the sympathetic ganglia. Lack of sweating, hyperthermia, and infections of bones are main features of the disorder; however, contradictory results have been published regarding eccrine sweat gland innervation. A 5-year-old male patient with typical clinical manifestations of congenital insensitivity to pain with anhidrosis is presented. Immunohistochemistry with antibodies against S100 protein and neuron-specific enolase failed to reveal nerve fibers in the vicinity of the eccrine sweat glands. The roles of the nerve growth factor and tyrosine kinase receptor gene mutations in the pathogenesis of the disease are also discussed.

Identification, by homozygosity mapping, of a novel locus for autosomal recessive congenital ichthyosis on chromosome 17p, and evidence for further genetic heterogeneity.

Autosomal recessive congenital ichthyosis (ARCI) comprises a group of severe disorders of keratinization, characterized by variable erythema and skin scaling. It is known for its high degree of genetic and clinical heterogeneity. Mutations in the gene for keratinocyte transglutaminase (TGM1) on chromosome 14q11 were shown in patients with ARCI, and a second locus was described, on chromosome 2q, in families from northern Africa. Three other loci for ARCI, on chromosomes 3p and 19p, were identified recently. We have embarked on a whole-genome scan for further loci for ARCI in four families from Germany, Turkey, and the United Arab Emirates. A novel ARCI locus was identified on chromosome 17p, between the markers at D17S938 and D17S1856, with a maximum LOD score of 3.38, at maximum recombination fraction 0.00, at D17S945, under heterogeneity. This locus is linked to the disease in the Turkish family and in the German family. Extensive genealogical studies revealed that the parents of the German patients with ARCI were eighth cousins. By homozygosity mapping, the localization of the gene could then be refined to the 8.4-cM interval between D17S938 and D17S1879. It could be shown, however, that ARCI in the two Arab families is linked neither to the new locus on chromosome 17p nor to one of the five loci known previously. Our findings give evidence of further genetic heterogeneity that is not linked to distinctive phenotypes.

Cutaneous nocardiosis of the chest wall and pleura--10-year consequences of a hand actinomycetoma.

We report an unusual case of primary cutaneous nocardiosis due to Nocardia otitidiscaviarum presenting first as a mycetoma of the right hand and wrist. The patient refused treatment and was lost to follow-up until he showed up 10 years later with numerous discharging large sinuses and abscesses on the upper right quadrant of the chest wall and in the right armpit. Roentgenograms revealed pleural masses. Histology was in keeping with the diagnosis of mycetoma. Treatment with amikacin, rifampicin and co-trimaxole proved to be successful.

MR and other imaging methods in the investigation of mycetomas.

PURPOSE: To report features of mycetomas (actino- and eumycetoma infection), which belong to the so-called rare bone infections, as evaluated by MR and other imaging methods and to assess chemotherapy treatment. MATERIAL AND METHODS: Twenty patients (average age 57 years) were diagnosed by different modalities. Analyses of 57 plain films, 31 three-phase bone scans, 28 CT and 35 MR examinations were performed. The MR protocol included T1-weighting without and with contrast, T2-weighted, proton density and fat suppressing sequences. RESULTS: Signs of chronic osteomyelitis were seen in plain films of 10 patients (50%), but the healing process was difficult to assess. Bone scintigraphy was positive in 12 patients (60%). In 14 patients (70%), CT could demonstrate bone lesions, but the healing process was difficult to estimate in 4 patients. MR imaging provided accurate diagnostic information in 15 cases (75%). In 16 patients (80%), small lesions could be identified due to grains, which seemed to differentiate mycetoma from other infections and tumorous lesions. MR examination gave definitive answer about the healing process in 18 cases (90%). CONCLUSION: MR investigation was superior to the other imaging techniques in the evaluation of mycetoma and the assessment of therapy.

Haplotypes of the human renin gene associated with essential hypertension and stroke.

The human renin gene (REN) is a good candidate in studies aimed at unravelling the genetic basis of essential hypertension and stroke. We previously established that both a BglI and an MboI dimorphisms (located respectively in the first and ninth introns of the REN gene) were associated with essential hypertension in a population of hyperlipidaemic US subjects. In this association (retrospective case-control) study, we investigated the haplotype distribution of alleles defined by the combination of REN BglI and MboI dimorphic sites in 329 hyperlipidaemic US Caucasian subjects referred to UCSF Medical Center (140 hypertensives, 141 normotensives, and 48 hypertensive patients who had suffered a stroke). A statistically significant association was found between alleles determined by both (BglI(-)/MboI(+)) and (BglI(+)/MboI(+)) haplotypes and clinical diagnosis of EHT (combined odds ratios, OR = 3.35, corrected P < 10(-7)). Haplotypes (-,+) and (+,+) were also found to be associated with clinical diagnosis of stroke (OR = 4.31, P < 10(-7)). These associations do not occur through the effects of classical risk factors related to lipid, lipoprotein and apolipoprotein levels. We conclude that variations of the REN (or of a nearby) gene that may be in linkage disequilibrium with REN (BglI(-)/MboI(+)) and (BglI(+)/MboI(+)) alleles could play a role in contributing to increased individual's genetic susceptibility to EHT and to stroke. Journal of Human Hypertension(2001) 15, 49-55

Etiology of toe-web disease in Al-Ain, United Arab Emirates: bacteriological and mycological studies.

We examined and sampled 45 patients with toe-web intertrigo for bacteriological and mycological studies. Prominent isolated pathogens were the genus Candida (57.7%), genus Aspergillus (28.8%), Pseudomonas aeruginosa (26.7%) and coliforms (24.4%). Dermatophytes scored 4.4% (Trichophyton rubrum). There were 43 patents (95.5%) who presented with marked hyperkeratosis and maceration of the toe-webs involved. The tradition of the Emirati population of sitting cross-legged may, over time, induce in the toe-webs of overweight individuals a macerated pressure-reaction hyperkeratosis that is colonized by environmental germs. T. rubrum and T. mentagrophytes are uncommon in the Al-Ain environment and this may explain the rarity of dermatophytes in toe-web intertrigo in our study.

Etiology of toe-web disease in Al-Ain, United Arab Emirates: bacteriological and mycological studies

We examined and sampled 45 patients with toe-web intertrigo for bacteriological and mycological studies. Prominent isolated pathogens were the genus Candida [57.7%], genus Aspergillus [28.8%], Pseudomonas aeruginosa [26.7%] and coliforms [24.4%]. Dermatophytes scored 4.4% [Trichophyton rubrum]. There were 43 patents [95.5%] who presented with marked hyperkeratosis and maceration of the toe-webs involved. The tradition of the Emirati population of sitting cross-legged may, over time, induce in the toe-webs of overweight individuals a macerated pressure-reaction hyperkeratosis that is colonized by environmental germs. T. rubrum and T. mentagrophytes are uncommon in the Al-Ain environment and this may explain the rarity of dermatophytes in toe-web intertrigo in our study

Association of Acanthosis nigricans with risk of diabetes mellitus and hormonal disturbances in females.

OBJECTIVE: To determine the association of Acanthosis nigricans, hyperinsulinemia, and hormonal levels in female subjects from the United Arab Emirates (UAE). DESIGN: Prospective study. SETTING: Tawam Teaching Hospital of Faculty of Medicine & Health Sciences. SUBJECTS: Ninety-two females (age range 16-65 years) were recruited. METHODS: Height, weight, and sitting blood pressure were recorded on 92 female subjects with A. nigricans. Fasting blood samples were obtained for measurement of uric acid, glucose, cholesterol, high-density lipoprotein- (HDL) cholesterol, and triglyceride levels. Serum levels of thyroid stimulating hormone (TSH), testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin are obtained by radio-immunoassay. RESULTS: Ninety-two females with A. nigricans were enrolled in the study. Of the 92 females, 36 subjects were considered to have diabetes mellitus (DM) and 56 euglycemic subjects. The analysis showed that in cases of family history of DM, HDL-cholesterol (mmol/l) and uric acid (mmol/l) levels were higher. Overall, DM subjects had significantly higher values for hormone levels of TSH, FSH, LH, progesterone, testosterone, cortisol, prolactin, (growth hormone) GH, and ferritin. CONCLUSION: Patients with A. nigricans have a high prevalence of DM and insulin resistance in UAE. Since A. nigricans is rather prevalent in the UAE, identifying this skin lesion can help detect those subjects with a higher risk of DM and hormonal disturbances.

Abnormal myelin formation in rhizomelic chondrodysplasia punctata type 2 (DHAPAT-deficiency).

The case of a Yemeni girl with isolated peroxisomal acyl-CoA:dihydroxyacetonephosphate acyltransferase (DHAPAT) deficiency is reported. She had rhizomelic chondrodysplasia punctata, microcephaly, failure to thrive, delayed motor and mental development, and spastic quadriplegia. Deficient de novo plasmalogen synthesis in her fibroblasts as a result of low DHAPAT activity was found, while her very-long-chain fatty acid profile, phytanic acid concentration, alkyl-dihydroxyacetonephosphate synthase (alkyl-DHAP synthase) activity, and peroxisomal 3-ketoacyl-CoA thiolase protein were normal. A mutation in her DHAPAT complementary DNA resulted in the substitution of an arginine residue in the protein at position 211 by a histidine (R211H). Magnetic resonance imaging showed abnormal white matter signal in the centrum semiovale involving the arcuate fibers, while the corpus callosum was normal. DHAPAT and alkyl-DHAP synthase initiate the synthesis of plasmalogens, which are major constituents of myelin phospholipids. The reported girl's abnormal formation of myelin is probably related to the inadequacy of plasmalogen biosynthesis, which is likely to be due to deficient DHAPAT activity.

Diffuse calcinosis cutis in a patient with congenital leukemia and leukemia cutis.

We report an unusual case of congenital leukemia with leukemia cutis (LC) and diffuse calcinosis cutis. A newborn girl presented with widespread dusky red and yellowish cutaneous nodules and papules. Bone marrow morphology was consistent with the diagnosis of acute monocytic leukemia of the FAB M5 type. Skin biopsy specimens confirmed the presence of a leukemic infiltrate and revealed calcium salt deposition in the papillary and reticular dermis. Calcinosis was diffuse in the whole skin but spared other organs. Vascular calcification was not present. Serum calcium levels oscillated between 2.5 and 2.86 mmol/l, and phosphorus, parathyroid hormone and 25-hydroxyvitamin D(3) levels were normal. There were diffuse osteoporosis and spontaneous fractures of small tubular bones. The patient responded to chemotherapy but, following consolidation treatment, developed sepsis and died at 120 days of age. Congenital leukemia is rare and LC is uncommon. Hypercalcemia may be a complication of leukemia, which leads to multiorgan metastatic calcification. Despite the absence of frank hypercalcemia, the presence of bone lesions suggests that the patient's calcinosis cutis was of the metastatic type. However, the cutaneous leukemic infiltrate may also represent a triggering factor for calcium deposition in the skin.