| Popis: |
Contains fulltext : 49466.pdf (Publisher’s version ) (Open Access) In this thesis the results are described of clinical and molecular investigation of human syndromes with congenital patellar malformations as a hallmark feature, with emphasis on nail patella syndrome, small patella syndrome, isolated patellar aplasia or hypoplasia, and Meier-Gorlin syndrome. The elucidation of the underlying genetic defects is of important for gaining insight in the proteins and the molecular regulatory mechanisms crucial for normal limb development. Detailed phenotype studies of these syndromes and animal models with congenital patellar malformations contribute to understanding the role of these genes in normal and disturbed development of the limb and additional organs affected. Chapter 2.1 summarizes the literature on the clinical and molecular findings in human NPS and animal models for NPS up to 2002. Chapter 2.2 describes the identification of the first mutations in eight Dutch NPS families. Chapter 2.3 reports on the molecular investigation of candidate modifying genes in a family with high prevalence of NPS nephropathy. In Chapter 2.4 the molecular pathologic studies of kidneys of individuals with NPS nephropathy is described. Chapter 2.5 presents detailed genotype-phenotype studies of 32 NPS families expanding the clinical spectrum and revealing a first genotype-phenotype association involving NPS nephropathy. In Chapter 3.1 clinical and haplotype studies of small patella syndrome (SPS) families are reported and diagnostic criteria of SPS are defined. Chapter 3.2 describes the discovery of human TBX4 mutations underlying SPS and the role of TBX4 in the development of pelvis, patellar, and (meta)tarsal bones. Chapter 3.3 focuses on haplotype analysis of a candidate chromosome region for isolated patella aplasia-hypoplasia in a family with isolated patella aplasia-hypoplasia. Chapter 4 presents the clinical characterisation of eight patients with Meier-Gorlin syndrome. In the addenda, recommendations for diagnostic-workup and clinical management and aspects in genetic counselling of patients with patellar malformation syndromes and their families are presented. RU Radboud Universiteit Nijmegen, 02 februari 2006 Promotores : Knoers, N.V.A.M., Kampen, A. van Co-promotor : Bokhoven, J.H.L.M. van 216 p. |
