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The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na(+)/Cl(-) cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension. Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms-rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)-using the Snapshot method. The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2-15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5-11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02). Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted.

Background: Recent reports have found genetic mutations in up to one quarter of patients harbouring pheochromocytoma and/or paraganglioma. This high prevalence was mainly due to the discovery of the role of SDH genes. While SDHD has been more frequently associated with the pathogenesis of head and neck paragangliomas, SDHB mutations were mainly associated with malignant and/or extra-adrenal pheochromocytoma/paraganglioma., Objective: To look for mutations in susceptibility genes and genotype-phenotype correlations in patients with pheochromocytoma and/or paraganglioma from Belgium., Methods: Screening of the coding parts of SDH, VHL and RET genes was performed by SSCP in patients with pheochromocytoma and/or paraganglioma diagnosed at or referred to the Cliniques Universitaires Saint Luc from May 2003 to May 2006., Results: Fifty-six unrelated patients were included (36 head and neck paragangliomas, including six familial cases and 30 sporadic cases; 18 abdominal pheochromocytoma/paraganglioma and two paraganglioma of the cauda equina). The overall prevalence of mutations was 41% (n = 23 including 19 head and neck paragangliomas and four abdominal pheochromocytoma/paraganglioma), mainly due to SDH mutations. While SDHD mutations were found in all patients with familial head and neck paragangliomas, in sporadic cases, the prevalence of SDHB mutations (n = 8, 27%) was twice that of SDHD mutations (n = 4, 13%). Patients harbouring SDHB mutations had unilateral late-onset head and neck tumours without evidence of recurrence or malignancy., Conclusion: This Belgian series confirms the elevated prevalence of predisposing mutations in patients with head and neck and extra-adrenal paragangliomas, but differs from previous reports by the high frequency of SDHB mutations associated with head and neck paragangliomas without evidence of recurrence or malignancy.

Cleft lip with or without cleft palate is the most frequent craniofacial malformation in humans ( approximately 1/700). Its etiology is multifactorial; some are a result of a genetic mutation, while others may be due to environmental factors, with genetic predisposition playing an important role. The prevalence varies widely between populations and the mode of inheritance remains controversial. The interferon regulatory factor-6 (IRF6) gene has been shown to harbor mutations in patients with van der Woude syndrome, a dominant form of clefts associated with small pits of the lower lip. Moreover IRF6 has been associated with nonsyndromic cleft of the palate (CL/P) in two separate studies. We investigated the role of IRF6 in a set of 195 trios from Belgium. Cleft occurred as an isolated feature. We studied association of the IRF6 locus using two variants: one in the IRF6 gene and the other 100 kpb 3' of the gene. Our independent study group confirms that the IRF6 locus is associated with nonsyndromic cleft lip with or without palate. This result, with previous studies performed in the United States and Italy, shows for the first time the implication of IRF6 in isolated CL/P in northern Europe. It is likely that association to this locus can be identified in various populations and that the IRF6 locus thus represents an important genetic modifier for this multifactorial malformation.

Objectives: To develop clinical criteria that permit clinical distinction between inherited glomuvenous malformation (GVM), known as glomangioma, and inherited cutaneomucosal venous malformation and to test these criteria on sporadic lesions., Design: Clinical data were compiled for 1685 patients with inherited or sporadic cutaneous venous anomalies. Based on a cohort of patients with a mutation in the TIE2 or glomulin gene or a histologic diagnosis, we defined clinical criteria for inherited GVM and cutaneomucosal venous malformation. We then applied these criteria to sporadic cases in a blinded manner and genetically or histologically confirmed this clinical diagnosis whenever possible., Results: Glomuvenous malformations accounted for 5.1% of venous anomalies and were frequently inherited (63.8%), whereas venous malformations were rarely familial (1.2%). Glomuvenous malformations were nodular and scattered, or plaque-like and segmental, with color varying from pink to purplish dark blue, whereas most venous malformations (VMs) were soft, blue, and often localized vascular lesions. Glomuvenous malformations were mainly located on the extremities and involved skin and subcutis, whereas VMs commonly affected muscles and joints (P<.001). Glomuvenous malformations had a distinct raised, often hyperkeratotic cobblestone-like appearance and could not be completely emptied by compression, unlike VMs. Glomuvenous malformations were painful by compression, whereas VMs were painful on awakening, after activity, or with hormonal changes. Elastic compressive garments aggravated pain in GVMs, in contrast to VMs., Conclusions: This large series of patients with superficial venous anomalies established clinical features that distinguish VMs and GVMs. This differential diagnosis is essential, as the outcome and the treatment for GVMs differ.