Van Buchem disease: Clinical, biochemical, and densitometric features of patients and disease carriers

Abstract

Van Buchem disease (VBD) is a rare bone sclerosing dysplasia caused by the lack of a regulatory element of the SOST gene, which encodes for sclerostin, an osteocyte-derived negative regulator of bone formation. We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation. The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%. The clinical course of the disease appeared to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or development of complications with time. Carriers of the disease had none of the clinical features or complications of the disease. Sclerostin could be detected in the serum in all but 1 VBD patients (mean 8.0 pg/mL; 95% confidence interval [CI], 4.9-11.0 pg/mL), and were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5-32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5-41.0 pg/mL; p < 0.). Serum procollagen type 1 amino-terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6-137.4 ng/mL versus mean 47.8; 95% CI, 39.4-56.2 ng/mL, p ¼ 0.003 in carriers and mean 37.8; 95% CI, 34.5-41.0 ng/mL, p ¼ 0.028 in healthy controls) and declined with age. Bone mineral density (BMD) was markedly increased in all patients (mean Z-score 8.7 AE 2.1 and 9.5 AE 1.9 at the femoral neck and spine, respectively); BMD of carriers was significantly lower than that of patients but varied widely (mean Z-scores 0.9 AE 1.0 and 1.3 AE 1.5 at the femoral neck and spine, respectively). Serum sclerostin levels were inversely correlated with serum P1NP levels (r ¼ -0.39, p ¼ 0.018) and BMD values (femoral neck r ¼ -0.69, p < 0.001; lumbar spine r ¼ -0.78, p < 0.001). Our results show that there is a gene-dose effect of the VBD deletion on circulating sclerostin and provide further in vivo evidence of the role of sclerostin in bone formation in humans. The small amounts of sclerostin produced by patients with VBD may explain their milder phenotype compared to that of patients with sclerosteosis, in whom serum sclerostin is undetectable. ß

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…PINP is the larger precursor of collagen type I that, when cleaved to its mature form, constitutes 90% of all collagens in bone (Parfitt et al 1987;Prockop and Kivirikko 1995;Young 2003). Serum from VBD patients contains a low level of sclerostin coupled with a significant increase in PINP, whereas heterozygous carriers display sclerostin and PINP levels intermediate between those in unaffected controls and homozygous patients (van Lierop et al 2014). Sclerostin protein levels are undetectable in SOST1 patients, explaining the more severe phenotype in this disease in comparison to VBD (van Lierop et al 2011).…”

“…Deletion of a long-range regulatory element distal to the SOST gene results in decreased expression of sclerostin, the protein product of the SOST gene, and causes a form of sclerosing bone dysplasia known as Van Buchem disease (VBD) (Wergedal et al 2003;Loots et al 2005;van Lierop et al 2013). Patients with VBD develop progressive increased thickness in calvaria, ribs, diaphysis of long bones, and tubular bones of hand and feet accompanied by hearing impairment and facial palsy (Van Buchem et al 1962;Fryns and Van den Berghe 1988;Van Hul et al 1998;Brunkow et al 2001;Balemans et al 2002;Staehling-Hampton et al 2002;Wergedal et al 2003;van Lierop et al 2013).…”

“…Patients with VBD develop progressive increased thickness in calvaria, ribs, diaphysis of long bones, and tubular bones of hand and feet accompanied by hearing impairment and facial palsy (Van Buchem et al 1962;Fryns and Van den Berghe 1988;Van Hul et al 1998;Brunkow et al 2001;Balemans et al 2002;Staehling-Hampton et al 2002;Wergedal et al 2003;van Lierop et al 2013).…”

SOST Polymorphisms and Response to Alendronate Treatment in Postmenopausal Chinese Women With Osteoporosis

“…Sclerostin is encoded by SOST gene, which locates on chromosome 17q12-q21 [13]. Loss-of-function mutations of SOST lead to rare genetic skeletal disorders such as sclerosteosis and Van Buchem disease, asso- ciating with a high BMD phenotype and low risk of fractures [16]. Antisclerostin antibodies were associated with increased BMD and bone formation [17,18].…”

Inhibition of sclerostin in the management of osteoporosis: results of a phase 2 clinical trial meet expectations

“…8 The stabilization of the clinical course of sclerosteosis and van Buchem disease in adulthood and the negative relationship between serum P1NP and age in patients and disease carriers suggested that in sclerostin deficiency bone formation is not elevated to the same extent throughout life and that the lack of sclerostin does not stimulate bone formation at the same rate with time. 8,9 This may be due to the available pool of osteoblasts (high in the growing skeleton and lower in the mature skeleton), as sclerostin is produced at late stages of the mineralization process. These observations raise the question of whether prolonged treatment with a sclerostin inhibitor will be associated with a sustained anabolic effect on bone or whether the stimulatory effect on bone formation will be attenuated with time.…”