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Didier Lacombe

Publications and source records attributed to Didier Lacombe.

At least 37 records · Page 2Linked to original sources
PubMed2004

Self-healing congenital verruciform hyperkeratosis.

We report on an apparently previously undescribed neonatal diffuse congenital hyperkeratosis with spontaneous improvement. The child, born to consanguinous parents, presented at birth with a verrucous hyperkeratosis involving face, trunk, and limbs, but sparing palms and soles. No visceral or skeletal abnormality was associated and neurosensory status was normal. The skin condition improved dramatically during the first month of life. At age 7 years, the child was healthy with normal psychomotor development and growth. He had an abnormal curvature of nose, ulerythema ophryogenes, and large ears. The skin was moderately dry. This favorable clinical outcome led us to propose the term "regressive congenital hyperkeratosis" until further molecular characterization of this new phenotype.

Adult↗
PubMed2004

Axenfeld-Rieger anomaly: a novel mutation in the forkhead box C1 (FOXC1) gene in a 4-generation family.

OBJECTIVE: To characterize DNA mutations in a pedigree of Axenfeld-Rieger anomaly (ARA) (Online Mendelian Inheritance of Man 601631), a clinically and genetically heterogeneous, autosomal dominantly inherited disorder associated with anterior chamber abnormalities and glaucoma. DESIGN: Observational case-control and DNA linkage and screening studies. PARTICIPANTS: Affected (10 cases) and unaffected (5 controls) members of a family with ARA. METHODS: Clinical characteristics of ARA were documented by history or physical examination of symptomatic individuals. With their informed consent, a blood sample was collected from each of 10 affected and 5 unaffected family members. DNA was tested for linkage to the IRID1 locus at chromosome 6p25, a known locus for ARA/Rieger syndrome. A candidate gene previously mapped at this locus, FOXC1, was screened for mutations in cases and controls. Main Outcome Measure Linkage of the ARA phenotype at the 6p25 locus and mutation detected in FOXC1. RESULTS: Direct sequencing of FOXC1 detected a new mutation, T272C, that segregated with the ARA phenotype in this family and was not detected in DNA from family members without ARA. This mutation, a T-->C transition, is predicted to result in a change of isoleucine to threonine (Ile9lThr) in a highly conserved location within the first helix of the forkhead domain. CONCLUSION: Characterization of the FOXC1 mutation in family members with ARA furthers our understanding of the molecular origin of developmental glaucoma and other anterior segment disorders.

Adult↗
PubMed2004

Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR.

Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome characterized by facial abnormalities, broad thumbs, broad big toes, and growth and mental retardation as the main clinical features. RTS was shown to be associated with disruption of the CREB-binding protein gene CBP (CREBBP), either by gross chromosomal rearrangements or by point mutations. Translocations and inversions involving chromosome band 16p13.3 form the minority of CBP mutations, whereas microdeletions occur more frequently (about 10%). Most deletion studies in RTS are performed by FISH analysis, and five cosmids must be used to cover the whole of the CBP gene, which spreads over 150 kb. Here we report the design of gene dosage assays by real-time quantitative PCR that are targeted on three exons located respectively at the 5' end (exon 2), in the middle (exon 12), and at the 3' end (exon 30) of the CBP gene. This technique proved to be efficient and powerful in finding deletions and complementary to the other available techniques, since it allowed us to identify deletions at the 3' end of the gene that had been missed by FISH analysis, and to refine some deletion breakpoints. Our results therefore suggest that real-time quantitative PCR is a useful technique to be included in the deletion search in RTS patients.

CREB-Binding Protein↗
PubMed2004

Molecular characterization of an 11q14.3 microdeletion associated with leukodystrophy.

Leukodystrophies represent a heterogeneous group of rare hereditary diseases affecting the central nervous system. The underlying molecular defect remains unknown in almost 50% of cases. We previously assigned a new locus for leukodystrophy of unknown cause to chromosome 11q14.3 by identifying a de novo microdeletion in a sporadic case. We now report the precise molecular characterization of this microdeletion. Physical mapping of the region of interest allowed us to identify and analyze candidate gene(s) possibly implicated in leukodystrophy.

Cathepsin C↗
PubMed2004

Glycerol kinase deficiency: residual activity explained by reduced transcription and enzyme conformation.

Four unrelated patients with glyceroluria ranging from 7 to 170 mmol/l were studied. The activity of glycerol kinase (GK) in cultured fibroblasts was determined with a specific enzyme assay and with two indirect methods, that is, incorporation into macromolecules of [(14)C] from [(14)C]glycerol and its oxidation to [(14)C]CO(2). Exon amplification and RT-PCR were used to identify mutations. In patient 1, with low activity in all three assays, we identified a c.1194A>C (E398D) missense mutation. In patient 2 with a considerable activity of the GK enzyme (22% of reference), oxidation to [(14)C]CO(2) (37%) and a high incorporation of [(14)C] into macromolecules (92%), we identified a c.182T>C (L61P) mutation that causes the enzyme to have a higher K(m) for glycerol ( approximately 300 microM) than normals (2-8 microM). In patient 3, the GK activity estimated by the three different methods ranged from 16 to 22% of reference. Analysis of mRNA from the GK gene revealed three alternatively spliced transcripts. A mutation in intron 3 (g.16835G>A) resulted in an insertion of a cryptic exon between exon 2 or 3 and exon 4. Patient 4 with minor glyceroluria (7 mmol/l) and normal plasma glycerol concentration had normal activity with all three assay methods, thus excluding GK deficiency (GKD) as a cause of slight glyceroluria. To evaluate fully patients with glyceroluria, one needs to measure the GK activity and relate this and the clinical data to genetic findings. Residual enzyme activities in cultured fibroblasts can be found in GKD patients with severe clinical symptoms.

Alternative Splicing↗
PubMed2004

Oculo-ectodermal syndrome: a new tumour predisposition syndrome.

We report a new case of oculo-ectodermal syndrome who developed giant cell granulomas of the jaw, similar to the patient previously described by Toriello et al. (1999). We review reported cases to better delineate the clinical spectrum of this rare condition. Giant cell granulomas developing in childhood seem to be part of the oculo-ectodermal syndrome. This condition appears to be a new tumour predisposition syndrome.

Alopecia↗
PubMed2003

Costello syndrome and neurological abnormalities.

Costello syndrome is a rare but increasingly recognized syndrome of unknown etiology. Neurological abnormalities are not rare in this syndrome and consist of structural and electrophysiological disorders. Ventricular dilatation is observed in more than 40% of cases. Other reported cerebral anomalies are brain atrophy, Chiari malformation and syringomyelia. Although there is insufficient data to propose strict guidelines, it seams reasonnable to have a low threshold for neuroimaging, in general, and particularly when neurologic signs or symptoms are present. Screening including cerebral MRI and EEG should be proposed after a diagnosis of Costello syndrome. The frequency of testing in such children should be guided by neurological follow-up.

Abnormalities, Multiple↗
PubMed2003

Further delineation of the congenital form of X-linked dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome).

Hoyeraal-Hreidarsson syndrome represents a severe variant of dyskeratosis congenita (Zinsser-Cole-Engman syndrome). This X-linked recessive, progressive, multisystemic disorder reported so far in 12 pedigrees is characterised by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, mental retardation, progressive combined immune deficiency and aplastic anaemia. Mutations in the DKC1gene on Xq28 have been identified in the X-linked form of dyskeratosis congenita and in some Hoyeraal-Hreidarsson syndrome patients. We report on two sibs and two other unrelated patients with the striking clinical features of Hoyeraal-Hreidarsson syndrome. Noticeably, all four had early digestive problems, with chronic, bloody diarrhoea and feeding problems causing one of the most difficult problems in the supportive treatment of this uniformly lethal condition. Pathological changes in the proliferative compartment of the digestive mucosa included alterations of the glandular architecture and focal rarefaction of the glands. This aspect seems consistent with altered telomerase function associated with a dyskerin mutation which may decrease the proliferative capacity of digestive epithelial cells. A missense mutation 146 C-->T (Thr49Met) in the DKC1gene was found in two unrelated patients, whereas mutation screening was negative for one single case. The absence of mutations of the DKC1gene in patients with Hoyeraal-Hreidarsson syndrome emphasises the probable implication of one or more other loci.

Cell Cycle Proteins↗
PubMed2003

Donnai-Barrow syndrome: four additional patients.

In 1993, Donnai and Barrow reported a new syndrome in two sets of sibs and in an unrelated child, including diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness. Since then, only four similar patients have been documented. We describe four additional patients, including two sibling pairs from healthy parents. This report firmly establishes this syndrome as a distinct clinical entity and provides further evidence for its previously postulated autosomal recessive inheritance.

Adult↗
PubMed2003

Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH.

Deletions of the long arm of chromosome 18 occur in approximately 1 in 10,000 live births. Congenital aural atresia (CAA), or narrow external auditory canals, occurs in approximately 66% of all patients who have a terminal deletion 18q. The present report describes a series of 20 patients with CAA, of whom 18 had microscopically visible 18q deletions. The extent and nature of the chromosome-18 deletions were studied in detail by array-based comparative genomic hybridization (arrayCGH). High-resolution chromosome-18 profiles were obtained for all patients, and a critical region of 5 Mb that was deleted in all patients with CAA could be defined on 18q22.3-18q23. Therefore, this region can be considered as a candidate region for aural atresia. The array-based high-resolution copy-number screening enabled a refined cytogenetic diagnosis in 12 patients. Our approach appeared to be applicable to the detection of genetic mosaicisms and, in particular, to a detailed delineation of ring chromosomes. This study clearly demonstrates the power of the arrayCGH technology in high-resolution molecular karyotyping. Deletion and amplification mapping can now be performed at the submicroscopic level and will allow high-throughput definition of genomic regions harboring disease genes.

Chromosome Banding↗
PubMed2003

Craniofacial dysmorphology and three-dimensional ultrasound: a prospective study on practicability for prenatal diagnosis.

OBJECTIVE: The aim of this study is to compare two-dimensional and three-dimensional ultrasound for the visualization and diagnosis of craniofacial dysmorphism. METHODS: In this prospective study, we performed three-dimensional (3D) ultrasound following good-quality two-dimensional (2D) ultrasound in an at-risk population. Findings from 2D and 3D examination were noted. RESULTS: Our series included 41 patients. In 20 cases, 3D performed better than 2D, and in two cases 2D was more informative. In 9 cases, there was no difference between the performance of the two, and in two cases both 2D and 3D gave inadequate results. However, in 7 cases 3D images could not be obtained. CONCLUSION: Although it is rarely decisive, 3D ultrasound is of interest when it comes to the precise description of craniofacial dysmorphisms and the study of the fetal ears.

Adult↗
PubMed2003

Spectrum of PTCH1 mutations in French patients with Gorlin syndrome.

Gorlin syndrome or nevoid basal cell carcinoma syndrome is an autosomal dominant disease characterized by developmental abnormalities and a predisposition to cancers. The responsible gene for this syndrome is the PTCH tumor suppressor gene encoding for the Sonic Hedgehog receptor. We screened for PTCH mutations in 65 French Gorlin syndrome families or sporadic cases for the first time. Nineteen novel mutations and five new polymorphisms were identified in this group of patients. One microdeletion without frameshift underlines the importance of one amino acid for Ptc receptor function. Although no mutation hot-spot was described, we identified a recurrent mutation.

Adolescent↗
PubMed2003

Prevalence of mutations in AGPAT2 among human lipodystrophies.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients' cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL patients from 30 families with mutations in AGPAT2. Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies, including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and AGPAT2 are the two major genes involved in the etiology of BSCL.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed2002

Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review.

The Hennekam syndrome is an infrequently reported heritable entity characterized by lymphedema, lymphangiectasia, and developmental delay. Here we add an additional 8 patients, and compare their findings to the 16 cases from the literature. The lymphedema is usually congenital, can be markedly asymmetrical, and, often, gradually progressive. Complications such as erysipelas are common. The lymphangiectasias are present in the intestines, but have also been found in the pleura, pericardium, thyroid gland, and kidney. Several patients have demonstrated congenital cardiac and blood vessel anomalies, pointing to a disturbance of angiogenesis in at least some of the patients. Facial features are variable, and are chiefly characterized, in a typical patient, by a flat face, flat and broad nasal bridge, and hypertelorism. Facial features are thought to mirror the extent of intrauterine facial lymphedema, or may be caused by lymphatic obstruction that affects the early migration of neural crest tissue. Other anomalies have included glaucoma, dental anomalies, hearing loss, and renal anomalies. The psychomotor development varies widely, even within a single family, from almost normal development to severe mental retardation. Convulsions are common. The existence of 10 familial cases, equal sex ratio, increased parental consanguinity rate (4/20 families), and absence of vertical transmission are consistent with an autosomal recessive pattern of inheritance. It seems likely that most (but not all) manifestations of the entity can be explained as sequences of impaired prenatal and postnatal lymphatic flow, suggesting that the causative gene(s) should have a major function in lymphangiogenesis.

Abnormalities, Multiple↗
PubMed2002

Association of external auditory canal atresia, vertical talus, and hypertelorism: confirmation of Rasmussen syndrome.

In 1979, Rasmussen et al. reported six members of a family with congenital, bilateral, symmetrical, and isolated subtotal atresia of the external auditory canal, bilateral foot abnormalities, and increased interocular distance. The family history suggested autosomal dominant inheritance of the syndrome. We report a 3-year-old girl whose symptoms are compatible with this diagnosis. Therefore, we suggest confirmation of the description by Rasmussen et al. as a distinct entity and suggest the term Rasmussen syndrome for this condition.

Abnormalities, Multiple↗
PubMed2002

Osteopathia striata cranial sclerosis: non-random X-inactivation suggestive of X-linked dominant inheritance.

Osteopathia striata with cranial sclerosis (OS-CS) is a rare syndrome comprising macrocephaly, minor anomalies, conductive hearing loss, and mild mental retardation. The diagnosis is based on radiological findings, including cranial sclerosis and longitudinal striations of metaphyses of long bones. Here we report on 10 new cases of OS-CS, including two sporadic cases and three families, with an excess of affected females (9F/1M). Phenotypic variability was observed in our patients as well as several unusual findings. Hirschsprung disease, Pierre Robin sequence, coronal craniostenosis, and laryngotracheomalacia were associated with a poor prognosis. The X-inactivation pattern of peripheral blood lymphocytes in a mildly affected mother and her severely affected boy demonstrated a non-random X-inactivation in the mother. This finding, in combination with a sex ratio in favor of females and an increased morbidity and mortality in males, is highly suggestive of X-linked dominant inheritance.

Abnormalities, Multiple↗