Raoul C M Hennekam

Cedars-Sinai Medical Center, Los Angeles, California, United States

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Publications (458)2372.32 Total impact

  • European journal of human genetics: EJHG 12/2014; · 3.56 Impact Factor
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    ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine metabolism. Deficiency of this enzyme leads to an accumulation of thymine and uracil and a deficiency of metabolites distal to the catabolic enzyme. The disorder presents with a wide clinical spectrum, ranging from asymptomatic to severe neurological manifestations, including intellectual disability, seizures, microcephaly, autistic behavior, and eye abnormalities. Here, we report on an 11-year-old Malaysian girl and her 6-year-old brother with DPD deficiency who presented with intellectual disability, microcephaly, and hypotonia. Brain MRI scans showed generalized cerebral and cerebellar atrophy and callosal body dysgenesis in the boy. Urine analysis showed strongly elevated levels of uracil in the girl and boy (571 and 578 mmol/mol creatinine, respectively) and thymine (425 and 427 mmol/mol creatinine, respectively). Sequence analysis of the DPYD gene showed that both siblings were homozygous for the mutation c.1651G>A (pAla551Thr).
    Molecular syndromology 12/2014; 5(6):299-303.
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    ABSTRACT: The internet pre-eminently marks an era with unprecedented chances for patient care. Especially individuals with rare disorders and their families can benefit. Their handicap of low numbers vanishes and can become a strength, as small, motivated and well-organized international support groups allow easily fruitful collaborations with physicians and researchers. Jointly setting research agendas and building wikipedias has eventually led to building of multi-lingual databases of longitudinal data on physical and behavioural characteristics of individuals with several rare disorders which we call waihonapedias (waihona meaning treasure in Hawaiian). There are hurdles to take, like online security and reliability of diagnoses, but sharing experiences and true collaborations will allow better research and patient care for fewer costs to patients with rare disorders. Copyright © 2014. Published by Elsevier Masson SAS.
    European Journal of Medical Genetics 11/2014; · 1.49 Impact Factor
  • Journal of Cranio-Maxillofacial Surgery 11/2014; · 2.60 Impact Factor
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    ABSTRACT: Dihydropyrimidine dehydrogenase is a crucial enzyme for the degradation of 5-fluorouracil (5FU). DPYD, which encodes dihydropyrimidine dehydrogenase, is prone to acquire genomic rearrangements because of the presence of an intragenic fragile site FRA1E. We evaluated DPYD copy number variations (CNVs) in a prospective series of 242 stage I-III colorectal tumours (including 87 patients receiving 5FU-based treatment). CNVs in one or more exons of DPYD were detected in 27% of tumours (deletions or amplifications of one or more DPYD exons observed in 17% and 10% of cases, respectively). A significant relationship was observed between the DPYD intragenic rearrangement status and dihydropyrimidine dehydrogenase (DPD) mRNA levels (both at the tumour level). The presence of somatic DPYD aberrations was not associated with known prognostic or predictive biomarkers, except for LOH of chromosome 8p. No association was observed between DPYD aberrations and patient survival, suggesting that assessment of somatic DPYD intragenic rearrangement status is not a powerful biomarker to predict the outcome of 5FU-based chemotherapy in patients with colorectal cancer.The Pharmacogenomics Journal advance online publication, 28 October 2014; doi:10.1038/tpj.2014.68.
    The Pharmacogenomics Journal 10/2014; · 5.51 Impact Factor
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    ABSTRACT: Using exome sequencing and linkage analysis in a 3-generation family with an unique dominant Mycolonus-Dystonia-like syndrome with cardiac arrhythmias we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2. This mutation (c.4166G>A;p.Arg1389His) is a disruptive missense mutation in the outer region of the ion pore. The functional consequences of the identified mutation was studied using whole cell and single channel patch recordings. High resolution analyses at the single channel level showed that, when open, R1389H CaV2.2 channels carried less current compared to WT channels. Other biophysical channel properties were unaltered in R1389H channels including ion selectivity, voltage-dependent activation or voltage-dependent inactivation. CaV2.2 channels regulate transmitter release at inhibitory and excitatory synapses. Functional changes could be consistent with a gain-of-function causing the observed hyperexcitability characteristic of this unique Myoclonus-Dystonia-like syndrome associated with cardiac arrhythmias.
    Human Molecular Genetics 10/2014; · 6.68 Impact Factor
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    ABSTRACT: BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were i
    Journal of Medical Genetics 08/2014; · 5.64 Impact Factor
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    ABSTRACT: We describe an adolescent Peruvian male with marked, aggressive ingrowth of conjunctiva (pterygium-like) over the cornea associated with keloid formation on his distal limbs. He has in addition camptodactyly of all fingers and to some extent of his toes, and unusual skin pigmentations. He resembles an earlier described family from Norway in which a mother and two children showed a similar combination of signs. We present the follow-up of the Norwegian family. The entity resembles the Penttinen syndrome but can be differentiated due to the early aging in the latter, which is lacking in the presently reported entity. We suggest naming this entity ocular pterygium–digital keloid dysplasia. The condition follows likely an autosomal dominant pattern of inheritance. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 08/2014; 164(11). · 2.30 Impact Factor
  • Philippe M. Campeau, Raoul C. Hennekam
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    ABSTRACT: DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, mental Retardation, Seizures) is characterized mainly by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficiency, and seizures. Half of the patients with all clinical features have mutations in TBC1D24. We review here the manifestations of patients clinically diagnosed with DOORS syndrome. In this cohort of 32 families (36 patients) we detected 13 individuals from 10 families with TBC1D24 mutations. Subsequent whole exome sequencing in the cohort showed the same de novoSMARCB1 mutation (c.1130G>A), known to cause Coffin-Siris syndrome, in two patients. Distinguishing features include retinal anomalies, Dandy-Walker malformation, scoliosis, rocker bottom feet, respiratory difficulties and absence of seizures, and 2-oxoglutaric aciduria in the patients with the SMARCB1 mutation. We briefly discuss the heterogeneity of the DOORS syndrome phenotype and the differential diagnosis of this condition. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 08/2014; 166(3). · 3.54 Impact Factor
  • John M. Graham Jr, Raoul C. Hennekam
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    ABSTRACT: Advanced technology has recently allowed us to study rare Mendelian disorders in an unprecedented manner. The same technology should allow us also to study more common malformations. Many of these are not caused by a variant in a single Mendelian gene but by interplay between series of genetic variants and exogenous influences. Likely the site from which the DNA is derived is of great importance in studying malformations as mosaicism may be much more common than earlier anticipated. Factors other than simple variants in our genomic DNA should be considered in the studies as well. Not only is recognition of someone’s liability to disease important, but also determining exogenous factors involved in malformations should receive more attention as it may allow us decrease the burden of malformations in humans.
    European Journal of Medical Genetics 08/2014; · 1.49 Impact Factor
  • Sérgio B. Sousa, Raoul C. Hennekam
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    ABSTRACT: Nicolaides–Baraitser syndrome (NCBRS) is an intellectual disability (ID)/multiple congenital anomalies syndrome caused by non-truncating mutations in the ATPase region of SMARCA2, which codes for one of the two alternative catalytic subunits of the BAF chromatin remodeling complex. We analyzed 61 molecularly confirmed cases, including all previously reported patients (n = 47) and 14 additional unpublished individuals. NCBRS is clinically and genetically homogeneous. The cardinal features (ID, short stature, microcephaly, typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present. There is variability however, as ID can range from severe to mild, and sparse hair may be present only in certain age groups. There may be a correlation between the severity of the ID and presence of seizures, absent speech, short stature and microcephaly. SMARCA2 mutations causing NCBRS are likely to act through a dominant-negative effect. There may be some genotype–phenotype correlations (mutations at domain VI with severe ID and seizures; mutations affecting residues Pro883, Leu946, and Ala1201 with mild phenotypes) but numbers are still too small to draw definitive conclusions. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 08/2014; 166(3). · 3.54 Impact Factor
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    ABSTRACT: Background Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomalies-intellectual disability syndrome. One of the complications is keloid formation. Keloids are proliferative fibrous growths resulting from excessive tissue response to skin trauma.Objectives To describe the clinical characteristics of keloids in individuals with RSTS reported in literature and in a cohort of personally evaluated RSTS individuals.Methods We performed a literature search for descriptions of RSTS individuals with keloids. All known RSTS individuals in the Netherlands filled out three dedicated questionnaires. All individuals with (possible) keloids were personally evaluated. A further series of RSTS individuals from the UK were personally evaluated.ResultsReliable data were available on 62 of the 83 Dutch RSTS individuals and showed 15 RSTS individuals (24%) to have keloids. The 15 Dutch and 12 UK RSTS individuals with keloids demonstrated that most patients have multiple keloids (n>1: 82%; n>5: 30%). Mean age of onset is 11.9 years. The majority are located on shoulders and chest. Mean length x width of the largest keloid was 7.1 x 2.8 cm, mean thickness was 0.7 cm. All affected individuals complained of itching. Generally, treatment results were disappointing.Conclusions Keloids occur in 24% of individuals with RSTS, either spontaneously or after a minor trauma, usually starting in early puberty. Management schedules have disappointing results. RSTS is a Mendelian disorder of known molecular basis, and offers excellent opportunities to study the pathogenesis of keloids in general and search for treatments.This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 08/2014; · 3.76 Impact Factor
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    ABSTRACT: Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism.
    Nature Genetics 07/2014; · 29.65 Impact Factor
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    ABSTRACT: Rubinstein–Taybi syndrome (RSTS) is an autosomal dominant disorder characterized by variable degrees of intellectual disability, an unusual face, distal limb anomalies including broad thumbs and broad halluces, a large group of variable other major and minor anomalies, and decreased somatic growth. The aim of the present study was to construct up-to-date growth charts specific for infants and children with RSTS. We collected retrospective growth data of 92 RSTS individuals of different ancestries. Data were corrected for secular trends and population of origin to the Dutch growth charts of 2009. On average, 17.9 measurements were available per individual. Height, weight and body mass index (BMI) references for males and females were constructed using the lambda, mu, sigma method. RSTS individuals had normal birth weight and length. Mean final heights were 162.6 cm [−2.99 standard deviation score (SDS)] for males and 151.0 cm [−3.01 SDS] for females. BMI SDS compared to the general Dutch population were −0.06 and 1.40 SDS for males and females, respectively. Head circumference SDS compared to the general Dutch population was −1.89 SDS for males and −2.71 SDS for females. This is the first study to publish growth charts using only molecularly proven RSTS individuals. These syndrome-specific growth charts can be used in managing problems related to growth in RSTS individuals. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2014; · 2.30 Impact Factor
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    ABSTRACT: We report on a series of 514 consecutive diagnoses of skeletal dysplasia made over an 8-year period at a tertiary hospital in Kerala, India. The most common diagnostic groups were dysostosis multiplex group (n = 73) followed by FGFR3 (n = 49) and osteogenesis imperfecta and decreased bone density group (n = 41). Molecular confirmation was obtained in 109 cases. Clinical and radiographic evaluation was obtained in close diagnostic collaboration with expert groups abroad through Internet communication for difficult cases. This has allowed for targeted biochemical and molecular studies leading to the correct identification of rare or novel conditions, which has not only helped affected families by allowing for improved genetic counseling and prenatal diagnosis but also resulted in several scientific contributions. We conclude that (1) the spectrum of genetic bone disease in Kerala, India, is similar to that of other parts of the world, but recessive entities may be more frequent because of widespread consanguinity; (2) prenatal detection of skeletal dysplasias remains relatively rare because of limited access to expert prenatal ultrasound facilities; (3) because of the low accessibility to molecular tests, precise clinical-radiographic phenotyping remains the mainstay of diagnosis and counseling and of gatekeeping to efficient laboratory testing; (4) good phenotyping allows, a significant contribution to the recognition and characterization of novel entities. We suggest that the tight collaboration between a local reference center with dedicated personnel and expert diagnostic networks may be a proficient model to bring current diagnostics to developing countries. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2014; 164(9). · 2.30 Impact Factor
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    ABSTRACT: Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification (MLPA) analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner. This article is protected by copyright. All rights reserved.
    Human Mutation 06/2014; · 5.05 Impact Factor
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    ABSTRACT: The Hennekam lymphangiectasia-lymphedema syndrome is a genetically heterogeneous disorder. It can be caused by mutations in CCBE1 which are found in approximately 25 % of cases. We used homozygosity mapping and whole-exome sequencing in the original HS family with multiple affected individuals in whom no CCBE1 mutation had been detected, and identified a homozygous mutation in the FAT4 gene. Subsequent targeted mutation analysis of FAT4 in a cohort of 24 CCBE1 mutation-negative Hennekam syndrome patients identified homozygous or compound heterozygous mutations in four additional families. Mutations in FAT4 have been previously associated with Van Maldergem syndrome. Detailed clinical comparison between van Maldergem syndrome and Hennekam syndrome patients shows that there is a substantial overlap in phenotype, especially in facial appearance. We conclude that Hennekam syndrome can be caused by mutations in FAT4 and be allelic to Van Maldergem syndrome.
    Human Genetics 06/2014; · 4.52 Impact Factor
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    ABSTRACT: Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individual’s face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The ability to visualise and quantify face shape effects of gene dosage is of major benefit for determining whether a CNV is the cause of the phenotype of an individual and for predicting reciprocal consequences. It enables face shape to be used as a relatively simple and inexpensive functional analysis of the gene(s) involved.
    Human Genetics 06/2014; · 4.52 Impact Factor

Publication Stats

14k Citations
2,372.32 Total Impact Points


  • 2014
    • Cedars-Sinai Medical Center
      • Medical Genetics Institute
      Los Angeles, California, United States
  • 1993–2014
    • University of Amsterdam
      • • Faculty of Medicine AMC
      • • Department of Paediatrics
      Amsterdamo, North Holland, Netherlands
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Clinical Genetics
      • • Academic Medical Center
      • • Department of Paediatrics
      • • Department of Cardiology and Cardio-thoracic Surgery
      • • Department of Neonatology
      Amsterdamo, North Holland, Netherlands
  • 2013
    • Hospitais da Universidade de Coimbra
      Coímbra, Coimbra, Portugal
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
  • 2010–2013
    • Università degli Studi di Torino
      • Dipartimento di Scienze della Sanità Pubblica e Pediatriche
      Torino, Piedmont, Italy
  • 2005–2013
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
    • University of Groningen
      • Department of Clinical Genetics
      Groningen, Province of Groningen, Netherlands
  • 2012
    • Kariminejad & Najmabadi Pathology and Genetics Center
      Teheran, Tehrān, Iran
  • 2010–2012
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2005–2012
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Department of Clinical Genetics
      Londinium, England, United Kingdom
  • 2011
    • Lentis
      Amsterdamo, North Holland, Netherlands
    • Wroclaw Medical University
      • Department of Genetics
      Wrocław, Lower Silesian Voivodeship, Poland
    • Amrita Institute of Medical Sciences and Research Centre
      • Department of Pediatric Genetics
      Cochin, Kerala, India
  • 2010–2011
    • Ghent University
      • Department of Molecular Biotechnology
      Gent, VLG, Belgium
  • 2007–2011
    • University of Washington Seattle
      • • Department of Pediatrics
      • • Department of Genome Sciences
      Seattle, WA, United States
    • Ludwig Boltzmann Institute for Osteology
      Wien, Vienna, Austria
  • 2006–2011
    • University College London
      • • Department of Clinical and Experimental Epilepsy
      • • Institute of Child Health
      • • Centre for Cell Signalling and Molecular Genetics
      London, ENG, United Kingdom
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2005–2011
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 2006–2010
    • Università degli Studi di Genova
      • Dipartimento di Scienze Politiche (DISPO)
      Genova, Liguria, Italy
    • Tohoku University
      • Department of Medical Genetics
      Sendai, Kagoshima, Japan
  • 2009
    • Institute for Child Health Policy (ICHP)
      Florida, United States
    • Schneider Children's Medical Center of Israel
      Petah Tikva, Central District, Israel
    • IRCCS Ospedale Casa Sollievo della Sofferenza
      Giovanni Rotondo, Apulia, Italy
    • Haukeland University Hospital
      • Centre for Medical Genetics and Molecular Medicine
      Bergen, Hordaland, Norway
  • 2005–2009
    • National Human Genome Research Institute
      Maryland, United States
  • 1993–2009
    • Leiden University
      • Faculty of Social and Behavioural Sciences
      Leiden, South Holland, Netherlands
  • 2008
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 2007–2008
    • Clinical Molecular Genetics Society
      Londinium, England, United Kingdom
    • University of London
      Londinium, England, United Kingdom
  • 2000–2006
    • Leiden University Medical Centre
      • Department of Clinical Genetics
      Leiden, South Holland, Netherlands
    • IRCCS Istituto G. Gaslini
      Genova, Liguria, Italy
  • 2004
    • Universitair Ziekenhuis Ghent
      • Centre for Medical Genetics
      Gand, Flanders, Belgium
  • 2003
    • Erasmus Universiteit Rotterdam
      • Department of Clinical Genetics
      Rotterdam, South Holland, Netherlands
  • 1997–2000
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Children's Hospital of Eastern Ontario
      Ottawa, Ontario, Canada
  • 1990–2000
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 1992–1997
    • VU University Amsterdam
      • Department of Clinical Genetics
      Amsterdam, North Holland, Netherlands
  • 1996
    • Accare – Kinder- en Jeugdpsychiatrie
      Assen, Drenthe, Netherlands
  • 1993–1996
    • University of Antwerp
      • Medische Genetica (MEDGEN)
      Antwerpen, VLG, Belgium
  • 1990–1993
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands