Smail Hadj-Rabia

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.

A Prevalent Mutation with Founder Effect in Xeroderma Pigmentosum Group C from North Africa

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder that is associated with an inherited defect of the nucleotide excision repair pathway (NER). In this study, we investigated the involvement of XP genes in 86 XP patients belonging to 66 unrelated families, most of them consanguineous and originating from Maghreb. Sequencing analysis was performed either directly (44 probands) or after having previously characterized the involved XP gene by complementation assay (22 families). XPC and XPA mutations were respectively present in 56/66 and 8/66 probands. Strikingly, we identified the same homozygous frameshift mutation c.1643_1644delTG (p.Val548AlafsX25) in 87% of XP-C patients. Haplotype analysis showed a common founder effect for this mutation in the Mediterranean region, with an estimated age of 50 generations or 1,250 years. Among 7/8 XP-A patients, we found the previously reported nonsense homozygous XPA mutation (p.Arg228X). Six mutations--to our knowledge previously unreported--(five in XPC, one in XPA) were also identified. In conclusion, XPC appears to be the major disease-causing gene concerning xeroderma pigmentosum in North Africa. As the (p.Val548AlafsX25) XPC mutation is responsible for a huge proportion of XP cases, our data imply an obvious simplification of XP molecular diagnosis, at least in North Africa.

Family burden in inherited ichthyosis: creation of a specific questionnaire

BackgroundThe concept of individual burden, associated with disease, has been introduced recently to determine the “disability” caused by the pathology in the broadest sense of the word (psychological, social, economic, physical). Inherited ichthyosis belong to a large heterogeneous group of Mendelian Disorders of Cornification. Skin symptoms have a major impact on patients’ Quality of Life but little is known about the burden of the disease on the families of patients.ObjectivesTo develop and validate a specific burden questionnaire for the families of patients affected by ichthyosis.MethodsTwo steps were required. First, the creation of the questionnaire which followed a strict methodological process involving a multidisciplinary team and families. Secondarily, the validation of the questionnaire, including the assessment of its reliability, external validity, reproducibility and sensitivity, was carried out on a population of patients affected by autosomal recessive congenital ichthyosis. A population of parents of patients affected by ichthyosis was enrolled to answer the new questionnaire in association with the Short Form Q12 questionnaire (SF-12) and a clinical severity score was filled for each patient.ResultsNinety four families were interviewed to construct the verbatim in order to create the questionnaire and a cognitive debriefing was realized. The concept of burden could be structured around five components: “economic”, “daily life”, “familial and personal relationship”, “work”, and “psychological impact”. As a result, “Family Burden Ichthyosis” (FBI) reproducible questionnaire of 25 items was created.Forty two questionnaires were analyzable for psychometric validation. Reliability (Cronbach’s alpha coefficientu2009=u20090.89), reflected the good homogeneity of the questionnaire. The correlation between mental dimensions of the SF-12 and the FBI questionnaire was statistically significant which confirmed the external validity. The mean FBI score was 71.7u2009±u200918.8 and a significant difference in the FBI score was shown between two groups of severity underlining a good sensitivity of the questionnaire.ConclusionsThe internal and external validity of the “FBI” questionnaire was confirmed and it is correlated to the severity of ichtyosis. Ichthyoses, and other chronic pathologies, are difficult to assess by clinical or Quality of Life aspects alone as their impact can be multidimensional. “FBI” takes them all into consideration in order to explain every angle of the handicap generated.

Unexpected extradermatological findings in 31 patients with xeroderma pigmentosum type C.

Backgroundu2002 Xeroderma pigmentosum type C (XP‐C) is a rare, autosomal, recessive condition characterized by the association of various clinical manifestations mostly involving the skin and eyes.

Clinical characteristics predicting internal neurofibromas in 357 children with neurofibromatosis-1: results from a cross-selectional study

ObjectiveTo identify clinical characteristics associated with internal neurofibromas in children with NF1, as a means of ensuring the early identification of patients at high risk for malignant peripheral nerve-sheath tumors developed from preexisting internal neurofibromas.Patients and methodsWe used data from two NF1 populations, in France and North America, respectively. The French database comprised 1083 patients meeting NIH diagnostic criteria for NF1 and the Neurofibromatosis Institute Database of North America comprised 703 patients. Patients younger than 17 years of age were eligible for our study if they had been evaluated for internal neurofibromas using computed tomography and/or magnetic resonance imaging. Clinical characteristics associated with internal neurofibromas by univariate analysis (Pu2009≤u20090.15) were entered into a multiple logistic regression model after checking for potential interactions and confounding. Multiple imputation was used for missing values.ResultsAmong the 746 children in the two databases, 357 (48%) met our inclusion criteria. Their mean age was 7.7u2009±u20095.0 years and there were 192 (53.8%) males. Internal neurofibromas were present in 35 (9.8%) patients. Internal neurofibromas developed earlier in females than in males and their prevalence increased during adolescence. Factors independently associated with internal neurofibromas were age (ORu2009=u20091.16 [1.07-1.27]), xanthogranulomas (ORu2009=u20095.85 [2.18-15.89]) and presence of both subcutaneous and plexiform neurofibromas (ORu2009=u20096.80 [1.52-30.44]).ConclusionsSeveral easily recognizable clinical characteristics indicate a high risk of internal neurofibromas in children with NF1 and, therefore, a need for very close monitoring.