Schimke Immunoosseous Dysplasia

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 an 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.

The diagnosis of SIOD is established in a proband with the characteristic clinical and radiographic features. Identification of biallelic pathogenic variants in SMARCAL1 on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

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: Vaccinations according to the protocol for other T-cell immunodeficiencies (i.e., an avoidance of live attenuated vaccines) in individuals with severe early-onset disease; prophylaxis against Pneumocystis jirovecii pneumonia; prophylactic acyclovir or valacylovir if recurrent oral herpetic infections or shingles occur.

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; live attenuated 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. Carrier testing and prenatal testing are possible if both pathogenic variants in the family are known.

Suggestive Findings

Schimke immunoosseous dysplasia (SIOD) should be 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
• Spondyloepiphyseal dysplasia (75%). 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; this generally 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. The T cells are predominantly of a memory (CD45R0+CD45RA-) surface phenotype.
• Characteristic facial features that include a wide, depressed nasal bridge (65%) and a broad nasal tip (78%)
• Hyperpigmented macules (70%) on the trunk and occasionally extending onto the arms, neck, and legs

Establishing the Diagnosis

The diagnosis of SIOD is established in a proband with the above clinical features. Identification of biallelic pathogenic variants in SMARCAL1 on molecular genetic testing (see Table 1) confirms the diagnosis if clinical features are inconclusive.

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of SMARCAL1 is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes SMARCAL1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of SIOD. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Schimke immunoosseous dysplasia (SIOD) is a multisystem progressive disorder. Table 2 indicates the frequency of clinical findings in this condition based on published reports.

Growth. 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. Height in those who have survived to adulthood is 136-157 cm for men and 98.5-143 cm for women.

Skeletal features. 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.

Renal disease. 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]. Increased NOTCH signaling is a known cause of FSGS [Niranjan et al 2008, Murea et al 2010].

Hematologic abnormalities. T-cell deficiency causes lymphopenia in approximately 80% of affected individuals. Those T cells that are present are predominantly of a memory (CD45R0+) rather than a naïve (CD45RA+) surface phenotype, consistent with reduced production of T cells by the thymus [Sanyal et al 2015]. 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. The T-cell deficiency is associated with a lack of interleukin 7 receptor alpha expression on the T cells of patients with SIOD [Sanyal et al 2015]. This receptor is critical for T-cell development and has been previously implicated in severe combined immunodeficiency [Puel et al 1998, Roifman et al 2000].

Immunodeficiency increases the risk of opportunistic infections such as Pneumocystis jiroveciii pneumonia. More than half of individuals with SIOD have recurrent infections with various bacteria, viruses (including herpes simplex virus, varicella-zoster virus, cytomegalovirus), and fungi (e.g., oral and/or cutaneous candida) [Boerkoel et al 2000, Boerkoel et al 2002]. Infection is a common cause of death.

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

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; 66% have had microdontia, hypodontia and/or malformed deciduous and permanent molars [Morimoto et al 2012a], 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.

Central nervous system (CNS) symptoms, atherosclerosis and hypertension. Nearly half of affected individuals have severe migraine-like headaches, transient neurologic 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.

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 [Urbán et al 2002]. The reduction in elastin expression in the SIOD aorta appears to arise from reduced transcription of ELN as well as increased post-transcriptional ELN mRNA decay [Morimoto et al 2015].

Hypothyroidism. A third 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.

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

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].

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 11 years. Causes of death include infection (23%), stroke (13%), pulmonary hypertension and congestive heart failure (13%), renal failure (11%), complications of organ transplantation (9%), 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.

In five multiplex families, the phenotype of sibs 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 pathogenic variants, one presented with growth failure at age six years [Bökenkamp et al 2005], while the other had normal growth at age ten years [unpublished data].
• Of three sibs reported by Lama et al [1995], one died as a child with severe disease, one had normal stature and died of a pulmonary infection at 43 years, and one has survived into the fourth decade.
• Of three sibs reported by Dekel et al [2008] the elder brother demonstrated severe disease from age 3.5 years and two younger non-identical twin brothers had relatively mild disease.

As a group, those individuals with prominent features of SIOD without detectable SMARCAL1 pathogenic variants 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

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

• 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
• Immunology evaluations to evaluate the numbers of memory and naïve CD4 and CD8 T cells and B cells and immunoglobulin levels
• Assessment of developmental status with referral for formal evaluation if significant developmental delays or schooling delays are identified
• Dental evaluation after teeth are present
• Ophthalmologic evaluation
• Detailed history for headaches or neurologic abnormalities
• Orthopedic evaluation for symptoms of joint pain or evidence of scoliosis or kyphosis
• Assessment for osteopenia
• Thyroid function studies
• Consultation with a clinical geneticist and/or genetic counselor

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