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

Acrodysostosis in a kuwaiti boy: a brief clinical report

This report describes a Kuwaiti boy with Acrodysostosis. This disorder is characterized by short nose, open mouth, prognathism and short hands/feet. Mental deficiency is frequent and cone epiphyses occur in this condition. Clinical examination, skeletal survey, echocardiography, ultra-sonography and chromosomal analysis were carried out. On examination he had short stature mainly acromelic and the hands did not show the trident sign of dyschondroplasia. He had also a characteristic facies with broad/flat nasal bridge, short nose with upturned nostrils, congenital heart [VSD] and mental retardation. Radiographic examination showed acromelia, cone-shaped epiphyses of bones of hands/feet and scoliosis of thoracolumber region of the spine. CT-scan brain showed mild ventriculomegaly and brain atrophy. Our patient could be a typical case of acrodysostosis with auto-somal dominant mode of inheritance

Females with gonadal dysgenesis: cytogenetic and molecular analysis

Gonadal dysgenesis [GD] is a congenital defect in gonadal development related to abnormalities of genes controlling sexual differentiation and includes a wide spectrum of patients with variable phenotypes and chromosomal constitutions. This study aimed at studying the spectrum of chromosomal abnormalities as related to the phenotypic variability of GD cases and to detect the presence of Y-ctiromosome specific sequences in these patients by using molecular techniques in order to allow, early prophylactic management. Seventy females presenting with female GD were referred to the Human genetic clinic, National Research Center for cytogenetic analysis and genetic counseling. Patients were subjected to clinical examination, pedigree construction, cytogenetic and molecular analysis. Hormonal studies, pelvic ultrasonogrophy, Laparoscopy and gonadal biopsy were performed whenever possible. Patients were classified according to their Karyotypes into 9 groups. The most frequent Karyotype, was 45, X [34.3%]. The association of 45, X with other cell lines were found at a rate of 28.6%. The age of studied cases ranged between 15 days to 31.07 years [mean=14:0.9 years]. The total parental consanguinity rate reached 44.3%. Gonadal dysgenesis and short stature are the two cardinal signs in these patients. Skeletal features were detected among all studied groups with highest scores in patients having complete X monosomy [44.6%]. Neck webbing was a characteristic sign of patients with non-mosaic 45, X karyotype. Dysmorphic features were detected in all groups with the exception of groups with 46, XX and 46, XY Karyotypes. Hirsutism and other virilizing signs were not commonly detected among the studied cases. Gonadoblastoma was detected in only one case among the 5 cases examined by Laparoscopic biopsy. Unidentified sex chromosomes markers constituted 35% of all our 45, X mosaic patterns. Molecular analysis of the markers using PCR technique proved the presence of Y specific sequences, SRY, in three cases. The over all rate of Y chromosomal material detected among these patients either by cytogenetic or molecular methods was 14, 3%

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

Computed cranial tomography in microcephaly

Thirty patients with clinical diagnosis of microcephaly were examined by CT head scan. They were fourteen males and sixteen females and their ages ranged between six months and twelve years. CT scan revealed structural brain anomalies whether of genetic or environmental etiology. CT scan was of great help in diagnosing patients with known preceding destructive brain insult. It also provides supportive data in the diagnosis of some dysmorphic syndromes. Previously unsuspected information regarding the basis of the underlying disease process is able to provide a more specific development prognosis

Comparative ultrastructural studies of gingiva and pulp in the marfan syndrome and homocystinuria

The study comprised four cases; two cases of Marfan syndrome and two cases of homocystinuria. The studied cases with Marfan syndrome clinically presented with myopia, tall stature, mild joint laxity, scoliosis, long slender limbs and arachnodactyly. One case was familial with father affected while the other case was sporadic. The two cases of homocystinuria were from two different families with affected sibs and positive parental consanguinity. The two probands of homocystinuria presented mainly with ectopia lentis, mental retardation, kyphosis and thrombo - embolic manifestations were noted. Utrastructural studies of pulp and gingiva in the Marfan syndrome cases showed active fibroblast cells, collagen fibers with accumulation of precollagen material and increased elastic fibers which showed degenerative changes. In Homocystinuria we noted accumulation of finely granular and fibrillar material between elastic and collagen fibers and in the nerve endings. Few elastic and pre - elastic fibers were seen. The precollagen material formed meshwork of fine filaments and granules. Collagen fibers were twisted, frayed, fragmented, split with increased density. The normal periodicity of collagen was lost in many areas. We can conclude that gingival and pulpal biopsies could be a reflection of molecular differences in the two disorders

Comparison of cytogenetic effects of two anti-bilharzial drugs

Chemotherapy is one of the most valuable methods for the control of schistosomiasis. Remarkable advances have occured in the last 10 years in chemotherapy of bilharziasis, the unconquered parasite. This has raised diligence in evaluating the mutagenecity of these recently used drugs in man, especially that a large percent of treated cases are children and a mass based treatment is sometimes thought of or possibly approached. This work aimed at assessing possible cytogenetic changes caused by two widely used antihelminthic drugs: metrifonate and praziquantel in bilharzial patients. Cytogenetic study in the form of conventional Giemsa, Giemsa-trypsin banding, sister chromatid exchange and micronucleus test were performed in bilharzial patients before and after treatment. These tests are in vivo tests, they measure the effects of the drugs as well as their metabolites. Metrifonate had a mutagenic activity at the level of the three tests used [Chromosomal aberrations, micronucleus test and sister chromatid exchanges]. Comparison of break points induced by this drug and oncogene sites suggested a relationship between them. Praziquantel although had no mutagenic activity at the level of chromosomal aberrations, sister chromatid exchanges, yet had positive results by the use of the micronucleus test. Therefore anti-bilharzial drugs should be used only as treatment when the case is diagnosed and not as mass treatment. The present investigation indicates that praziquantel which is used for treatment of all types of bilharziasis is less clastogenic than metrifonate. In testing chemical mutagenecity in general and for anti-schistosomal drugs in particular, a combination of the three mutagenecity tests included in the study is prefered for more informative results

Environmental factors in the etiology of congenital malformations in Egyptians

Among 500 cases with birth defects referred to the Human Genetics Department, National Research Center over a period of one year, 16 cases [3.2%], were selected for this study because they had positive history of exposure to teratogenic agents during early pregnancy. None of the studied cases had history of exposure to mutagenic or teratogenic agents prior to pregnancy.Environmental agents associated with the malformations were as follows: hormonal treatment in 9 cases, maternal diabetes in 3 cases, maternal rubella in 2 cases, maternal exposure to irradiation in one case, and lastly maternal intake of antimalarial drugs in one case. From this study we can emphasize the role played by environmental factors in the etiology of malformations in our country as it represents 3.2% of the referred cases with birth defects. We also confirm the recommendation to avoid the use of sex-steroid hormones and other teratogenic drugs during the period of organogenesis. Pregnant mothers should avoid exposure to irradiation and be immunized against viral infections particularly rubella before being pregnant. Diabetes should be adequately controlled by the use of insulin especially that no proof exists for its teratogenicity

New observations in the Laurence-Moon and Bardet-Biedl syndromes

Over a period of four years we studied eleven families of probands with features of Laurence-Moon or Bardet-Biedl syndromes. Although previously thought to represent on entity the Laurence-Moon-Bardet-Biedl syndrome, recent Literature [Toledo et al, 1977] suggests their classification into two distinct autosomal recessive syndromes. The Laurence-Moon syndrome [LMS] first described in 1866 and the Bardel-Biedl syndrome [BBS] first described by Bardet [1920] and Biedl [1922]. The main features of BBS are marked obesity, postaxial polydactyly in addition to all the features of the Laurence-Moon syndrome without paraplegia. In the present work we classified the eleven families comprising 17 cases into: one sporadic case with Laurence-Moon syndrome and 16 cases in 10 families with the Bardet-Biedl syndrome. This emphasized the rarity of LMS in relation to BBS as was noted before. Orodental anomalies were more obvious in the BBS in the form of high arched palate high caries index microstomia and xerostomia The study confirmed the significantly high whorl pattern in the BBS pateints as previously suggested by Temtamy and Shalash [1975]. Although the present study indicates new differences between BB and LM syndrome more cases need to be studied to confirm our findings

Biochemical screening for certain inborn errors of metabolism that cause mental retardation in Egyptian children

Among 1268 patients with genetic diseases referred of the human Genetics Department [NRC]. 197 cases [15.5%] had isolated mental retardation. The present study deals with biochemical screening of certain metabolic abnormalities in these 197 cases. Biochemical screening was by qualitative chemical tests on urine for the detection of certain defects in amino acid. Carbohydrate and mucopolysaccharide metabolism and by thin layer chromatographic detection of specific amino acids in plasma and urine. Quantitative determinations of urea, creatinine, ammonia and uric acid in plasma, argininosuccinase and arginase enzyme activities in erythrocytes; mucopolysacchrides and creatinine in urine were done when indicated. Our results indicated that 83 patienls of the 197 [42.13%] had inborn errors of metabolism: 77.1%, of them had amino acidopathies and urea cycle disorders and 22.9% had mucopolysacharidosis. Parental consanguity rate was high [61%]. From the results of this investigation we recommend the need to avoid consanguineous marriages in our society and to initiate neonatal screening programs for early detection and treatment of these defects whenever possible and for proper genetic counseling and prenatal diagnosis in subsequent pregnancies

Effect of novalgin on chromosomes of rattus norvegicus

Novalgin; the sodium sulphonate derivative of aminopyrine, is an analgesic, antipyretic drug, widely used in Egypt. In spite of its well known hematologic complications, mutagenicity tests are deficient in the literature. The main aim of the present work was to study the cytogenetic effects of novalgin on bone marrow cells of Rattus norvegicus, using the method recommended by the Ad Hoc Committee of Mutagenicity Testing [1972]; Novalgin induced significant Chromosomal aberrations of both chromatid and chromosome type, and depression of mitosis 48 hours after treatment with the maximum tolerated dose in the acute study and after sub-acute treatment with the clinical dose, The results of the study suggest that novalgin is mutagenic and causes depression of mitosis when administered at very high doses, or after prolonged use of the clinical dose

Genetic studies on rare limb malformations in Egyptian children

A study was conducted on four cases with rare limb malformations. These cases were diagnosed as Nager acrofacial dysotosis, craniosynostosis/radial dysphasia, bilateral tibial aplasia and probable diabetic embryopathy. A proper diagnosis was reached through combined clinical and genetic studies including prenatal, natal and post natal history, clinical examination as well as family, cytogenetic, dermatoglyphic and radiological studies. Our findings confirm the importance of such an approach for proper genetic counseling