Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes

Thompson, Errington C.; Abdalla, Ebtesam; Superti‐Furga, Andrea; McAlister, William H.; Kratz, Lisa E.; Unger, Sheila; Royer‐Bertrand, Béryl; Campos‐Xavier, Belinda; Mittaz-Crettol, Lauréane; Amin, Asmaa K.; DeSanto, C.L.; Wilson, David B.; Douglas, Ganka; Kozel, Beth A.; Shinawi, Marwan

doi:10.1016/j.bone.2018.11.006

Cited by 11 publications

(13 citation statements)

References 17 publications

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“…The homozygous LBR variant c.1534C>T (p.Arg512Trp) in this report was previously reported in a similarly affected boy with LBR‐R‐SMD (Thompson et al, 2019). Compared to this boy, vertebral endplate irregularity, femoral bowing, and distal humeral/femoral metaphyseal flaring were barely observable in the father reported herein, suggesting that these findings may become less conspicuous during adolescence.…”

Section: Discussionsupporting

confidence: 74%

“…The prenatal manifestation of LBR‐R‐SMD was previously described as “shortened limbs on 20 weeks prenatal ultrasound assessed to be a lethal skeletal dysplasia” (Thompson et al, 2019). The fetal phenotype we report here is essentially similar to previously reported neonatal manifestations of LBR‐R‐SMD, however, with more significant platyspondyly, and mildly retarded pubic ossification in addition.…”

Section: Discussionmentioning

confidence: 99%

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Antenatal diagnostic dilemma in a pseudodominant pedigree with lamin‐B receptor (LBR)‐related regressive spondylometaphyseal dysplasia

Turgut

Güleç

Sivrikoz

et al. 2021

American J of Med Genetics Pt A

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The lamin‐B receptor (LBR) encodes a dual‐functioning inner nuclear membrane protein essential for cholesterol biosynthesis and chromatin organization. LBR pathogenic variants cause distinct phenotypes due to the dual function of LBR, including Pelger–Huët anomaly (PHA), PHA with mild skeletal anomalies (PHASK; MIM# 618019), LBR‐related regressive type of spondylometaphyseal dysplasia (LBR‐R‐SMD), Greenberg dysplasia (MIM# 215140). We here report the first case with radiological manifestations of LBR‐R‐SMD in the fetal period, and milder skeletal findings in the similarly affected father. Direct sequencing of LBR revealed homozygous c.1534C>T (p.Arg512Trp) in exon 12 in both affected individuals. Our report further refines the early phenotype in LBR‐R‐SMD, and demonstrates that the p.Arg512Trp mutation is associated with PHA. We propose that LBR‐R‐SMD should be considered as a differential diagnosis in pregnancies with sonographic evidence of short and bowed tubular bones with narrow thorax. Evaluating peripheral blood smears of expectant parents for the presence of PHA may lead to a clinical diagnosis, allowing for comprehensive prenatal genetic counseling.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Antenatal diagnostic dilemma in a pseudodominant pedigree with lamin‐B receptor (LBR)‐related regressive spondylometaphyseal dysplasia

Turgut

Güleç

Sivrikoz

et al. 2021

American J of Med Genetics Pt A

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“…Further confirmation is provided by the evidence that the healthy mother of the fetus with Greenberg dysplasia reported by Waterham et al showed hypolobulated nuclei in 60% of her granulocytes, a classic feature of Pelger–Huët anomaly and representing the heterozygous state of 3β‐hydroxysterol Δ 14 ‐reductase deficiency (Waterham et al, ). Further studies on sterol metabolism support the association,(Borovik et al, ; Sobreira et al, ; Thompson et al, ; Tsai, Zhao, Turner, & Schlieker, ), and Giorgio et al recently described in detail how variants in different functional domains, and different types of mutations lead to a continuum of LBR‐ associated phenotypes ( LBR genotype–phenotype correlation) (Giorgio et al, ).…”

Section: Discussionmentioning

confidence: 92%

“…Homozygosity and compound heterozygosity for LBR variants cause Pelger–Huët anomaly with mild skeletal anomalies (PHASK, OMIM #618019), a mild and self‐regressing condition (Borovik, Modaff, Waterham, Krentz, & Pauli, ; Hoffmann et al, ; Sobreira et al, ). Another phenotype with moderately severe skeletal dysplasia was also recently described, broadening the spectrum of LBR‐ related disorders (Thompson et al, ).…”

Section: Introductionmentioning

confidence: 88%

A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley–Kendall dysplasia are allelic disorders

Gregersen

McKay

Walsh

et al. 2020

Molec Gen & Gen Med

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Background Greenberg dysplasia is a rare, autosomal recessive, prenatal lethal bone dysplasia caused by biallelic pathogenic variants in the lamin B receptor (LBR) gene. Pathogenic variants in LBR are also associated with Pelger–Huët anomaly, an autosomal dominant benign abnormality of the nuclear shape and chromatin organization of blood granulocytes, and Pelger–Huët anomaly with variable skeletal anomalies, a mild, regressing to moderate–severe autosomal recessive condition. Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X‐linked dominant chondrodysplasia punctata, Conradi–Hünermann type, and CHILD syndrome, and other conditions with unknown genetic etiology display very similar features, for example, dappled diaphyseal dysplasia and Astley–Kendall dysplasia. Methods We present a fetus with typical clinical and radiographic features of Greenberg dysplasia, and review the literature. Results Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR. Conclusion Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley–Kendall dysplasia, we suggest that these are allelic disorders.

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“…These two conditions may represent different allele patterns of the same disorder for some mutations [53,55]. The less common homozygous Pelger-Huët is clinically more severe with round or ovoid granulocyte nuclei and some cases with mild skeletal abnormalities [56,57]. This highlights the role of the lamin B receptor sterol reductase function as essential in prenatal development but also the phenotypic continuum that can occur for various allele combinations of the LBR gene.…”

Section: Disorders Of the Post-squalene Cholesterol Pathway 31 Hydrops-ectopic Calcification-moth-eaten Skeletal Dysplasiamentioning

confidence: 99%

Human Cholesterol Biosynthesis Defects

Anderson¹,

Coman²

2020

Apolipoproteins, Triglycerides and Cholesterol

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Cholesterol plays an essential role in normal embryogenesis and perturbations in its de novo synthesis are responsible for organ malformations in the cholesterol biosynthesis defects. Ten distinct inherited disorders have been linked to different enzyme defects in the isoprenoid/cholesterol biosynthetic pathway: mevalonic aciduria, hyperimmunoglobulinemia syndrome, squalene synthase deficiency, lanosterol synthase deficiency, hydrops-ectopic calcification-moth-eaten (Greenberg) skeletal dysplasia, X-linked dominant chondrodysplasia punctata, congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome, lathosterolosis, Smith-Lemli-Opitz syndrome and desmosterolosis. These Mendelian disorders are clinically heterogeneous with protean manifestations reflecting the important role of cholesterol, and its intermediary metabolites, in embryogenesis and development. Key clinical features commonly represented by the cholesterol biosynthesis defects include structural brain malformations, axial skeletal developmental anomalies and genital and cardiac malformations. The aetiology of the underlying pathophysiology is unclear and multifactorial but may be due to lowered cholesterol and/or the elevated, teratogenic levels of the intermediate sterol precursors. Herein, we will review clinical, biochemical and molecular aspects of the known human cholesterol biosynthesis defects.

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Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes

Cited by 11 publications

References 17 publications

Antenatal diagnostic dilemma in a pseudodominant pedigree with lamin‐B receptor (LBR)‐related regressive spondylometaphyseal dysplasia

Antenatal diagnostic dilemma in a pseudodominant pedigree with lamin‐B receptor (LBR)‐related regressive spondylometaphyseal dysplasia

A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley–Kendall dysplasia are allelic disorders

Human Cholesterol Biosynthesis Defects

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