Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant : a case report

BackgroundLoss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height.Case presentationWe describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature.ConclusionOur report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.Peer reviewe

Compromised Peak Bone Mass in Patients with Inflammatory Bowel Disease-A Prospective Study

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Association between joint hypermobility, scoliosis, and cranial base anomalies in paediatric Osteogenesis imperfecta patients : a retrospective cross-sectional study

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A History of Cow's Milk Allergy Is Associated with Lower Vitamin D Status in Schoolchildren

Background/Aims: Vitamin D insufficiency is common in children. We aimed to evaluate the main determinants of vitamin D status in Finnish school-aged children, including the history of allergic diseases. Methods: We conducted a cross-sectional study on 171 ten-year-olds where serum 25-hydroxyvitamin D (25[OH] D) levels were measured, and data on food consumption and use of vitamin D supplements were collected. The history of allergic diseases was evaluated with a validated questionnaire. Results: Vitamin D insufficiency (Peer reviewe

Vitamin D Status in Children With Hemato-Oncological Diseases in Northern Finland

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Increased Burden of Common Risk Alleles in Children With a Significant Fracture History

Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 x 10(-5)). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 x 10(-10)). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. (c) 2020 American Society for Bone and Mineral Research.Peer reviewe

Impaired WNT signaling and the spine-Heterozygous WNT1 mutation causes severe age-related spinal pathology

Background: WNT signaling plays a major role in bone and cartilage metabolism. Impaired WNT/beta-catenin signaling leads to early-onset osteoporosis, but specific features in bone and other tissues remain inadequately characterized. We have identified two large Finnish families with early-onset osteoporosis due to a heterozygous WNT1 mutation c.652T>G, p.C218G. This study evaluated the impact of impaired WNT/beta-catenin signaling on spinal structures. Methods: Altogether 18 WNT1 mutation-positive (age range 11-76 years, median 49 years) and 14 mutation negative subjects (10-77 years, median 43 years) underwent magnetic resonance imaging (MRI) of the spine. The images were reviewed for spinal alignment, vertebral compression fractures, intervertebral disc changes and possible endplate deterioration. The findings were correlated with clinical data. Results: Vertebral compression fractures were present in 78% (7/9) of those aged over 50 years but were not seen in younger mutation-positive subjects. All those with fractures had several severely compressed vertebrae. Altogether spinal compression fractures were present in 39% of those with a WNT1 mutation. Only 14% (2/14) mutation -negative subjects had one mild compressed vertebra each. The mutation-positive subjects had a higher mean spinal deformity index (4.0 +/- 7.3 vs 0.0 +/- 0.4) and more often increased thoracic kyphosis (Z-score > + 2.0 in 33% vs 0%). Further, they had more often Schmorl nodes (61% vs 36%), already in adolescence, and their intervertebral discs were enlarged. Conclusion: Compromised WNT signaling introduces severe and progressive changes to the spinal structures. Schmorl nodes are prevalent even at an early age and increased thoracic kyphosis and compression fractures become evident after the age of 50 years. Therapies targeting the WNT pathway may be an effective way to prevent spinal pathology not only in those harboring a mutation but also in the general population with similar pathology. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

FGF23 gene variation and its association with phosphate homeostasis and bone mineral density in Finnish children and adolescents

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Novel variants in natriuretic peptide receptor 2 in unrelated patients with acromesomelic dysplasia type Maroteaux

Acromesomelic dysplasia are a heterogeneous group of disorders with variable spectrum and severity of skeletal anomalies in the affected individuals. Acromesomelic dysplasia type Maroteaux (AMDM) is characterized by extreme shortening of the forelimbs and disproportionate short stature. Several homozygous inactivating mutations in NPR2 have been identified in different AMDM patients. We report five novel variants in affected individuals in four different families. These include two nonsense and three missense variants. This study broadens the genotypic spectrum of NPR2 mutations in individuals with AMDM and also describes the intra- and inter-familial phenotypic variability due to NPR2 variants.Peer reviewe

Decreased telomere length in children with cartilage-hair hypoplasia

Background Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features. Methods The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2 years, range 6.0-70.8 years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR. Results Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=-0.482, p <0.001) and non-carriers (r=-0.498, p Conclusions Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.Peer reviewe