Last update 01 Nov 2024

Sclerosteosis

Last update 01 Nov 2024

Basic Info

Synonyms

CORTICAL HYPEROSTOSIS WITH SYNDACTYLY, Cortical Hyperostosis with Syndactyly, Cortical hyperostosis with syndactyly

+ [6]

Introduction

An autosomal recessive form of craniotubular hyperostosis due to loss-of-function mutation(s) in the SOST gene, encoding sclerostin. Clinical features include tall stature, enlarged jaw and facial bones, and cranial nerve compression leading to hearing loss and facial palsy. About two-thirds of patients have syndactyly and/or nail malformations. Increased intracranial pressure due to the thickened calvaria and skull base can occur.

Drugs associated with Sclerosteosis

HNC1058

Target

autotaxin

Mechanism

autotaxin inhibitors

Active Org.

Guangzhou Koncen Bioscience Co., Ltd.

Originator Org.

Guangzhou Koncen Bioscience Co., Ltd.

Active Indication

Idiopathic Pulmonary Fibrosis [+2]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Sitaxentan Sodium

Target

ETA

Mechanism

ETA antagonists

Active Org.

Timber Pharmaceuticals LLCStartup

Originator Org.

Pfizer Inc.

Active Indication

Scleroderma, Systemic [+1]

Inactive Indication

Chronic Kidney Diseases [+6]

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.

EU [+3]

First Approval Date10 Aug 2006

AFM-30a

Target

PAD2

Mechanism

PAD2 inhibitors

Active Org.

UMass Chan Medical School

Originator Org.

UMass Chan Medical School

Active Indication

Breast Cancer [+2]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Sclerosteosis

100 Translational Medicine associated with Sclerosteosis

0 Patents (Medical) associated with Sclerosteosis

161

Literatures (Medical) associated with Sclerosteosis

01 Oct 2024·Biochemical Pharmacology

Therapeutic targeting of Wnt antagonists by small molecules for treatment of osteoporosis

Review

Author: Chand, Diwan ; Mohanan, Kishor ; Chattopadhyay, Naibedya ; Ahamad, Shakir ; Srivastava, Kinshuk R ; Abhishek Shah, Aarti ; Chourasia, Manish K ; Srivastava, Kinshuk R. ; Porwal, Konica ; Chourasia, Manish K.

Wnt signaling is one of the key regulators of bone development and homeostasis. Wnt signaling regulates key biological events, including stem cell fate and osteoblast and osteoclast activity, leading to the maintenance of bone mass and strength. Wnt ligands are secreted glycoproteins that bind to Frizzled (FZD) receptors and their coreceptors, lipoprotein receptor-related proteins-5/6 (LRP5/6). Binding of Wnts to FZD triggers canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. In canonical Wnt signaling, stabilized β-catenin translocates to the nucleus, where it promotes osteoblast differentiation by activating target genes, including Runx2 and Osterix. The negative regulators of Wnt or so-called Wnt antagonists, including CXXC5, sFRP, sclerostin, DKK1, and Notum, compete for Fzd binding, attenuating Wnt signaling. The critical roles of Wnt signaling in bone homeostasis have been established by various bone diseases caused by mutations in Wnt signaling pathways. Loss-of-function mutations in the LRP5 gene cause osteoporosis-pseudoglioma syndrome, whereas gain-of-function mutations are linked to osteopetrosis characterized by high bone density. Sclerosteosis and Van Buchem disease are caused by mutations affecting the SOST gene, which encodes sclerostin, a natural inhibitor of Wnt signalling. Loss-of-function mutations in SOST result in excessive bone growth, markedly increased bone density, and other skeletal abnormalities due to uncontrolled Wnt activity. Considering the clinical relevance of Wnt signaling, targeting Wnt inhibitors is being intensely pursued using small molecules that work by inhibiting endogenous Wnt agonists. We used a computational biology approach to review current data on pharmacophores of Wnt antagonists, assessing their potential as therapeutic candidates for postmenopausal osteoporosis.

01 Feb 2024·European Journal of Medical Genetics

LRP4 site-specific variants in the third β-propeller domain causes congenital myasthenic syndrome type 17

Review

Author: Al Jabry, Tariq ; Al-Hashmi, Nadia ; Abdelhadi, Basem ; Al-Maawali, Almundher

LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate cell surface receptor at the neuromuscular junction and is central to its development, maintenance, and function. Pathogenic variants of LRP4 that specifically affect the canonical WNT signaling pathway are known to be associated with Cenani-Lenz syndactyly syndrome or the overlapping condition sclerosteosis. However, site-specific pathogenic variants of LRP4 have been associated with the congenital myasthenic syndrome (CMS) type 17 with no abnormal bone phenotype. Only two studies reported biallelic variants of LRP4 associated with CMS17 that presented during childhood. All three reported variants (NM_002334.4: p.Glu1233Ala, p.Glu1233Lys, or p.Arg1277His) are located within the 3'-edge of the third β-propeller domain of LRP4. We report on a patient with a biallelic variant of the LRP4 gene presenting with a severe and neonatal lethal phenotype; we also provide a literature review of the previously reported patients. A female neonate, born to healthy consanguineous parents, presented with severe hypotonia, congenital diaphragmatic hernia, pulmonary hypertension, and progressive hypoxemia. Two of her siblings presented with a similar condition in the past, and all three died shortly after birth. Clinical exome sequencing revealed homozygosity for the pathogenic variant NM_002334.4:c.3698A > C (p.[Glu1233Ala]).

01 Aug 2023·Journal of International Medical Research

Sclerostin: clinical insights in muscle–bone crosstalk

Review

Author: Iolascon, Giovanni ; Moretti, Antimo

Sclerostin, a protein encoded by the sclerostin ( SOST) gene, is mostly expressed in osteocytes. First described in the pathogenesis of three disorders, sclerosteosis, van Buchem’s disease, and craniodiaphyseal dysplasia, sclerostin has been identified as an important regulator of bone homeostasis, controlling bone formation by osteoblasts through inhibition of the canonical Wnt signaling pathway. Recent studies have highlighted a hypothetical role of sclerostin in myogenesis, thus modulating the interaction between bone and muscle. This narrative review provides an overview of the clinical implications of sclerostin modulation on skeletal muscle mass and function, and bone metabolism. Improving knowledge about muscle–bone crosstalk may represent a turning point in the development of therapeutic strategies for musculoskeletal disorders, particularly osteosarcopenia.

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Sclerosteosis

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