Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome.

Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.

Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia.

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.

Endocrine function in a 48,XXYY adult with type 2 diabetes: case report with a review of the literature.

We present the clinical, biological, endocrinal and psychological characteristics of a 48,XXYY adult. The 43-year-old male examined is the first reported case of this XY polysomy concomitant with type 2 diabetes. Endocrine investigations suggested dysfunction of Leydig and Sertoli cells whereas the pituitary function appeared normal. We compare the phenotypic, behavioral and pathological features of the syndrome in our patient with other reports in the literature.

Characterisation of supernumerary chromosomal markers: a study of 13 cases.

Marker chromosomes are defined as 'structurally abnormal chromosomes in which no part can be identified' (ISCN 1995). Supernumerary marker chromosomes (SMC) are 'additional markers' whose origin and composition cannot be determined by conventional cytogenetics. Molecular cytogenetic methods are necessary to identify these additional chromosomal markers. In one third, the SMCs are clinically well-defined in the literature, the remaining two thirds present a major problem for genetic counselling in prenatal diagnosis. At present, different molecular cytogenetic methods are used to determine the origin of SMCs. In this work, we studied 13 SMCs detected by RHG-banding, completed by C-banding and/or NOR-staining. 24-color FISH was used as the primary technique when the chromosomal origin was unknown. Targeted FISH procedures with specific probes (whole chromosome painting, centromeric probe, locus-specific identifier, BAC, etc.) were then performed to confirm and/or specify the chromosomal material present in the SMC. Seven SMCs were found to be associated with phenotypic abnormalities. Five derived from autosomes and two from gonosomes; these are: der(12)t(4;12), dic(15), i(18p), r(19), der(22)t(11;22), r(X), and der(Y). Two markers, r(8) and idic(15), were identified during investigations of infertile couples. Three cases seemed to be phenotypically normal. Four were discovered prenatally: r(2) and r(19) referred for elevated maternal serum markers, der(13/21) referred for advanced maternal age. The fourth SMC, der(14/22), was found during familial investigation following the identification of the same marker in an infertile son. The precise characterisation of the SMCs is of utmost importance for genetic counselling, especially in prenatal diagnosis.

Detection of an unexpected subtelomeric 15q26.2 --> qter deletion in a little girl: clinical and cytogenetic studies.

Unlike the small proximal 15q deletions causing Prader-Willi and/or Angelman syndrome, distal deletions of the terminal long arm of chromosome 15 have rarely been described. To the best of our knowledge, only four patients with a pure terminal 15q deletion have been documented in the literature. We report here on an unexpected abnormal hybridization pattern for the 15q specific subtelomeric control probe (clone 154P1) of the commercial SNRPN probe in a girl referred for suspicion of Angelman syndrome. Investigation by fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones defined a partial monosomy 15q26.2 --> 15qter for a minimal critical region of approximately 5.7 Mb, which is the most distal de novo 15qter deletion reported to date. All the de novo 15qter deletion cases, including ours, presented with pre- and post-natal growth retardation related to the loss of one copy of the IGF1R gene. Based on the comparaison with the previous published cases and owing to the clinical phenotype of our patient, we define a new subtelomeric 15qter syndrome which would be characterized by intrauterine growth retardation and global post-natal growth failure, variable mental retardation, facial anomalies including relative micrognathia and triangular facies and minor malformations of the extremities including proximally placed thumbs, cubitus valgus, and brachydactyly with tappering of the digits.

Identification by PCR of Fusarium culmorum strains producing large and small amounts of deoxynivalenol.

Thirty deoxynivalenol-producing F. culmorum strains, isolated from wheat grains, were incubated in vitro and analyzed for trichothecene production. Seventeen strains produced more than 1 ppm of deoxynivalenol and acetyldeoxynivalenol and were considered high-deoxynivalenol-producing strains, whereas 13 F. culmorum strains produced less than 0.07 ppm of trichothecenes and were considered low-deoxynivalenol-producing strains. For all strains, a 550-base portion of the trichodiene synthase gene (tri5) was amplified and sequenced. According to the tri5 data, the F. culmorum strains tested clustered into two groups that correlated with in vitro deoxynivalenol production. For three high-producing and three low-producing F. culmorum strains, the tri5-tri6 intergenic region was then sequenced, which confirmed the two separate clusters within the F. culmorum strains. According to the tri5-tri6 sequence data, specific PCR primers were designed to allow differentiation of high-producing from low-producing F. culmorum strains.

Toxigenic potential of Fusarium culmorum strains isolated from French wheat.

Sixty F. culmorum strains were isolated from wheat grains collected from different wheat-growing areas in France and from different cultivars. The isolates were grown on autoclaved wheat grain to assess their ability to produce trichothecenes and zearalenone. Fungal biomass was evaluated through the ergosterol grain content. All the isolates produced zearalenone (0.39-1660 mg kg(-1)). Thirty-five of the 60 F. culmorum produced nivalenol (0.11-11.7 mg kg(-1)), 12 of 60 produced fusarenone X (0.05-8.42 mg kg(-1)), five of 60 produced 15-acetyldeoxynivalenol (0.48-27.7 mg kg(-1)), 13 of 60 produced 3-acetyldeoxynivalenol (0.07-21.0 mg kg(-1) and 24 of 60 produced deoxynivalenol (0.92-51.9 mg kg(-1)). According to the results, the distribution of the different chemotypes as well as the high and the low mycotoxin-producing Fusarium strains could not be associated to geographical origin.