Cortical-Bone Fragility - Insights from sFRP4 Deficiency in Pyle's Disease

BACKGROUND Cortical-bone fragility is a common feature in osteoporosis that is linked to non - vertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger se - quencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS In all affected patients, we found biallelic truncating mutations in SFR P4 , the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4 , like persons with Pyle’s disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treat - ment of Sfrp4- deficient mice with a soluble Bmp2 receptor (RAP-661) or with anti - bodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical- bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss Na - tional Foundation and the National Institutes of Health.

A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategie

Chromosome Analysis In The Assessment For Gender Affirmation Process: A Retrospective Study

Objective: Gender dysphoria refers to the experienced discomfort related to the incongruence between gender identity and the sex assigned at birth. Current treatment approach for this clinical condition is gender affirmation procedures. International guidelines about gender affirmation do not recommend routine genetic evaluation. In Turkey, provision of health insurance for medical expenses incurred by these procedures requires genetic consultation which frequently involves chromosome analysis (karyotyping). However, the contribution of routine chromosome analysis to the assessment and management of gender dysphoria is not established. This study aims to mess the results of chromosome analysis and its effect on the management of gender dysphoria. Method: The completed chromosome analysis results and observational records of 217 individuals among a total of 281 evaluated for gender affirmation in the psychiatry polyclinic were investigated retrospectively. Results: The chromosome analysis results of 213 (98.2 %) of the 217 individuals investigated were congruent with the sex assigned at birth. Variations were found in the karyotypes of 4 individuals with female sex assigned at birth, only 1 of whom had been diagnosed with a disorder of sex development. In the other cases, however, chromosome analysis did not affect the diagnosis or the clinical intervention. Conclusion: Finding that routine chromosome analysis during the assessment for gender affirmation process rarely affected the clinical diagnosis and the treatment was consistent with the reports of previous studies and supported the recommendation that chromosome analysis should be carried out only in cases where history, physical examination and the required imaging investigations suggested a disorder sex development.WoSScopu

Infantile Systemic Hyalinosis: A Case Report

Infantile systemic hyalinosis (ISH) is an autosomal recessive, rare disorder in which hyaline deposition occurs in multiple organ systems, including the skin. It is characterised by painful joint contractures, gingival hypertrophy, generalized osteopenia, small pearly papules on the head, flesh nodules in the perianal region, and usually thickened skin. The onset occurs within the first few weeks of life and death occurs by two years of age as a result of recurrent pulmonary infections and diarrhea. Unfortunately, treatment is primarily palliative as there is no cure currently available. Herein, we report an 8-month-old boy who is diagnosed with ISH with the characteristic clinical presentation and histopathological findings. (Turkderm 2009; 43: 112-5)Wo

A Novel De Novo Mutation Involving the Mll2 Gene in a Kabuki Syndrome Patient Presenting with Seizures

Kabuki syndrome is a rare multiple congenital anomaly disorder. Although mental retardation is one of the main features, various neurological symptoms such as hypotonia and seizures can occur. Here we report on a 18-year-old Turkish male patient who was diagnosed previously as Kabuki syndrome. Molecular genetic analysis showed a novel de novo heterozygous mutation (c. 12964C>T [p.Gln4322*]) in the MLL2 gene, that leads to the synthesis of a truncated protein. The aim of the present report is to increase the awareness of Kabuki Syndrome among adult neurologistsWoSScopu

Anauxetic Dysplasia: A Rare Clinical Entity

Cartilage hair hypoplasia and anauxetic dysplasia spectrum constitute a group of autosomal recessive disorders characterized by variable extent of metaphyseal to spondylometaepiphyseal involvement and various additional clinical features. Within this group, anauxetic dysplasia represents the severe end of the skeletal spectrum. However, extraskeletal features including immunodeficiency, hematological abnormalities, and hair hypoplasia are absent, despite the severe skeletal involvement. This disorder is caused by mutations in the gene encoding ribonuclease mitochondrial RNA-processing complex. We herein report on a patient with anauxetic dysplasia, who presented with severe roto-scoliosis and skeletal findings requiring surgical intervention, and in whom a homozygous RMRP mutation was detected.WoSScopu

Epigenotype And Phenotype Correlations In Patients With Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome (BWS) is one of the most common overgrowth syndromes. Cancer predisposition is an important feature of this clinically heterogeneous syndrome. Patients may have fetal and early childhood overgrowth, hemihyperplasia, macroglossia, facial dysmorphic features, abdominal wall defects, visceromegaly, and anomalies of the heart and the kidneys. Various previous investigations showed that heterogeneous molecular etiology may contribute to clinical variability and that epigenotype-phenotype correlations exist in BWS. This study was performed to detect the molecular etiology in 28 patients with BWS, to search for epigenotype-phenotype correlations and to provide appropriate individualized multidisciplinary approach. Four different molecular etiology groups were determined based on testing for copy number analysis and methylation status at 11p15. Sequencing for CDKN1C mutations were also performed. Groups were compared for various clinical findings. Differences between groups were not statistically significant owing to the small number of patients in individual groups. Statistical studies for epigenotype-phenotype correlations showed significance for only anterior ear lobe creases, visceromegaly and embryonal tumors. Additionally, one interesting patient had a mesenchymal tumor. Anticipating follow-up is clinically important in BWS.WoSScopu

Cryptic trisomy 5q35.2qter and deletion 1p36.3 characterised using FISH and array-based CGH

A 10(6/12)-year-old boy was referred to the genetics department because of mental retardation and dysmorphic findings including microcephaly, flat face, down-slanting palpebral fissures, strabismus, prominent ears, bulbous nasal tip, down-turned corners of the mouth, narrow palate, clinodactyly of the fifth fingers and generalised eczema. Cytogenetic analysis revealed a karyotype of 47,XY,+mar of paternal origin. Multicolour FISH showed the marker chromosome to be derived from chromosome 15. For further elucidation of the phenotype, array-based comparative genomic hybridisation (aCGH) was performed, which revealed dup(5)(q35.2qter) and del(1)(p36.3). Parental FISH analysis revealed that the translocation occurred de novo. Despite the presence of a clinical phenotype along with a microscopically visible chromosomal aberration, a complex cryptic cytogenetic abnormality was causative for the phenotype of the patient. Elucidation of this complex aberration required combination of the whole cytogenetic toolbox.status: publishe

Dermal Fibroblast Transcriptome Indicates Contribution Of Wnt Signaling Pathways In The Pathogenesis Of Apert Syndrome

Cranial sutures are unossified connective tissue structures between the cranial bones, which allow expansion of these bones during development. Premature ossification of these structures is called craniosynostosis. Apert syndrome is a well-defined genetic syndrome, which is characterized by craniosynostosis and arises as a result of two missense mutations in Fibroblast Growth Factor Receptor, type 2 gene (FGFR2). In this study, differentially expressed genes in dermal fibroblasts from individuals with Apert syndrome and controls were investigated to identify important pathways in the pathogenesis of Apert syndrome. For this purpose, primary skin fibroblast cultures obtained from 3 individuals with Apert syndrome and 3 controls without craniosynostosis were compared by transcriptome microarray, GeneChip Human Genome U133 Plus 2.0. As a result, 181 genes were shown to be differentially expressed between experimental groups. Among these, 10 genes, which significantly differ in Apert syndrome fibroblasts compared to controls, were shown to be involved in a common interaction network and have common Gene ontology (GO) biological processes terms. COLI 1A1, COMP, CPXM2, ITGA8, MGF and INC are differentially expressed genes that have GO terms associated with extracellular matrix (ECM) organization, while FRZB, SFRP2 and WNT2 are involved in WNT signaling pathway. Reorganization of ECM and changes in WNT signaling pathway show that Apert syndrome primary fibroblast cultures may have an increased potential for bone differentiation. The results of this study support craniosynostosis in Apert syndrome may be the result of fast and early differentiation of connective tissue along the sutures.Wo