Clinical, anthropometric, radiological and molecular characteristics of Egyptian achondroplasia patients

Achondroplasia is the most common form of non lethal skeletal dysphasia. It is a fully penetrant autosomal dominant disorder and the majority of cases are sporadic resulting from de novo mutations associated with advanced paternal age. The phenotype of achondroplasia is related to disturbance in endochondral bone formation due to mutations in the fibroblast growth factor receptor-3 [FGFR3] gene. Evaluation of the cardinal phenotypic features in achondroplasia, the body physique using anthropometric measurements, the characteristic radiological signs in the patients as a main tool for diagnosis and detection of the most common mutations in achondroplasia patients in the studied sample. From 42 cases referred to us as achondroplasia, we selected 20 cases where clinical manifestations were consistent with achondroplasia. Cases were subjected to full clinical examination, detailed anthropometric measurements, whole body skeletal survey and molecular studies of the most common mutations of the FGFR3 gene using PCR amplification technique. Nineteen cases were sporadic [95%] and one case had an affected father [5%]. A paternal age above 35 years at the time of child's birth was present in 7 cases [35%]. Paternal exposure to occupational heat was noted in 6 cases [30%] and parental exposure to chemicals in 3 cases [15%]. All cases showed typical clinical and radiological manifestations of achondroplasia. Anthropometric measurements quantitatively confirmed the body physique in the studied eases. G380R common mutations of the FGFR3 gene were detected in 15/18 cases [83%] with the G to A transition at nucleotide 1138 in 14 cases [77%]. Agenesis of corpus callosum, not previously reported in association with achondroplasia, was present in the only case with the G-C transversion mutation at nucleotide 1138 [5%]. Awareness of the cardinal features of achondroplasia, proper anthropometric measurements and detailed skeletal survey are the key for accurate diagnosis, genetic counseling and avoidance of over diagnosis. The majority of studied Egyptian achondroplasia patients have the same common mutation that has been most often defined in patients with achondroplasia from other countries

Genetic heterogeneity in spondylo-epi-metaphyseal dysplasias: a clinical and radiological study

Spondylo-epi-metaphyseal dysplasias [SEMD] are a heterogeneous group of skeletal disorders characterized by defective growth and modeling of the spine and long bones. Different types are described in the literature. Accurate classification of SEMDs is essential for proper genetic counseling. This study included 20 cases of SEMDs diagnosed by clinical and radiological findings. Cases were classified based on additional associated clinical and/or radiological features into 7 subtypes. Different subtypes were discussed with review of the literature. The study illustrated the heterogeneity of SEMDs and emphasized the importance of detailed and meticulous clinical genetic and biochemical evaluation in addition to comprehensive radiological investigations for such group of disorders. It also recommends further molecular studies to identify the molecular bases of the different types

Genetic studies of limb reduction defects

Limb reduction defects are an important group of congenital limb malformations that requires thorough assessment. They can be isolated or associated with other malformations as a part of syndrome. Causes of limb deficiencies include single gene disorders, chromosomal abnormalities or teratogens. However, the etiology remains unknown in many cases. The present study aimed at the proper diagnosis and classification of cases with limb defects referred to the Limb Malformations Clinic, NRC in order to provide accurate and efficient genetic counseling. The study included 22 cases [14 males, 8 females] with limb reduction defects, their ages at presentation ranged between 20 days and 16 years. Detailed history including teratogen exposure and affected family members, three generation pedigree analysis, complete examination of different body systems with specific studies of different parts of the limbs documented by radiological examination, photography and basic anthropometric measurements were conducted for all cases. Dermatoglyphic analysis, cytogenetic studies and other investigations were done whenever indicated. Cases were classified according to Temtamy and McKusick [1] based on both anatomical and genetic considerations into 8 groups; isolated terminal transverse defects [n=5, cases 1-5= 22.7%], terminal transverse defect as a part of syndrome [n=1, case 6= 4.54%], isolated radial defect [n=1, case 7= 4.54%], radial defect as a part of syndrome [n= 7, cases 8-14= 31.8%], isolated ulnar defect [n= 2, cases 15, 16= 9.09%], ulnar defect as a part of syndrome [n= 3, cases .17-19= 13.6%], pre and postaxial defect [n= 1, case 20= 4.54%] and axial defect as a part of syndrome [n=2, cases 21, 22= 9.09%]. The results of this study have shown that limb absence or reduction defects are not an uncommon malformation among Egyptian children. Delineation of the exact cause, correct classification and proper diagnosis are needed to face this disabling chronic problem. Molecular studies are recommended for proper diagnosis, genetic counseling and understanding of the pathogenesis

Genetic studies of congenital contractures of limbs

Congenital contractures of limbs comprise a category of limb malformations that poses a difficult diagnostic and therapeutic problem. They can occur as an isolated defect or as part of syndromes. This study included 46 patients with congenital contractures of limbs. Cases were referred to the Limb and Skeletal Anomaly Clinic at the National Research Centre. Detailed family history, pedigree construction, physical and orodental examination, anthropometric measurements and radiological studies were carried out for all cases. Cytogenetic analysis using G-banding and high resolution techniques were carried out for 36 cases. Biochemical and neurophysiologic studies were conducted for selected cases. According to clinical phenol-type, cases were classified into 4 main categories, which were further subdivided into 16 entities. Category [I]: included congenital contractures that affected primarily the musculoskeletal system, 18 cases were in this category comprising 8 entities. Category [II]: Twenty cases had musculoskeletal involvement in addition to other system malformations or anomalies comprising 5 entities, of which 11 cases had multiple pterygium syndrome. Category [III]: Six patients in this study had musculoskeletal involvement plus lethality, CNS anomalies or mental retardation. Four were diagnosed as Pena-Shokeir syndrome, one with Aase-Smith syndrome and another case showed dup [1] [p36.1-36.2]. Category [IV]: Contracture deformities of limbs due to environmental factors, which were present in 2 cases only. Detailed genetic and clinical analysis of different cases with congenital contractures of limbs are presented in this study. Our work proved that contracture deformities of limbs due to genetic causes were the most common [44 cases], while those related to environmental causes were only present in 2 cases. This emphasizes the importance of careful clinical examination and categorization o patients with congenital contracture! of limbs and the necessity of proper genetic counseling of affected families. The study of the molecular causes of these disorders is important for the understanding of the pathogenesis hoping for their prevention, early intervention and gene therapy