Browsing by Subject "skeletal dysplasia"

Sort by: Order: Results:

Now showing items 1-5 of 5
  • Vakkilainen, Svetlana; Taskinen, Mervi; Klemetti, Paula; Pukkala, Eero; Mäkitie, Outi (2019)
    Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95% CI = 4.3-11); most commonly from malignancy (n = 7, SMR = 10, 95% CI = 4.1-21) and lung disease (n = 4, SMR = 46, 95% CI = 9.5-130). Mortality associated with birth length below-4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95% CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio= 3.9, 95% CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95% CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95% CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95% CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.
  • GEMSTONE Working Grp 3 COST Action; Formosa, Melissa M.; Bergen, Dylan J. M.; Gregson, Celia L.; Mäkitie, Outi (2021)
    Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.
  • Heinonen, Maria (Helsingin yliopisto, 2021)
    Skeletal dysplasias are a group of rare monogenic bone disorders affecting joints and the skeleton. An increasing number of gene defects have been associated with skeletal dysplasias, but many cases remain without a known cause or a clear diagnosis. Exome sequencing data of the family with two siblings affected with an undiagnosed type of bone dysplasia was examined in this study with the aim of determining the genetic cause behind the phenotype. The causal variant was assumed to be in a novel disease-causing gene, since a previously performed gene panel of skeletal disease-causing genes had not revealed any positive results. The search for potential rare pathogenic variants in genes linked to the skeleton was done with VarAFT filtering software. The search revealed a short list of candidate variants confirmed first with Broad Institute’s Integrative Genomics Viewer (IGV) and then with targeted Sanger sequencing. Conservation analysis on the affected amino acids, in silico functional analysis on the variants and a comprehensive literature review on all candidate genes were performed to evaluate the likelihood of them being the variant behind the phenotype. A shortlist of three genes were obtained with the analyses, with one of them seeming to be the most likely candidate. However, to assuredly identify the disease-causing variant, further testing should be performed. Functional analyses should be done to test the functions of the proteins encoded by the candidate genes and the consequences of the pathogenic variants.
  • Härkönen, Helmi; Loid, Petra; Mäkitie, Outi (Helsingin yliopisto, 2021)
    Diastrofinen dysplasia (DTD) on harvinainen SLC26A2 -geenin mutaatioiden aiheuttama autosomaalinen, resessiivisesti periytyvä osteokondrodysplasia, jolle tunnusomaista on lyhytraajainen lyhytkasvuisuus ja nivelten dysplasia. Sairaus on erityisen yleinen Suomessa, mutta sen esiintyvyyttä ja potilaiden kliinisiä piirteitä ei ole hiljattain tutkittu. Tutkimuksen tarkoituksena oli selvittää DTD:n rekisteriin perustuvaa ilmaantuvuutta Suomessa, luonnehtia kliinisesti suomalaisten 2000-luvulla syntyneiden potilaiden kohorttia, sekä tarkastella tautia koskevaa kirjallisuutta. Potilaat tunnistettiin kansallisesta luustodysplasiarekisteristä ja 2000-2020 syntyneiden potilaiden geneettiset ja kliiniset piirteet kerättiin sairaalan potilastietojärjestelmästä. SLC26A2-mutaatioihin liittyvä luuston dysplasia tunnistettiin neljällätoista potilaalla. Heistä kaksitoista oli fenotyyppisesti luokiteltu DTD potilaiksi ja kaksi resessiivinen multippeli epifyseaalinen dysplasia (rMED) -potilaiksi. Potilaista, joilla geneettisiä tietoja oli saatavilla, 75% (9/12) oli homotsygoottisia suomalaisen perustajamutaation (founder-mutaatio), c.-26+2T>C suhteen. Kaksi potilasta, fenotyypiltaan rMED, olivat heterotsygootteja p.Arg279Trp ja p.Thr512Lys varianttien suhteen. Yleisimpiä kliinisiä piirteitä lyhytkasvuisuuden ohella olivat käden poikkeavuudet, kaularangan kyfoosi, polvien valgusvirheasento, patellan lateraalinen sijainti, pieni leuka ja ACL:n löysyys/puute. Nämä piirteet todettiin yli 70%:lla potilaista. Kohorttimme potilaiden vaihtelevat fenotyypit korostavat kliinisten piirteiden laajaa kirjoa aina erittäin vakavasta DTD-muodosta lievempiin muotoihin. DTD:n ilmaantuvuus Suomessa on vähentynyt merkittävästi viime vuosikymmenten aikana, mikä johtuu todennäköisesti lisääntyneestä prenataalisesta diagnostiikasta.
  • Härkönen, Helmi; Loid, Petra; Mäkitie, Outi (2021)
    Diastrophic dysplasia (DTD) is a rare osteochondrodysplasia characterized by short-limbed short stature and joint dysplasia. DTD is caused by mutations in SLC26A2 and is particularly common in the Finnish population. However, the disease incidence in Finland and clinical features in affected individuals have not been recently explored. This registry-based study aimed to investigate the current incidence of DTD in Finland, characterize the national cohort of pediatric subjects with DTD and review the disease-related literature. Subjects with SLC26A2-related skeletal dysplasia, born between 2000 and 2020, were identified from the Skeletal dysplasia registry and from hospital patient registry and their clinical and molecular data were reviewed. Fourteen subjects were identified. Twelve of them were phenotypically classified as DTD and two, as recessive multiple epiphyseal dysplasia (rMED). From the subjects with available genetic data, 75% (9/12) were homozygous for the Finnish founder mutation c.-26+2T>C. Two subjects with rMED phenotype were compound heterozygous for p.Arg279Trp and p.Thr512Lys variants. The variable phenotypes in our cohort highlight the wide spectrum of clinical features, ranging from a very severe form of DTD to milder forms of DTD and rMED. The incidence of DTD in Finland has significantly decreased over the past decades, most likely due to increased prenatal diagnostics.