Clinical characteristics.

Schimke immunoosseous dysplasia (SIOD) is 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 ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. 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. 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 a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated.

Diagnosis/testing.

The diagnosis of SIOD is established in a proband with the characteristic clinical, laboratory, and radiographic features and/or biallelic pathogenic variants in SMARCAL1 identified on molecular genetic testing.

Management.

Treatment of manifestations: Treatment of scoliosis and kyphosis per orthopedist; pain management and hip replacement as needed in older individuals for degenerative hip disease; standard treatments for osteopenia; consider cyclosporin A, tacrolimus, or corticosteroids for renal disease; renal transplantation as indicated using mild immunosuppressive therapy; acyclovir for recurrent herpetic infections and/or shingles; imiquimod and cidofovir for severe disseminated cutaneous papilloma virus infections; vaccine protocol (avoidance of live vaccines as for T cell immunodeficiency); consider antibiotic prophylaxis for Pneumocystis jirovecii pneumonia; granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for neutropenia; hematopoietic stem cell transplantation as indicated; immunosuppressive therapy for those with autoimmune manifestations; thrombopoietin receptor agonists; transfusions when indicated for thrombocytopenia and/or anemia; standard treatment of dental manifestations; developmental support as needed; medical therapy for migraine headaches as needed; agents that improve blood flow or decrease coagulability to treat transient ischemic attacks or strokes; blood pressure control; levothyroxine for hypothyroidism; treatment of malignancy per oncologist.

Surveillance: Annually: monitor growth; monitor for scoliosis/kyphosis and hip degeneration; monitor renal, immune, and hematologic status; assess for enteropathy, dental issues, and developmental concerns; assess for headaches or neurologic abnormalities; thyroid function studies; complete blood count with differential, complete metabolic panel, T and B cell flow cytometry, abdominal ultrasound, and clinical evaluation for lymphadenopathy to monitor for malignancy. At each visit: monitor blood pressure.

Agents/circumstances to avoid: Avoid hypertension; heat, stress, and lack of sleep; and live attenuated immunizations in those who are T cell deficient. Use DNA-damaging anti-cancer therapies with caution due to evidence of susceptibility to genotoxic agents.

Genetic counseling.

SIOD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SMARCAL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic SMARCAL1 pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SMARCAL1 pathogenic variants. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.

Suggestive Findings

SIOD should be suspected in individuals with the following clinical, laboratory, and radiographic features.

Clinical features

• Disproportionate short stature (99%) often of prenatal onset (70%) with short neck and trunk, lumbar lordosis, and protruding abdomen
• Characteristic facial features. Wide, depressed nasal bridge and a broad nasal tip
• Hyperpigmented macules (70%) on the trunk and occasionally extending onto the extremities, neck, and face
• Recurrent infections (60%-80%). Bacterial, viral, and fungal
• Dental anomalies (66%). Microdontia, hypodontia, and/or malformed molars
• Neurologic manifestations. Migraines, transient ischemic attacks, and/or strokes
• Development often normal but can be delayed due to recurrent cerebral ischemic events and/or chronic illness
• Corneal opacities

Laboratory features

• Progressive steroid-resistant nephropathy. Proteinuria (99%) that generally evolves into end-stage renal disease
• T cell deficiency (80%). Decreased CD4 and CD8 cells with normal CD4-to-CD8 ratio. The T cells are predominantly of a memory (CD45R0+CD45RA-) surface phenotype.

Radiographic features of spondyloepiphyseal dysplasia. Features are progressive:

• Ovoid and mildly flattened vertebral bodies; endplate irregularities, wedged vertebrae, and narrowed vertebral spaces have been reported.
• Small ilia with hypoplastic basilar portions and shallow dysplastic acetabular fossae
• Capital femoral epiphyses are small, deformed, and laterally displaced; flattened epiphyses at the knees and shoulders.

Establishing the Diagnosis

The diagnosis of SIOD can be established in a proband with characteristic clinical, laboratory, and radiographic features and/or biallelic pathogenic (or likely pathogenic) variants in SMARCAL1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic SMARCAL1 variants of uncertain significance (or of one known SMARCAL1 pathogenic variant and one SMARCAL1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SIOD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Schimke immunoosseous dysplasia (SIOD) is characterized by a constellation of clinical findings that affect a variety of organ systems. Nearly all affected individuals have disproportionate short stature, spondyloepiphyseal dysplasia causing hip disease, nephrotic syndrome that progresses to end-stage renal disease (ESRD), hyperpigmented macules, and immunodeficiency (primarily cellular immunodeficiency). Central nervous system vasculopathy (migraines, transient ischemic attacks, strokes), thyroid dysfunction, and cytopenias are also common. Secondary complications include hypertension, anemia, elevated lipids, recurrent infections, and osteopenia. Although not defining features of SIOD, bone marrow failure and lymphoproliferative disease have been reported [Boerkoel et al 2000, Baradaran-Heravi et al 2012b, Ramdeny et al 2021]. Based on review of the medical literature to date, more than 100 individuals have been identified with biallelic pathogenic variants in SMARCAL1. The following description of the phenotypic features associated with this condition is based on these reports.

Disproportionate short stature. The mean age of diagnosis of disproportionate growth deficiency is 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 cm to 157 cm for men and 98.5 cm to 143 cm for women.

Short stature 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 of leg length. Therefore, a sitting height / leg length ratio of lower than 0.83 is suggestive of SIOD in persons with chronic kidney disease [Lücke et al 2006a].

Skeletal features. Vertebrae are ovoid in more than 75% of individuals with dorsal flattening. Endplate irregularities and narrowed vertebral spaces can be seen. Short neck and trunk with lumbar lordosis are common and become more evident with age. Thoracic kyphosis and scoliosis have also been reported.

Hypoplastic pelvis and epiphyseal dysplasia leads to degenerative hip disease and chronic joint pain. Surgical intervention may be necessary, and treatment of hematopoietic and renal anomalies has not been shown to alter bony disease. The shoulder and other large joints are relatively spared.

Less frequent skeletal findings include a widened sella turcica and osteopenia. Individuals with SIOD and osteopenia are at risk for fractures. Systemic corticosteroids should be used with caution.

Renal disease. Nephropathy usually develops before age 12 years and progresses to ESRD within the subsequent one to 11 years. Both early onset (by age 5 years) and juvenile onset (typically after age 10 years) have been reported [Lipska-Ziętkiewicz et al 2017]. Usually, the diagnosis of nephropathy is made concurrent with or within five years following the diagnosis of growth deficiency. Focal segmental glomerulosclerosis (FSGS) is the predominant renal pathology in individuals with SIOD.

Immune deficiency. T cell deficiency is reported 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 T cell deficiency is associated with a lack of interleukin-7 (IL-7) receptor alpha expression on the T cells of individuals with SIOD and their poor response to recombinant IL-7 [Sanyal et al 2015]. The IL-7 receptor is critical for T cell development and has been previously implicated in severe combined immunodeficiency [Puel et al 1998, Roifman et al 2000]. The B cell count is usually normal to slightly elevated. Hypogammaglobulinemia and poor antibody responses to immunization have been reported, and affected individuals may require replacement immunoglobulin therapy. Immunization with live vaccines is contraindicated in individuals with T cell immunodeficiency.

Neutropenia is also reported in 38% of individuals with SIOD and is likely a reflection of relative hypoplasia of the neutrophil lineage in the bone marrow [Bertaina et al 2022]. Most individuals with neutropenia have concurrent autoimmune thrombocytopenia, autoimmune hemolytic anemia, or pancytopenia from bone marrow failure [Boerkoel et al 2000, Clewing et al 2007a].

Immunodeficiency increases the risk of opportunistic infections such as Pneumocystis jirovecii pneumonia. More than half of individuals with SIOD have recurrent infections with various bacteria, viruses (e.g., herpes simplex virus, varicella-zoster virus, cytomegalovirus), and fungi (e.g., oral and/or cutaneous candida) [Lipska-Ziętkiewicz et al 2017]. Several individuals have developed viral cutaneous papillomas refractory to multiple antivirals that have negatively affected quality of life. Severe bacterial, viral, and/or fungal infection is a common cause of death.

Autoimmune disease. About 20% of individuals with SIOD have features of autoimmune disease. These manifestations include immune thrombocytopenia, hemolytic anemia, Evans syndrome (a combination of hemolytic anemia and immune thrombocytopenia), enteropathy, and pericarditis with anti-cardiolipin antibodies [Lipska-Ziętkiewicz et al 2017].

In one affected individual with thrombocytopenia, the autoimmune features resolved spontaneously; in one they resolved after steroid and intravenous immunoglobulin treatments, and in one they cleared after splenectomy. One individual who developed immune thrombocytopenia two years after renal transplantation was not responsive to intravenous immunoglobulin or systemic corticosteroids and required plasmapheresis and thrombopoietin-receptor agonist therapy [Grenda et al 2016]. All other affected individuals, excepting one with Evans syndrome, were successfully treated with immunosuppressive therapy such as steroids, cyclophosphamide, or intravenous immunoglobulin.

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. A few individuals have been transfusion dependent due to anemia or thrombocytopenia. The individual with Evans syndrome was resistant to treatment with steroids, cyclosporin A, and rituximab [Zieg et al 2011].

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].

Physical features. Characteristic features include triangular facies, wide, depressed nasal bridge with a broad nasal tip, short neck, short trunk, and protruding abdomen. Most affected individuals have hyperpigmented macules on the trunk and occasionally on the extremities, neck, and face. Fine and/or sparse hair is present following the transition from soft newborn hair; 66% of individuals have had microdontia, hypodontia, and/or malformed deciduous and permanent molars [Morimoto et al 2012a]; corneal opacities are also reported.

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 cases likely a consequence 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 ischemic attacks (TIAs), or strokes [Kilic et al 2005]. Reported migraine-like headaches had no aura and included throbbing, photophobia, nausea, and vomiting. The TIAs are usually focal and can present as hemiplegia, dysarthria, and aphasia. Some affected individuals also have heat intolerance and develop CNS symptoms (e.g., headache, aphasia) during hot weather [Baradaran-Heravi et al 2012a]. Generally, those with TIAs 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 onset of chronic hypertension, though variable, is often within two years of diagnosis in early-onset disease.

The cause of the severe migraine-like headaches is unknown. Two case reports describe individuals presenting with severe headaches progressing to hemiplegia, aphasia, and seizures in whom brain imaging demonstrated reversible vasoconstriction and diminished cerebral perfusion [Severino et al 2018, Haffner et al 2019]. Their presentation, consistent with reversible cerebral vasoconstriction syndrome, describes a new mechanism for headaches, TIAs, and strokes in individuals with SIOD.

Half of individuals with SIOD have symptoms suggestive of atherosclerosis (e.g., hypertension, cerebral ischemia, renal occlusive disease). 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]. Moyamoya disease has also been described in SIOD-associated CNS disease. 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].

Hypothyroidism. One third of affected individuals have subclinical hypothyroidism that persists after renal transplantation. The concentration of thyroid-stimulating hormone is increased and free, and total T3 and T4 concentrations are reduced.

Malignancy. Individuals with SIOD are at increased risk for hematologic malignancies including both non-Hodgkin lymphoma and leukemia. There is one reported [Baradaran-Heravi et al 2012b] and one unpublished instance of osteosarcoma as well as several unpublished instances of solid organ malignancies. A diagnosis of undifferentiated sinus carcinoma has also been reported in one individual with SIOD [Collins et al 2018]. Individuals who have received renal transplants are also at risk for post-transplant lymphoproliferative disease (PTLD), although the risk of PTLD is not definitively higher when compared to all individuals following renal transplant. No definitive mechanism has been reported, but the SMARCAL1 protein product has been shown to have a role in hypersensitivity to genotoxic agents in vivo [Baradaran-Heravi et al 2012b].

Prognosis. SIOD varies in severity, ranging from prenatal growth deficiency with death in the first few years of life to a slowly progressive course with survival 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 deficiency. 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, it is unknown if any individuals with SIOD have reproduced. Women develop menses, although the menstrual cycle is usually irregular. Men develop secondary sexual characteristics, but histopathologic examination of the testes has identified azoospermia [Clewing et al 2007a].

Genotype-Phenotype Correlations

The early-onset, more severe phenotype has been associated with truncating SMARCAL1 variants that lead to absence of protein product. It has been suggested that compound heterozygous missense variants that result in present but unstable protein may cause a milder nonrenal phenotype. However, no genotype-phenotype correlations have been confirmed; there was no association between type/severity of disease-causing variant and severity of renal disease [Lipska-Ziętkiewicz et al 2017].

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.

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], Schimke immunoosseous dysplasia is referred to as SMARCAL1-related immuno-osseous dysplasia (Schimke type) and included in the spondyloepi(meta)physeal dysplasias group.

Prevalence

The prevalence is unknown. The incidence is estimated at 1:1,000,000 to 1:3,000,000 live births.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Schimke immunoosseous dysplasia (SIOD), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Avoid the following:

• 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.
• Heat, stress, and lack of sleep. 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.
• Vaccinations with live vaccines. The T cell deficiency is substantial and there have been serious infections in some individuals. Therefore, in those with T cell immunodeficiency, vaccination with all live vaccines should be avoided, including rotavirus, measles-mumps-rubella (MMR), varicella, bacillus Calmette-Guérin (BCG), oral Salmonella typhi, and yellow fever virus vaccines.

Note: Cells from individuals with SIOD 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].

Evaluation of Relatives at Risk

It is appropriate to evaluate (see Diagnosis) older and younger sibs of a proband in order to identify as early as possible those who would benefit from surveillance and prompt management of renal disease, immunodeficiency, and other complications.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

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 2005, Lücke et al 2006b].

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 presumed to be heterozygous for a SMARCAL1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a SMARCAL1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a SMARCAL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic SMARCAL1 pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SMARCAL1 pathogenic variants.
• Sibs with biallelic SMARCAL1 pathogenic variants can have variable phenotypes (see Genotype-Phenotype Correlations).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with SIOD are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SMARCAL1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SMARCAL1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the SMARCAL1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for SIOD are possible.

Ultrasound examination. The diagnosis may be suspected in a fetus with intrauterine growth restriction (IUGR) and an affected sib; however, approximately 30% of affected fetuses will not have IUGR (IUGR is reported in 70% of individuals with a confirmed molecular diagnosis of SIOD).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SMARCAL1 encodes SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 (also referred to as HARP or SMARCAL1), the SNF2-related protein 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 reanneal open strands of DNA [Yusufzai & Kadonaga 2008]. Such DNA structures are commonly seen during DNA replication, repair, and transcription. At these sites, HARP reanneals the single-stranded DNA, thereby preventing 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] and to shortened telomeres as a result of impaired telomere maintenance [Poole & Cortez 2017, Bertaina et al 2022]. Also, as a modulator of DNA structure, HARP regulates gene expression [Baradaran-Heravi et al 2012a, Morimoto et al 2012b]. In summary, HARP-mediated maintenance of genomic integrity is required for the basic cellular processes of modulating DNA replication, DNA repair and transcription, and possibly DNA recombination.

Mechanism of disease causation. Pathogenic variants in SMARCAL1 are predicted to cause loss of function in HARP. Pathogenic variants are distributed throughout SMARCAL1. The abnormalities reported for SMARCAL1 are gene deletions eliminating expression, pathogenic truncating variants, or single-nucleotide variants. Pathogenic missense variants occur at amino acids conserved across species.

Author Notes

The David B Lewis laboratory at the Stanford University School of Medicine is pursuing studies with primary cells and induced pluripotent stem cells from individuals with Schimke immunoosseous dysplasia (SIOD) and their parents in order to determine how biallelic SMARCAL1 pathogenic variants result in the unique phenotype of SIOD and to compile a clinical registry of individuals with SIOD to further advance our knowledge of this disease. Dr Lewis can be contacted by email at dblewis@stanford.edu.

Acknowledgments

The authors gratefully acknowledge the Kruzn' for a Kure Foundation, Muscle Shoals, Alabama, and the Little Giants Foundation, Omaha, Nebraska, for their support of research on the mechanisms of disease and treatment of SIOD.

Author History

Alireza Baradaran-Heravi, MD; University of British Columbia (2011-2016)
Cornelius F Boerkoel, MD, PhD (2002-present)
Leah I Elizondo, BSc; Baylor College of Medicine (2006-2011)
David B Lewis, MD (2016-present)
Elizabeth Lippner, MD (2022-present)
Shu Lou, MD; Baylor College of Medicine (2002-2006)
Thomas Lücke, MD, PhD (2006-present)
Marie Morimoto, BSc; University of British Columbia (2011-2022)
Carlos Salgado, MD (2022-present)

Revision History

• 30 March 2023 (sw) Revision: "SMARCAL1-Related Immuno-osseous Dysplasia (Schimke Type)" added as synonym; Nosology of Genetic Skeletal Disorders: 2023 Revision [Unger et al 2023] added to Nomenclature
• 14 April 2022 (sw) Comprehensive update posted live
• 11 February 2016 (sw) Comprehensive update posted live
• 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 live
• 30 August 2004 (me) Comprehensive update posted live
• 1 October 2002 (me) Review posted live
• 18 June 2002 (cfb) Original submission

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