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ABSTRACT: Wij beschrijven een pasgeborene die zich presenteerde met asfyxie en een ernstige aangeboren hartafwijking. In het beloop
bleek er daarnaast sprake te zijn van bewegingsarmoede en congenitale contracturen. Na het overlijden werd door middel van
dna-diagnostiek de diagnose sma type 1, de ziekte van Werdnig-Hoffman, gesteld. De combinatie sma type 1 met een congenitale hartafwijking is bekend uit de medische literatuur, waarvan wij een overzicht geven. Kinderartsen
dienen ook bij een kind met een congenitale hartafwijking alert te zijn op bijkomende (neurologische) verschijnselen. Het
stellen van de diagnose sma type 1 heeft belangrijke genetische consequenties voor de ouders.
A newborn baby presented with asphyxia and a severe congenital heart malformation. In the clinical course congenital contractures
and scarcity of spontaneous movements appeared. Post mortem, the diagnosis sma type 1, Werdnig-Hoffmann's disease, was made by demonstrating a homozygous smn1 deletion in dna from stored tissue. The combination sma type 1 and a congenital heart malformation is known in the medical literature, of which an overview is given. Paediatricians
have to be alert on concurring (neurological) symptoms in a child with a congenital heart defect to make this diagnosis, which
has important genetic consequences for the parents.
Tijdschrift voor kindergeneeskunde 04/2012; 74(5):214-217.
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ABSTRACT: Osteogenesis imperfecta is a hereditary connective tissue disorder characterized primarily by fractures with no or small causal antecedent; in most patients this is a consequence of diminished or abnormal production of collagen type I. It is a clinically heterogeneous disorder: it has been proposed recently to classify osteogenesis imperfecta in types I-V on the basis of the clinical picture and radiology. It is also a genetically heterogeneous disorder; 90% of cases are due to autosomal dominant mutations, while the remaining 10% are due to autosomal recessive mutations or of unknown cause. Osteogenesis imperfecta type I and to a lesser extent type IV are important differential diagnostic considerations in case of suspicion of non-accidental injury (NAI). When osteogenesis imperfecta is suspected, DNA analysis of the dominant COL1A1 and COL1A2 genes is currently the starting point for laboratory diagnosis unless there are strong indications for a recessive cause. Protein analysis based on skin biopsy remains indicated in specific cases.
Nederlands tijdschrift voor geneeskunde 01/2012; 156(21):A4585.
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ABSTRACT: Osteogenesis imperfecta (OI) is characterized by susceptibility to bone fractures, with a severity ranging from subtle increase in fracture frequency to prenatal fractures. The first scientific description of OI dates from 1788. Since then, important milestones in OI research and treatment have, among others, been the classification of OI into 4 types (the 'Sillence classification'), the discovery of defects in collagen type I biosynthesis as a cause of most cases of OI and the use of bisphosphonate therapy. Furthermore, in the past 5 years, it has become clear that OI comprises a group of heterogeneous disorders, with an estimated 90% of cases due to a causative variant in the COL1A1 or COL1A2 genes and with the remaining 10% due to causative recessive variants in the 8 genes known so far, or in other currently unknown genes. This review aims to highlight the current knowledge around the history, epidemiology, pathogenesis, clinical/radiological features, management, and future prospects of OI. The text will be illustrated with clinical descriptions, including radiographs and, where possible, photographs of patients with OI.
Molecular syndromology 12/2011; 2(1):1-20.
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ABSTRACT: We report an Indonesian patient with bone fragility and congenital joint contractures. The initial diagnosis was Osteogenesis Imperfecta type III (OI type III) based on clinical and radiological findings. Because of (i) absence of COL1A1/2 mutations, (ii) a consanguineous pedigree with a similarly affected sibling and (iii) the existence of congenital joint contractures with absence of recessive variants in PLOD2, mutation analysis was performed of the FKBP10 gene, recently associated with Bruck syndrome and/or recessive OI. A novel homozygous deletion in FKBP10 was discovered. Our report of the first Indonesian patient with clinically Bruck syndrome, confirms the role of causative recessive FKBP10 mutations in this syndrome.
European journal of medical genetics 10/2011; 55(1):17-21. · 1.57 Impact Factor
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J Ped Develop Path. 01/2011; 14(3):228-234.
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ABSTRACT: We report a boy with asymmetric crying facies and bilateral absence of the 5th ray of the feet. In addition, craniofacial computed tomography showed a solitary median maxillary central incisor in combination with a narrow apertura piriformis. To our knowledge this intriguing combination of congenital abnormalities has not been described before.
European journal of medical genetics 12/2010; 54(3):284-6. · 1.57 Impact Factor
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F.S. van Dijk,
M. Huizer,
A. Kariminejad,
C.L. Marcelis,
A.S. Plomp,
P.A. Terhal,
H. Meijers-Heijboer,
J. Weiss,
R.R. van Rijn, J.M. Cobben,
G. Pals
Gen Med. 01/2010; 12(11):736-741.
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ABSTRACT: In 1979 Sillence proposed a classification of Osteogenesis Imperfecta (OI) in OI types I, II, III and IV. In 2004 and 2007 this classification was expanded with OI types V-VIII because of distinct clinical features and/or different causative gene mutations. We propose a revised classification of OI with exclusion of OI type VII and VIII since these types have been added because of genetic criteria (autosomal recessive inheritance) while the clinical and radiological features are indistinguishable from OI types II-IV. Instead, we propose continued use of the Sillence criteria I, II-A, II-B, II-C, III and IV for clinical and radiological classification of OI with additional mentioning of the causative mutated gene to this classification. OI type V and VI are still part of this revised classification, because of the distinguishing clinical/radiological and/or histological features observed in these types.
European journal of medical genetics 10/2009; 53(1):1-5. · 1.57 Impact Factor
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ABSTRACT: This review focuses on the heart and vascular system in patients with Down syndrome. A clear knowledge on the wide spectrum of various abnormalities associated with this syndrome is essential for skillful management of cardiac problems in patients with Down syndrome. Epidemiology of congenital heart defects, cardiovascular aspects and thyroid-related cardiac impairment in patients with Down syndrome will be discussed.
Journal of Intellectual Disability Research 03/2009; 53(5):419-25. · 1.88 Impact Factor
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ABSTRACT: We report two families in which the probands have compound-heterozygous Marfan syndrome (MFS). The proband of family 1 has the R2726W FBN1 mutation associated with isolated skeletal features on one allele and a pathogenic FBN1 mutation on the other allele. The phenotype of the compound-heterozygous probands appears to be more severe than that of their heterozygous family members which underlines the possibility that certain trans-located FBN1 mutations might act as modifiers of phenotype explaining some of the intrafamilial variability in Marfan syndrome.
European journal of medical genetics 12/2008; 52(1):1-5. · 1.57 Impact Factor
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ABSTRACT: Thirty-four children with genetically proven SMA type I (age at onset <6 months, unable to sit during study period) were included in a 3-year prospective cohort study and neurologically followed-up until death or the end of the study. At the end of the study period 31/34 children had died. The median age at death was 176 days (95% Confidence Interval 150-214 days), the median survival from the time of diagnosis was 158 days (95% CI 137-232 days). The median survival after diagnosis did not differ significantly between children diagnosed at birth (median survival 137 days, 95% CI 111-232 days) and those diagnosed later (median survival 159 days, 95% CI 141-256), implying that SMA I cases with different ages of onset show the same progression rate of the disease. The number of SMN2 copies was not clearly correlated with survival duration, possibly because of lack of statistical power due to the small number of cases with 1 or 3 SMN2 copies. The three cases alive at the end of the study had either three or an unknown number of SMN2 copies, which is in agreement with previously described cases showing longer survival with increasing number of SMN2 copies. All deceased children died of respiratory insufficiency and/or an intercurrent lung infection, indicating that the susceptibility of the child with SMA type I to respiratory infections plays an important role in determining the survival.
Neuromuscular Disorders 07/2008; 18(7):541-4. · 2.80 Impact Factor
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Eur J Med Gen. 01/2008; 51(5):488-496.
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ABSTRACT: The presentation of sonographic and perinatal findings of tetrasomy 9p.
Chorionic villus sampling and amniocentesis were performed at 19 weeks of gestation because of the sonographic findings of Dandy-Walker malformation with bilateral ventriculomegaly. Cytogenetic analysis showed 47,XX,+i psu dic(9)(pter->q12::q12>-pter). The pregnancy was terminated at 20 weeks of gestation at the request of the parents. At post-mortem examination, the presumed hypoplasia of the vermis could not be confirmed for technical reasons. No other pathological findings were seen.
From our experience and from the literature, we conclude that Dandy-Walker malformation is an important finding in tetrasomy 9p. Chromosomal studies should be carried out in fetuses with sonographically detected Dandy-Walker malformation, even in the absence of other abnormalities.
Prenatal Diagnosis 11/2004; 24(10):796-8. · 2.11 Impact Factor
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ABSTRACT: Prenatal testing for a BRCA mutation, the hereditary trait for mammary and ovarian carcinoma, with the intention of selective termination of pregnancy in case of a female carrier is a controversial ethical issue. Based on a review of the (limited) medical literature as well as of Dutch policy statements relating to this subject, the following conclusions and recommendations are proposed: (a) the decision to opt for prenatal BRCA testing and selective termination of pregnancy in case of a BRCA mutation in the foetus cannot immediately be judged unacceptable from an ethical point of view; (b) prenatal BRCA testing is morally defensible only in case of a female foetus and if the parents at least have the intention to terminate the pregnancy if the foetus is a carrier, although the final decision is in any case up to the parents only; (c) prental testing for a BRCA mutation should only be done after extensive counselling of the parents, during which not only the medical genetic aspects but also the ethical aspects of prenatal BRCA testing are discussed.
Nederlands tijdschrift voor geneeskunde 09/2002; 146(31):1461-5.
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American Journal of Medical Genetics 06/2002; 109(3):246; author reply 247.
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ABSTRACT: A family with primary infertility and two members with mental retardation and subtle facial dysmorphism is described. In the two retarded persons chromosomal rearrangements (partial monosomy of chromosome 5 and partial trisomy of chromosome 7) were detected. One member of the family had died with major congenital malformations. Her fibroblasts had been stored and her chromosomes showed the inverse pattern (partial trisomy of chromosome 5 and partial monosomy of chromosome 7). It appeared that in familial mental retardation with or without congenital malformations FISH-techniques should be used to detect submicroscopic chromosomal aberrations, which are not detectable by routine chromosome studies.
Genetic counseling (Geneva, Switzerland) 02/2002; 13(1):49-54. · 0.50 Impact Factor
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ABSTRACT: The majority of patients with hereditary proximal spinal muscular atrophy (SMA) have a homozygous deletion of the survival motor neuron gene (SMN1). The number of SMN2 gene copies modifies the phenotype, which ranges from a lethal infantile disorder to an adult-onset disease causing mild impairment and disability. The SMN protein plays a role in an apparently essential cell metabolism process, the splicing of pre-mRNA in the spliceosomes. Why SMN1 deletions are only clinically expressed in motor neuron cells and not in other cell types is still unknown. DNA analysis, prenatal diagnosis and carrier testing as means of diagnosing SMA are all routinely available in the Netherlands and are currently performed at the DNA laboratory of the University of Groningen.
Nederlands tijdschrift voor geneeskunde 01/2002; 145(52):2525-7.
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ABSTRACT: With a prevalence of approximately 1/10 000, and a carrier frequency of 1/40-1/60 the proximal spinal muscular atrophies (SMAs) are among the most frequent autosomal recessive hereditary disorders. Patients can be classified clinically into four groups: acute, intermediate, mild, and adult (SMA types I, II, III, and IV, respectively). The complexity and instability of the genomic region at chromosome 5q13 harbouring the disease-causing survival motor neuron 1 (SMN1) gene hamper molecular diagnosis in SMA. In addition, affected individuals with SMA-like phenotypes not caused by SMN1, and asymptomatic individuals with two mutant alleles exist. The SMN gene is present in at least one telomeric (SMN1) and one centromeric copy (SMN2) per chromosome in normal (non-carrier) individuals, although chromosomes containing more copies of SMN1 and/or SMN2 exist. Moreover, the two SMN genes (SMN1 and SMN2) are highly homologous and contain only five base-pair differences within their 3' ends. Also, a relatively high de novo frequency is present in SMA. Guidelines for molecular analysis in diagnostic applications, carrier detection, and prenatal analysis using direct and indirect approaches are described. Overviews of materials used in the molecular diagnosis as well as Internet resources are included.
European Journal of HumanGenetics 08/2001; 9(7):484-91. · 4.40 Impact Factor
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ABSTRACT: We report a prenatal case of a maternally inherited abnormal chromosome 16, originally interpreted as a pericentric inversion only, but after family studies re-interpreted as a pericentric inversion (16) accompanied by an unbalanced (7;16) translocation. Because of the inversion 16 and an elder son with developmental delay and craniofacial dysmorphic features, in the past karyotyped as 46,XY, the chromosomes 16 of the mother and son were carefully re-examined. Using a whole chromosome 16 paint and sub-telomere probes of 16p and 16q, the karyotype of the mother was shown to be 46,XX,inv(16)(p11.2q23.2).ish t(7;16)(q36;p13.3)inv(16). Subsequently one chromosome 16 of the elder son appeared to be a der(16)t(7;16)(q36;p13.3). This is probably the result of a meiotic crossover between the chromosomes 16 in the mother. The prenatal karyotype was finally interpreted as 46,XY,inv(16)(p11.2q23.2).ish der(16)t(7;16)(q36;p13.3)inv(16). This is the same cytogenetic imbalance as his elder brother: a partial trisomy of chromosome 7 (q36-->qter) and a partial monosomy of chromosome 16 (p13.3-->pter).
Prenatal Diagnosis 07/2001; 21(7):550-2. · 2.11 Impact Factor
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ABSTRACT: Spinal muscular atrophy (SMA) results from mutations of the survival motor neuron (SMN) gene on chromosome 5. The SMN gene exists in two highly homologous copies, telomeric (SMN1) and centromeric (SMN2). SMA is caused by mutations in SMN1 but not SMN2. The clinical phenotype of SMA appears to be related to the expression of SMN2. Patients suffering from the milder forms of SMA carry more copies of the SMN2 gene compared with patients with more severe SMA. It is suggested that the SMN2 gene is translated into an at least partially functional protein that protects against loss of motor neurons.
To investigate whether genetic mechanisms implicated in motor neuron death in SMA have a role in ALS.
The presence of deletions of exons 7 and 8 of SMN1 and SMN2 was determined in 110 patients with sporadic ALS and compared with 100 unaffected controls.
The presence of a homozygous SMN2 deletion was overrepresented in patients with ALS compared with controls (16% versus 4%; OR, 4.4; 95% CI, 1.4 to 13.5). Patients with a homozygous SMN2 deletion had a shorter median time of survival (p < 0.009). Furthermore, multivariate regression analysis showed that the presence of an SMN2 deletion was independently associated with survival time (p < 0.02). No homozygous deletions in SMN1 were found. Carrier status of SMA appeared to be equally present in patients and controls (1 in 20).
These results indicate that, similar to SMA, the SMN2 gene can act as a prognostic factor and may therefore be a phenotypic modifier in sporadic ALS. Increasing the expression of the SMN2 gene may provide a strategy for treatment of motor neuron disease.
Neurology 04/2001; 56(6):749-52. · 8.31 Impact Factor
