SUMMARY

 

1.  Schimke Immuno-Osseous Dysplasia (SIOD) is an autosomal recessive syndrome characterized by the following clinical features: 

Intrauterine growth retardation
Short stature 
Spondyloepiphyseal dysplasia 
Progressive renal failure 
Immunodeficiency 
Multiple hyperpigmented macules (lentigines) 
Characteristic facial features 
Early onset atherosclerosis and cerebral ischemic attacks

 

2.  The immunodeficiency in SIOD is characterized by T cell lymphopenia, reduced mitogen proliferation, normal B cell numbers, and reduced immunoglobulin levels (variable).  

 

3.  Patients with SIOD may suffer from bacterial infections (sinusitis, pneumonia, sepsis) as well as opportunistic infections (Pneumocystis jiroveci, CMV, HSV, EBV, Candida, and mycobacteria).

 

4.  Rarely, a SCID-like phenotype can occur with severe lymphopenia and marked T and B cell dysfunction. A bone marrow failure phenotype has also been reported.   

 

5.  SIOD is caused by mutations in the SMARCAL1 gene, which encodes a SW1/SNF2 ATP-dependent chromatin remodeling protein.  

 

6.  The clinical features of skeletal and growth abnormalities, progressive renal disease, and immunodeficiency suggest the diagnosis of SIOD.  Skeletal imaging can be quite useful for identifying pathognomonic skeletal features of this syndrome.  The definitive diagnosis is made by sequencing of the SMARCAL1 gene.  

 

7.  Supportive therapies such as immunoglobulin replacement therapy or prophylactic antibiotics may be implemented for patients with immunodeficiency.  Renal transplantation may be required for treatment of renal failure.  HSCT may be required for patients with a SCID phenotype or bone marrow failure. 

 

 

 

 

OVERVIEW

 

     Schimke Immuno-Osseous Dysplasia (SIOD) is an autosomal recessive syndrome characterized by the following clinical features: 

 

Intrauterine growth retardation
Short stature (from truncal shortening)
Spondyloepiphyseal dysplasia - This is characterized by flattened and ovoid vertebrae, lumbar 
          lordosis, small and laterally displaced  femoral epiphyses, and shallow dysplastic acetabular fossae.   
Progressive renal failure - The renal failure begins with proteinuria and progresses to end-stage renal failure.  Histopathology typically reveals focal segmental glomerulosclerosis.     
Immunodeficiency - Patients exhibit T cell lymphopenia, reduced mitogen proliferation, normal B cell numbers, and reduced immunoglobulin levels (variable).  
Multiple hyperpigmented macules (lentigines) - These macules measure a few millimeters and are mainly present on the trunk and extremities.  
Characteristic facial features (broad low nasal bridge and bulbous nasal tip) 
Early onset atherosclerosis and cerebral ischemic attacks

 

     Patients with SIOD may suffer from bacterial infections (sinusitis, pneumonia, sepsis) as well as opportunistic infections (Pneumocystis jiroveci, CMV, HSV, EBV, Candida, and mycobacteria).

 

     Rarely, a SCID-like phenotype can occur with severe lymphopenia and marked T and B cell dysfunction. These patients have an increased susceptibility to life-threatening opportunistic and invasive infections and are candidates for stem cell transplantation.  Very rarely, a bone marrow failure phenotype can also occur.   

         

 

 

PATHOGENESIS

 

 SIOD is caused by mutations in the SMARCAL1 gene, which encodes a SW1/SNF2 ATP-dependent chromatin remodeling protein.  This protein participates in DNA-nucleosome restructuring that occurs during gene regulation and DNA replication and recombination.  

 

 

 

 

EVALUATION

 

The clinical features of skeletal and growth abnormalities, progressive renal disease, and immunodeficiency suggest the diagnosis of SIOD.  
    
 Step 1:  Immune Evaluation 

 

-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-T-cell proliferation to Mitogens (PHA)
-IgG, IgA, IgM, IgE levels 
-Specific Antibody levels (if older than 6 months)

 

-The absolute lymphocyte count (ALC) should be calculated from the CBC.  The ALC may be decreased due to T cell lymphopenia. 
-Low CD4 and CD8 T cell numbers may be present while B cell numbers are typically normal.   
-Low T-cell proliferation to mitogens is commonly seen.  Markedly decreased mitogen proliferation is seen in patients with a SCID phenotype.  
-Hypogammaglobulinemia has been described in some patients with SIOD
-Vaccine responses to protein (Tetanus, Diphtheria)and polysaccharide (pneumococcal) antigens should be evaluated.  Specific antibody deficiency may be present.

 

Step 2:  Imaging Studies

 

-Spine Radiograph
-Hip Radiograph

 

-Spine X-ray shows flattened and ovoid vertebral bodies as well as lumbar lordosis and thoracic kyphosis.
-Hip X-ray shows shallow dysplastic acetabular fossae and small capital femoral epiphyses which are displaced.  The iliac wings may be hypoplastic.  

 

 

Step 3:  Gene sequencing


-SMARCAL1 Gene Sequencing 

 

-Sequencing of this gene is currently available commercially through the Center for Nephrology and Metabolic Disorders (Weisswasser, Germany).   www.moldiag.com/en

 

 

 

 

MANAGEMENT


      Supportive therapies such as immunoglobulin replacement therapy or prophylactic antibiotics may be implemented for patients with immunodeficiency.  Renal transplantation may be required for treatment of renal failure.  HSCT may be required for patients with a SCID phenotype or bone marrow failure. 

 

 

 

                                                                           

RESOURCES

 

Literature Resources

 

1.  Saraiva 2000 
     SIOD case report and review of 25 patients
     

2.  Boerkoel 2000 
     Manifestations and Treatment of SIOD
     

3  Petty 2000 
    Successful HCST for SIOD (case report)