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:

• Disproportionate short stature (96% of individuals) manifests as a short neck and trunk with lumbar lordosis and a protruding abdomen

• Dysmorphism that includes a broad, low nasal bridge (65%) and a bulbous nasal tip (80%)

• Hyperpigmented macules (76%) on the trunk and occasionally extending onto the arms, neck, and legs.

• Spondyloepiphyseal dysplasia (80%). 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 (98%) individuals with SIOD have proteinuria; in 74% this evolves into ESRD. The renal pathology has been reported as focal segmental glomerulosclerosis without pathognomonic features in 79% of individuals.

• T-cell deficiency (83% 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 mutation is known to be associated with SIOD [Boerkoel et al 2002].

Evidence for locus heterogeneity. Only 50%-60% of individuals with clinical features of SIOD have identifiable mutations in SMARCAL1 [Clewing et al 2007b], suggesting that mutations in other unidentified genes can also cause SIOD.

Clinical testing

• Sequence analysis. Sequence analysis of SMARCAL1 is available clinically on a limited basis.

Table 1. Summary of Molecular Genetic Testing Used in Schimke Immunoosseous Dysplasia

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
SMARCAL1	Sequence analysis	Sequence variants 2	~ 90%	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

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 50%-60% 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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

To date, mutations of SMARCAL1 have not been identified in any other disorders.

Natural History

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 currently published reports.

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 or sparse hair, microdontia or adontia, 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, and in most of these, the delay can be ascribed to the deleterious consequences of chronic illness.

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 thoracic kyphosis, scoliosis, and osteopenia. Affected individuals do not usually have joint pain until they develop degenerative hip disease.

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.

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.

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, submitted-b]. This gene encodes for 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, submitted-b]. 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].

Central nervous system (CNS) symptoms. Nearly half of affected individuals have severe migraine-like headaches, transient ischemic attacks (TIAs), or strokes [Kilic et al 2005]. Some affected individuals also have heat intolerance and develop CNS symptoms during hot weather [Baradaran-Heravi et al 2012]. 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 9.2 years (range: 3-15 years) [Clewing et al 2007b]. Causes of death include stroke (17%), renal failure (15%), infection (23%), pulmonary hypertension and congestive heart failure (15%), bone marrow failure (3%), complications of organ transplantation (9%), gastrointestinal bleeding (6%), Complications of lymphoproliferative disease (9%), and unspecified acute restrictive lung disease (3%).

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 2012]. 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

Treatment of Manifestations

Renal transplantation effectively treats the nephropathy and neither nephropathy nor arteriosclerosis recurs in the graft [Clewing et al 2007a, Elizondo et al 2006, Lücke et al 2004]. Immunosuppressive monotherapy seems to improve the outcome after renal transplantation [Lücke et al 2009].

Some affected individuals who have survived beyond childhood have required hip replacement.

Treatment of scoliosis and/or kyphosis is standard.

Affected individuals with recurrent herpetic infections benefit from treatment with acyclovir.

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 one patient died 105 days after BMT.

A few individuals have been transfusion dependent because of anemia or thrombocytopenia.

Individuals with transient ischemic attacks or strokes usually have 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.

The 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.

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

A few patients have developed severe disseminated cutaneous papilloma virus infections that have improved with imiquimod and cidofovir.

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

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.

Prevention of Primary Manifestations

Although it has been hypothesized that environmental and other genetic factors can contribute to the penetrance as well as severity of SIOD, 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.

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, submitted].

Heat. Avoidance of heat stress such as hot weather is recommended [Baradaran-Heravi et al 2012].

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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

European Society for Immunodeficiencies (ESID) Registry
University Medical Center Freiburg Centre of Chronic Immunodeficiency
Phone: 49-761-270-34450
Email: registry@esid.org
Web: www.esid.org

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].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 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.

• 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 family members is possible if the disease-causing mutations in the family have been identified.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must have been identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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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

• 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