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Background Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous blistering skin disease, but in countries such as Kuwait, there are very limited data on the clinical and molecular pathology of EB. To improve understanding of EB in Kuwait, we report the experience of a local tertiary referral center over a 17.5 year period (January 2000-June 2017) in establishing clinical and molecular diagnoses. Methods Review of hospital records and diagnostic reports. Individual cases were diagnosed by combinations of clinical assessment, skin biopsy (immunohistochemistry and transmission electron microscopy), Sanger sequencing of EB genes, and whole exome sequencing. Results Fifty-four families with EB were registered with the clinic over this period, 41 of whom (84 patients) participated in diagnostic studies. Thirty-seven of these 41 families had consanguineous marriages; 34 had recessive forms of EB, while only seven had dominant subtypes. Recurrent mutations were observed in epidermal dystonin, transglutaminase 5, and type VII collagen. Conclusions The prevalence of EB in Kuwait is approximately three times that of internationally cited rates with an over-representation of autosomal recessive variants. Establishing the molecular basis of EB in Kuwait with accurate diagnostic subtyping provides a basis for determining healthcare requirements and improving patient management of EB.

Background/Objectives The manifestations of cutaneous lupus erythematosus (CLE) and their relevance to systemic disease are well characterized in adults, but data are limited in children. The objective of the current study was to examine the spectrum of CLE and its relationship to systemic disease in children from a tertiary care pediatric dermatology clinic. Materials and Methods An analysis of 26 children with CLE registered consecutively over 14 years was performed. Results Ninety-six percent of the patients were of Arab ethnicity. They included seven (27%) cases with neonatal lupus erythematosus (LE) (71% females and 29% males). Of the other 19 children with CLE, 95% were female. The mean and median age at diagnosis was 11 years. Eighty-nine percent of the patients fulfilled the criteria for systemic LE. All patients had LE-specific lesions and 83% had LE-nonspecific manifestations. Atypical initial presentations were recorded in 28% of the patients, and 22% of the patients had the rare LE variants. Of the LE-specific manifestations, acute CLE was seen in 83%, subacute in 44%, and chronic in 22%. Autoimmune associations were recorded in 44% and a positive family history of autoimmune diseases in 61%. Conclusion This study highlights a striking female predominance, higher risk of systemic disease in children presenting with CLE, higher prevalence of atypical presentation and rare CLE variants, and underrepresentation of discoid LE in children and signifies the need for more surveys to delineate the spectrum of pediatric CLE in different parts of the world.

Poikiloderma in neonates and infants often presents a diagnostic challenge, with the differential diagnosis including rare inherited disorders such as Rothmund-Thomson syndrome, Bloom syndrome, dyskeratosis congenita, Baller-Gerold syndrome, poikiloderma with neutropaenia, Weary syndrome and Kindler syndrome.1 Moreover, the differential diagnosis may also include subtypes of porphyria and xeroderma pigmentosum, as well as other rare metabolic, neoplastic, mitochondrial or premature ageing disorders, including Werner syndrome.

Summary 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.

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192T>C (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445T>A (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease.

Naevus sebaceus has recently been shown to result from post-zygotic mutations in HRAS, KRAS or occasionally NRAS. We present details of a neonate with extensive naevus sebaceus in whom we identified a pathogenic mutation in HRAS (c.37G > C; p.Gly13Arg), but only in lesional skin DNA, consistent with a mosaic RASopathy. This case highlights the clinicopathological and molecular findings of this naevoid disorder as well as the key issues in the clinical assessment and management of such patients.

Mycosis fungoides (MF) is a low-grade lymphoproliferative disorder that is histologically characterized by an epidermotropic proliferation of small or medium-sized atypical T lymphocytes with cerebriform nuclei and is primarily a disease of the elderly. It is rare in children and adolescents; in large series of MF published in the literature, only a small percentage of patients were observed to have onset of MF below adolescence. It was believed that a younger age of onset of MF may herald a poorer prognosis. Recently, with improved knowledge of the basic nature of the disease and refined diagnostic facilities, a few series of MF among children and adolescence have appeared and have drawn more awareness to the behavior of MF in this age group. This review summarizes the clinicoepidemiological features, treatment and prognosis of MF among children and adolescents based on the current literature.

Phacomatosis pigmentovascularis is a rare group of syndromes characterized by the co-existence of a vascular nevus and a pigmentary nevus with or without extracutaneous systemic involvement. The existing classifications of phacomatosis pigmentovascularis are based on phenotypic characteristics. We report four new cases of phacomatosis pigmentovascularis, three with phacomatosis cesioflammea demonstrating phenotypic variability, and one with phacomatosis cesiomarmorata. Extracutaneous manifestations were observed in three patients (75%) that included central nervous system involvement in three, bilateral congenital glaucoma in two, and cardiovascular system involvement in one. The molecular basis of phacomatosis pigmentovascularis is yet to be elucidated. Whether the various subtypes of phacomatosis pigmentovascularis are separate molecular entities or phenotypic variants of the same disease needs to be settled.

Incontinentia pigmenti (IP) is a rare multi-system X-linked dominant genetic disorder caused by mutations in IKBKG, encoding inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK- γ). Functionally, the encoded IKK- γ protein participates in nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signalling to regulate inflammatory and immune responses and prevent apoptosis. Loss-of-function mutations in IKBKG, as occurs in IP, leave mutant cells vulnerable to apoptosis when exposed to tumour necrosis factor alpha.

Background Mycosis fungoides (MF) is an indolent, most common type of cutaneous T-cell lymphoma (CTCL) with an average estimated incidence of 0.5 cases per 100,000 persons per year in the western world. Although various clinical and epidemiological features are well delineated in the western population, the data is scarce from our region. Objectives To study the clinicoepidemiological features of MF from Kuwait. Setting A referral photobiology unit for cutaneous lymphomas in a national dermatology department in collaboration with three other dermatology departments in Kuwait and Kuwait cancer center. Patients and methods One hundred and ninety-three cases of MF registered between July 1991 and June 2006 were included for this study. Results Eighty-six percent of our MF cases were of Arab ethnicity. Males outnumbered the females by 2:1 ratio. Mean age at diagnosis was 35.20 ± 14.37 years, and 16% of the patients were diagnosed by the age 20 years. The annual incidence rate (IR) of MF in Kuwait was observed to be 0.43 cases per 100,000 persons with a significantly higher IR among Arabs as compared to non-Arab Asians (RR = 4.4; 95% CI = 2.9–6.6). A successive rise in the IR of MF was noticed with the advancing age. The annual IR among males was more or less comparable to that of females. Skin patches were the most prevalent skin lesions (67%) at diagnosis, and 22% of the patients had a pure hypopigmented variant. Patients with hypopigmented MF were observed to have younger mean age at diagnosis (27.60 ± 12.42 years) as compared to other MF cases (38.14 ± 14.37 years) (P = 0.000). Ninety-two percent of the patients had the early stage (IA, IB, and IIA) of disease. Conclusions Our patients with MF were observed to have a relatively younger age at diagnosis, with a high proportion of patients diagnosed by the age 20 years. Arabs were observed to have a higher annual IR of MF as compared to non-Arab Asians. Hypopigmented MF is prevalent in our population. The study highlights the ethnic and/or regional variations in the clinicoepidemiological characteristics of MF.

Mycosis fungoides (MF) is rare in children and adolescents. This study was aimed to determine the clinicoepidemiologic features of juvenile onset (≤18 yrs) MF in Kuwait. Thirty-six children and adolescents (≤18 yrs) with MF registered in a referral photobiology unit for cutaneous lymphomas between July 1991 and June 2009 were included in this study. Children and adolescents were observed to constitute 16.6% of the total number of patients with MF, with 97% of patients of Arab ethnicity. The age-adjusted incidence rate of MF in children and adolescents among the total population was 0.29/100,000 persons/year. Among 36 Arab children and adolescents, boys outnumbered girls by 1.25:1. Mean and median age at onset of disease was 9 years, and age at diagnosis was 13 years. Patch stage disease was the most common clinical variant (75%) with 56% with pure hypopigmented MF-variant. The majority of patients (75%) had stage IB (TNM and B staging) disease. The study highlights a high prevalence and incidence of juvenile MF in Kuwait with a predominantly hypopigmented presentation.

Naevus sebaceus has recently been shown to result from post-zygotic mutations in HRAS, KRAS or occasionally NRAS. We present details of a neonate with extensive naevus sebaceus in whom we identified a pathogenic mutation in HRAS (c.37G C; p.Gly13Arg), but only in lesional skin DNA, consistent with a mosaic RASopathy. This case highlights the clinicopathological and molecular findings of this naevoid disorder as well as the key issues in the clinical assessment and management of such patients.

Summary 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.

The association of noninfectious cutaneous granulomas with primary immunodeficiency disorders (PIDs) is a rare but well-recognized phenomenon. With the recent advent of new classification and broadening of the list of PIDs, there is now ever-growing number of PIDs having being reported with noninfectious cutaneous granulomas or granulomatous tissue reactions. The authors observed 4 patients with cutaneous granulomas associated with PIDs that constitute 2% of total PIDs registered with them. In this report, the authors describe these 4 patients with cutaneous granulomas/granulomatous skin reactions associated one each with common variable immunodeficiency, Omenn syndrome, combined immunodeficiency, and Blau syndrome (BS), and briefly review the literature on various clinicopathological patterns of cutaneous granulomas with possible underlying pathogenetic mechanisms responsible for such tissue reactions in patients with PID.

Individuals with inherited skin diseases often pose one of the most difficult diagnostic challenges in dermatology. The hunt for the underlying molecular pathology may involve candidate gene screening or linkage analysis, which is usually determined by the initial history, the physical findings and laboratory tests. Recent technical advances in DNA sequencing, however, are shifting the diagnostic paradigm. Notably, next-generation sequencing allows a more comprehensive approach to diagnosing inherited diseases, with potential savings of both time and money. In the setting of a paediatric dermatology genetics clinic in Kuwait, we therefore performed whole-exome sequencing on seven individuals without a priori detailed knowledge of the patients' disorders: from these sequencing data, we diagnosed X-linked hypohidrotic ectodermal dysplasia (two cases), acrodermatitis enteropathica, recessive erythropoietic protoporphyria (two siblings) and localized recessive dystrophic epidermolysis bullosa (two siblings). All these groups of disorders are clinically and genetically heterogeneous, but the sequencing data proved inherently useful in improving patient care and avoiding unnecessary investigations. Our observations highlight the value of whole-exome sequencing, in combination with robust bioinformatics analysis, in determining the precise molecular pathology and clinical diagnosis in patients with genetic skin disorders, notably at an early stage in the clinical evaluation of these often complex disorders and thereby support a new paradigm for future diagnostics.

Mycosis fungoides (MF) is an indolent, most common type of cutaneous T-cell lymphoma (CTCL) with an average estimated incidence of 0.5 cases per 100,000 persons per year in the western world. Although various clinical and epidemiological features are well delineated in the western population, the data is scarce from our region.To study the clinicoepidemiological features of MF from Kuwait.A referral photobiology unit for cutaneous lymphomas in a national dermatology department in collaboration with three other dermatology departments in Kuwait and Kuwait cancer center.One hundred and ninety-three cases of MF registered between July 1991 and June 2006 were included for this study.Eighty-six percent of our MF cases were of Arab ethnicity. Males outnumbered the females by 2:1 ratio. Mean age at diagnosis was 35.20 ± 14.37 years, and 16% of the patients were diagnosed by the age 20 years. The annual incidence rate (IR) of MF in Kuwait was observed to be 0.43 cases per 100,000 persons with a significantly higher IR among Arabs as compared to non-Arab Asians (RR = 4.4; 95% CI = 2.9-6.6). A successive rise in the IR of MF was noticed with the advancing age. The annual IR among males was more or less comparable to that of females. Skin patches were the most prevalent skin lesions (67%) at diagnosis, and 22% of the patients had a pure hypopigmented variant. Patients with hypopigmented MF were observed to have younger mean age at diagnosis (27.60 ± 12.42 years) as compared to other MF cases (38.14 ± 14.37 years) (P = 0.000). Ninety-two percent of the patients had the early stage (IA, IB, and IIA) of disease.Our patients with MF were observed to have a relatively younger age at diagnosis, with a high proportion of patients diagnosed by the age 20 years. Arabs were observed to have a higher annual IR of MF as compared to non-Arab Asians. Hypopigmented MF is prevalent in our population. The study highlights the ethnic and/or regional variations in the clinicoepidemiological characteristics of MF.

Mycosis fungoides (MF) is rare in children and adolescents. This study was aimed to determine the clinicoepidemiologic features of juvenile onset (≤18 yrs) MF in Kuwait. Thirty-six children and adolescents (≤18 yrs) with MF registered in a referral photobiology unit for cutaneous lymphomas between July 1991 and June 2009 were included in this study. Children and adolescents were observed to constitute 16.6% of the total number of patients with MF, with 97% of patients of Arab ethnicity. The age-adjusted incidence rate of MF in children and adolescents among the total population was 0.29/100,000 persons/year. Among 36 Arab children and adolescents, boys outnumbered girls by 1.25:1. Mean and median age at onset of disease was 9 years, and age at diagnosis was 13 years. Patch stage disease was the most common clinical variant (75%) with 56% with pure hypopigmented MF-variant. The majority of patients (75%) had stage IB (TNM and B staging) disease. The study highlights a high prevalence and incidence of juvenile MF in Kuwait with a predominantly hypopigmented presentation.

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.