Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi.

BACKGROUND: Genotype-phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management. OBJECTIVES: To characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype-phenotype and genotype-outcome associations. METHODS: We conducted a large cohort study in which we undertook MC1R genotyping from blood, and high-sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%]. RESULTS: Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild-type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild-type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF-mutant multiple CMN, however, this genotype is rare. CONCLUSIONS: CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70-80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases. There has been debate about genotypic association with different sizes of CMN, and no data on genotype-outcome. What does this study add? NRAS mosaicism was found in 68%, BRAF in 7% and double wild-type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN, but was nearly universal in projected adult size > 60 cm. BRAF is often associated with a distinct multinodular clinical/histological phenotype. Adverse outcomes did not differ between genotypes on current numbers.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Clinical features and WNT10A mutations in seven unrelated cases of Schöpf-Schulz-Passarge syndrome.

BACKGROUND: Schöpf-Schulz-Passarge syndrome (SSPS) is an autosomal recessive form of ectodermal dysplasia resulting from mutations in WNT10A. OBJECTIVES: To document the spectrum of clinical features and search for pathogenic mutations in seven unrelated cases of SSPS. METHODS: Clinical examination of patients and Sanger sequencing of genomic DNA spanning the coding exons and flanking spice sites of WNT10A. RESULTS: Most subjects had bilateral eyelid cysts and some degree of palmoplantar keratoderma, although nail, hair, and teeth abnormalities were variably present. Bi-allelic pathogenic mutations in WNT10A were found in all seven subjects. New mutations comprised p.Glu390*, p.Ser270Arg, and p.Cys362Arg; the recurrent mutations were p.Cys107* and p.Ala131Thr. CONCLUSIONS: This study reveals the range of ectodermal pathology in cases of SSPS that result from WNT10A mutations. Eyelid cysts provide a useful clinical clue to diagnosing SSPS which may be less rare than is currently appreciated.

A cutaneous lymphoma international prognostic index (CLIPi) for mycosis fungoides and Sezary syndrome.

BACKGROUND: There is no prognostic index for primary cutaneous T-cell lymphomas such as mycosis fungoides (MF) and Sezary syndrome (SS). METHOD: Two prognostic indices were developed for early (IA-IIA) and late stage (IIB-IVB) disease based on multivariate data from 1502 patients. End-points included overall survival (OS) and progression free survival (PFS). External validation included 1221 patients. FINDINGS: Significant adverse prognostic factors at diagnosis consisted of male gender, age >60, plaques, folliculotropic disease and stage N1/Nx for early stage, and male gender, age >60, stages B1/B2, N2/3 and visceral involvement for late stage disease. Using these variables we constructed two separate models each defined using 3 distinct groups for early and late stage patients: 0-1 (low risk), 2 (intermediate risk), and 3-5 factors (high risk). 10 year OS in the early stage model was 90.3% (low), 76.2% (intermediate) and 48.9% (high) and for the late stage model 53.2% (low), 19.8% (intermediate) and 15.0% (high). For the validation set significant differences in OS and PFS in early stage patients (both p<0.001) were also noted. In late stage patients, only OS differed between the groups (p=0.002). INTERPRETATION: This proposed cutaneous lymphoma prognostic index provides a model for prediction of OS in early and late stage MF/SS enabling rational therapeutic choices and patient stratification in clinical trials.

MBTPS2 mutation in a British pedigree with keratosis follicularis spinulosa decalvans.

Keratosis follicularis spinulosa decalvans (KFSD; OMIM 308800) is an X-linked disorder characterized by widespread hyperkeratotic follicular papules (including keratosis pilaris-like lesions), facial erythema, hypotrichosis and scarring alopecia. KFSD results from mutations in the MBTPS2 gene. Mutations in this gene also underlie ichthyosis follicularis, alopecia and photophobia syndrome. We report a British pedigree with KFSD resulting from the mutation p.Asn508Ser. This particular mutation has been reported in three other pedigrees with KFSD (Dutch, American, British) and is the only pathogenic mutation reported in this disorder to date. However, the same mutation has also been reported in a Chinese pedigree with IFAP syndrome, highlighting the clinical heterogeneity and overlapping molecular pathology of these two disorders.

Eczema and cancer risk: a critical appraisal and review of the literature.

AIM: Hwang et al. aimed to evaluate the risk of malignancy among individuals with eczema, allergic rhinitis (AR) and asthma, compared with the general Taiwanese population. HYPOTHESIS: People with atopic conditions, including eczema, have an altered risk of malignancy. SETTING AND DESIGN: This was a prospective nationwide cohort study. The authors used the Taiwanese National Health Insurance Research Database (NHIRD) to compare the incidence of cancers among people with established allergic disease relative to the risk in the general population. STUDY EXPOSURE: Exposure was the presence of one or more atopic conditions (eczema, AR or asthma). Data were extracted on 997,729 randomly selected people registered on the NHIRD at any time point between 1996 and 2008. Eczema was identified via ICD-9-CM codes with the diagnosis being made by a dermatologist, paediatrician or allergist. Follow-up was until 2008, date of first cancer or death. OUTCOMES: The outcome was a new diagnosis of malignancy, identified via catastrophic illness insurance certificates, again using ICD-9-CM diagnostic codes. PRIMARY OUTCOME MEASURE: Standardized incidence ratios (SIRs) for cancers overall and different types of malignancy among patients with eczema, AR or asthma were calculated against the expected number of cancer cases in the general population, adjusted for age and sex. RESULTS: The number of patients identified with eczema, AR and asthma was 34,263, 225,315 and 107,601, respectively. Overall cancer rates in patients with these conditions were not significantly different from those in the general population [SIR eczema = 0·97 (95% confidence interval 0·87-1·09), SIR AR = 1·02 (0·98-1·05) and SIR asthma = 1·01 (0·97-1·04)]. However, when the results for eczema were stratified by age, people aged between 20 and 39 years appeared to have a 56% increase in risk in relation to 'any cancer' [SIR = 1·56 (1·13-2·09)]. Looking at individual cancer types in patients with eczema, only the risk of brain cancer was significantly raised [SIR = 2·52 (1·15-4·79)]. Patients who had had all three allergic conditions had a reduced SIR for 'cancers overall' [SIR = 0·59 (0·37-0·88)]. This inverse association was less strong for those with eczema and asthma [SIR = 0·73 (0·55-0·97)] or asthma and AR [SIR = 0·79 (0·73-0·84)] and statistically only of borderline significance for those with eczema and AR [SIR = 0·85 (0·67-1·07)]. CONCLUSIONS: Hwang et al. conclude that the relationship between allergic diseases and cancer risk is complex and site specific. The risk of malignancy was highest in all atopic conditions in the 20-39-year age group. In patients with eczema, the incidence of brain cancer was higher than expected, which the authors note is at odds with previous studies. However, numbers were too small to allow stratification by histological subtypes. The authors warn against deriving conclusions for rarer cancers and that borderline SIRs must be interpreted with caution.