Osteogenesis imperfecta type V: Clinical and radiographic manifestations in mutation confirmed patients

Kim, Ok Hwa; Jin, Dong Kyu; Kosaki, Keisuke; Kim, Jung Wook; Cho, Sung Yoon; Yoo, Won Joon; Choi, In Ho; Nishimura, Gen; Ikegawa, Shiro; Cho, Tae Joon

doi:10.1002/ajmg.a.36024

Cited by 30 publications

(27 citation statements)

References 20 publications

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“…A wide variability in the age of the first fracture, as well as the total number of fractures, was seen in the patients in the current study. This is consistent with previous reports that included patients with the same mutation, which find that the number of fractures is indeed highly variable; frequencies from 0 to 30 fractures have been reported [Cho et al, 2013;Kim et al, 2013;Lazarus et al, 2014;Reich et al, 2015]. Zhang et al [2013] described 4 Chinese families with individuals aged between 4 and 29 years with the occurrence of 3-11 fractures.…”

Section: Discussionsupporting

confidence: 92%

“…Two previous studies have described the occurrence of vertebral fractures in 87 and 100% of the cases [Lee et al, 2006;Shapiro et al, 2013], and scoliosis was observed at a frequency between 50 and 76% in 5 studies involving 98 individuals [Glorieux et al, 2000;Zeitlin et al, 2006;Kim et al, 2013;Rauch et al, 2013]. Also relevant, the investigators in all these cases observed the patients to exhibit a pyramidal shape of the chest and ribs with an unusual form and downward slanting [Kim et al, 2013]. The cause for this alteration of the rib position and shape is unknown, and this feature has not been described in other types of OI.…”

Section: Discussionmentioning

confidence: 99%

“…The main features are absence of DI, HPC, CIM, and DRH with frequencies around 64, 88, and 78%, respectively [Cho et al, 2012;Semler et al, 2012;Takagi et al, 2013;Balasubramanian et al, 2013;Grover et al, 2013; Kim et al, 2013;Rauch et al, 2013;Shapiro et al, 2013;Zhang et al, 2013;Guillén-Navarro et al, 2014;Lazarus et al, 2014;Reich et al, 2015]. However, some studies including patients with clinical diagnosis of OI-V were published before this specific related mutation was found in 2012 [Glorieux et al, 2000;Lee et al, 2006;Zeitlin et al, 2006].…”

Section: Discussionmentioning

confidence: 99%

“…[Cho et al, 2012;Semler et al, 2012;Balasubramanian et al, 2013;Grover et al, 2013;Kim et al, 2013;Rauch et al, 2013;Shapiro et al, 2013;Takagi et al, 2013;Zhang et al, 2013;Guillén-Navarro et al, 2014;Lazarus et al, 2014;Reich et al, 2015]. Guillén-Navarro et al, 2014].…”

Section: Discussionunclassified

“…The product of the IFITM5 gene, located on chromosome region 11p15.5, is also known as bone-restricted IFITM-like protein, a protein with 132 amino acids that has 2 transmembrane domains and an intracellular loop [Cho et al, 2012;Semler et al, 2012]. After this specific mutation was published, several studies reported cases of individuals with the same mutation and phenotype of OI-V [Cho et al, 2012;Semler et al, 2012;Takagi et al, 2013;Balasubramanian et al, 2013;Grover et al, 2013;Kim et al, 2013;Rauch et al, 2013;Shapiro et al, 2013;Zhang et al, 2013;Guillén-Navarro et al, 2014;Lazarus et al, 2014;Reich et al, 2015].…”

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confidence: 99%

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Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V

et al. 2015

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Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5′UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionunclassified

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confidence: 99%

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Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V

et al. 2015

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A Nonclassical IFITM5 Mutation Located in the Coding Region Causes Severe Osteogenesis Imperfecta With Prenatal Onset

Hoyer‐Kuhn

Semler

Garbes

et al. 2013

Journal of Bone and Mineral Research

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Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder characterized by a wide range of skeletal symptoms. Most patients have dominantly inherited or de novo mutations in COL1A1 or COL1A2. Up to 5% of patients have OI type V, characterized by hyperplastic callus formation after fractures, calcification of the interosseous membrane of the forearm, and a mesh-like lamellation pattern observed in bone histology. Recently, a heterozygous mutation in the 5 0 -untranslated region (UTR) of IFITM5 (c.-14C > T) was identified as the underlying cause of OI type V, and only this specific mutation was subsequently identified in all patient cohorts with this OI subtype. We now present a case of a heterozygous mutation within the coding region of IFITM5 (c.119C > T; p.S40L). The mutation occurred de novo in the patient and resulted in severe OI with prenatal onset and extreme short stature. At the age of 19 months, the typical clinical hallmarks of OI type V were not present. Our finding has important consequences for the genetic "work-up" of patients suspected to have OI, both in prenatal and in postnatal settings: The entire gene-not only the 5 0 -UTR harboring the "classical" OI type V mutation-has to be analyzed to exclude a causal role of IFITM5. We propose that this should be part of the initial diagnostic steps for genetic laboratories performing SANGER sequencing in OI patients.

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Hypermineralization and High Osteocyte Lacunar Density in Osteogenesis Imperfecta Type V Bone Indicate Exuberant Primary Bone Formation

Blouin

Fratzl‐Zelman

Glorieux

et al. 2017

Journal of Bone and Mineral Research

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In contrast to “classical” forms of Osteogenesis imperfecta (OI) types I to IV, caused by a mutation in COL1A1/A2, OI type V is due to a gain-of-function mutation in the IFITM5 gene, encoding the interferon-induced transmembrane protein 5, or bone-restricted ifitm-like protein (BRIL). Its phenotype distinctly differs from OI types I to IV by absence of blue sclerae and dentinogenesis imperfecta, by the occurrence of ossification disorders like hyperplastic callus and forearm interosseous membrane ossification. Little is known about the impact of the mutation on bone tissue/material level in untreated and bisphosphonate treated patients. Therefore investigations of transiliac bone biopsy samples from a cohort of OI type V children (n=15, 8.7±4 years old) untreated at baseline and a subset (n=8) after pamidronate treatment (2.6 years in average) were performed. Quantitative backscattered electron imaging (qBEI) was used to determine bone mineralization density distribution (BMDD) as well as osteocyte lacunar density. The BMDD of type V OI bone was distinctly shifted towards higher degree of mineralization. The most frequently occurring calcium concentration (CaPeak) in cortical (Ct) and cancellous (Cn) bone was markedly increased (+11.5%, +10.4%, respectively, P<0.0001) compared to healthy reference values. Treatment with pamidronate resulted in only a slight enhancement of mineralization. The osteocyte lacunar density derived from sectioned bone area was elevated in OI type V Ct and Cn bone (+171%, P<0.0001 and +183.3%, P<0.01, respectively) versus controls. The high osteocyte density was associated with an overall immature primary bone structure (”mesh-like”) as visualized by polarized light microscopy. In summary the bone material from OI type V patients is hypermineralized, similarly to other forms of OI. The elevated osteocyte lacunar density in connection with lack of regular bone lamellation points to an exuberant primary bone formation and an alteration of the bone remodeling process in OI type V.

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Osteogenesis imperfecta type V: Clinical and radiographic manifestations in mutation confirmed patients

Cited by 30 publications

References 20 publications

Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V

Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V

A Nonclassical IFITM5 Mutation Located in the Coding Region Causes Severe Osteogenesis Imperfecta With Prenatal Onset

Hypermineralization and High Osteocyte Lacunar Density in Osteogenesis Imperfecta Type V Bone Indicate Exuberant Primary Bone Formation

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