Long-Term Follow-Up Outcomes of 19 Patients with Osteogenesis Imperfecta Type XI and Bruck Syndrome Type I Caused by FKBP10 Variants

Ülker, Aylin Yüksel; Alkaya, Dilek Uludağ; Elkanova, Leyla; Şeker, Ali; Akpınar, Evren; Akarsu, Nurten; Uyguner, Zehra Oya; Tüysüz, Beyhan

doi:10.1007/s00223-021-00879-4

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…Our study noted two cases of children born with a combination of BS-I and EB in consanguineous Tajik families (F12-P13 and F13-P14). Previously, similar phenotypes were identified in patients from the northern part of Turkey and convincingly demonstrated a founder effect [6,15]. Considering these data, a search for previously registered homozygous variants in the FKBP10 gene c.321_353del (p.Met107_Leu117del) and KRT14 (c.612T>A (p.Tyr204Ter) was conducted by direct Sanger sequencing in our examined patients, which confirmed the presence of these variants.…”

Section: Discussionsupporting

confidence: 84%

“…Furthermore, two unrelated patients (F12-P13 and F13-P14) with BS combined with congenital simple EB were found to have a homozygous deletion of 33 base pairs in the reading frame (c.321_353del), leading to the deletion of 11 amino acids (p.Met107_Leu117del) in the FKBP10 gene and a homozygous variant c.612T>A (p.Tyr204Ter) in the KRT14 gene. These same homozygous variants had been previously identified in patients from the northern part of Turkey [6,15].…”

Section: Resultssupporting

confidence: 76%

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Presentation of Rare Phenotypes Associated with the FKBP10 Gene

Merkuryeva,

Markova,

Kenis

et al. 2024

Genes

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Pathogenic variants in the FKBP10 gene lead to a spectrum of rare autosomal recessive phenotypes, including osteogenesis imperfecta (OI) Type XI, Bruck syndrome Type I (BS I), and the congenital arthrogryposis-like phenotype (AG), each with variable clinical manifestations that are crucial for diagnosis. This study analyzed the clinical-genetic characteristics of patients with these conditions, focusing on both known and newly identified FKBP10 variants. We examined data from 15 patients, presenting symptoms of OI and joint contractures. Diagnostic methods included genealogical analysis, clinical assessments, radiography, whole exome sequencing, and direct automated Sanger sequencing. We diagnosed 15 patients with phenotypes due to biallelic FKBP10 variants—4 with OI Type XI, 10 with BS I, and 1 with the AG-like phenotype—demonstrating polymorphism in disease severity. Ten pathogenic FKBP10 variants were identified, including three novel ones, c.1373C>T (p.Pro458Leu), c.21del (p.Pro7fs), and c.831_832insCG (p.Gly278Argfs), and a recurrent variant, c.831dup (p.Gly278Argfs). Variant c.1490G>A (p.Trp497Ter) was found in two unrelated patients, causing OI XI in one and BS I in the other. Additionally, two unrelated patients with BS I and epidermolysis bullosa shared identical homozygous FKBP10 and KRT14 variants. This observation illustrates the diversity of FKBP10-related pathology and the importance of considering the full spectrum of phenotypes in clinical diagnostics.

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Section: Discussionsupporting

confidence: 84%

Section: Resultssupporting

confidence: 76%

Presentation of Rare Phenotypes Associated with the FKBP10 Gene

Merkuryeva,

Markova,

Kenis

et al. 2024

Genes

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“…The bone density values were available for only six patients because of inability to prefer the investigation because of multiple contractures and spinal deformities (Table 1). However, as reported elsewhere, despite the improvement in fracture rate and bone density the walking was signi cantly affected with only four out of 11 being mobile [31]. Surgical correction of the contracture using guided growth or osteotomy at the knee was not very successful in restoring mobility or correcting the deformity.…”

Section: Discussionmentioning

confidence: 64%

Clinical and genetic landscape of Bruck syndrome in the Indian population

Selina,

Kandagaddala,

Danda

et al. 2024

Preprint

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Background Bruck syndrome (BS) is a rare form of Osteogenesis imperfecta (OI) with congenital large joint contractures and bone fragility fractures. Evaluation of phenotypic and genotypic profiles of 14 children with FKBP10 and PLOD2 gene variants causing Bruck syndrome (BS) and highlighting the severe deformities in response to poor surgical treatment in the Indian cohort. Methods Patients with bone fragility were clinically evaluated. After informed consent, genotyping was done by next-generation sequencing, and the variants were validated by Sanger sequencing. These children were treated surgically and pamidronate was administered. Results Out of 14 children, 12 were with FKBP10 gene variants, and two with PLOD2 gene variants. The age at diagnosis varied from birth to four years. All were classified as type III by modified Sillence classification. twelve had joint contractures, mainly in the knees and elbows. Clubfeet was identified in seven, scoliosis in three, and severe kyphoscoliosis in three. Two had skull deformities, six with wormian bones, one with basilar invagination and another showing severe cervical compression myelopathy. Rib fractures in six, vertebral compression in nine, and protrusion acetabulae in three were noted. Surgical correction of the deformities by soft tissue release and bone shortening was partially successful, while growth modulation was unsuccessful as the implant failed. Nine of the patients were non-ambulant. Bone density was decreased in all, and the response to pamidronate was partial. This cohort had four novel FKBP10 variants and two PLOD2 variants. Conclusion The study highlights the proportionate representation of the two genes in our population, the severe deformities with poor response to surgical treatment, and novel variants in the population.

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“…Despite a variable phenotype and severity, ranging from perinatally lethal cases to a relatively mild level of disability (Moravej et al, 2015; Shaheen et al, 2010, 2011), clinical features are indistinguishable in both BRKS1 and BRKS2 genotypes (Ha‐Vinh et al, 2004; Kelley et al, 2011). In addition to Bruck syndrome, pathogenic variants in FKBP10 can also cause OI type XI and contractures alone, and PLOD2 mutations can cause OI without contractures and skeletal dysplasia syndromes (kyphomelic dysplasia; Leal et al, 2018; Schwarze et al, 2013; Shaheen et al, 2010, 2011; Yuksel Ulker et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotype of Bruck syndrome: Severe limb deformity, arthrogryposis, congenital cardiac disease and pulmonary hemorrhage

Sandy

Perez

Goh

et al. 2022

American J of Med Genetics Pt A

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Bruck syndrome is a rare collagen disorder with autosomal recessive inheritance caused by pathogenic variants in either FKBP10 or PLOD2 genes. It is characterized by bone fragility and fractures similar in severity and variability to osteogenesis‐imperfecta as well as congenital joint contractures. This article describes an infant with a homozygous (partial) gene deletion of PLOD2 that includes the start codon and would be expected to lead to nonfunctional protein product. The infant had a severe phenotype of Bruck syndrome and is the only reported case of Bruck syndrome with congenital cardiac disease (triscuspid valve dysplasia with severe regurgitation, mitral valve prolapses with moderate regurgitation, and pulmonary hypertension) and pulmonary hemorrhage. We hypothesize that the additional feature of congenital cardiac disease in this case was due to the underlying defect in type I collagen, and that the pulmonary hemorrhage was multifactorial, with underlying vessel fragility, rib fractures, and high pulmonary pressures likely to be major contributing factors. Management was largely supportive with the use of bisphosphonates to assist in pain management. Care was complicated by comorbid cardiopulmonary compromise, limited evidence‐base guiding care, and difficulties in discussing end‐of‐life care.

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Long-Term Follow-Up Outcomes of 19 Patients with Osteogenesis Imperfecta Type XI and Bruck Syndrome Type I Caused by FKBP10 Variants

Cited by 7 publications

References 25 publications

Presentation of Rare Phenotypes Associated with the FKBP10 Gene

Presentation of Rare Phenotypes Associated with the FKBP10 Gene

Clinical and genetic landscape of Bruck syndrome in the Indian population

Expanding the phenotype of Bruck syndrome: Severe limb deformity, arthrogryposis, congenital cardiac disease and pulmonary hemorrhage

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