Consanguineous‐derived homozygous WNT1 mutation results in osteogenesis imperfect with congenital ptosis and exotropia

Chen, Peng; Chen, Jiaxi; Yang, Zhilin; Yang, Lifang; Shen, Liping; Zhou, Kai; Ye, Shenyi; Shen, Bo

doi:10.1002/mgg3.1350

Cited by 5 publications

(2 citation statements)

References 19 publications

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“…Notably, different Wnt proteins are expressed in bone, but Wnt1 is mainly responsible for bone homeostasis during skeletal development, bone mass accrual, and microarchitectural regulation ( 48 , 49 ). It has been speculated that WNT1 mutations may reduce Wnt1 ability to induce Wnt/β-Catenin pathway in varying degrees according to the homo or heterozygous nature ( 12 , 43 , 47 ), suggesting the presence of a phenotypic threshold effect. Indeed, our proband showed a clinical picture characterized by early-onset osteoporosis associated with multiple fragility vertebral fractures.…”

Section: Discussionmentioning

confidence: 99%

Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene

et al. 2022

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The WNT1 gene is crucial for bone development and homeostasis. Homozygous mutations in WNT1 cause severe bone fragility known as osteogenesis imperfecta type XV. Moreover, heterozygous WNT1 mutations have been found in adults with early-onset osteoporosis. We identified a 35 year-old Caucasian woman who experienced multiple vertebral fractures two months after her second pregnancy. There was no history of risk factors for secondary osteoporosis or family history of osteoporosis. Dual-energy X-ray absorptiometry confirmed a marked reduction of bone mineral density (BMD) at the lumbar spine (0.734 g/cm2, Z-score -2.8), femoral neck (0.48 g/cm2, Z-score -3.5), and total hip (0.589 g/cm2, Z-score -3.0). Blood tests excluded secondary causes of bone fragility. Genetic analysis revealed a heterozygous missense mutation (p.Leu370Val) in the WNT1 gene. Varsome classified it as a variant of uncertain significance. However, the fact that the Leucine residue at position 370 is highly conserved among vertebrate species and the variant has a very low allelic frequency in the general population would exclude the possibility of a polymorphism. The patient was treated for two years with teriparatide therapy associated with calcium and vitamin D supplements. During the follow-up period she did not report further clinical fractures. After 24 months of teriparatide, BMD increased at lumbar spine (+14.6%), femoral neck (+8.3%) and total hip (+4.9%) compared to baseline. We confirm that the heterozygous WNT1 mutation could cause a variable bone fragility and low turnover osteoporosis. We suggest that teriparatide is one of the most appropriate available therapies for this case.

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Section: Discussionmentioning

confidence: 99%

Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene

et al. 2022

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“…Patients with WNT1 mutations have lower bone mineral density, more fractures, a shorter stature, and blue sclera (4)(5)(6)(7)(8)(9), and some also had cognitive difficulties, developmental delays, and central nervous system problems. Over the past few years, congenital ptosis has been described in a few cases (8,10,11). No congenital hearing impairment (inner ear hypoplasia) or encephalomalacia has been reported in children heterozygous for the WNT1 mutation.…”

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confidence: 99%

Type XV osteogenesis imperfecta: A novel mutation in the <i>WNT1 </i>gene, c.620G >A (p.R207H), is associated with an inner ear deformity

Zhu

et al. 2023

IRDR

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type XV osteogenesis imperfecta, heterozygous mutation, WNT1, inner ear dysplasiaThe Wnt signaling pathway is vital in encouraging bone growth. WNT1 gene mutations have been identified as the major cause of type XV osteogenesis imperfecta (OI). Described here is a case of complex heterozygous WNT1 c.620G>A (p.R207H) and c.677C >T (p.S226L) OI caused by a novel mutation at locus c.620G >A (p.R207H). The female patient had type XV OI, distinguished by poor bone density, frequent fractures, a small stature, skull softening, lack of dentine hypoplasia, a brain malformation, and obvious blue sclera. A CT scan of the temporal bone revealed abnormalities of the inner ear, necessitating a hearing aid 8 months after birth. There was no family history of such disorders in the proband's parents. The proband inherited complex heterozygous WNT1 gene variants c.677C>T (p.S226L) and c.620G>A (p.R207H) from her father and mother, respectively. Presented here is a case of OI with inner ear deformation caused by c.620G>A (p.R207H), which is a novel WNT1 site mutation. This case broadens the genetic spectrum of OI and it provides a rationale for genetic testing of mothers and a medical consultation to estimate the risk of fetal illness.

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Cornea and Sclera

Yanoff,

Sassani

2025

Ocular Pathology

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Consanguineous‐derived homozygous WNT1 mutation results in osteogenesis imperfect with congenital ptosis and exotropia

Cited by 5 publications

References 19 publications

Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene

Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene

Type XV osteogenesis imperfecta: A novel mutation in the <i>WNT1 </i>gene, c.620G >A (p.R207H), is associated with an inner ear deformity

Cornea and Sclera

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