Molecular Basis of Proxysomal Disorders in Zellweger Syndrome

Peroxisomes are organelles present in all eukaryotic cells from yeast to human cells. It is now well known that approximately fifty different biochemical reactions occur within the peroxisome, including synthesis of bile acids, cholesterol, ether-phospholipids (plasmalogens), docosahexaenoic acid and catabolism of certain fatty acids, particularly very long chain fatty acids (VLCFAs). Proteins involved in peroxisomal function are known as peroxins. At least 29 peroxins are required for peroxisome membrane biogenesis, fission, and protein import. So far, mutations in 13 genes that encode peroxins are associated with human disease. Peroxisomal disorders currently falling into one of three groups peroxisome biogenesis disorders (PBDs), peroxisomal multi-enzyme disorders, and peroxisomal single-enzyme disorders. Infantile Refsum’s disease (IRD), neonatal adrenoleukodystrophy (NALD) and Zellweger’s syndrome (ZS) are different variants of a group of congenital diseases known as peroxisome biogenesis disorders. These disorders are characterized by the absence of normal peroxisomes in the cells of the body which mostly are fatal. Here we describe molecular events that cause these deficiencies and we introduce current molecular approaches for diagnosis of these disorders like mutation analysis and fibroblasts characterization derived from the patients

Hereditary bilateral conductive hearing loss caused by total loss of ossicles: A report of familial expansile osteolysis

Objective: The objective of this study was to report on three members of a family with familial expansile osteolysis; the important point about these patients was that none of them had middle-ear ossicles. Study Design and Subjects: A retrospective case review including three cases with familial expansile osteolysis. Setting: Department of Otolaryngology in a tertiary referral center. Interventions: Each patient underwent computerized tomography of the temporal bone in the coronal view, audiometric and tympanometric evaluations, biochemical investigation, whole body isotope scans by Tc-99 mMDP and X-ray. Also the patients' pedigree was studied. Two of the patients had exploratory middle-ear surgery as well. Results: The temporal-bone computed-tomography scan in the coronal view of all three patients and also exploratory middle-ear surgery, which was done on two of the patients, showed no ossicles in the middle ear of either ear in all three cases. This feature hadn't been reported in previous studies. Hearing loss was revealed in the medical histories since childhood. Audiometry indicated mild to moderate conductive and mixed hearing loss and also an AD-type tympanogram pattern along with an absence of acoustic reflexes in both ears of the cases. Both serum alkaline phosphatase and hydroxyproline levels were elevated. There was an increase in uptake and activity at multiple foci of the whole skeleton. No improvement in hearing thresholds was obtained after reconstruction of the middle ear. Conclusion: The total absence of middle-ear ossicles can probably be regarded as a new symptom in some patients with familial expansile osteolysis. Common ossiculoplasty for improving the hearing thresholds in this condition may be unsuccessful; therefore, both surgeons and patients must be completely aware of the contingent undesirable results. © 2005, Otology & Neurotology, Inc

Phenotypic overlap of Roberts and Baller-Gerold syndromes in two patients with craniosynostosis, limb reductions, and ESCO2 mutations

Baller-Gerold (BGS, MIM#218600) and Roberts (RBS, MIM#268300) syndromes are rare autosomal recessive disorders caused, respectively, by biallelic alterations in RECQL4 (MIM*603780) and ESCO2 (MIM*609353) genes. Common features are severe growth retardation, limbs shortening and craniofacial abnormalities which may include craniosynostosis. We aimed at unveiling the genetic lesions underpinning the phenotype of two unrelated children with a presumptive BGS diagnosis: patient 1 is a Turkish girl with short stature, microcephaly, craniosynostosis, seizures, intellectual disability, midface hemangioma, bilateral radial and thumb aplasia, tibial hypoplasia, and pes equinovarus. Patient 2 is an Iranian girl born to consanguineous parents with craniosynostosis, micrognathism, bilateral radial aplasia, thumbs, and foot deformity in the context of developmental delay. Upon negative RECQL4 test, whole exome sequencing (WES) analysis performed on the two trios led to the identification of two different ESCO2 homozygous inactivating variants: a previously described c.1131+1G>A transition in patient 1 and an unreported deletion, c.417del, in patient 2, thus turning the diagnosis into Roberts syndrome. The occurrence of a Baller-Gerold phenotype in two unrelated patients that were ultimately diagnosed with RBS demonstrates the strength of WES in redefining the nosological landscape of rare congenital malformation syndromes, a premise to yield optimized patients management and family counseling

J. Med. Genet.

Background: Primary microcephaly (MCPH) is a genetically heterogeneous disorder showing an autosomal recessive mode of inheritance. Affected individuals present with head circumferences more than three SDs below the age- and sex-matched population mean, associated with mild to severe mental retardation. Five genes (MCPH1, CDK5RAP2, ASPM, CENPJ, STIL) and two genomic loci, MCPH2 and MCPH4, have been identified so far. Methods and results: In this study, we investigated all seven MCPH loci in patients with primary microcephaly from 112 Consanguineous Iranian families. In addition to a thorough clinical characterisation, karyotype analyses were performed for all patients. For Homozygosity mapping, microsatellite markers were selected for each locus and used for genotyping. Our investigation enabled us to detect homozygosity at MCPH1 (Microcephalin) in eight families, at MCPH5 (ASPM) in thirtheen families. Three families showed homozygosity at MCPH2 and five at MCPH6 (CENPJ), and two families were linked to MCPH7 (STIL). The remaining 81 families were not linked to any of the seven known loci. Subsequent sequencing revealed eight, 10 and one novel mutations in Microcephalin, ASPM and CENPJ, respectively. In some families, additional features such as short stature, seizures or congenital hearing loss were observed in the microcephalic patient, which widens the spectrum of clinical manifestations of mutations in known microcephaly genes. Conclusion: Our results show that the molecular basis of microcephaly is heterogeneous; thus, the Iranian population may provide a unique source for the identification of further genes underlying this disorder

Investigation of chromosomal abnormalities and microdeletion/ microduplication(s) in fifty Iranian patients with multiple congenital anomalies

Objective: Major birth defects are inborn structural or functional anomalies with long-term disability and adverse impacts on individuals, families, health-care systems, and societies. Approximately 20 of birth defects are due to chromosomal and genetic conditions. Inspired by the fact that neonatal deaths are caused by birth defects in about 20 and 10 of cases in Iran and worldwide respectively, we conducted the present study to unravel the role of chromosome abnormalities, including microdeletion/microduplication(s), in multiple congenital abnormalities in a number of Iranian patients. Materials and Methods: In this descriptive cross-sectional study, 50 sporadic patients with Multiple Congenital Anomalies (MCA) were selected. The techniques employed included conventional karyotyping, fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridisation (array-CGH), according to the clinical diagnosis for each patient. Results: Chromosomal abnormalities and microdeletion/microduplication(s) were observed in eight out of fifty patients (16). The abnormalities proved to result from the imbalances in chromosomes 1, 3, 12, and 18 in four of the patients. However, the other four patients were diagnosed to suffer from the known microdeletions of 22q11.21, 16p13.3, 5q35.3, and 7q11.23. Conclusion: In the present study, we report a patient with 46,XY, der(18)12/46,XY, der(18), +mar8 dn presented with MCA associated with hypogammaglobulinemia. Given the patient�s seemingly rare and highly complex chromosomal abnormality and the lack of any concise mechanism presented in the literature to justify the case, we hereby propose a novel mechanism for the formation of both derivative and ring chromosome 18. In addition, we introduce a new 12q abnormality and a novel association of an Xp22.33 duplication with 1q43q44 deletion syndrome. The phenotype analysis of the patients with chromosome abnormality would be beneficial for further phenotype-genotype correlation studies. © 2019 Royan Institute (ACECR). All rights reserved

The Epidemiology, Genetics and Future Management of Syndactyly

Syndactyly is a condition well documented in current literature due to it being the most common congenital hand defect, with a large aesthetic and functional significance

Prenatal diagnosis in a mentally retarded woman with mosaic ring chromosome 18

We present a pregnant woman with mental retardation and mosaic for ring 18 referred for prenatal diagnosis. Major clinical features included short stature with clinodactyly in feet, foot deformity and club feet, hypotonia, kyphosis, and absence of breast development, low set ears, high arched palate, dental decay and speech disorder. Prenatal diagnosis was carried. Using amniocentesis. The fetus had a normal karyotype described as 46,XX. The fetus was evaluated for clinical features after delivery; she was healthy with no abnormal clinical characterizations

Yunis-Varón Syndrome: The First Report of Two Iranian Cases

The Yunis-Varón syndrome represents a rare autosomal recessive syndrome of easy recognition characterized by defective growth of the cranial bone along with complete or partial absence of the clavicles (cleidocranial dysplasia), absence of thumbs and halluces, distal aphalangia, ectodermal anomalies, growth retardation and poor outcome. The molecular genetic basis is unknown. Here, we report an 8 months old girl with Yunis-Varón syndrome, born to a consanguineously married, with normal parents. She had micrognathia, wide fontanels, prominent eyes, poor sucking, congenital heart diseases, asymmetric face, ambiguous genitalia, reduction anomaly in right hand including thumb, and hypoplastic distal phalanges of 3th fingers, and hypo plastic clavicles. She has glaucoma and lenses opacity. There is another similar case in her family. Karyotype is normal. She is the first Iranian known case of Yunis-Varón syndrome

Fraccaro Syndrome: Report of Two Iranian Cases: An Infant and an Adult in A Family

49,XXXXY is rare chromosomal pattern and these patients have mental retardation, small penis, cryptorchidism and skeletal anomalies. We reported a 10 month-old boy who has hypotonia, microcephaly, hypertelorism, depressed nasal bridge, epicanthic folds and bilateral multiple ear tags, high arched palate, down set ears, micrognathia and congenital heart disease such as patent ductus arteriosus (PDA), Atrial septal defect (ASD), mild pulmonary stenosis. Among the skeletal anomalies, he has kyphoscoliosis, clinodactyly of the fourth and fifth fingers of both hands, and bilateral club foot and unilateral dysplasia of the hip. Karyotype was found as 49,XXXXY[44]/48,XXXY[6] and this cytogenetic analysis was help to establish clinical diagnosis Fraccaro syndrome