Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family.

Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder for which subtyping through molecular analysis can help determine the eventual phenotype and prognosis. We used whole-exome sequencing to identify a new homozygous splice-site mutation in ST14 (IVS5+1G>A), encoding matriptase, in a 4-year-old girl with ARCI from a consanguineous Kuwaiti family. Clinically, she also had hypotrichosis, which supported a diagnosis of ARCI type 11. Only four previous examples of pathogenic mutations in ST14 have been reported, and our findings expand the genotype-phenotype correlation for this subtype of ARCI. Our patient was the second child born to these parents; the first (deceased) and third children had congenital brain and eye abnormalities, of uncertain aetiology and with no precise diagnosis. Further analysis of our patient's exome dataset revealed heterozygosity for a splice-site mutation in POMT1 (IVS4+1G>T), encoding the protein O-mannosyltransferase, a gene implicated in Walker-Warburg syndrome. DNA sequencing in the third child showed homozygosity for this mutation in POMT1. The first-cousin parents were both heterozygous for the splice-site mutations in ST14 and POMT1. In this family, whole-exome sequencing provided accurate subtyping of a form of ARCI in one child and provide an explanation for an undiagnosed developmental disorder in two other children, findings that improve the prospects for diagnostic accuracy and genetic counselling, and demonstrate the impact of next-generation sequencing technologies on clinical genetics.

Founder mutation in dystonin-e underlying autosomal recessive epidermolysis bullosa simplex in Kuwait.

Only two homozygous nonsense mutations in the epidermal isoform of the dystonin gene, DST-e, have been reported previously in autosomal recessive epidermolysis bullosa simplex (EBS); the affected pedigrees were Kuwaiti and Iranian. This subtype of EBS is therefore considered to be a rare clinicopathological entity. In this study, we identified four seemingly unrelated Kuwaiti families in which a total of seven individuals had predominantly acral trauma-induced blistering since infancy. All affected individuals were homozygous for the mutation p.Gln1124* in DST-e, the same mutation that was identified in the originally reported family from Kuwait. Haplotype analysis in the five pedigrees (including the previous case) revealed a shared block of ~60 kb of genomic DNA across the site of the mutation, consistent with a founder effect. Most heterozygotes had no clinical abnormalities although one subject had mild transient skin fragility during childhood, an observation noted in the previously reported Iranian pedigree, suggesting that the condition may also be semidominant in some pedigrees rather than purely autosomal recessive. Our study reveals propagation of a mutant ancestral allele in DST-e throughout Kuwait, indicating that this subtype of EBS may be more common in Kuwait, and perhaps other Middle Eastern countries, than is currently appreciated.

Impact of psoriasis on quality of life in Kuwait.

BACKGROUND: Psoriasis can seriously affect the quality of life (QOL) of patients and has a strong impact on social relations, psychological status and daily activities. OBJECTIVE: The aim of this study was to describe the impact of different grades of severity in psoriasis on QOL in patients in Kuwait. PATIENTS/METHODS: We used the Dermatology Quality Of Life scale (DQOLS) developed by Morgan and then validated for use in Kuwait to study a sample of 330 out-patients with psoriasis. RESULTS: Overall, physical activities were affected in greater than 50% of cases. This figure increased significantly with increased severity of psoriasis. Also, social relationships were disrupted in more than half of the patients but with no significant difference between different grades of severity. All psychological feeling items were affected by psoriasis to variable degrees. However, significant differences related to the severity of psoriasis were detected: feeling embarrassed, feeling short tempered, feeling depressed, and feeling a lack of hope. One third of cases declared their sexual activities were affected by psoriasis. CONCLUSION: Data provided should improve the physicians' awareness of the importance of patients' QOL and enhance psychological evaluation of the psoriatic patient which will promote his/her positive outcome and compliance with treatment.

The effect of whole-body sunbed ultraviolet A exposure on the pharmacokinetics of the photolabile drug nifedipine.

The calcium antagonist nifedipine absorbs ultraviolet A (UVA) radiation and readily photodegrades in vitro to a toxic nitroso-pyridine photoproduct. We examined whether whole body exposure of normal subjects to sunbed UVA radiation would affect the pharmacokinetics of nifedipine. Eight healthy, male, Caucasian volunteers (phototypes I-III) participated in this ethically approved, randomised, cross-over study. Each subject attended on 2 occasions, one week apart, and on each occasion was given a single oral dose (10 mg) of nifedipine following which blood samples were collected at 0, 0.5, 1. 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 7 h. During one of the visits, 15 min after nifedipine ingestion, a whole-body UVA (sunbed comprising Philips R-UVA lamps) dose of 70% of the individual's predetermined minimal phototoxic dose was delivered over a period of 17-36 min. Plasma nifedipine levels were measured using a standard reverse-phase high-performance liquid chromatography method. The area under the plasma concentration-time curve (AUC) of nifedipine during the UVA irradiation session (median 206 ng x ml(-1) x h(-1)) was significantly higher than during the non-irradiation control session (median 174.5 ng x ml(-1) x h(-1)) (P=0.03; 95% C.I. for difference in medians 9.9 to 55.9 ng x ml(-1) x h(-1)). UVA irradiation did not significantly affect any of the other measured pharmacokinetic parameters (Cmax, t 1/2, tmax). We demonstrate that sunbed UVA irradiation does not lead to in vivo photodegradation of nifedipine in healthy humans after a single dose. The apparent increase in AUC during UVA irradiation may be due to slightly slower metabolism of nifedipine in the presence of toxic photoproduct(s) or due to blood distribution changes affecting liver blood flow.

Erythema and melanogenesis action spectra in heavily pigmented individuals as compared to fair-skinned Caucasians.

The protective role of epidermal melanin pigmentation against chronic exposure to ultraviolet radiation is widely accepted, although its photoprotective effect against acute exposure is less certain. In this study, the action spectra of erythema and melanogenesis in heavily pigmented individuals (skin type V) were determined at 295, 305, 315, and 365 nm, and compared with those of skin types I and II. When the erythema and melanogenesis action spectra for skin type V were normalized to 295 nm, they were identical to the corresponding action spectra for fair-skinned individuals, indicating that the photoprotection of epidermal melanin pigmentation is essentially independent of wavelength. The ratio of values for the minimum erythema dose (MED) between skin type V and skin types I and II was 2.29, which is close to the ratio of pigment in these skin types, as measured by diffuse reflectance spectroscopy in the visible range. The minimum immediate pigment darkening dose (IPD) and the minimum melanogenic dose (MMD) at 365 nm, and the MED and MMD at 315 nm were the same for all skin types, while the variation of MED for every skin type was maximum at 305 and 365 nm. The results provide circumstantial evidence that erythema and melanogenesis have the same mechanism at short-wavelength UVB (295 and 305 nm), and different mechanisms in UVA (365 nm). Furthermore, the 24 h MED at 305 nm appears to be a sensitive indicator of skin type.

A comparison of the photosensitizing potential of trovafloxacin with that of other quinolones in healthy subjects.

Treatment with some quinolones is associated with an abnormal skin reaction following exposure to sunlight (photosensitivity). The objective of the current study was to compare the photosensitizing potential of a new quinolone, trovafloxacin, with that of ciprofloxacin, lomefloxacin and placebo. Forty-eight healthy males (age range 19-45 years) were randomized to receive a 7 day course of treatment with: (i) trovafloxacin 200 mg od; (ii) ciprofloxacin 500 mg bd; (iii) lomefloxacin 400 mg od; or (iv) placebo bd. Minimal erythema doses (MEDs) were assessed using a monochromator at baseline and on day 5 of treatment, for wavelengths of 305 +/- 5, 335 +/- 30, 365 +/- 30, 400 +/- 30 and 430 +/- 30 nm; 335 +/- 30 and 365 +/- 30 nm are within the UVA range. Immediate reaction MEDs were similar in all treatment groups. However, between baseline and day 5, the mean decreases in delayed-reaction MED (24 h) at 335 +/- 30 nm were only 18.99% for trovafloxacin versus placebo (P = 0.1267), compared with 53.77% (P 0.0001) and 64.13% (P 0.0001) for ciprofloxacin and lomefloxacin, respectively. Similarly, at 365 +/- 30 nm, trovafloxacin produced the smallest reduction in delayed MED versus placebo (43.66%), compared with ciprofloxacin (61.53%) and lomefloxacin (75.81%). These differences between trovafloxacin and ciprofloxacin and lomefloxacin were significant at both 335 +/- 30 and 365 +/- 30 nm (P 0.029). All MED values returned to baseline levels within 2 days of drug cessation. These results show that trovafloxacin has significantly less photosensitizing potential than either ciprofloxacin or lomefloxacin. This photosensitivity appears to be induced only by wavelengths in the UVA region, is maximal at 24 h and is a short-term effect.

Childhood lichen planus: a report of 23 cases.

Lichen planus (LP) in children is a rare entity. We report 23 cases of childhood LP seen over a period of 7 years. Ninety-six percent of the children were of Arab ancestry. There were 52% boys and 48% girls. Classic LP was the most common clinical variant (70%), followed by eruptive generalized LP (13%). A majority of the patients had mild, localized disease. Oral involvement was seen in 39% of patients. Topical steroids were the mainstay of treatment in most of the cases. Children with chronic and recurrent disease responded to dapsone therapy, whereas in those with eruptive and widespread disease, UVB phototherapy was found to be safe and effective. The present report highlights the salient clinical features, treatment, and course of LP in children in Kuwait compared to those reported in children of other countries as well as those of adults.