Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

BACKGROUND: Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown. METHODS: We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients. RESULTS: Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression. CONCLUSIONS: This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Schimke immuno-osseous dysplasia: a clinicopathological correlation.

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.

Schimke immunoosseous dysplasia: suggestions of genetic diversity.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Schimke versus non-Schimke chronic kidney disease: an anthropometric approach.

Schimke-immuno-osseous dysplasia is a rare autosomal-recessive multisystem disorder with the main clinical features of disproportionate growth deficiency, defective cellular immunity, and progressive renal disease. It is caused by mutations of SMARCAL1, a gene encoding a putative chromatin remodeling protein of unknown function. Because a detailed description of the clinical features is an essential first step in elucidating the function of SMARCAL1, we present the first detailed anthropometric data for Schimke-immuno-osseous dysplasia patients. By comprehensive anthropometric examination (28 parameters) of 8 patients (3 females) with the typical findings of Schimke-immuno-osseous dysplasia (mean age: 14.8 years; range: 4.9-30.5 years) and 304 patients (117 females) with congenital and hereditary chronic kidney disease (mean age: 10.7 +/- 4.8 years; range: 3-21.8 years), we show that Schimke-immuno-osseous dysplasia patients differ significantly from those with other forms of chronic kidney disease. z scores were calculated with reference limits derived from 5155 healthy children (2591 females) aged 3 to 18 years. The key finding was that, in the latter group, median leg length was significantly more reduced than sitting height, whereas in Schimke-immuno-osseous dysplasia patients, the reduction of sitting height was significantly more pronounced than for leg length. Therefore, the ratio of sitting height/leg length might be a simple tool for the clinician to distinguish Schimke-immuno-osseous dysplasia from other chronic kidney disease patients. Schimke-immuno-osseous dysplasia is very likely if this ratio is < 0.83. However, other forms of chronic kidney disease have to be discussed in case of a ratio > 1.01.