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- Gkourogianni, Alexandra, et al.
(författare)
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Clinical and Radiological Manifestations in a Large Swedish Family with a Pathogenic Heterozygous ACAN Variant
- 2018
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Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 90:Suppl.1, s. 424-424
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: Heterozygous mutations in the aggrecan gene (ACAN) are associated with idiopathic short stature, with or without advanced bone age (BA), osteochondritis dissecans (OCD) and early onset of severe osteoarthritis (OA). Variable features also include midface hypoplasia, brachydactyly, short thumbs and intervertebral disc degenerative disease.Methods: We reviewed 173 radiographs in 22 individuals (8F:14M), (3shoulders, 10hands, 10wrists, 17spines, 10pelvis, 31hips, 79knees, 5 lower-legs, 4ankles, 4feet).Furthermore 2 computed tomography scans (1hip; 1knee), and 5 magnetic resonance scans (2hips; 3knees). All included individuals belong to a five generation Swedish family with short stature, OCD, and early onset OA (MIM#165800), caused by a pathogenic sequence variant, p.V2303M, in the C-type lectin domain of ACAN.Results: In the group of children (n=6; age ≤15yo; 3F:3M), six had moderately advanced BA (range:6-17.5months). There was no clear sign of a metaphyseal or epiphyseal dysplasia, but subtle defects of the distal radial growth plate were present in four children. There were 3 males with OCD in the knees and one of them also present-ed OCD of the hip, scoliosis and schmorl’s nodes of intervertebral discs. Actually he went through a derotation osteotomy in both hips and later a proximal tibia osteotomy and distal fibula osteotomy.Among 16 adult patients (5F:11M), 16 had OCD (7elbows,4 hips,13 knees, 5 patellas), 13 developed early onset (>40y) OA, (1shoulder, 5elbows, 3 spines, 1 metatarsophalangeal joint, 6 hips, 12 knees, 1 patella). Radiological manifestations of the spine were detected in 4 patients and included 1 scoliosis, 1 spina bifida occulta, 1 platyspondyly, 1 schmorl’s nodes, and 3 with lowering of the intervertebral discs.Moreover 8 adult patients (3F:5M) have been operated, 4 pa-tients had hip replacement (1F:3M;3bilateral;1unilateral) and 5 knee arthroplasties (2F:3M; 3bilateral;2unilateral) in particular 5 patients had tibia osteotomy of which one had combined tibia and fibula osteotomy. We measured all phalanges of eight adult hand x-rays and found no brachydactyly.Conclusions: The pathogenic heterozygous p.V2303M variant in the ACAN gene causes mildly disproportionate short stature with early-onset OA and intervertebral disc degeneration often requiring multiple orthopedic interventions. Radiologic findings, included moderately advanced BA, OCD in knees, hips, and elbows as well as OA in 13 individuals. Further studies are needed to identify preventive measures that may slow the progression of OA and intervertebral disc disease and to determine the role of rhGH to improve final height
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| 3. |
- Hallgrimsdottir, Sigrun, et al.
(författare)
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Premature epiphyseal fusion induced by a retinoic acid agonist in a young girl with fibrodysplasia ossificans progressiva
- 2021
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Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 95-95
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Retinoic acid receptor agonists can have dramatic negative effects on growth and even induce premature growth cessation and epiphyseal fusion (1, 2).An 11 5/12-year-old, prepubertal girl with fibrodysplasia ossificans progressiva presented in our pediatric skeletal disorders clinic with the concern of early growth cessation. She had participated in a clinical trial of Palovarotene (“MOVE”, NCT03312634), a retinoic acid receptor-gamma agonist, since the age of 9 10/12 years. At the visit, she had recently discontinued her participation in the study. During the 19 months since starting on Palovarotene, her height had only increased 1.9 cm to 136.4 cm. A skeletal survey detected fusion of several growth plates that normally remain open until the end of puberty including the growth plates of proximal humerus, distal ulna and distal radius. One year after stopping Palovarotene, she was in early puberty and her height had increased another 3.9 cm to 140.3 cm (-2.6 SDS). Measurements of height, sitting height, and arm span confirmed that growth of arms and legs had ceased, whereas growth of the spine continued.This report supports previous findings indicating that highdose retinoic acid receptor agonists can induce premature epiphyseal fusion even before puberty and may therefore cause significant, disproportionate short stature if used in young children. The finding that growth of the spine, but not legs and arms, resumed after the treatment was discontinued suggests that long bones are more susceptible than vertebrae to retinoic acid-induced epiphyseal fusion.1. De Luca F, Uyeda JA, Mericq V, Mancilla EE, Yanovski JA, Barnes KM, et al. Retinoic acid is a potent regulator of growth plate chondrogenesis. Endocrinology. 2000;141(1):346–53.2. Pease CN. Focal retardation and arrestment of growth of bones due to vitamin A intoxication. JAMA. 1962;182:980–5.
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| 4. |
- Hallgrimsdottir, Sigrun, et al.
(författare)
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Premature epiphyseal fusion induced by Palovarotene in a young girl with fibrodysplasia ossificans progressiva
- 2021
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Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 213-213
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Retinoic acid receptor agonists can have dramatic negative effects on growth and even induce premature growth cessation and epiphyseal fusion (1, 2).An 11 5/12-year-old, prepubertal girl with fibrodysplasia ossificans progressiva presented in our pediatric skeletal disorders clinic with the concern of early growth cessation. She had participated in a clinical trial of Palovarotene (“MOVE”, NCT03312634), a retinoic acid receptor-gamma agonist, since the age of 9 10/12 years. At the visit, she had recently discontinued her participation in the study. During the 19 months since starting on Palovarotene, her height had only increased 1.9 cm to 136.4 cm. A skeletal survey detected fusion of several growth plates that normally remain open until the end of puberty including the growth plates of proximal humerus, distal ulna and distal radius. One year after stopping Palovarotene, she was in early puberty and her height had increased another 3.9 cm to 140.3 cm (-2.6 SDS). Measurements of height, sitting height, and arm span confirmed that growth of arms and legs had ceased, whereas growth of the spine continued.This report supports previous findings indicating that high-dose retinoic acid receptor agonists can induce premature epiphy-seal fusion even before puberty and may thus cause significant, disproportionate short stature if used in young children. The finding that growth of the spine, but not legs and arms, resumed after the treatment was discontinued suggests that long bones are more susceptible than vertebrae to retinoic acid-induced epiphyseal fusion.References1. De Luca F, Uyeda JA, Mericq V, Mancilla EE, Yanovski JA, Barnes KM, et al. Retinoic acid is a potent regulator of growth plate chondrogenesis. Endocrinology. 2000;141(1):346–53.2. Pease CN. Focal retardation and arrestment of growth of bones due to vitamin A intoxication. JAMA. 1962;182:980–5.
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| 5. |
- Zhao, Sen, et al.
(författare)
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Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders
- 2022
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Ingår i: NPJ genomic medicine. - : Nature Publishing Group. - 2056-7944. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.
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