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Schimke Immunoosseous Dysplasia

Synonym: Spondyloepiphyseal Dysplasia, Autosomal Recessive

, BSc, , MD, PhD, , MD, PhD, and , MD, PhD.

Author Information
, BSc
Department of Medical Genetics
University of British Columbia
Vancouver, British Columbia, Canada
, MD, PhD
Department of Biochemistry and Molecular Biology
University of British Columbia
Vancouver, British Columbia, Canada
, MD, PhD
Department of Neuropediatrics
Children’s Hospital
University of Bochum
Bochum, Germany
, MD, PhD
Department of Medical Genetics
University of British Columbia
Vancouver, British Columbia, Canada

Initial Posting: ; Last Update: August 22, 2013.

Summary

Clinical characteristics.

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small deformed capital femoral epiphyses, and shallow dysplastic acetabular fossae. Adult height is 136-157 cm for men and 98.5-143 cm for women. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease (ESRD). The majority of tested individuals have T-cell deficiency and associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with death early in life to a juvenile or milder later-onset form with survival into adulthood if renal disease is appropriately treated.

Diagnosis/testing.

SIOD is diagnosed on the basis of clinical findings. SMARCAL1 is the only gene in which mutations are known to cause SIOD.

Management.

Treatment of manifestations: Renal transplantation as indicated using mild immunosuppressive therapy; hip replacement as needed in older individuals; granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for neutropenia; bone marrow transplantation as indicated; immunosuppressive therapy for those with autoimmune manifestations; acyclovir for recurrent herpetic infections; imiquimod and cidofovir for severe disseminated cutaneous papilloma virus infections; agents that improve blood flow or decrease coagulability to treat transient ischemic attacks or strokes; standard treatment for hypothyroidism.

Prevention of secondary complications: Prophylaxis against Pneumocystis carinii pneumonia.

Surveillance: Regular monitoring of the hips; annual monitoring of renal, immune, and hematologic status.

Agents/circumstances to avoid: Hypertension; heat, stress and lack of sleep; certain immunizations in those who are T-cell deficient; DNA damaging anti-cancer therapies.

Genetic counseling.

SIOD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Carrier testing and prenatal testing are possible if the disease-causing mutations are identified in the family.

Diagnosis

Clinical Diagnosis

Schimke immunoosseous dysplasia (SIOD) is diagnosed on the basis of clinical findings. The clinical diagnosis of SIOD is suspected in individuals with the following:

  • Short stature (99% of individuals) that typically manifests as a short neck and trunk with lumbar lordosis and a protruding abdomen
  • Dysmorphism that includes a wide, depressed nasal bridge (67%) and a broad nasal tip (80%)
  • Hyperpigmented macules (72%) on the trunk and occasionally extending onto the arms, neck, and legs
  • Spondyloepiphyseal dysplasia (77%). The most commonly observed radiologic abnormalities are ovoid and mildly flattened vertebral bodies, small deformed capital femoral epiphyses, and shallow dysplastic acetabular fossae. Other bony abnormalities are less common.
  • Progressive steroid-resistant nephropathy. Almost all (99%) individuals with SIOD have proteinuria; in 73% this evolves into ESRD. The renal pathology has been reported as focal segmental glomerulosclerosis without pathognomonic features in 83% of individuals.
  • T-cell deficiency (76% of tested individuals). In general, both CD4 and CD8 cells are reduced and the CD4/CD8 ratio is normal.

Molecular Genetic Testing

Gene. SMARCAL1 is the only gene in which mutations are known to be associated with SIOD [Boerkoel et al 2002].

Evidence for locus heterogeneity. The presence of individuals with clinical features of SIOD who do not have identifiable mutations in SMARCAL1 [Clewing et al 2007b] suggests that mutations in other, as-yet unidentified genes can also cause SIOD.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Schimke Immunoosseous Dysplasia

Gene Symbol 1Test Method Mutations Detected 2Mutation Detection Frequency by Test Method 3
SMARCAL1Sequence analysisSequence variants 4~90% 5
1.

See Table A. Genes and Databases for chromosome locus and protein name.

2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a mutation that is present in the indicated gene

4.

Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Of individuals diagnosed with SIOD based on co-occurrence of spondyloepiphyseal dysplasia, renal failure, T-cell deficiency and typical facial features.

Testing Strategy

To confirm/establish the diagnosis in a proband. SIOD is diagnosed based on clinical features. Molecular genetic testing confirms the diagnosis and detects the causative mutations in approximately 90% of affected individuals.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Characteristics

Clinical Description

Schimke immunoosseous dysplasia (SIOD) is a multisystem progressive disorder that was first described by Schimke et al [1971] and later defined by Ehrich et al [1990], Spranger et al [1991], and Ehrich et al [1995]. Table 2 indicates the frequencies of the clinical findings in this condition based on published reports.

Table 2.

Frequency of Disease Features in Individuals with SIOD with Biallelic SMARCAL1 Mutations

FeatureNumber of Affected Individuals with FeatureTotal Individuals with SIOD 1
Physical features
Wide and depressed nasal bridge45 (67%)67
Broad nasal tip52 (80%)65
Microdontia25 (48%)52
Pigmented macules48 (72%)67
Unusual hair34 (62%)55
Short neck52 (83%)63
Short trunk54 (82%)66
Lumbar lordosis48 (74%)65
Protruding abdomen50 (77%)65
Corneal opacities10 (19%)53
Development
Schooling delay8 (26%)31
Developmental delay19 (30%)64
Growth
IUGR 247 (68%)69
Decreased postnatal growth rate/short stature69 (99%)70
Endocrine
Abnormal TFTs21 (38%)55
Skeleton
Ovoid flat vertebrae47 (80%)59
Hypoplastic pelvis39 (68%)57
Abnormal femoral heads52 (87%)60
Hematology
T-cell deficiency42 (76%)55
Lymphopenia52 (79%)66
Neutropenia23 (40%)58
Thrombocytopenia17 (27%)63
Anemia35 (57%)61
Kidney
Proteinuria or nephropathy70 (99%)71
FSGS40 (83%)48
Vasculature
Headaches24 (47%)51
TIAs28 (44%)64
Strokes25 (43%)58
Miscellaneous
Non-Hodgkin lymphoma 33 (4%)72

IUGR = intrauterine growth retardation

TFT = thyroid function test

FSGS = focal segmental glomerulosclerosis

TIA = transient ischemic attack

1. Total individuals with SIOD for whom the feature of interest has been reported to be present or absent

2. IUGR is defined as having a birth weight and/or birth length at or below the 3rd percentile for gestational age.

3. EBV-positive and negative non-Hodgkin lymphoma

Physical features. Most affected individuals have hyperpigmented macules on the trunk and occasionally on the extremities, neck, and face. Less common ectodermal abnormalities include fine and/or sparse hair, microdontia and/or hypodontia, and corneal opacities.

Development. Most individuals with SIOD have normal intellectual and neurologic development until the onset of cerebral ischemic events. A few have developmental delay; in most of these, the delay can be ascribed to the deleterious consequences of chronic illness and/or early recurrent cerebral ischemic events.

Growth and endocrine findings. Most affected children have prenatal and postnatal disproportionate growth failure. A few have normal intrauterine growth followed by postnatal growth failure. The observed disproportionate growth deficiency is not a result of renal failure. Comparison of the anthropometric measurements of persons with SIOD to persons with non-SIOD chronic kidney disease found that in nearly all parameters, persons with SIOD differed significantly from those with non-SIOD chronic renal disease. The most marked difference is that in non-SIOD chronic kidney disease, the median leg length is significantly more reduced than trunk length, while in persons with SIOD, the reduction in trunk length was significantly more than that for leg length. Therefore, a sitting height/leg-length ratio of less than 0.83 is suggestive of SIOD in persons with chronic kidney disease [Lücke et al 2006a].

The mean age of diagnosis with growth failure was two years (range: age 0-13 years) [Clewing et al 2007b]. Generally, affected individuals have a normal growth hormone axis and no response to growth hormone supplementation. Heights of those who have survived to adulthood are 136-157 cm for men and 98.5-143 cm for women.

Nearly half of affected individuals have subclinical hypothyroidism that persists after renal transplantation. The concentration of thyroid stimulating hormone (TSH) is increased and free and total T3 and T4 concentrations are reduced.

Skeletal findings. In addition to the prominent vertebral and femoral abnormalities, less frequent skeletal problems include a widened sella turcica, thoracic kyphosis, scoliosis, and osteopenia. Affected individuals do not usually have joint pain until they develop degenerative hip disease.

Dental findings. Of individuals with SIOD who have identified biallelic SMARCAL1 mutations, 66% have had microdontia, hypodontia, and/or malformed deciduous and permanent molars [Morimoto et al 2012a].

Hematologic findings and infection. T-cell deficiency causes lymphopenia in approximately 80% of affected individuals. The B-cell count is usually normal to slightly elevated. In addition to T-cell deficiency, several individuals with SIOD have had deficiencies of other blood cell lineages. See Table 2 for types and frequency.

Because of immunodeficiency, affected individuals have an increased risk for opportunistic infections such as Pneumocystis carinii pneumonia and more than half have recurrent infections with various bacteria, viruses (including Herpes simplex, Herpes zoster, cytomegalovirus), and fungi (oral and/or cutaneous candida) [Boerkoel et al 2000, Boerkoel et al 2002]. Infection is a common cause of death.

Autoimmune findings. About 20% of individuals with SIOD have features of autoimmune disease. These manifestations include thrombocytopenia, hemolytic anemia, enteropathy, pericarditis with anti-cardiolipin antibodies, and Evans syndrome (a combination of hemolytic anemia and thrombocytopenia) [Zieg et al 2011].

Renal findings. Nephropathy usually develops before age 12 years and progresses to ESRD within the subsequent one to 11 years. Usually the diagnosis of nephropathy is made concurrent with or within the five years following the diagnosis of growth failure. Focal segmental glomerulosclerosis (FSGS) is the predominant renal pathology in individuals with SIOD. The FSGS of SIOD is associated with a significant increase in expression of the NOTCH receptors and ligands in the renal glomeruli [Morimoto et al, submitted-a]. Increased NOTCH signaling is a known cause of FSGS [Niranjan et al 2008, Murea et al 2010].

Gastrointestinal findings. A few individuals with SIOD have enteropathy. In most of these individuals, the enteropathy results from infection, e.g., Heliobacter pylori. However, one individual without evidence of infection had gastrointestinal villous atrophy that improved with corticosteroid therapy [Kaitila et al 1998].

Atherosclerosis and hypertension. Half of individuals with SIOD have symptoms suggestive of atherosclerosis.

Vascular changes observed on postmortem tissue from three individuals included focal intimal lipid deposition, focal myointimal proliferation, macrophage invasion, foam cells, fibrous transformation, and calcium deposits [Spranger et al 1991, Lücke et al 2004, Clewing et al 2007a]. The pulmonary and systemic hypertension that persisted despite renal transplantation described by Lücke et al [2004] could be explained by myointimal hyperplasia [Clewing et al 2007a].

Also, gene expression studies have identified a significant decrease in the expression of ELN in individuals with SIOD [Morimoto et al 2012b]. This gene encodes for the precursor to elastin protein, which is critical for maintaining the integrity of the arterial wall. Histopathologic analysis of postmortem arterial tissue from three individuals with SIOD showed splitting and fragmentation of elastin fibers [Clewing et al 2007a, Morimoto et al 2012b]. Reduction in the elastin protein results in the increased proliferation of smooth muscle cells in arterial walls and leads to intimal hyperplasia [Urban et al 2002]. The reduction in elastin expression in the SIOD aorta appears to arise from both aberrant methylation of the ELN promoter [Morimoto et al, submitted-b] and from marked changes in expression of transcriptional regulators of ELN [Morimoto et al 2012b].

Central nervous system (CNS) symptoms. Nearly half of affected individuals have severe migraine-like headaches, transient neurological attacks (TNAs), or ischemic events [Kilic et al 2005]. The TNAs are usually focal and generally do not have an ischemic origin. Some affected individuals also have heat intolerance and develop CNS symptoms during hot weather [Baradaran-Heravi et al 2012a]. Generally, those with transient ischemic attacks or strokes have diffuse, progressive cerebral arteriosclerosis, whereas those with only migraine-like headaches do not. Frequently the cerebral ischemic events are precipitated by hypertension. The cause of the severe migraine-like headaches is unknown.

Clinical course and outcome. SIOD varies in severity, ranging from in utero onset of growth retardation with death in the first few years of life to a slowly progressive course with survival into adulthood. Classically, SIOD has been divided into an infantile- or severe early-onset form and a juvenile- or milder later-onset form. SIOD follows a continuum such that affected individuals with early-onset and severe symptoms usually die early in life, whereas those with mild symptoms survive into adulthood if ESRD is treated with renal dialysis and/or renal transplantation. Severity and age of onset of symptoms do not, however, invariably predict survival; a few individuals have survived beyond age 20 years despite having relatively severe early-onset disease [Lou et al 2002, Lücke et al 2004].

In five multiplex families, the phenotype of siblings has been variable:

  • A boy succumbed to a stroke at age 3.7 years after developing ESRD; his sister succumbed to bone marrow failure at age 2.75 years before developing renal failure and without symptoms of cerebral ischemia [Lou et al 2002].
  • Of two brothers, one had severe disease and the other had relatively mild disease [Lücke et al 2005a].
  • Of two brothers with homozygous SMARCAL1 mutations, one presented with growth failure at age six years and the other had no symptoms at age seven years [Bökenkamp et al 2005].
  • Of three siblings reported by Lama et al [1995], one died as a child and two have survived into their fourth and fifth decades.
  • Of three siblings reported by Dekel et al [2008] the elder brother demonstrated severe disease started at age of 3.5 years and two younger non-identical twin brothers had relatively mild disease.

Most affected individuals develop other symptoms within one to five years of the diagnosis of growth failure. Those with severe symptoms usually die within four to eight years. The mean age of death is 10.3 years. Causes of death include infection (23%), stroke (13%), pulmonary hypertension and congestive heart failure (13%), renal failure (12%), complications of organ transplantation (8%), lymphoproliferative disease (4%), gastrointestinal complications (4%), respiratory failure (4%), bone marrow failure (2%), non-Hodgkin lymphoma (2%), pancreatitis (2%), and other causes not reported (13%).

Among those who have survived beyond puberty, none has reproduced yet. Women develop menses, although the menstrual cycle is usually irregular. Men develop secondary sexual characteristics, but histopathologic examination of the testes identified azoospermia [Clewing et al 2007a].

Genotype-Phenotype Correlations

Ongoing correlations of genotype to phenotype have shown that genotype does not predict disease severity or outcome either within or among families [Bökenkamp et al 2005, Lücke et al 2005a, Clewing et al 2007b, Dekel et al 2008, Baradaran-Heravi et al 2012a]. The phenotypic heterogeneity and variable expressivity suggest that SIOD is modified by factors such as environment, epigenetics, and oligogenic inheritance. As a group, those individuals with prominent features of SIOD without detectable SMARCAL1 mutations have a lower frequency of hyperpigmented macules, lymphopenia, focal segmental glomerulosclerosis, and cerebral ischemic symptoms and a higher frequency of cognitive impairment [Clewing et al 2007b, Baradaran-Heravi et al 2008].

Nomenclature

In 1971, Schimke described a new disease combining the cardinal signs of nephritic syndrome, defective cellular immunity, and possibly chondroitin-6-sulphaturia [Schimke et al 1971]. Twenty years later Spranger et al [1991] designated the co-occurrence of growth retardation, immunopathy, and nephritic syndrome “Schimke-immuno-osseous dysplasia.” At roughly the same time Ehrich et al [1990] contributed to the clinical description of the disease; thus in parts of Germany the term “morbus Ehrich” has also been used.

Prevalence

The prevalence is unknown. However, based on referrals and published birth rates, the incidence in North America is estimated at 1:1,000,000 to 1:3,000,000 live births [Author, personal observation].

SIOD is pan ethnic.

Differential Diagnosis

The differential diagnosis of Schimke immunoosseous dysplasia (SIOD) depends on the presenting features of the individual.

Table 3 lists those hereditary osteochondrodysplasias associated with nephrotic syndrome or immune defects.

Table 3.

Hereditary Osteochondrodysplasias Associated with Nephrotic Syndrome or Immune Defects

SyndromeImmune Cell DefectOMIM Number
Associated with nephrotic syndrome
Conorenal syndrome266920
Nail-patella syndrome 161200
Schimke immunoosseous dysplasiaT cell242900
Braegger syndrome B cell
Associated with immune defects
Skeletal dysplasia with combined immune deficiencyT & B cell200900
Cartilage-hair hypoplasiaT & B cell250250
Short-limbed skeletal dysplasia with humoral immune deficiencyB cell
Roifman syndromeB cell300258
Kenny-Caffey syndromeT cell & phagocytes127000, 244460
Sanjad-Sakati syndromeT cell & phagocytes241410
Immunodeficiency-centromeric instability-facial anomalies syndrome B cell242860
MacDermot syndromeT cell, B cell, & phagocytes
Spondylo-mesomelic-acrodysplasiaT & B cells
Ramaan syndromeT & B cells

The co-occurrence of T-cell deficiency, disproportionate short stature with spondyloepiphyseal dysplasia, and progressive nephropathy is unique to SIOD.

Short stature resulting from renal failure can be distinguished from that of SIOD by the disproportion in body measures [Lücke et al 2006a]. Among individuals with chronic renal failure, median leg length was significantly more reduced than sitting height, whereas in individuals with SIOD, the reduction of sitting height was significantly more pronounced than for leg length. SIOD is very likely if this ratio is less than 0.83. However, other forms of chronic kidney disease have to be considered if the ratio is greater than 1.01.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Schimke immunoosseous dysplasia (SIOD), the following evaluations are recommended:

  • Detailed history for headaches or neurologic abnormalities
  • Assessment of developmental status using Denver Developmental Assessment, with referral for formal evaluation if significant developmental delays or schooling delays are identified
  • Measurement of growth and assessment of body proportions, with plotting on age-appropriate growth charts [Lücke et al 2006a]
  • Evaluation of renal function by measurement of serum concentrations of creatinine and urea, protein excretion in urine, and creatinine clearance
  • Referral to a nephrologist for evaluation
  • Hematology evaluations to assess lymphopenia, anemia, neutropenia, and thrombocytopenia
  • Orthopedic evaluation for symptoms of joint pain or evidence of scoliosis or kyphosis
  • Assessment for osteopenia
  • Thyroid function studies
  • Ophthalmologic evaluation
  • Dental evaluation after teeth are present
  • Medical genetics consultation

Treatment of Manifestations

Renal manifestations

  • The renal disease progresses from proteinuria to ESRD at variable rates and is not prevented by any known drug therapies, although a few affected individuals treated with cyclosporin A, tacrolimus, or corticosteroids have had a transient reduction in the rate of renal disease progression.
  • Renal transplantation effectively treats the nephropathy and neither nephropathy nor arteriosclerosis recurs in the graft [Lücke et al 2004, Elizondo et al 2006, Clewing et al 2007a]. Mild immunosuppressive therapy, such as immunosuppressive monotherapy, seems to improve the outcome after renal transplantation [Lücke et al 2009].

Orthopedic manifestations

  • Some affected individuals who have survived beyond childhood have required hip replacement.
  • Treatment of scoliosis and/or kyphosis is standard.

Immunologic manifestations

  • Neutropenia usually responds well to supplementation with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor.
  • One affected individual has been successfully treated by bone marrow transplantation (BMT) [Petty et al 2000, Thomas et al 2004], and four affected individuals have died after BMT [Baradaran-Heravi et al 2013].
  • Individuals with autoimmune problems have had variable responses to treatment.
    • A few individuals have been transfusion dependent because of anemia or thrombocytopenia.
    • In one affected individual with thrombocytopenia, the autoimmune features resolved spontaneously; in one they resolved after steroid and IVIG treatments, and in one they cleared after splenectomy. All other affected individuals, excepting one with Evans syndrome, were successfully treated with immunosuppressive therapy such as steroids, cyclophosphamide, or IVIG. The individual with Evans syndrome was resistant to treatment with steroids, cyclosporine A, and rituximab [Zieg et al 2011].

Infectious disease manifestations. Individuals with recurrent infections, opportunistic infections, or declining lymphocytes or T-cell counts frequently require the care of an immunologist.

  • Affected individuals with recurrent herpetic infections benefit from treatment with acyclovir.
  • A few affected individuals have developed severe disseminated cutaneous papilloma virus infections that have improved with imiquimod and cidofovir.

Neurologic manifestations

  • Individuals with transient ischemic attacks or strokes usually show temporary improvement upon treatment with agents that improve blood flow or decrease coagulability (pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin, heparin). To date, no curative or effective long-term therapies have been identified.
  • Migraine headaches are often difficult to treat since response to anti-migraine medication is variable. Medications that have helped some individuals include ergotamine, sumatriptan, verapamil, and propranolol. Note: Use of ergotamine and sumatriptan is contraindicated in individuals with SIOD with severe vasoocclusive disease or cerebral ischemic events.

Endocrinologic manifestations. TSH concentrations are corrected with levothyroxine supplementation; however, supplementation does not have an ameliorative effect on the renal disease or T-cell deficiency.

Prevention of Primary Manifestations

It has been hypothesized that environmental and other genetic factors can contribute to the penetrance as well as severity of SIOD; however, no specific factor has been elucidated yet.

Prevention of Secondary Complications

Because of the increased risk of opportunistic infection, prophylaxis against Pneumocystis carinii pneumonia is usually recommended.

If recurrent oral herpetic infections or shingles occur, prophylactic acyclovir may reduce the morbidity.

Surveillance

The following are appropriate:

  • Regular monitoring of the hips
  • Annual monitoring of renal, immune, and hematologic status

Agents/Circumstances to Avoid

Hypertension. Poor blood pressure control can exacerbate or evoke cerebral ischemia. In particular, the hypertension arising from using high-dose steroids for empiric treatment of the nephrotic syndrome can evoke cerebral ischemia.

Transient neurologic attacks. Individuals with transient neurologic attacks that are not of an ischemic origin have found that heat, stress, and lack of sleep can precipitate the attacks.

Immunizations. Individuals with severe early-onset disease are best vaccinated according to the protocol for other T-cell immunodeficiencies.

Anti-cancer therapies. SIOD cells and model organisms are hypersensitive to DNA damaging agents [Bansbach et al 2009, Ciccia et al 2009, Postow et al 2009, Yuan et al 2009, Yusufzai et al 2009, Bansbach et al 2010, Baradaran-Heravi et al 2012b].

Heat. Avoidance of heat stress (e.g., hot weather) is recommended [Baradaran-Heravi et al 2012a].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Combined renal and bone marrow transplantation may be discussed as an approach in patients with declining renal and immune function prior to the onset of end-stage disease.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Individuals with SIOD usually have normal growth hormone studies. No affected individual treated with growth hormone supplementation has responded with improved growth.

Anemia does not often respond to supplementation with erythropoietin or renal transplantation. However, it is possible that erythropoietin has a protective effect on the endothelia.

Because of the T-cell defect, individuals with SIOD usually require milder immunosuppressive therapy for bone marrow transplantation than those undergoing transplantation for other diseases.

Studies of mitochondrial function and nitrous oxide production have not detected any impairment; therefore, empiric treatments addressing such etiologies would be expected to have little effect [Lücke et al 2005b, Lücke et al 2006b].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Schimke immunoosseous dysplasia (SIOD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of inheriting biallelic SMARCAL1 mutations and being at risk of developing SIOD, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Not all individuals with biallelic SMARCAL1 mutations have developed SIOD [Bökenkamp et al 2005, Baradaran-Heravi et al 2012a].
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. No affected individual has reproduced.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. The diagnosis may be suspected in a fetus with intrauterine growth retardation and an affected sibling.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: ContactUs@magicfoundation.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Schimke Immunoosseous Dysplasia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Schimke Immunoosseous Dysplasia (View All in OMIM)

242900IMMUNOOSSEOUS DYSPLASIA, SCHIMKE TYPE
606622SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A-LIKE PROTEIN 1; SMARCAL1

Normal allelic variants. SMARCAL1 contains 18 exons spanning approximately 70 kb. Normal variants of SMARCAL1 have not been catalogued.

Pathologic allelic variants. Mutations are distributed throughout SMARCAL1. The abnormalities reported for SMARCAL1 are gene deletions eliminating expression, truncating mutations, or point mutations. Missense mutations occur at amino acids conserved across species.

Normal gene product. SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1) encodes HARP, the SNF2-related protein [Boerkoel et al 2002] most similar to the prokaryotic HepA proteins [Coleman et al 2000]. SNF2-related proteins participate in the DNA-nucleosome restructuring that commonly occurs during gene regulation and DNA replication, recombination, methylation, repair, and transcription [Pazin & Kadonaga 1997, Havas et al 2001]. HARP binds DNA at single-to-double strand transitions and hydrolyzes ATP [Muthuswami et al 2000] to produce energy to re-anneal open strands of DNA [Yusufzai & Kadonaga 2008]. Such DNA structures are commonly seen during DNA replication and repair and transcription. At these sites, HARP re-anneals the single-stranded DNA and prevents further DNA damage. Consequently, HARP deficiency leads to increased DNA damage and hypersensitivity to DNA-damaging agents [Bansbach et al 2009, Ciccia et al 2009, Postow et al 2009, Yuan et al 2009, Yusufzai et al 2009, Baradaran-Heravi et al 2012b]. Also, as a modulator of DNA structure SMARCAL1 regulates gene expression [Baradaran-Heravi et al 2012a, Morimoto et al 2012b]. In summary, SMARCAL1 maintenance of genomic integrity is required for the basic cellular processes of modulating DNA replication, DNA repair and transcription, and possibly DNA recombination.

Abnormal gene product. Mutations in SMARCAL1 are predicted to cause loss of function in HARP (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1).

References

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Chapter Notes

Author History

Alireza Baradaran-Heravi, MD (2011-present)
Cornelius F Boerkoel, MD, PhD (2002-present)
Leah I Elizondo; Baylor College of Medicine (2006-2011)
Shu Lou, MD; Baylor College of Medicine (2002-2006)
Thomas Lücke, MD, PhD (2006-present)
Marie Morimoto, BSc (2011-present)

Revision History

  • 22 August 2013 (me) Comprehensive update posted live
  • 29 December 2011 (cd) Revision: prenatal testing available clinically
  • 22 March 2011 (me) Comprehensive update posted live
  • 7 December 2006 (me) Comprehensive update posted to live Web site
  • 30 August 2004 (me) Comprehensive update posted to live Web site
  • 1 October 2002 (me) Review posted to live Web site
  • 18 June 2002 (cfb) Original submission
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