Schimke immuno-osseous dysplasia: a clinicopathological correlation

Abstract

Background: Schimke immuno-osseous dysplasia (SIOD) is a fatal autosomal recessive disorder caused by loss-of-function mutations in swi/snf-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1). Methods: Analysis of detailed autopsies to correlate clinical and pathological findings in two men severely affected with SIOD. Results: As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified. Clinically unexpected findings included a paucity of B cells in the peripheral lymphoid organs, emperipolesis-like (penetration of one cell by another) abnormalities in the adenohypophysis, fatty infiltration of the cardiac right ventricular wall, pulmonary emphysema, testicular hypoplasia with atrophy and azospermia, and clustering of small cerebral vessels. Conclusions: A regulatory role for the SMARCAL1 protein in the proliferation of chondrocytes, lymphocytes and spermatozoa, as well as in the development or maintenance of cardiomyocytes and in vascular homoeostasis, is suggested. Additional clinical management guidelines are recommended as this study has shown that patients with SIOD may be at risk of pulmonary hypertension, combined immunodeficiency, subcortical ischaemic dementia and cardiac dysfunction.

Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

“…Additional features include hypothyroidism, abnormal dentition, bone marrow failure, thin hair, corneal opacities, arteriosclerosis, cerebral ischemia, and migraine-like headaches [2–5]. …”

“…FSGS is the predominant renal pathology and is refractory to treatment with glucocorticoids, cyclosporine A, and cyclophosphamide [4, 6]. Suggesting a cell autonomous mechanism for the renal disease, renal transplantation is efficacious, and the disease does not recur in the graft [2, 4, 5]. …”

Cardiovascular abnormalities in primary immunodeficiency diseases

“…CVS abnormalities: Vascular abnormalities occur in many patients, including transient ischemic attacks and (or) cerebral ischemia, putatively secondary to early onset, and progressive arteriosclerosis (Boerkoel et al 2000;Clewing et al 2007). A recent study among more than 50% of SIOD patients found arteriosclerosis associated with vascular intimal and medial hyperplasia, smooth muscle cell hyperplasia, and fragmented and disorganized elastin fibers (Morimoto et al 2012).…”

“…This gene encodes a protein involved in chromatin remodeling, but the pathogenic mechanism of SIOD is still unclear (Clewing et al 2007). …”

“…Pathogenesis: SIOD is caused by biallelic loss-offunction mutations in the SMARCAL1 gene (Clewing et al 2007). This gene encodes a protein involved in chromatin remodeling, but the pathogenic mechanism of SIOD is still unclear (Clewing et al 2007).…”