Perinatal lethal osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heterogeneous group of genetic bone disorders that are characterised by decreased bone mass, increased bone fragility and susceptibility to fractures. The severe, perinatal lethal form (Type II) (OMIM 166210) is characterised by bone fragility, with perinatal fractures, severe bowing of long bones, undermineralisation, and death in the perinatal period owing to respiratory insufficiency. The overall prevalence of OI Type II is unknown. There are three subtypes of OI Type II (A, B and C) that are characterised by different radiological features, and may be caused by different genetic faults. Two fetuses with OI Type IIA are presented

An audit of thyroid function tests in a cohort of South African children with Down Syndrome

M.Med. (Medical Genetics)--University of the Witwatersrand, Faculty of Health Sciences, School of Pathology, 2012Down syndrome (DS) (OMIM #190685), the most common viable chromosome abnormality, is associated with an increased risk of medical complications. The most frequent endocrine abnormalities observed in children with DS involve the thyroid gland, and the risk of thyroid dysfunction increases with age. Global studies have documented a wide spectrum of thyroid dysfunction in children with DS. Due to the paucity of data from sub-Saharan Africa regarding thyroid function in African children with DS, this study was conceived. The main aim of the study was to document the range of thyroid function in a cohort of 391 South African children with DS, seen at the Genetic Clinics from 2003 to 2008. Referral and treatment practices at two tertiary hospitals in Johannesburg were also documented. The majority (84%) of children had at least one thyroid function test (TFT) performed, and the most common form of thyroid dysfunction encountered was subclinical hypothyroidism (25.3%). Notably, up to one third of patients with abnormal TFT results were not referred to the Endocrine Clinics for evaluation, and were thus not receiving the necessary treatment. There were 13 neonates with congenital hypothyroidism; at least two of them were not referred, and thus not treated during the sensitive neonatal period. A significant difference was noted between the results from Chris Hani Baragwanath Hospital and those from the other two hospitals. The difficulties in interpretation of results obtained from different biochemical machines and different populations, as compared to those used to derive the reference ranges, were raised. Problems with regular follow-up of patients and annual thyroid surveillance were also highlighted. The clinical features of hypothyroidism may be difficult to distinguish from the phenotypic features of DS. Thus, regular biochemical screening, even in the absence of physical signs and symptoms, is warranted in this group of children to ensure that hypothyroidism is treated, and further, irreversible neurological and physical impairment prevented

Thyroid dysfunction in a cohort of South African children with Down syndrome

Background. While international studies show thyroid dysfunction occurs more commonly in individuals with Down syndrome (DS) than in the general population, there is a paucity of available data from sub-Saharan Africa.Objectives. To document the range of thyroid function in a cohort of South African children with DS, and to assess referral and treatment practices when thyroid dysfunction was present. Methods. A retrospective file-based study of 391 children with DS seen at the genetic clinics at three Johannesburg hospitals from 2003 to 2008. Thyroid function test (TFT) results (thyroid-stimulating hormone and free thyroxine) and demographic details were collected for each child. Endocrine clinic files from two of the hospitals were reviewed for additional referral and treatment information.Results. The majority (83.6%) of children had at least one TFT, in most cases performed between the ages of 2 and 12 months. The most common form of thyroid dysfunction was subclinical hypothyroidism (SCH) (28.7%). Up to one-third of the patients, including several neonates with abnormal results, were not referred for further evaluation and were therefore not receiving the necessary treatment. Inter- laboratory biochemical discrepancies and lack of population-specific reference ranges complicated the interpretation of results. The controversy surrounding whether, and how, to treat SCH influenced treatment practices. Conclusions. Thyroid dysfunction is prevalent in South African children with DS. There is an urgent need to address the laboratory biochemical discrepancies, and to establish guidelines for surveillance and treatment to prevent further irreversible neurological and physical impairment.

Pseudoachondroplasia: Report on a South African family

Pseudoachondroplasia is an autosomal dominant skeletal dysplasia that results in disproportionately short stature, severe brachydactyly with strikingly lax small joints, malalignments of the lower limbs, and characteristic radiological features. Although named ‘false achondroplasia’, the entity is a distinct condition, in which affected individuals are born with normal length and have a normal facies, but is often only recognised after the age of 2 years, when the disproportion and waddling gait become evident. We report on an affected South African father and daughter, and highlight their clinical and radiographic features

Altered FGF signalling in congenital craniofacial and skeletal disorders

The fibroblast growth factor (FGF) signalling pathway has been the focus of intense genetic and functional research for several decades. The emerging data implicate FGF signalling in diverse regulatory processes, both in the developing embryo as well as in the adult organism. Alterations in this tightly regulated pathway can lead to a number of pathological conditions, ranging from well-recognized congenital disorders to cancer. In order to mediate their cellular processes, FGFs signal through a subfamily of tyrosine kinase receptors, called FGF receptors (FGFRs). In humans, four FGFRs are described, and, to date, mutations in FGFR1, FGFR2, and FGFR3 have been shown to underlie human developmental disorders. FGFs/FGFRs are known to be key players in both endochondral and intramembranous bone development. In this review, we focus on the major developmental craniofacial and skeletal disorders which result from altered FGF signalling. (C) 2015 Published by Elsevier Ltd

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI

Genomic basis of syndromic short stature in an Algerian patient cohort

Short stature is one of the most common reasons for a referral to the pediatric endocrinology clinic. Thousands of patients with short stature are assessed annually at the Department of Endocrine and Metabolic Diseases (DEMD) at Bab el Oued University Hospital in Algiers, Algeria. However, diagnostic rates in patients with syndromic short stature are not optimal due to the unavailability of next generation sequencing (NGS) technology. Here, we enrolled 10 Algerian patients with syndromic short stature in a pilot study to test the impact of genetic and genomic approaches in the DEMD. Using a combination of two different NGS modalities, namely exome sequencing and the Mendeliome (TruSight (TM) One sequencing panel) along with single gene testing, we were able to establish a confirmed molecular diagnosis in 7/10 patients (70%) and to identify strong likely disease-causing variants in a further two patients. Novel variants in NPR2 and VPS13B were identified. Using copy number variation analysis on the exome data, we also identified a de novo deletion of the short arm of chromosome X. These definitive diagnoses have made a substantial impact on patient treatment, management and genetic counseling. Genomic testing has the ability to transform clinical practice, and is an essential diagnostic tool in any tertiary pediatric clinic, particularly in resource limited settings