Skin cancers in patients of skin phototype V or VI with xeroderma pigmentosum type C (XP-C): A retrospective study.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare genetic disease comprising 7 subgroups, A to G, all of which are associated with early onset of several forms of skin cancer. Our main objective was to determine the prevalence of skin cancers in a cohort of dark-skinned XP-C patients in Mayotte. PATIENTS AND METHODS: A single-centre cohort consisting of all XP patients was followed in the island of Mayotte from December 2015 to May 2017 by dermatologists from the University Hospital of Saint-Denis (Reunion) during the course of dermatological missions. RESULTS: Eighteen patients of median age 12.9 years (7 female/11 male) belonging to 14 families were included. All had XP-C and carried the same mutation. Median age at clinical diagnosis of XP was 1.8 years. A total of 144 skin cancers (94 squamous cell carcinomas [SCC], 30 basal cell carcinomas [BCC], 14 melanomas, 5 sarcomas and 1 sarcomatoid carcinoma) were observed in 11 of the 18 patients (61%). Eleven patients (61%) had at least 1 SCC, 6 (33%) had at least 1 BCC, 6 (33%) had at least 1 melanoma, and 4 (22%) had at least 1 sarcoma. In all, 95.5% of the cancers occurred in light-exposed skin areas. Median age was 5.4 years for the initial cancer and 6.4 years for the second. SCCs and sarcomas occurred earlier than CBCs and melanomas (P<0.0001). All patients had mild to severe poikiloderma and presented photophobia, and 50% had pigmented palmoplantar lesions. One-third had oral mucosal involvement while 78% had ocular or palpebral lesions. Nail and hair involvement was recorded in 17% of patients. The median sun protection score (evaluated on a 7-item scale) was 6/7. The median score on the quality-of-life questionnaire (DLQI) was 4/30. Severity of poikiloderma was significantly correlated with the occurrence of skin cancers. DISCUSSION AND CONCLUSION: Our cohort showed a high prevalence of skin cancer in XP-C patients of phototype V and VI exposed to UV radiation in a tropical region. SCCs were the most common tumours. The prevalence of melanoma was high, with major risk compared to controls of the same skin phototype. In addition, we found a high prevalence of sarcomas (5 patients). Initial cancers occurred early (5.4 years) compared to data from the literature, and SCCs and sarcomas occurred significantly sooner than melanomas and BCCs.

A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

[Charcot-Marie-Tooth disease associated with periaxin mutations (CMT4F): Clinical, electrophysiological and genetic analysis of 24 patients]. / Maladie de Charcot-Marie-Tooth associée au gène de la périaxine (CMT4F) : description clinique, électrophysiologique et génétique de 24 patients.

Autosomal recessive Charcot-Marie-Tooth disease (AR-CMT) is often characterized by onset in early childhood and severe phenotype compared to the dominant forms. CMT disease associated with periaxin gene (PRX) is rare and characterized by demyelination limited to the major peripheral nerves. Following the discovery of a high frequency of a specific periaxin gene mutation (E1085fsX4 homozygote) in the Reunion Island, we examined all French patients known as carriers of the periaxin gene mutation. There were 24 patients. Eighteen were from the Reunion Island (6 families and 10 sporadic cases). The six remaining patients were in two families, each with two affected individuals, and two sporadic cases. The series included 17 female and seven male patients. Walking was acquired late, on average at 3.4±1.6 years. One patient never learned to walk. The Charcot Marie Tooth Neuropathy Score (CMTNS) averaged 24.5±8.1. Seven patients had been wheelchair-bound since the age of 24±22. Other symptoms were: scoliosis most often observed after the age of 12 years and sometimes complicated by a restrictive respiratory syndrome; foot deformity in 24 patients; strabismus; glaucoma; myopia. When conduction recordings are available, median nerve motor conduction was slow (<10m/s), associated with a major lengthening of distal latencies. Study of the periaxin gene should be considered in patients with severe demyelinating neuropathy associated with early infantile scoliosis. This disease leads to major disability (29% of patients in this series were wheelchair-bound) and to respiratory insufficiency. Genetic counselling is highly recommended for consanguineous families.

SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype.

OBJECTIVE: Germline loss-of-function mutations in the SPRED1 gene have recently been identified in patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1 (neurofibromin 1) mutation found, suggesting a neurofibromatosis type 1-like syndrome. METHODS: 61 index cases with NF1 clinical diagnosis but no identifiable NF1 mutation were screened for SPRED1 mutation. RESULTS: We describe one known SPRED1 mutation (c.190C>T leading to p.Arg64Stop) and four novel mutations (c.637C>T leading to p.Gln213Stop, c.2T>C leading to p.Met1Thr, c.46C>T leading to p.Arg16Stop, and c.1048_1060del leading to p.Gly350fs) in five French families. Their NF1-like phenotype was characterised by a high prevalence of café-au-lait spots, freckling, learning disability, and an absence of neurofibromas and Lisch nodules in agreement with the original description. However, we did not observe Noonan-like dysmorphy. It is noteworthy that one patient with the p.Arg16Stop mutation developed a monoblastic acute leukaemia. CONCLUSIONS: In our series, SPRED1 mutations occurred with a prevalence of 0.5% in NF1 patients and in 5% of NF1 patients displaying an NF1-like phenotype. SPRED1 mutated patients did not display any specific dermatologic features that were not present in NF1 patients, except for the absence of neurofibromas that seem to be a specific clinical feature of NF1. The exact phenotypic spectrum and the putative complications of this NF1 overlapping syndrome, in particular haematological malignancies, remain to be further characterised. NIH diagnostic criteria for NF1 must be revised in view of this newly characterised Legius syndrome in order to establish a specific genetic counselling.

Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome.

Respiratory chain complex I deficiency represents a genetically heterogeneous group of diseases resulting from mutations in mitochondrial or nuclear genes. Mutations have been reported in 13 of the 14 subunits encoding the core of complex I (seven mitochondrial and six nuclear genes) and these result in Leigh or Leigh-like syndromes or cardiomyopathy. In this study, a combination of denaturing high performance liquid chromatography and sequence analysis was used to study the NDUFS3 gene in a series of complex I deficient patients. Mutations found in this gene (NADH dehydrogenase iron-sulphur protein 3), coding for the seventh and last subunit of complex I core, were shown to cause late onset Leigh syndrome, optic atrophy, and complex I deficiency. A biochemical diagnosis of complex I deficiency on cultured amniocytes from a later pregnancy was confirmed through the identification of disease causing NDUFS3 mutations in these cells. While mutations in the NDUFS3 gene thus result in Leigh syndrome, a dissimilar clinical phenotype is observed in mutations in the NDUFV2 and NDUFS2 genes, resulting in encephalomyopathy and cardiomyopathy. The reasons for these differences are uncertain.

[Oculocutaneous albinism in French overseas territories (Reunion, French Guyana, Martinique) and Mayotte. Study of 21 cases in 16 families]. / L'albinisme oculocutané dans les départements français d'Outre-Mer (Réunion, Guyane, Martinique) et à Mayotte: à propos de 21 observations dans 16 familles.

The dual purpose of this study was to determine the genotype of patients with oculocutaneous albinism type 1 and 2 based on analysis of tyrosinase and P gene mutations and to attempt to establish a correlation between phenotype and genotype. This study included a total of 21 Caucasian, Indian and Black African patients from La Reunion, la Martinique, French Guyana and Mayotte. PCR-sequencing of genomic DNA was performed to detect tyrosinase gene mutations and PCR-separation of PCR products by agarose gel electrophoresis was performed to detect 2.7kb deletion allele of the P gene. Tyrosinase gene mutations were identified in two cases, i.e., on eheterozygous guanine "g" deletion (c.572 delG) with a frameshift (Gly191fs) resulting in apremature termination signal at codon 225 in a Caucasian patient from La Reunion and one homozygous missense mutation, Glycine419Arginine, in an Indian patient from La Reunion. The 2.7-kb deletion allele of the P gene was detected in three Black African patients, i.e. two in the homozygous state in siblings from Mayotte and one in the heterozygous state in a girl from la Martinique. The latter patient whose mother was from la Martinique inherited the mutation from her father who was from Cameroon. This study shows that characterization of tyrosinase and P gene mutations in albinos patients is crucial to (a) differentiate subjects with oculocutaneous albinism types 1 and 2 and establish a correlation between phenotype and genotype, (b) identify healthy heterozygous carriers among the patient's immediate family (parents and siblings) and (c) allow prenatal diagnosis during subsequent pregnancies in couples who have already engendered albino children with severe visual phenotype and documented mutation(s).

An imidazopyridine anxiolytic alters glucose tolerance in patients: a pilot investigation.

We have recently shown that compounds with high affinity for peripheral-type benzodiazepine receptors inhibited glucose-induced insulin secretion in vitro. We therefore performed an oral glucose tolerance test in anxious inpatients treated with the imidazopyridine derivative alpidem, which has been shown to display high affinity for these binding sites. The test was performed before and after 1 week of daily administration of the drug. As compared with pretreatment values, a significant alteration of the insulin response to glucose was observed. It is suggested that daily administration of alpidem, at therapeutically effective doses for the treatment of anxiety, may alter glucose tolerance.

Progressive osseous heteroplasia. Report of a family.

We report a case of progressive osseous heteroplasia in a female infant who had progressive ossification of the skin and deep connective tissues. Isolated dermal ossification is present in her father and younger sister suggesting an autosomal dominant mode of inheritance with variable expressivity or possible somatic mosaicism. This report of a family with progressive osseous heteroplasia contributes to the understanding of this uncommon genetic disorder, which must be distinguished from fibrodysplasia ossificans progressiva and Albright's hereditary osteodystrophy. The paucity of familial cases of progressive osseous heteroplasia currently limits the use of a genome-wide linkage analysis, but linkage exclusion analysis with promising candidate genes is a possibility.

[Severe anorexia in infants in Reunion: a new autosomal recessive disease?]. / L'anorexie sévère du nourrisson réunionnais: une nouvelle affection autosomique récessive?

BACKGROUND: Infantile anorexia is usually considered as a psychogenic disorder with benign prognosis. However, unusually severe characteristics of infantile anorexia, seen in the south of the island, seem to us in favor of a new metabolic etiology. POPULATION AND METHODS: Among 38 known cases, we retrospectively studied the best documented observations of 24 children admitted over the last 25 years to our institution. RESULTS: The sex ratio was ten females and 14 males. Twenty-three of the 24 infants lived in formerly isolated localities of the island where other hereditary diseases have been observed with an unusually high frequency. The family pedigrees favoured an autosomal recessive heredity. Severe anorexia, accompanied by irrepressible vomiting (91%), appeared at the age of 8.5 months +/- 3.5. Parenteral (54.2%) or enteral (54.2%) feeding was necessary but did not always avoid death, which occurred in 45.8% of the cases at the age of 24 months +/- 3.5. All of the children which survived had neurological disorders (pyramidal syndrome, ataxia, laryngeal palsy, mental retardation, seizures) which occurred sometimes at an early stage. The investigations did not allow the identification of any known cause. DISCUSSION: The elevated level of lactic acid in the cerebral spinal fluid seemed to indicate a possible mitochondrial disorder, eventually a mutation of an autosomal gene of the pyruvate dehydrogenase complex because of the normal lactate/pyruvate ratio, but enzymatic activities were normal. The cerebral MRI showed features of leukodystrophy. On the other hand, the elevated level of plasma serotonin seemed to indicate a disorder of the serotonin metabolism, for which an animal model exists. CONCLUSION: We propose to name this new syndrome by the acronym 'RAVINE' which associates Reunion, Anorexia, Vomiting which is Irrepressible, and Neurological signs. Linkage study might allow the localization and isolation of a gene and allow one to start understanding the biological mechanism which we suspect to be an hereditary neurobiological eating disorder.

[Clinical aspects and genetic specificities of cystic fibrosis in Reunion Island]. / Aspects cliniques et spécificités génétiques de la mucoviscidose à l'île de la Réunion.

OBJECTIVES: Evaluation of the phenotype-genotype correlation of a specific mucoviscidosis mutation, "Y122X", in Reunion Island. This mutation represents 25% of our cases. PATIENTS AND METHODS: Retrospective study of a cohort of 84 children presenting cystic fibrosis (CF) during a 5-year period (1994-1998). Diagnosis was based on one or two identified genetic mutations and/or minimum two abnormal chloride sweat tests (Cl > 70 mmol/l). Follow-up of this cohort was performed in the two referral centers of the Island following the French national guidelines (INSERM U 155). RESULTS: In our population, we identified 10 mutations, of which three of them represented more than 80% of the cases: Delta F508 (51.8%), Y122X (24.4%) and 3120 + 1G --> A (4.8%). The authors report clinical significant differences in children with the homozygote mutation Y122X as compared with children presenting the Delta F508 CF-mutation: failure to thrive affecting mainly the height with, paradoxically, a relatively normal weight development, and a better pulmonary function. CONCLUSION: The frequent Y122X CF-mutation reported in "la Reunion" seems to affect mainly height in children with a relatively good nutritional outcome. This failure to thrive does not seem to be of digestive origin. These results suggest that growth gene(s) located nearby the cystic fibrosis transmembrane conductance regulator (CFTR) may have suffered the same segregation than the Y122X mutation or that clusters of this specific Caucasian population known as "petits blancs" in la Reunion are smallest for ethnic reasons.

[Antenatal discovery of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) at 12 weeks gestation]. / Découverte anténatale à 12 semaines d'aménorrhée d'un syndrome "intestinal hypoperistalsis mégacystis-microcolon" (MMIHS).

Megacystis on antenatal scan in female fetuses is rare and has diagnostic implications. We report a case of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) in a female infant. The antenatal scan revealed abnormalities, but the diagnosis was not established until after delivery. MMIH is a rare autosomal recessive condition which is usually lethal in the first year of life. Prenatal diagnosis is hampered by the lack of specific diagnostic ultrasound findings and the absence of an identified genetic locus.

[Subependymal pseudocysts in the fetal brain revealing Zellweger syndrome]. / Pseudo-kystes subépendymaires au sein du cerveau foetal: découverte d'un syndrome de Zellweger.

Prognosis of subependymal pseudocyst is poor when associated with other anomalies. They can be caused by infectious, vascular, chromosomal or metabolic disorders but are rarely described in the antenatal period. We report the prenatal diagnosis of subependymal pseudocyst by MRI after prenatal detection of isolated ventriculomegaly at 23 weeks gestation. The karyotype was normal. The diagnostic of Zellweger syndrome was suspected and was confirmed after birth by metabolic studies. Metabolic studies with culture of chorionic villus cell is indicated for subsequent pregnancies.

[About six observations of double discrepancy of the heart: feasibility of prenatal diagnosis?]. / À propos de six observations de double discordance cardiaque : faisabilité du diagnostic anténatal ?

The double discrepancy (DD) is an exceptional cardiopathy, manifested by atrioventricular and ventriculo-arterial discordances. DD is rarely diagnosed in the antenatal period and is often found in adults when cardiac complications occur. We describe six cases of DD, the different forms, their ultrasound semiology, and the assessment of prognosis, correlated with the existence of associated cardiac anomalies.

Antenatal presentation of isolated femoral hypoplasia discovered at 18 weeks of gestation.

Prenatal diagnosis performed by ultrasound scan is now a routine part of antenatal care in France. A case of congenital short femur in an otherwise healthy infant is described. Antenatal diagnosis was made at 18 weeks of gestation and ultrasonic follow-up was performed. The right femur was shorter than the left. Further sonographic exploration demonstrated unilateral femoral hypoplasia without another anomaly. In this case, the occurrence of congenital short femur was sporadic. The diagnosis was confirmed after delivery. Prenatal sonographic features, differential diagnosis, prognosis and management are discussed. This case illustrates the importance of ultrasound as an early detector of certain congenital anomalies and as a useful tool in their follow-up.

Maxillo-nasal dysplasia (binder syndrome): antenatal discovery and implications.

Binder syndrome (BS) or maxillo-nasal dysplasia is an uncommon developmental anomaly affecting primarily the anterior part of the maxilla and nasal complex. The characteristic findings are a failure of development in the premaxillary area with associated deformities of the nasal skeleton and the overlying soft tissues. Affected individuals typically have an unusually flat, underdeveloped midface (midfacial hypoplasia), with an abnormally short nose and flat nasal bridge, underdeveloped upper jaw, relatively protruding lower jaw and/or a 'reverse overbite' (or class III malocclusion). A case of BS was diagnosed at 24 weeks of gestation using two- and three-dimensional ultrasound. The first sign was an isolated flattened fetal nose in the mid-sagittal plane. Further ultrasound imaging showed the absence of the naso-frontal angle, giving impression of flat forehead and small fetal nose. We discuss about this entity.

Spectrum of CFTR mutations on Réunion Island: impact on neonatal screening.

The large heterogeneity in the cystic fibrosis (CF) gene is the main difficulty for genotype characterization. Numerous studies have reported considerable variations in frequencies of CF transmembrane conductance regulator (CFTR) mutations in different populations, such as African, Asian, or European populations. To completely characterize the spectrum of mutations in the CFTR gene in the Réunion Island population, we screened 228 CF chromosomes using denaturing high-pressure liquid chromatography and denaturing gradient gel electrophoresis following by direct sequencing. We identified 27 mutations, accounting for 93% of CF chromosomes. They included three novel mutations (M1T, 3121-3C-->G, and L1324P), which are described in this paper. The detection of such a high proportion of Réunion Island CFTR mutations is important for improving neonatal screening of CF on Réunion Island.

Simultaneous detection of the two prevalent mutations in the cystic fibrosis gene in Reunion Island.

A rapid method for the diagnosis of the most frequent cystic fibrosis mutations in the Reunion Island is described based on a coamplification polymerase chain reaction (PCR) followed by a single digestion using MseI. We have used this strategy to detect the two most frequent mutations in this area: delta F508 (in exon 10) and Y122X (in exon 4). These two mutations account for 70% of the CF chromosomes. This diagnosis method, which is rapid, easy, direct, and inexpensive, allows adult and neonatal carrier screening in this population.

A splicing mutation in intron 16 of the cystic fibrosis transmembrane conductance regulator gene, associated with severe disease, is common on Reunion Island.

In addition to the frequent delta F508 and Y122X mutations on cystic fibrosis (CF) chromosomes of patients from Reunion Island, one splicing mutation, 3120+1G-->A is observed relatively frequently (12.5%) in this group, in comparison with the French metropolitan population (<0.001 %). This mutation, disrupting the 5' splice donor site of intron 16, can be detected easily by restriction enzyme BstNI digestion. In 2 CF patients homozygous for this mutation, the clinical pattern was severe, with both pancreatic insufficiency and respiratory symptoms.