Shwachman–Diamond syndrome is associated with low-turnover osteoporosis

Toiviainen-Salo, Sanna; Mäyränpää, Mervi K; Durie, Peter R.; Richards, Nicole; Grynpas, Marc D.; Ellis, Lynda; Ikegawa, Shiro; Cole, William G.; Rommens, Johanna M.; Marttinen, Eino; Savilahti, Erkki; Mäkitie, Outi

doi:10.1016/j.bone.2007.08.035

Cited by 48 publications

(45 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The patients were clinically diagnosed with SDS at a median age of 14 months (range 4 months to 14.5 years); all had exocrine pancreatic dysfunction and persistent or cyclic neutropenia at diagnosis, as reported previously [Toiviainen-Salo et al, 2007, 2008. All patients except Patients #1 and #3, who were included in the study at the time of their diagnosis, had commenced pancreatic enzyme supplementation after the diagnosis.…”

Section: Clinical Featuresmentioning

confidence: 97%

“…During a nation-wide research project assessing clinical and imaging features of SDS, a total of 12 patients with SDS and SBDS mutations were identified in Finland [Toiviainen-Salo et al, 2007, 2008. Exclusion criteria for the present study were (i) age <5 years, to avoid need for anesthesia during the imaging, and (ii) history of brain damage or serious head trauma with loss of consciousness.…”

Section: Patientsmentioning

confidence: 99%

See 1 more Smart Citation

Shwachman–Diamond syndrome is associated with structural brain alterations on MRI

Toiviainen-Salo

Mäkitie

Mannerkoski

et al. 2008

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Shwachman-Diamond syndrome (SDS) is an autosomal recessive condition that results from mutations in the SBDS gene, at chromosome 7q11. Main features include exocrine pancreatic failure, neutropenia and skeletal dysplasia. This study investigated brain structures by magnetic resonance imaging (MRI) in patients with SDS. MRI of the brain was performed in nine patients (7 males, age range 7-37 years) with SDS and mutations in the SBDS gene and in 18 age- and gender-matched controls. MRI images were assessed visually, and volumetric analyses of the brain matter and structural midsagittal measurements were performed. Eight out of nine SBDS mutation-verified patients reported learning difficulties. Patients with SDS had smaller occipitofrontal head circumferences than the controls (Z-score -1.3 vs. +0.3, P = 0.021), and decreased global brain volume (1.74 L vs. 1.94 L, P = 0.019); both gray matter (P = 0.042) and white matter (P = 0.007) volumes were reduced. Patients with SDS had no macroscopic brain malformations, but they had significantly smaller age- and head size-adjusted areas of posterior fossa (P = 0.006), vermis (P = 0.002), corpus callosum (P = 0.020), and pons (P = 0.002), and significantly larger cerebrum-vermis ratio (P < 0.0001) than the healthy controls. SDS patients had structurally smaller posterior fossa and cerebellar vermis, corpus callosum, and brainstem than the healthy controls. The MRI findings may be related to the neuropsychological features described in SDS.

show abstract

Section: Clinical Featuresmentioning

confidence: 97%

Section: Patientsmentioning

confidence: 99%

Shwachman–Diamond syndrome is associated with structural brain alterations on MRI

Toiviainen-Salo

Mäkitie

Mannerkoski

et al. 2008

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

show abstract

“…8 In addition, a subset of patients showed early signs of osteoporotic vertebral deformities and disturbances in bone homeostasis manifesting in low-turnover osteoporosis. 8,9 Oral and dental diseases and conditions, including periodontitis, delayed eruption of the permanent dentition, increased caries risk in primary and permanent dentitions, and increased soft tissue pathoses, have also been reported. 10 SDS results from mutations in the ubiquitously expressed, conserved Shwachman-Bedian-Diamond syndrome gene (SBDS).…”

Section: Introductionmentioning

confidence: 99%

Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis

Leung

Cuddy

Wang

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

Shwachman-Diamond syndrome (SDS) results from mutations in the SBDS gene, characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. Neutropenia and neutrophil dysfunction are hallmark features of SDS; however, causes for the bone defects are unknown. Dysfunction of boneresorbing osteoclasts, formed by the fusion of monocytic progenitors derived from the same granulocytic precursors as neutrophils, could be responsible. We report that Sbds is required for in vitro and in vivo osteoclastogenesis (OCG).Sbds-null murine monocytes formed osteoclasts of reduced number and size because of impaired migration and fusion required for OCG. Phenotypically, Sbdsnull mice exhibited low-turnover osteoporosis consistent with findings in SDS patients. Western blotting of Rho GTPases that control actin dynamics and migration showed a 5-fold decrease in Rac2, whereas Rac1, Cdc42, and RhoA were unchanged or only mildly reduced. Although migration was rescued on Rac2 supplementation, OCG was not. This was attributed to impaired signaling downstream of receptor activator of nuclear factor-B (RANK) and reduced expression of the RANK-ligand-dependent fusion receptor DC-STAMP. We conclude that Sbds is required for OCG by regulating monocyte migration via Rac2 and osteoclast differentiation signaling downstream of RANK. Impaired osteoclast formation could disrupt bone homeostasis, resulting in skeletal abnormalities seen in SDS patients. (Blood. 2011;117(6): 2044-2053) IntroductionShwachman-Diamond syndrome (SDS) is an autosomal recessive disorder with hallmark features of bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities. [1][2][3] Neutropenia is the most common clinical manifestation of bone marrow failure, but patients may also experience pancytopenia, anemia, and thrombocytopenia, and be at increased risk of developing aplastic anemia and acute myeloid leukemia. 4 In early crosssectional studies, metaphyseal dysostosis was observed in 40% to 80% of SDS patients, and rib and/or thoracic cage abnormalities in 30% to 50% of SDS patients. [5][6][7] More recently, in a longitudinal study, all of the SDS patients studied displayed various skeletal abnormalities, including delayed appearance of secondary ossification centers, variable widening, and irregularity of the metaphyses in early childhood followed by progressive thickening and irregularity of the growth plates, and generalized osteopenia. 8 In addition, a subset of patients showed early signs of osteoporotic vertebral deformities and disturbances in bone homeostasis manifesting in low-turnover osteoporosis. 8,9 Oral and dental diseases and conditions, including periodontitis, delayed eruption of the permanent dentition, increased caries risk in primary and permanent dentitions, and increased soft tissue pathoses, have also been reported. 10 SDS results from mutations in the ubiquitously expressed, conserved Shwachman-Bedian-Diamond syndrome gene (SBDS). 11 The exact function of the SBDS protein remains unclear; h...

show abstract

“…SDS osteoporosis is characterized by reduced numbers of osteoclasts and osteoblasts and low bone turnover and may be directly related to the bone marrow dysfunction and neutropenia. Malabsorption could be an additional risk factor [4]. Rosendahl et al [5] reported an adult SDS patient with DM and osteoporosis such as this case.…”

mentioning

confidence: 93%