What is SIOD?

Schimke Immuno-Osseous Dysplasia (SIOD) is a multisystem disorder that is inherited in an autosomal recessive pattern. It usually manifests first with growth failure. Other features of the disease are generally noted in the ensuing evaluation of the growth failure or develop in the following years. According to the severity of the clinical features and the age of onset, SIOD has been divided into an infantile or severe early-onset form and a juvenile or milder late-onset form. Affected individuals with early-onset manifest severe symptoms and have a mean age of death at 9.2 years. These individuals have died from strokes, severe opportunistic infections, bone marrow failure, complications of kidney failure, congestive heart failure, and unspecified lung disease. On the other hand, those with milder disease have survived into the fifth decade if symptomatically treated. However, severity and age of onset of symptoms do not invariably predict survival as a few of those with early-onset disease have survived into the third and fourth decade.

- National Organization for Rare Disorders

Signs & Symptoms

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SIOD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Two mutations in the swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAl1) gene are found in 50 to 60% of individuals clinically diagnosed with SIOD. The individuals without detectable mutations in SMARCAL1 have a lower frequency of hyperpigmented macules and lymphopenia and higher frequency of cognitive impairment. This suggests that they have might have a subtly different disorder or SIOD secondary to another genetic cause.

The mutations identified in SMARCAL1 suggest that SIOD arises from loss of function in the encoded protein. These mutations include gene deletions as well as nonsense, frame shift, splicing and missense mutations. Mutations in SMARCAL1 have not been found to cause any other disease.

With the exception of the sibling of an affected patient, all identified patients with two mutations in SMARCAL1 have had SIOD and none of the tested unaffected siblings have had two mutations. The asymptomatic boy with two mutations was 2 years when first described and may develop symptoms later.

Despite extensive analysis, there are no predictable relationships between particular SMARCAL1 mutations and the severity of the symptoms or the outcome. This has led to the idea that SIOD is the result of the interaction between the SMARCAL1 mutations and environmental, genetic, and epigenetic factors.

The SMARCAL1 gene encodes the SMARCAL1 enzyme which has a role in DNA repair and the DNA stress response, participates in activating stalled DNA replication forks and reannealing single stranded DNA to double stranded DNA. SMARCAL1 deficiency in tissue culture cells also impairs normal replication of telomere DNA at the ends of the chromosomes. Recent studies of some SIOD patients with SMARCAL1 deficiency caused by two SMARCAL1 mutations has found significantly shortened telomeres in white blood cells, including T cells. The deficiency of SMARCAL1 causes non-random, global changes in gene expression and changes in gene expression cause the arteriosclerosis, renal disease and immunodeficiency. The arteriosclerosis appears to be a consequence of reduced expression of elastin. The renal disease appears to arise from overexpression and activity of the WNT and NOTCH pathways. The T-cell deficiency arises from lack of expression of IL7 receptor alpha chain expression and is associated with hypermethylation of the IL7R promotor as well as the shortened telomere length. These changes in gene expression might well develop from the changes in epigenetic marks associated with replication fork stalling and collapse.

-National Organization for Rare Disorders

Affected Populations

SIOD is pan-ethnic with an unknown prevalence. As deduced from referrals and published birth rates, the incidence is approximately 1 per million live births in North America. 

- National Organization for Rare Disorders

Diagnosis

The diagnosis of SIOD is made on clinical findings. The most definitive diagnostic findings are skeletal dysplasia (spondyloepiphyseal dysplasia), renal dysfunction (urinary protein loss), T lymphocyte deficiency (particularly for naïve CD4 and CD8 T cells), dysmorphic facial features, and hyperpigmented macules. Anthropometry can help to distinguish SIOD from other forms of chronic kidney disease: a sitting height: leg length ratio of < 0.83 is consistent with a diagnosis of SIOD whereas a ratio of > 1.01 is indicative of non-SIOD chronic kidney disease. DNA testing for mutations in the SMARCAL1 gene is available to confirm the diagnosis.

-National Organization for Rare Disorders

Standard Therapies & Treatment

Treatments are selected to address individual symptoms as they develop. Renal transplantation effectively treats renal disease, and bone marrow transplantation effectively treats immunodeficiency and other hematological abnormalities. Blood-thinning medications such as pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin, and heparin can transiently improve blood flow through the atherosclerotic arteries but do not provide enduring relief from cerebral ischemia. Treatment with acyclovir and some antibacterial agents has been beneficial for preventing or reducing the frequency of opportunistic infections. Hip replacement effectively treats degenerative hip disease.

-National Organization for Rare Disorders