Schimke immunoosseous dysplasia

Other Names: Spondyloepiphyseal dysplasia nephrotic syndrome; Schimke syndrome; Immunoosseous dysplasia, Schimke type; SIOD; Schimke immuno-osseous dysplasia

Schimke immunoosseous dysplasia (SIOD) is a condition that results in short stature, kidney disease (nephropathy), and a weakened immune system. Some people develop a severe form in early childhood, and others develop a milder form in childhood or later.

Epidemiology

Schimke immuno-osseous dysplasia is a very rare condition. The prevalence in North America is estimated to be one in 1 million to 3 million people.

Cause

Mutations in the SMARCAL1 gene increase the risk of Schimke immuno-osseous dysplasia. The SMARCAL1 gene provides instructions for producing a protein whose specific function is unknown. The SMARCAL1 protein can attach (bind) to chromatin, which is the complex of DNA and protein that packages DNA into chromosomes. Based on the function of similar proteins, SMARCAL1 is thought to influence the activity (expression) of other genes through a process known as chromatin remodeling. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development. When DNA is tightly packed, gene expression is lower than when DNA is loosely packed.

Mutations in the SMARCAL1 gene are thought to lead to disease by affecting protein activity, protein stability, or the protein's ability to bind to chromatin. It is not clear if mutations in the SMARCAL1 gene interfere with chromatin remodeling and the expression of other genes.

The mutations associated with Schimke immuno-osseous dysplasia disrupt the usual functions of the SMARCAL1 protein or prevent the production of any functional protein. People who have mutations that cause a complete lack of functional protein tend to have a more severe form of this disorder than those who have mutations that lead to an active but malfunctioning protein. However, in order for people with SMARCAL1 gene mutations to develop Schimke immuno-osseous dysplasia, other currently unknown genetic or environmental factors must also be present.

Approximately half of all people with Schimke immuno-osseous dysplasia do not have identified mutations in the SMARCAL1 gene. In these cases, the cause of the disease is unknown.

Inheritance

Autosomal recessive inheritance, a 25% chance

Mutations in the SMARCAL1 gene are inherited in an autosomal recessive pattern, which means that an increased risk of Schimke immuno-osseous dysplasia results from mutations in both copies of the SMARCAL1 gene in each cell. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Schimke immunoosseous dysplasia (SIOD) affects multiple parts of the body. Slow growth is often the first sign of SIOD. People usually develop a short neck and trunk (disproportionately short stature) due to spondyloepiphyseal dysplasia. Bone abnormalities typically develop in the spine or hips. Many people with SIOD eventually need hip replacement surgery. Kidney disease is present at the time of diagnosis or develops within a few years, and it ultimately progresses to renal failure. Nearly all people with SIOD have a blood cell deficiency, most commonly of T-cells. This causes an increased risk for infections, which can be life-threatening. Other signs and symptoms may include:

• Reduced thyroid function
• Protruding abdomen
• Patches of increased skin color (hyperpigmented macules)
• Progressive atherosclerosis beginning in early childhood
• Transient ischemic attacks or stroke
• Severe, migraine-like headaches
• Lung complications including pulmonary emboli, pulmonary hypertension, and lung disease

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal T cell morphology
• Abnormality of epiphysis morphology(Abnormal shape of end part of bone)
• Anemia(Low number of red blood cells or hemoglobin)
• Bulbous nose
• Cellular immunodeficiency
• Depressed nasal bridge(Depressed bridge of nose)
• Disproportionate short-trunk short stature(Disproportionate short-trunked dwarfism)
• Glomerulopathy
• Hip dislocation(Dislocated hips)
• Hyperlordosis(Prominent swayback)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Lymphopenia(Decreased blood lymphocyte number)
• Melanocytic nevus(Beauty mark)
• Microdontia(Decreased width of tooth)
• Nephrotic syndrome
• Ovoid vertebral bodies
• Platyspondyly(Flattened vertebrae)
• Proteinuria(High urine protein levels)
• Short neck(Decreased length of neck)
• Thrombocytopenia(Low platelet count)

30%-79% of people have these symptoms

• Multiple cafe-au-lait spots

Diagnosis

The diagnosis of SIOD is suspected in people with the following key features:

• Short stature
• Spondyloepiphyseal dysplasia
• Progressive kidney disease
• T-cell deficiency
• Characteristic facial features
• Patches of increased skin color (hyperpigmented macules)

The diagnosis can be established after a clinical examination. Genetic testing to identify mutations in the SMARCAL1 gene can confirm the diagnosis.

Treatment

Treatment of Schimke immunoosseous dysplasia (SIOD) depends on the severity and individual symptoms in each person. Regular monitoring of the hips, kidneys, immune system and blood is recommended. Examples of treatments that may be needed for SIOD include:

• Kidney dialysis or transplant
• Hip replacement
• Treatment of neutropenia with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor
• Bone marrow transplantation for immune deficiency (although several deaths after transplantation have been reported)
• Medications to suppress the immune system for those with autoimmune symptoms
• Acyclovir for recurrent herpes infections
• Imiquimod and cidofovir (an antiviral) for severe papilloma virus infections of the skin
• Agents that improve blood flow or decrease blood clotting to treat transient ischemic attacks ("mini strokes") or strokes
• Standard treatment of hypothyroidism
• Standard treatment of scoliosis

Prognosis

Schimke immunoosseous dysplasia (SIOD) varies in severity. Those with an early-onset form generally have severe symptoms and an average lifespan of about 9 years. Causes of death may include stroke, severe opportunistic infection, bone marrow failure, complications of kidney failure, congestive heart failure, or lung disease. Those with milder symptoms survive into adulthood if kidney disease is well-managed. However, it is important to note that severity and age of onset do not necessarily predict life expectancy, because some people with severe, early-onset SIOD have survived into their 20s and 30s.

NIH genetic and rare disease info

• NIH info on Schimke immunoosseous dysplasia

Schimke immunoosseous dysplasia is a rare disease.

Schimke immunoosseous dysplasia Resources
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