Schimke immuno-osseous dysplasia is a condition characterized by short stature, kidney disease, and a weakened immune system. In people with this condition, short stature is caused by flattened spinal bones (vertebrae), resulting in a shortened neck and trunk. Adult height is typically between 3 and 5 feet. Kidney (renal) disease often leads to life-threatening renal failure and end-stage renal disease (ESRD). Affected individuals also have a shortage of certain immune system cells called T cells. T cells identify foreign substances and defend the body against infection. A shortage of T cells causes a person to be more susceptible to illness.

Other features frequently seen in people with this condition include an exaggerated curvature of the lower back (lordosis); darkened patches of skin (hyperpigmentation), typically on the chest and back; and a broad nasal bridge with a rounded tip of the nose.

Less common signs and symptoms of Schimke immuno-osseous dysplasia include an accumulation of fatty deposits and scar-like tissue in the lining of the arteries (atherosclerosis), reduced blood flow to the brain (cerebral ischemia), migraine-like headaches, an underactive thyroid gland (hypothyroidism), decreased numbers of white blood cells (lymphopenia), underdeveloped hip bones (hypoplastic pelvis), abnormally small head size (microcephaly), a lack of sperm (azoospermia) in males, and irregular menstruation in females.

In severe cases, many signs of Schimke immuno-osseous dysplasia can be present at birth. People with mild cases of this disorder may not develop signs or symptoms until late childhood.

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.

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.

Normal Function

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, the SMARCAL1 protein 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.

Health Conditions Related to Genetic Changes

Schimke immuno-osseous dysplasia

More than 40 mutations in the SMARCAL1 gene have been found to increase the risk of Schimke immuno-osseous dysplasia. 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. 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 how SMARCAL1 mutations contribute to short stature, kidney disease, and a weakened immune system in people with Schimke immuno-osseous dysplasia. 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.

Other Names for This Gene

• HARP
• HepA-related protein
• HHARP
• SMAL1_HUMAN
• SMARCA-like protein 1
• SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1
• SWI/SNF-related matrix-associated actin-dependent regulator of chromatin a-like 1

Genomic Location

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.

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

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.

• 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