Brigitte Gilbert-Dussardier

Publications (13)58.69 Total impact

• Article: High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome.

  Virginie Bubien, Françoise Bonnet, Veronique Brouste, Stéphanie Hoppe, Emmanuelle Barouk-Simonet, Albert David, Patrick Edery, Armand Bottani, Valérie Layet, Olivier Caron, Brigitte Gilbert-Dussardier, Capucine Delnatte, Catherine Dugast, Jean-Pierre Fricker, Dominique Bonneau, Nicolas Sevenet, Michel Longy, Frédéric Caux
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  ABSTRACT: BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast and thyroid cancers. Because PHTS is rare, data regarding cancer risks and genotype-phenotype correlations are limited. The objective of this study was to better define cancer risks in this syndrome with respect to the type and location of PTEN mutations. METHODS: 154 PHTS individuals with a deleterious germline PTEN mutation were recruited from the activity of the Institut Bergonié genetic laboratory. Detailed phenotypic information was obtained for 146 of them. Age and sex adjusted standardised incidence ratio (SIR) calculations, cumulative cancer risk estimations, and genotype-phenotype analyses were performed. RESULTS: Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. The risk of cancer was two times greater in women with PHTS than in men with PHTS (p<0.05). CONCLUSIONS: This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype-phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.
  Journal of Medical Genetics 01/2013; · 6.36 Impact Factor
• Source

  Available from: Betty Gardie

  Article: Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.

  Betty Gardie, Audrey Remenieras, Darouna Kattygnarath, Johny Bombled, Sandrine Lefèvre, Victoria Perrier-Trudova, Pierre Rustin, Michel Barrois, Abdelhamid Slama, Marie-Françoise Avril, [......], Jean-Baptiste Meric, Virginie Verkarre, Gilbert Lenoir, Virginie Joulin, Sophie Deveaux, Veronica Cusin, Jean Feunteun, Bin Tean Teh, Brigitte Bressac-de Paillerets, Stéphane Richard
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  ABSTRACT: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene. As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations. This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.
  Journal of Medical Genetics 03/2011; 48(4):226-34. · 6.36 Impact Factor
• Article: Four-year follow-up of diagnostic service in USH1 patients.

  Anne-Françoise Roux, Valérie Faugère, Christel Vaché, David Baux, Thomas Besnard, Susana Léonard, Catherine Blanchet, Christian Hamel, Michel Mondain, Brigitte Gilbert-Dussardier, Patrick Edery, Didier Lacombe, Dominique Bonneau, Muriel Holder-Espinasse, Umberto Ambrosetti, Hubert Journel, Albert David, Geneviève Lina-Granade, Sue Malcolm, Mireille Claustres
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  ABSTRACT: The purpose of this study was to establish the mutation spectrum of an Usher type I cohort of 61 patients from France and to describe a diagnostic strategy, including a strategy for estimating the pathogenicity of sequence changes. To optimize the identification of Usher (USH)-causative mutations, taking into account the genetic heterogeneity, preliminary haplotyping at the five USH1 loci was performed to prioritize the gene to be sequenced, as previously described. Coding exons and flanking intronic sequences were sequenced and, where necessary, semiquantitative PCR and multiplex ligation-dependent probe amplification (MLPA) were performed to detect large genomic rearrangements. Four years ' experience confirms that the chosen approach provides an efficient diagnostic service. Sixty-one patients showed an abnormal genotype in one of the five USH1 genes. Genetic heterogeneity was confirmed, and, although MYO7A remains the major gene, involvement of other genes is considerable. Distribution of missense, splicing, premature termination codons (PTCs; due to point substitution and small deletions/ or insertions), and large genomic alterations was determined among the USH genes and clearly highlights the need to pay special attention to the diagnostic approach and interpretation, depending on the mutated gene. Over the 4 years of a diagnostic service offering USH1 patient testing, pathogenic genotypes were identified in most cases (>90%). The complexity and heterogeneity of mutations reinforces the need for a comprehensive approach. Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases.
  Investigative ophthalmology & visual science 03/2011; 52(7):4063-71. · 3.43 Impact Factor
• Source

  Available from: Laurence Jonard

  Article: Screening of SLC26A4, FOXI1 and KCNJ10 genes in unilateral hearing impairment with ipsilateral enlarged vestibular aqueduct.

  Laurence Jonard, Magali Niasme-Grare, Crystel Bonnet, Delphine Feldmann, Isabelle Rouillon, Natalie Loundon, Catherine Calais, Hélène Catros, Albert David, Hélène Dollfus, [......], Brigitte Gilbert-Dussardier, Catherine Gohler, Cyril Goizet, Hubert Journel, Thierry Mom, Marie-Françoise Thuillier-Obstoy, Remy Couderc, Eréa Noël Garabédian, Françoise Denoyelle, Sandrine Marlin
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  ABSTRACT: To investigate the implication of SLC26A4, FOXI and KCNJ10 genes in unilateral hearing impairment associated with ipsilateral inner ear malformation (Enlargement of the vestibular aqueduct and/or Mondini dysplasia). We have gathered 25 patients presenting unilateral hearing impairment and ipsilateral enlarged vestibular aqueduct. For each of the patients, we have analyzed SLC26A4, FOXI1 and KCNJ10 genes sequences. The analysis of SLC26A4 revealed only eight heterozygous SLC26A4 sequence variants, three of them being novel (p.Met147Ile, p.Asn538Asn and p.Leu627Arg). None of the patients carried a second mutation on the other allele. Moreover, the SLC26A4 locus was excluded by segregation analysis in two families. No mutations were present in FOXI1 and KCNJ10 genes. Together, these data suggest that SLC26A4, FOXI1 and KCNJ10 are not major determinants in unilateral deafness and enlarged vestibular aqueduct compared with their implication in Pendred syndrome and non-syndromic bilateral enlarged vestibular aqueduct.
  International journal of pediatric otorhinolaryngology 09/2010; 74(9):1049-53. · 0.85 Impact Factor
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  Available from: Christophe Grosset

  Article: A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia.

  Delphine Simon, Benoit Laloo, Malika Barillot, Thomas Barnetche, Camille Blanchard, Caroline Rooryck, Michèle Marche, Ingrid Burgelin, Isabelle Coupry, Nicolas Chassaing, Brigitte Gilbert-Dussardier, Didier Lacombe, Christophe Grosset, Benoit Arveiler
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  ABSTRACT: A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1. We have identified a variant (c.*281A>T) in the 3' untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease. The variant is located in the seed sequence of hsa-miR-433. Our data showed that, in MG63 osteosarcoma cells, hsa-miR-433 (miR433) down-regulated both the expression of endogenous HDAC6 and that of an enhanced green fluorescent protein-reporter mRNA bearing the wild-type 3'-UTR of HDAC6. This effect was totally abrogated when the reporter mRNA bore the mutated HDAC6 3'-UTR. The HDAC6 protein was found to be over-expressed in thymus from an affected male fetus. Concomitantly, the level of total alpha-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alpha-tubulin was found to be profoundly decreased. Skin biopsies were obtained from a female patient who presented a striking body asymmetry with hypotrophy of the left limbs. The mutated HDAC6 allele was expressed in 31% of left arm-derived fibroblasts, whereas it was not expressed in the right arm. Overexpression of HDAC6 was observed in left arm-derived fibroblasts. Altogether these results strongly suggest that this HDAC6 3'-UTR variant suppressed hsa-miR-433-mediated post-transcriptional regulation causing the overexpression of HDAC6. This variant is likely to constitute the molecular cause of this new form of X-linked chondrodysplasia. This represents to our knowledge the first example of a skeletal disease caused by the loss of a miRNA-mediated post-transcriptional regulation on its target mRNA.
  Human Molecular Genetics 02/2010; 19(10):2015-27. · 7.64 Impact Factor
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  Available from: Pierre Vabres

  Article: Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations.

  Guillaume Banneau, Mickaël Guedj, Gaëtan MacGrogan, Isabelle de Mascarel, Valerie Velasco, Renaud Schiappa, Valerie Bonadona, Albert David, Catherine Dugast, Brigitte Gilbert-Dussardier, Olivier Ingster, Pierre Vabres, Frederic Caux, Aurelien de Reynies, Richard Iggo, Nicolas Sevenet, Françoise Bonnet, Michel Longy
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  ABSTRACT: Breast carcinoma is the main malignant tumor occurring in patients with Cowden disease, a cancer-prone syndrome caused by germline mutation of the tumor suppressor gene PTEN characterized by the occurrence throughout life of hyperplastic, hamartomatous and malignant growths affecting various organs. The absence of known histological features for breast cancer arising in a PTEN-mutant background prompted us to explore them for potential new markers. We first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data. Unsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma. These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features.
  Breast cancer research: BCR 01/2010; 12(4):R63. · 5.24 Impact Factor
• Article: Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.

  Judith Calvo, Benoît Funalot, Robert A Ouvrier, Leila Lazaro, Annick Toutain, Philippe De Mas, Pierre Bouche, Brigitte Gilbert-Dussardier, Marie-Christine Arne-Bes, Jean-Pierre Carrière, Hubert Journel, Marie-Christine Minot-Myhie, Claire Guillou, Karima Ghorab, Laurent Magy, Franck Sturtz, Jean-Michel Vallat, Corinne Magdelaine
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  ABSTRACT: Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features. To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations. Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies. One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. Results of genetic analyses and phenotypic observations. Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduction velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections. MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy.
  Archives of neurology 12/2009; 66(12):1511-6. · 6.31 Impact Factor
• Article: Identification of gene copy number variations in patients with mental retardation using array-CGH: Novel syndromes in a large French series.

  Sylvie Jaillard, Séverine Drunat, Claude Bendavid, Azzedine Aboura, Amandine Etcheverry, Hubert Journel, Andrée Delahaye, Laurent Pasquier, Dominique Bonneau, Annick Toutain, [......], Brigitte Benzacken, Dominique Martin-Coignard, Catherine Henry, Albert David, Josette Lucas, Jean Mosser, Véronique David, Sylvie Odent, Alain Verloes, Christèle Dubourg
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  ABSTRACT: Array-CGH has revealed a large number of copy number variations (CNVs) in patients with multiple congenital anomalies and/or mental retardation (MCA/MR). According to criteria recently listed, pathogenicity was clearly suspected for some CNVs but benign CNVs, considered as polymorphisms, have complicated the interpretation of the results. In this study, genomic DNAs from 132 French patients with unexplained mental retardation were analysed by genome wide high-resolution Agilent 44K oligonucleotide arrays. The results were in accordance with those observed in previous studies: the detection rate of pathogenic CNVs was 14.4%. A non-random involvement of several chromosomal regions was observed. Some of the microimbalances recurrently involved regions (1q21.1, 2q23.1, 2q32q33, 7p13, 17p13.3, 17p11.2, 17q21.31) corresponding to known or novel syndromes. For all the pathogenic CNVs, further cases are needed to allow more accurate genotype-phenotype correlations underscoring the importance of databases to group patients with similar molecular data.
  European journal of medical genetics 10/2009; 53(2):66-75. · 1.57 Impact Factor
• Article: Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.

  David Baux, Lise Larrieu, Catherine Blanchet, Christian Hamel, Safouane Ben Salah, Anne Vielle, Brigitte Gilbert-Dussardier, Muriel Holder, Patrick Calvas, Nicole Philip, Patrick Edery, Dominique Bonneau, Mireille Claustres, Sue Malcolm, Anne-Françoise Roux
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  ABSTRACT: The usherin gene (USH2A) has been screened for mutations causing Usher syndrome type II (USH2). Two protein isoforms have been identified: a short isoform of 1,546 amino acids and a more recently recognized isoform extending to 5,202 amino acids. We have screened the full length by genomic sequencing. We confirm that many mutations occur in the exons contributing solely to the longer form. USH2 is an autosomal recessive disorder and, in contrast to previous studies, both mutations were identified in 23 patients and a single mutation in 2 out of 33 patients. A total of 34 distinct mutated alleles were identified, including one complex allele with three variants and another with two. A total of 27 of these are novel, confirming that most mutations in usherin are private. Many of the mutations will lead to prematurely truncated protein but as there are a substantial number of missense variants, we have used in silico analysis to assess their pathogenicity. Evidence that they are disease-causing has been produced by protein alignments and three-dimensional (3D) structural predictions when possible. We have identified a previously unrecognized cysteine rich structural domain, containing 12 dicysteine repeats, and show that three missense mutations result in the loss of one of a pair of the defining cysteine-cysteine pairs.
  Human Mutation 08/2007; 28(8):781-9. · 5.69 Impact Factor
• Article: Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement.

  Nicolas Chassaing, Brigitte Gilbert-Dussardier, Florence Nicot, Véronique Fermeaux, Férechté Encha-Razavi, Maryse Fiorenza, Annick Toutain, Patrick Calvas
  American Journal of Medical Genetics Part A 03/2007; 143(3):289-91. · 2.39 Impact Factor
• Article: Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network.

  Gaëtan Lesca, Carla Olivieri, Nelly Burnichon, Fabio Pagella, Marie-France Carette, Brigitte Gilbert-Dussardier, Cyril Goizet, Joelle Roume, Muriel Rabilloud, Jean-Christophe Saurin, Vincent Cottin, Jerome Honnorat, Florence Coulet, Sophie Giraud, Alain Calender, Cesare Danesino, Elisabetta Buscarini, Henri Plauchu
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  ABSTRACT: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2). Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening. Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P<0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P<0.001), as were cerebral abscesses (7.5 vs. 0.8%, P=0.002). Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P=0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P<0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2. This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies.
  Genetics in Medicine 02/2007; 9(1):14-22. · 4.76 Impact Factor
• Article: Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients.

  Gaëtan Lesca, Nelly Burnichon, Grégory Raux, Mario Tosi, Stéphane Pinson, Marie-Jeanne Marion, Emmanuel Babin, Brigitte Gilbert-Dussardier, Sophie Rivière, Cyril Goizet, Laurence Faivre, Henri Plauchu, Thierry Frébourg, Alain Calender, Sophie Giraud
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  ABSTRACT: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations and resulting from mutations in two major genes: ENG and ACVRL1. The aim of the present study was to estimate the prevalence of the mutations of ENG and ACVRL1 in HHT, based on the largest series of patients reported so far, recruited through a national network. We previously reported the first mutation screening of both genes, in French HHT patients, using heteroduplex analysis. This previous study, bringing 60 novel mutations, provided a significant improvement to the knowledge of molecular pathology in HHT. However, 32% (n=48) of the patients with a confirmed clinical diagnosis remained without mutation. In these patients, we performed an extensive molecular analysis that included the sequencing of the whole coding sequence, the search for large rearrangements, and screening of the potential 5' regulatory regions. Additionally, due to the lack of large pedigrees suitable for linkage analysis, and since SMAD4 germline mutations have been reported in families with combined HHT and juvenile polyposis, we screened this gene and five other genes involved in the TGF-beta/BMP pathway in the patients without mutation of ENG or ACVRL1. Only a novel SMAD1 non-conservative substitution was found in one patient, changing a poorly conserved methionine to an isoleucin. Twenty-three mutations were found in ACVRL1 and 8 in ENG (including a duplication of exons 4 to 8 and deletions of exons 1 to 3 and 9 to 14). Our results, combined with our previous data, increase the mutation rate to 88% (n=119/136) in French patients with a confirmed clinical diagnosis. Our results also emphasize the higher prevalence of large insertions/deletions in ENG and the predominance of ACVRL1 over ENG mutations.
  Human Mutation 07/2006; 27(6):598. · 5.69 Impact Factor
• Article: X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia.

  Nicolas Chassaing, Virginie Siani, Dominique Carles, Anne Lise Delezoide, Eve Marie Alberti, Jacques Battin, Jean François Chateil, Brigitte Gilbert-Dussardier, Isabelle Coupry, Benoit Arveiler, Robert Saura, Didier Lacombe
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  ABSTRACT: We describe a family with an X-linked dominant chondrodysplasia. Four males and six females were affected through four generations. Identification of skeletal abnormalities and hydrocephaly during the pregnancy of three male fetuses led to termination of the pregnancies. A fourth affected male died at 6 days of life. The four patients had chondrodysplasia, hydrocephaly, and facial features with microphthalmia. Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges. The affected females were less affected and showed small stature, sometimes associated with body asymmetry and mild mental retardation. This condition appears to be a previously unrecognized X-linked dominant chondrodysplasia.
  American Journal of Medical Genetics Part A 09/2005; 136A(4):307-12. · 2.39 Impact Factor