Essen, J.A. van

The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes (Article)

2010-09-01T00:00:00Z

Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P=0.043) and significantly more in SIX3: 10.5 vs 4.3% (P=0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance.

Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia (Article)

2008-06-01T00:00:00Z

Hypohidrotic ectodermal dysplasia (HED) can be caused by mutations in the X-linked ectodysplasin A (ED1) gene or the autosomal ectodysplasin A-receptor (EDAR) and EDAR-associated death domain (EDARADD) genes. X-linked and autosomal forms are sometimes clinically indistinguishable. For genetic counseling in families, it is therefore important to know the gene involved. In 24 of 42 unrelated patients with features of HED, we found a mutation in ED1. ED1-negative patients were screened for mutations in EDAR and EDARADD. We found mutations in EDAR in 5 of these 18 patients. One mutation, p.Glu354X, is novel. In EDARADD, a novel variant p.Ser93Phe, probably a neutral polymorphism, was also found. Clinically, there was a difference between autosomal dominant and autosomal recessive HED patients. The phenotype in patients with mutations in both EDAR alleles was comparable to males with X-linked HED. Patients with autosomal dominant HED had features comparable to those of female carriers of X-linked HED. The teeth of these patients were quite severely affected. Hypohidrosis and sparse hair were also evident, but less severe. This study confirms Chassaing et al's earlier finding that mutations in EDAR account for approximately 25% of non-ED1-related HED. Mutations leading to a premature stop codon have a recessive effect except when the stop codon is in the last exon. Heterozygous missense mutations in the functional domains of the gene may have a dominant-negative effect with much variation in expression. Patients with homozygous or compound heterozygous mutations in the EDAR gene have a more severe phenotype than those with a heterozygous missense, nonsense or frame-shift mutation.

Validation and application of intravascular ultrasound in endovascular treatment of abdominal aortic aneurysm (Doctoral Thesis)

2000-06-28T00:00:00Z

An abdominal aortic aneurysm (AAA) is a localized and permanent dilatation of the aorta that presents a clear danger for the patient because of the risk of rupture. The chance of rupture increases with the size of the aneurysm. Mortality after rupture is high: 60-70% of patients with a ruptured AAA will not reach the hospital alive. Furthermore, surgical treatment of ruptured AAA carries an additional mortality of 45-55%. Because of the poor prognosis of ruptured AAA, prophylactic exclusion of AAA is performed for AAA larger than 5.0 to 5.5 cm in diameter. The standard way of treating AAA is by elective open surgery. In this procedure, the diseased aortic segment is opened after proximal and distal cleaning of the vessel and the contents of the aneurysm are removed. A synthetic prosthesis is placed inside the aneurysm. The proximal and distal ends of the prosthesis are anastomosed via continuous sutures to the normal aorta and/or iliac arteries, after which the aneurysm wall is closed around the prosthesis. Elective surgery itself carries a mortality of 5_7% ,patients aged over 70 years, patients with congestive heart failure, cardiac ischemia, preexistent dysrythmia, renal impairment or pulmonary impairment are known to have an increased mortality.

Intravascular ultrasound evidence for coarctation causing symptomatic renal artery stenosis (Article)

1999-01-01T00:00:00Z

BACKGROUND: A recent study of human cadaveric renal arteries revealed that renal artery narrowing could be due not only to atherosclerotic plaque compensated for by adaptive remodeling, but also to hitherto undescribed focal narrowing of an otherwise normal renal arterial wall (ie, coarctation). The present study investigated whether vessel coarctation could be identified in patients with symptomatic renal artery stenosis (RAS). METHODS AND RESULTS: Consecutive symptomatic patients with angiographically proven atherosclerotic RAS who were referred for stent placement were studied by 30-MHz intravascular ultrasound before intervention (n=18) or after predilatation (n=18). Analysis included assessment of the media-bounded area and plaque area (PLA) at the most stenotic site and at a distal reference site (most distal cross-section in the main renal artery with normal appearance). Coarctation was considered present whenever the target/reference media-bounded area was