E A Haan

University of Melbourne, Melbourne, Victoria, Australia

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Publications (68)347.05 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The recent identification of TGFBR2 mutations in Marfan syndrome II (MFSII) [Mizuguchi et al. (2004); Nat Genet 36:855-860] and of TGFBR1 and TGFBR2 mutations in Loeys-Dietz aortic aneurysm syndrome (LDS) [Loeys et al. (2005); Nat Genet 37:275-281] [OMIM 609192] has provided direct evidence of abnormal signaling in transforming growth factors beta (TGF-beta) in the pathogenesis of Marfan syndrome (MFS). In light of this, we describe the phenotypes and genotypes of five individuals. Patient 1 had MFS and abnormal cranial dura. Patient 2 had severe early onset MFS and an abnormal skull. Patients 3 and 4 had probable Furlong syndrome (FS). Patient 5 had marfanoid (MD) features, mental retardation (MR), and a deletion of chromosome 15q21.1q21.3. All patients had a condition within the MFS, MD-craniosynostosis (CS) or MD-MR spectrum. The names of these entities may become redundant, and instead, come to be considered within the spectrum of TGF-beta signaling pathway disorders. Two recurrent heterozygous FBN1 mutations were found in Patients 1 and 2, and an identical novel heterozygous de novo TGFBR1 mutation was found in Patients 3 and 4, in whom altered fibrillin-1 processing was demonstrated previously [Milewicz et al. (2000); Am J Hum Genet 67:279]. A heterozygous FBN1 deletion was found in Patient 5. These findings support the notion that perturbation of extracellular matrix homeostasis and/or remodeling caused by abnormal TGF-beta signaling is the core pathogenetic mechanism in MFS and related entities including the MD-CS syndromes.
    American Journal of Medical Genetics Part A 06/2006; 140(10):1047-58. · 2.30 Impact Factor
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    ABSTRACT: The aims of this study were to provide a population-based prevalence for congenital talipes equinovarus (CTEV), to conduct an epidemiological investigation into the risk factors for CTEV and describe associated features. The study used a retrospective case-control design of CTEV notified to the South Australian Birth Defects Register between 1986 and 1996 inclusive, linking characteristics of mother and baby from the perinatal data collection. The prevalence of isolated CTEV was 1.1/1000 total births (n = 231). Four factors were significantly associated with an increased risk of CTEV: maternal Aboriginal race (ORadj = 2.0; 95% CI 1.1, 3.6), male gender (ORadj = 2.4; 95% CI 1.8, 3.2), maternal anaemia (ORadj = 1.8; 95% CI 1.0, 2.9) and maternal hyperemesis (ORadj = 3.6; 95% CI 1.3, 9.8). The prevalence of CTEV associated with another birth defect or syndrome (n = 157) was 0.7/1000 total births. CTEV was associated with specific birth defects and also with oligohydramnios when another birth defect was present.
    Paediatric and Perinatal Epidemiology 06/2005; 19(3):227-37. · 2.16 Impact Factor
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    ABSTRACT: PEHO syndrome is a rare progressive infantile encephalopathy with onset within the first few months of life. Few patients fulfilling the diagnostic criteria for PEHO syndrome have been reported outside Finland. Affected infants have facial dysmorphism and suffer from severe hypotonia, profound mental retardation, convulsions (often with a hypsarrhythmic EEG pattern), transient or persistent peripheral oedema, and optic atrophy. Cerebellar and brainstem atrophy are usually present on neuroimaging. A PEHO-like syndrome has been described, in which the affected individuals have neither optic atrophy nor the typical neuroradiological findings. We report five Australian patients, the first with classical features of PEHO syndrome, and four who have a PEHO-like disorder. We compare their features with other published cases. We suggest that PEHO or a PEHO-like syndrome may affect more patients than are currently identified, based on the original diagnostic criteria for this disorder.
    American Journal of Medical Genetics Part A 10/2003; 122A(1):6-12. · 2.30 Impact Factor
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    ABSTRACT: A 15-year-old-boy and his mother, both carrying a cryptic deletion within 12p13.33, are described. The proband has a mild phenotype with moderate mental retardation and severe behavioural problems. The mother had some learning difficulties at school. Conventional GTL-banded high-resolution chromosome analysis showed normal karyotypes. Subsequent analysis by fluorescence in situ hybridization using a set of probes specific for the subtelomeric regions of all chromosomes, plus a series of probes at 12p13.33 extending from the 12p telomere, showed that both mother and son carry a 1.65 Mb terminal deletion in this region. There are 10 predicted genes within the deleted region. The unanticipated familial nature of the deletion emphasizes the value of family studies in all cases with subtelomeric abnormalities. It also demonstrates the difficulty in making a clinical diagnosis of individuals with this deletion. To the best of the present authors' knowledge, the proband and his mother are the first patients described with a submicroscopic deletion at 12p13.33.
    Clinical Genetics 04/2002; 61(3):198-201. · 3.94 Impact Factor
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    ABSTRACT: Hemifacial microsomia (HFM) is a common birth defect involving first and second branchial arch derivatives. The phenotype is extremely variable. In addition to craniofacial anomalies there may be cardiac, vertebral and central nervous system defects. The majority of cases are sporadic, but there is substantial evidence for genetic involvement in this condition, including rare familial cases that exhibit autosomal dominant inheritance. As an approach towards identifying molecular pathways involved in ear and facial development, we have ascertained both familial and sporadic cases of HFM. A genome wide search for linkage in two families with features of HFM was performed to identify the disease loci. In one family data were highly suggestive of linkage to a region of approximately 10.7 cM on chromosome 14q32, with a maximum multipoint lod score of 3.00 between microsatellite markers D14S987 and D14S65. This locus harbours the Goosecoid gene, an excellent candidate for HFM based on mouse expression and phenotype data. Coding region mutations were sought in the familial cases and in 120 sporadic cases, and gross rearrangements of the gene were excluded by Southern blotting. Evidence for genetic heterogeneity is provided by the second family, in which linkage was excluded from this region.
    Human Genetics 01/2002; 109(6):638-45. · 4.63 Impact Factor
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    ABSTRACT: Of the 65 328 pregnancies of South Australian mothers screened by the South Australian Maternal Serum Antenatal Screening (SAMSAS) Programme between 1 January 1991 and 31 December 1997, 3431 (5.25%) were declared at increased risk of fetal Down syndrome. Fetal or neonatal karyotype was determined in 2737/3431 (79.8%) of these pregnancies, including 16 with early fetal loss. Interrogation of the database of the South Australian Neonatal Screening Service showed 643 live-born infants whose phenotype was not subsequently questioned among the 694 pregnancies whose karyotype was not determined. Of the remaining 51/3431 pregnancies, 19 ended in early fetal loss without karyotyping and no newborn screening or other records could be found for 32 cases. The 129 instances of abnormal karyotype found were Down syndrome (84), trisomy 18 (four), trisomy 13 (three), triploidy (two), female sex chromosome aneuploidy (six) and male sex chromosome aneuploidy (five), inherited balanced rearrangements (19), mosaic or de novo balanced abnormalities (four) and unbalanced karyotypes (two). In the pregnancies declared at increased risk of fetal Down syndrome, only the karyotype for Down syndrome occurred with a frequency greater than that expected for the general, pregnant population.
    Prenatal Diagnosis 08/2001; 21(7):553-7. · 2.68 Impact Factor
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    ABSTRACT: To evaluate a South Australian campaign to promote and implement knowledge that taking adequate folate/folic acid in the periconceptional period can reduce the risk of having a baby with a neural tube defect. The campaign, conducted in October 1994--August 1995, targeted women of reproductive age and health professionals. Evaluation was by computer-assisted telephone interviews undertaken by random dialling throughout the State before and after the campaign, and by self-administered questionnaires to health professionals and women in the postnatal period. Women of reproductive age and four groups of health professionals. Knowledge about folate, folate-rich foods and the periconceptional period; participation of health professionals in advising women about folate; use of periconceptional folic acid supplements; sales of folic acid tablets; and prevalence of neural tube defects. Significant increases in knowledge about folate followed the campaign. Health professionals and women in the postnatal period had higher initial levels of knowledge about folate, which also increased significantly. The proportions of women taking periconceptional folic acid supplements, and of health professionals advising women planning a pregnancy about folate, also increased significantly, and folic acid tablet sales doubled. Total prevalence of neural tube defects declined between 1966 and 1999 from a baseline of 2.0 per 1,000 births to 1.1 per 1,000 births (Poisson regression, P= 0.03; average decline of 1.0% per year). A short educational campaign with a limited budget ($40,000) can promote folate successfully, but alternative strategies such as food fortification are likely to be needed to achieve adequate periconceptional folate intake for a very high proportion of women.
    The Medical journal of Australia 07/2001; 174(12):631-6. · 2.85 Impact Factor
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    ABSTRACT: To describe the impact of maternal serum screening on the birth prevalence of Down's syndrome and on the use of amniocentesis and chorionic villus sampling in South Australia. A descriptive population-based study. South Australia (population 1.48 million persons; approximately 20,000 births per year). Women who had births or terminations of pregnancy with Down's syndrome in 1982-1996, women who had maternal serum screening in 1991-1996, amniocentesis or chorionic villus sampling in 1986-1996. Analysis of data from multiple sources on maternal serum screening, amniocentesis and chorionic villus sampling, births and terminations of pregnancy. Total prevalence and birth prevalence of Down's syndrome each year in 1982-1996; proportion of pregnant women using maternal serum screening in 1991-1996, and proportion using amniocentesis and chorionic villus sampling by indication in 1986-1996, by age group. Use of maternal serum screening for Down's syndrome increased from 17% when introduced in 1991 to 76% of women who gave birth in 1996. Between 1982 and 1986 and 1996, terminations of pregnancy for fetal Down's syndrome increased from 7.1 % to 75% and the birth prevalence of Down's syndrome fell by 60% from 1.05 to 0.42 per 1,000 births, against the background of an increase in total prevalence due to increasing maternal age. The use of amniocentesis increased from 5.8% in 1991 to 10.1% in 1996 mainly due to the increase among women younger than 35 years with maternal serum screening as the main reason. The increasing chorionic villus sampling rate among younger women stabilised at 0.4%, while the rate among older women decreased from 11.0% to 7.4%. The introduction of maternal serum screening in South Australia has resulted in increased use of any prenatal testing for Down's syndrome from about 7% (mainly older women having amniocentesis or chorionic villus sampling) to 84% of women (about 8% having direct amniocentesis or chorionic villus sampling and 76% having maternal serum screening first). This has resulted in a significant fall in the birth prevalence of Down's syndrome. maternal serum screening was the first indication of Down's syndrome for about half the terminations of pregnancy for Down's syndrome in 1993-1996, including three quarters of those in younger women.
    BJOG An International Journal of Obstetrics & Gynaecology 01/2001; 107(12):1453-9. · 3.76 Impact Factor
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    ABSTRACT: Three patients with accessory small ring chromosomes derived from chromosome 1 are presented together with additional clinical details and cytogenetic analyses of a previously reported patient. Cytogenetic analysis was undertaken by FISH using a reverse painting probe generated from one of the patients by microdissection of the r(1) chromosome and with a BAC923C6 which maps to 1p12. Results indicated that patients with r(1) chromosomes consisting of 1q12 heterochromatin and short arm pericentric euchromatin which extends to at least the BAC923C6 were associated with a normal or mild phenotype. Patients with abnormal phenotypes possessed two types of rings. One patient had evidence for contiguous pericentric short arm euchromatin which extended from the centromere to beyond the BAC923C6. Two patients showed molecular cytogenetic results which were compatible with non-contiguous chromosome 1 euchromatin. The diversity of origin of r(1)s will hamper attempts to define phenotype/genotype relationships.
    Journal of Medical Genetics 12/1999; 36(11):847-53. · 5.70 Impact Factor
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    ABSTRACT: We describe a 14-year-old male with dissection of the descending aorta, bilateral iris hypoplasia, striae distensae and brachytelephalangy, the latter being most marked in the thumbs. Inguinal herniae and a patent ductus arteriosus were surgically repaired in infancy. The pattern of abnormalities may constitute a previously undescribed syndrome. The proband died suddenly at the age of 17 years.
    Clinical Dysmorphology 11/1999; 8(4):269-76. · 0.38 Impact Factor
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    ABSTRACT: Homozygotes for the rare folate-sensitive autosomal fragile sites have never been recorded. Two non-folate-sensitive rare fragile sites (FRA10B and FRA17A) have been previously recorded in normal individuals. We document two unrelated normal individuals who are homozygotes for the rare fragile site FRA16B and record the patterns of induction of this fragile site with berenil. The existence of normal homozygotes for FRA16B suggests that this fragile site is not within a gene essential for normal development.
    Chromosome Research 02/1999; 7(7):553-6. · 2.85 Impact Factor
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    BMJ Clinical Research 11/1998; 317(7163):923-4. · 14.09 Impact Factor
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    ABSTRACT: A heterozygous deletion of a single base (A4704) from exon 37 of the fibrillin-1 gene was defined in a patient with Marfan syndrome and subsequently in his previously undiagnosed father. The deletion created a cryptic 5' splice site in exon 37 which was utilised in preference to the normal 5' splice site during pre-mRNA processing in skin fibroblasts cultured from the proband. The mutant mRNA showed a 48-bp deletion from the 3' end of exon 37 which was predicted to restore the reading frame in the mutant mRNA and result in the deletion of a 16-amino-acid sequence from a central eight-cysteine repeat motif of the fibrillin-1 molecule. Interestingly, the cryptic 5' splice site in exon 37 and the normal 5' splice site had equally strong consensuses for splice-site selection. The preferential utilisation of the cryptic site is discussed in relation to current theories on the mechanisms involved in pre-mRNA splicing. Analysis by reverse-transcription PCR indicated that, in the patients skin fibroblasts, the steady-state level of the mis-spliced mutant mRNA was close to that from the normal allele. In addition, evidence from immunoblotting and pulse-chase biosynthetic labelling indicated that close to normal amounts of fibrillin-1 were being synthesised and secreted by the cells. However, in contrast to control cells cultured from an unaffected individual, little fibrillin-1 was detected, either biosynthetically or by immunofluorescence, in the extracellular matrix produced by the proband's fibroblasts. Thus, the slightly shorter mutant fibrillin-1 molecules appeared to be exerting a powerful dominant-negative effect on the incorporation of normal fibrillin-1 molecules into microfibrils in this culture system. This severe inhibition of microfibril synthesis in cell culture contrasts with the 'classic' phenotype of the proband, suggesting that factors influencing microfibril formation may differ greatly between in vivo and in vitro environments.
    European Journal of Biochemistry 09/1998; 256(1):221-8. · 3.58 Impact Factor
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    ABSTRACT: The purpose of this study was to determine the prevalence, clinical characteristics, prenatal diagnosis and occurrence of other birth defects with abdominal wall defects in births and terminations of pregnancy in South Australia (SA) and Western Australia (WA) over the period 1980-90. Cases of gastroschisis, exomphalos, bladder exstrophy, cloacal exstrophy and body stalk anomaly were ascertained from the WA Birth Defects Registry (1980-90) and the SA Birth Defects Register (1986-90). The registers are comparable population-based data collections with information on livebirths and stillbirths of at least 400 g birthweight or 20 weeks' gestation, and terminations of pregnancy for fetal abnormality. The prevalence of gastroschisis was 1.65/10,000 births (59 cases) and of exomphalos 2.90/10,000 births (104 cases). There was no significant difference in prevalence of exomphalos or gastroschisis between SA and WA for the years 1986-90. However, if data from WA for the years 1980-85 were included, SA had a significantly higher prevalence of exomphalos (prevalence ratio 1.71, confidence interval [CI] 1.16-2.55), although not of gastroschisis (prevalence ratio 1.35, CI 0.79-2.32). Exomphalos was significantly more common in mothers < 20 years (odds ratio [OR] 2.45, CI 1.22-4.86) and in mothers of 40 years or older (OR 5.65, CI 1.69-16.77). Gastroschisis was more common in younger mothers (OR 8.76, CI 4.02-19.32). Both exomphalos and gastroschisis were associated with low birthweight, prematurity, intrauterine growth retardation and caesarean section. The reason for the higher prevalence of exomphalos in SA than WA was not clear, but may be related to differences in prenatal diagnosis. The association between maternal age < 20 years and exomphalos raises the possibility of common factors in the aetiology of gastroschisis and exomphalos.
    Paediatric and Perinatal Epidemiology 05/1998; 12(2):136-51. · 2.16 Impact Factor
  • Human Mutation 02/1998; Suppl 1:S257-9. · 5.21 Impact Factor
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    ABSTRACT: Wolf-Hirschhorn syndrome (WHS) caused by 4p16.3 deletions comprises growth and mental retardation, distinct facial appearance and seizures. This study characterized a subtle interstitial deletion of 4p16.3 in a girl with mild retardation and possessing facial traits characteristic of WHS. The patient had generalized seizures in conjunction with fever at 3 and 5 years of age. Fluorescence in situ hybridization (FISH) with a series of markers in the 4p16.3 region showed that the interstitial deletion in this patient was between the probes D4S96 and D4S182, enabling the size of the deletion to be estimated as less than 1.9 Mb. This is the smallest interstitial deletion of 4p16.3 which has been reported. The patient contributes to a refinement of the phenotypic map of the WHS region in 4p16.3. The critical region for the characteristic facial changes of WHS, failure to thrive and developmental delay is now localized to a region of less than 700 kb. The mental retardation of this patient was mild suggesting that small interstitial deletion may have less severe phenotypic consequences.
    American Journal of Medical Genetics 10/1997; 71(4):453-7.
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    ABSTRACT: Normal individuals express the two alternative transcripts, FMR2 and Ox19, from the FRAXE-associated CpG island. Molecular analysis of the Ox19 transcript suggests that it is a truncated isoform of the FMR2 gene with an alternative 3' end. Both isoforms showed a similar pattern of expression, with the Ox19 isoform expressed at a much lower level. Fibroblasts, chorionic villi and hair roots showed the highest level of FMR2 expression, whole blood cells and amniocytes showed very low expression, and the transcript was not detected in lymphoblasts. Fibroblasts of 11 individuals from seven families segregating FRAXE were assayed for FMR2 expression and FRAXE CpG island methylation. A man with an unmethylated expansion of 0.6 kb expressed FMR2 and represents a pre-mutation carrier. All chromosomes with FRAXE CCG expansions of 0.8 kb or greater were fully methylated and did not express the FMR2 gene, analogous to the mechanism of silencing the FMR1 gene in carriers of the FRAXA full mutation. The boundary between FRAXE pre-mutation and FRAXE full mutation is between 0.7 and 0.8 kb. Two men with absence of FMR2 expression in fibroblasts were not mentally impaired, suggesting that IQ in some men with FRAXE full mutation may remain within the normal range. Although molecular tools to study FRAXE non-specific mental retardation are now available, further psychometric and molecular studies are needed to characterize the effect of the FRAXE full mutation for the purpose of genetic counselling.
    Human Molecular Genetics 04/1997; 6(3):435-41. · 7.69 Impact Factor
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    ABSTRACT: The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis.
    The American Journal of Human Genetics 04/1997; 60(3):555-64. · 11.20 Impact Factor
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    ABSTRACT: To identify perinatal risk factors for developmental dysplasia of the hip (DDH) and define the risk for each factor. In this case control study, using logistic regression analysis, all 1127 cases of isolated DDH live born in South Australia in 1986-93 and notified to the South Australian Birth Defects Register were included; controls comprised 150130 live births in South Australia during the same period without any notified congenital abnormalities. Breech presentation, oligohydramnios, female sex and primiparity were confirmed as risk factors for DDH. Significant findings were an increased risk for vaginal delivery over caesarean section for breech presentation (as well as an increased risk for emergency section over elective section), high birthweight (> or = 4000 g), postmaturity and older maternal age; multiple births and preterm births had a reduced risk. There was no increased risk for caesarean section in the absence of breech presentation. For breech presentation, the risk of DDH was estimated to be at least 2.7% for girls and 0.8% for boys; a combination of factors increased the risk. It is suggested that the risk factors identified be used as indications for repeat screening at 6 weeks of age and whenever possible in infancy. Other indications are family history and associated abnormalities.
    Archives of Disease in Childhood - Fetal and Neonatal Edition 03/1997; 76(2):F94-100. · 3.45 Impact Factor
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    ABSTRACT: Five autosomal dominant craniosynostosis syndromes (Apert, Crouzon, Pfeiffer, Jackson-Weiss and Crouzon syndrome with acanthosis nigricans) result from mutations in FGFR genes. Fourteen unrelated patients with FGFR2-related craniosynostosis syndromes were screened for mutations in exons IIIa and IIIc of FGFR2. Eight of the nine mutations found have been reported, but one patient with Pfeiffer syndrome was found to have a novel G-to-C splice site mutation at-1 relative to the start of exon IIIc. Of those mutations previously reported, the mutation C1205G was unusual in that it was found in two related patients, one with clinical features of Pfeiffer syndrome and the other having mild Crouzon syndrome. This degree of phenotypic variability shows that the clinical features associated with a specific mutation do not necessarily breed true.
    Human Genetics 03/1997; 99(2):251-5. · 4.63 Impact Factor

Publication Stats

2k Citations
347.05 Total Impact Points

Institutions

  • 1998
    • University of Melbourne
      • Department of Paediatrics
      Melbourne, Victoria, Australia
  • 1997
    • Women`s and Children`s Hospital
      Tarndarnya, South Australia, Australia
  • 1988–1993
    • Royal Adelaide Hospital
      • Department of Genetic Medicine
      Tarndarnya, South Australia, Australia
    • University of Amsterdam
      • Department of Paediatrics
      Amsterdam, North Holland, Netherlands
  • 1990
    • Wellington Hospital
      Веллингтон, England, United Kingdom