This disorder was first described by Schimke et al. (1974) as 'chondroitin-6-sulfate mucopolysaccharidosis.' Later studies did not confirm the mucopolysacchariduria and excluded mucopolysaccharidosis (Spranger et al., 1981). The disorder is characterized by the combination of a spondyloepiphyseal dysplasia ... This disorder was first described by Schimke et al. (1974) as 'chondroitin-6-sulfate mucopolysaccharidosis.' Later studies did not confirm the mucopolysacchariduria and excluded mucopolysaccharidosis (Spranger et al., 1981). The disorder is characterized by the combination of a spondyloepiphyseal dysplasia (SED) with a peculiar clinical phenotype, numerous lentigines, a slowly progressive immune defect, and an immune-complex nephritis which leads to death at about age 8 years. Like ADA deficiency (102700), cartilage-hair hypoplasia (250250), and Shwachman syndrome (260400), this disorder combines abnormality of the immune and skeletal systems. Spranger et al. (1981) observed affected sibs. Schimke (1982) stated that in his case the chondroitin-6-sulfaturia disappeared as the child became older and renal failure progressed. The child died without benefit of autopsy. The history suggested that a previous child was similarly affected and died early in infancy. Spranger et al. (1991) reported 5 patients with identical clinical and skeletal phenotype and similar laboratory findings except for a lack of mucopolysacchariduria. The patients had rapidly progressive nephropathy, episodes of lymphopenia, and pigmentary skin changes. The patients included an affected brother and sister. In the sister, proteinuria and hypertension were identified at the age of 3.5 years. The radiographic changes were those of spondyloepiphyseal dysplasia. The child died at the age of 8 years. One of the patients had been reported previously by Ehrich et al. (1990). Spranger et al. (1991) commented on a similar facial appearance in the 5 patients: broad and depressed nasal bridge and bulbous nasal tip. The pigmentary skin changes consisted of multiple lentigines. Ludman et al. (1993) reported an affected girl, who died at age 5.7 years, and reviewed 9 reported patients. Manifestations included SED, lymphopenia, signs of defective cellular immunity, and progressive renal disease. Their patient had the additional findings of thrombocytopenia and microdontia. Hashimoto et al. (1994) and Santava et al. (1994) described isolated cases of this disorder. The case reported by Hashimoto et al. (1994) was that of a 16-year-old girl with SED, nephrotic syndrome, lymphopenia, and signs of defective cellular immunity. Growth retardation as an initial symptom was noted in early childhood and about 1 year after onset of progressive proteinuria. Skeletal abnormality was noted at age 10 as dislocation of the hip joints and the diagnosis of nephrotic syndrome was made at the age of 16 years. They considered this to be a juvenile variant of Schimke immunoosseous dysplasia. The first symptoms in the patient described by Santava et al. (1994) were growth retardation and myopia. Nephrotic syndrome was diagnosed at the age of 8 years, at which time skeletal roentgenograms showed SED. Renal biopsy showed nodular accumulations of PAS-positive hyaline material. There was lymphopenia with decreased CD4 and CD8 subpopulations. The child died unexpectedly at age 10 with clinical symptoms of encephalitis. Autopsy documented cytomegaloviral pneumonia and advanced mesangioproliferative glomerulonephritis. In the spleen there was PAS-positive hyaline material massively infiltrating the walls of the central arterioles of the splenic follicles. There was marked depletion of lymphocytes in the spleen and in lymph nodes. The clinical phenotype of Schimke immunoosseous dysplasia is characterized by growth retardation, renal failure, recurrent infections, cerebral infarcts, and skin pigmentation beginning in childhood. Kaitila et al. (1998) reported a 4-year-old male child who had all the characteristic symptoms of the disorder as well as vomiting and prolonged diarrhea. Studies suggested that malabsorption, demonstrated as increased serum immunoglobulin A anti-gliadan antibody, steatorrhea, and partial villous atrophy of the jejunum, is a previously unrecognized feature of Schimke immunoosseous dysplasia. Boerkoel et al. (1998) reported 2 girls, each of consanguineous parentage, who had Schimke immunoosseous dysplasia and cerebral ischemia associated with moyamoya phenomenon (252350). In addition, 1 patient also had absent or occluded left transverse sinus and diffuse aortic narrowing. Magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) were used to demonstrate these vascular abnormalities. The findings in the first patient included recurrent herpes labialis and steroid-resistant nephrotic syndrome with hypertension. The second patient likewise had nephrotic syndrome with hypertension and progressed to end-stage renal failure requiring hemodialysis. Saraiva et al. (1999) reported a patient with Schimke immunoosseous dysplasia. The child was referred at age 5 years because of short stature and proteinuria. He also had increased urinary excretion of chondroitin-6-sulfate, which was present in the patient reported by Schimke et al. (1974) but had rarely been described in later cases. He had radiographic features consistent with the diagnosis, and immunologic studies showed recurrent lymphopenia with persistent reduction of T lymphocytes. Renal biopsy showed focal segmental glomerulosclerosis that was not steroid-responsive. Including this patient, Saraiva et al. (1999) reviewed 25 cases of immunoosseous dysplasia and classified them into 2 groups: a severe form with prenatal onset of short stature, and a more benign form with later onset of symptoms. They concluded that, overall, the clinical features in the 2 groups were similar. Sigurdardottir et al. (2000) reported a 17-year-old patient with Schimke immunoosseous dysplasia, which they referred to as SID, who presented with mental retardation, partial complex seizures, and severely disruptive behaviors. MRI of the brain showed focal encephalomalacia in the parietal regions, and MRA showed narrowing of the middle cerebral arteries. The authors were unable to identify an immune defect. They suggested that seizure disorder, mental retardation, and behavior changes may be part of SID, and that an intrinsic vascular defect may be more important in the pathogenesis of SID than an immune deficit. Da Fonseca (2000) reported a patient with immunoosseous dysplasia and unusual dental findings. The patient's teeth had a gray-yellowish discoloration, and panoramic studies documented bulbous crowns with a marked cervical constriction of the primary and permanent molars. The pulp chambers were either small or obliterated. Both the enamel and dentin were softer than normal. Based on these findings, a tentative diagnosis of dentinogenesis imperfecta type II (125490) was made. The author suggested that future reports of immunoosseous dysplasia carefully document dental and oral findings to determine whether the condition includes dental abnormalities as one of its features. Boerkoel et al. (2000) identified reports of 25 patients with this disorder. They summarized the clinical findings, course, and treatment of the reported patients and included 14 additional patients. The stated criteria for ascertainment were (1) a family history consistent with autosomal recessive inheritance; (2) spondyloepiphyseal dysplasia with exaggerated lumbar lordosis and protruding abdomen; and (3) renal dysfunction. Sixteen of 33 patients had increased thyroid-stimulating hormone (see 188540), suggesting thyroid dysfunction. The manifestations of cerebral ischemia were found in 18 of 37 patients. Lymphopenia was present in 35 of 37 patients, and neutropenia, thrombocytopenia, and anemia were fairly frequent. A low nasal bridge and a bulbous nasal tip were noted in 26 of 32 and 28 of 33 patients, respectively. The possibility of genetic heterogeneity is obviously great and is suggested perhaps by the fact that 7 of 26 patients had corneal opacities. Did these patients represent a separate entity? Boerkoel et al. (2002) commented that approximately half of individuals with SIOD have hypothyroidism, half have episodic cerebral ischemia, and one-tenth have bone marrow failure. SIOD varies in severity, ranging from in utero onset of growth retardation and death within the first 5 years of life to a milder course with the onset of symptoms late in the first decade or early in the second decade of life. On the basis of data from 38 patients with SIOD in 33 families, Lou et al. (2002) suggested that disease severity and age at onset follow a continuum from early onset and severe symptoms with death early in life to later onset and mild symptoms with survival into adulthood. They concluded that the severity and age at onset do not, however, invariably predict survival because they reported a patient who had survived to age 20 years despite having a homozygous SMARCAL1 nonsense mutation and severe early onset disease. Taha et al. (2004) reported a case of a 5-year-old Saudi Arabian boy with SIOD who presented with fever of unknown origin secondary to B-cell lymphoma. They suggested that this was the first report of an SIOD patient with a primary lymphoproliferative disorder. The parents were first cousins. A male sib, who died at the age 3 years, was short with facies similar to that of the patient. The patient was homozygous for a 4-bp deletion that removed 2 nucleotides from the 3-prime end of exon 6 of the SMARCAL1 gene, and 2 nucleotides from the beginning of intron 6 (606622.0007). Elizondo et al. (2006) examined clinical data from 41 patients with SIOD and known SMARCAL1 mutations and found no consistent markers of autoimmune disease. In 14 patients who underwent renal transplantation, none of the transplanted kidneys had recurrence of focal segmental glomerulosclerosis. The lack of elevation of autoimmune markers together with the distinction between transplanted and nontransplanted tissue led Elizondo et al. (2006) to suggest that SIOD is a cell-autonomous defect rather than of autoimmune or hormonal origin. Clewing et al. (2007) presented detailed postmortem findings of 2 unrelated patients with genetically confirmed SIOD. Both died of cardiopulmonary failure at ages 13.7 and 23 years, respectively. Expected findings included T-cell deficiency in peripheral lymphoid organs, defective chondrogenesis, renal focal segmental glomerulosclerosis, cerebral ischemic lesions, and premature atherosclerosis. Unexpected findings included a paucity of B cells in the peripheral lymphoid organs, cellular abnormalities in the adenohypophysis, pulmonary emphysema, fatty infiltration of cardiac muscle, testicular hypoplasia with atrophy and azoospermia, and clustering of small cerebral vessels. Glomerular disease did not recur in the renal allograft of either patient. Clewing et al. (2007) suggested that the findings were consistent with a cell-autonomous mechanism involving differentiation and proliferation, rather than an autoimmune phenomenon. Lucke et al. (2007) described 3 patients with SIOD and atrophy of the caudal parts of the cerebellar vermis (posterior lobule) and of the cerebellar hemispheres. All 3 patients fulfilled the clinical criteria for the severe form of SIOD: premature birth, early renal insufficiency, and neurologic complications. SMARCAL1 mutations were detected in 2 of 3 patients from whom DNA was available. All 3 patients had widened cerebellar fissures consistent with reduced cerebellar volume. The caudal cerebellar vermis exhibited the greatest volume reduction. In addition, all 3 patients had supratentorial white matter lesions similar to those observed in ischemia. Lucke et al. (2007) evaluated imaging studies of 1 patient, who had first been reported by Lucke et al. (2004), at age 12 years and 22 years. No cerebellar atrophy was noted at age 12 years. By age 22, there was marked volume reduction of the posterior lobule of the cerebellar vermis and widening of the cerebellar fissures. Lucke et al. (2007) hypothesized that the cerebellar abnormalities are a continuum of the ongoing vascular disease in severe SIOD.
Elizondo et al. (2009) characterized the effects of various SIOD-associated SMARCAL1 mutations, including E848X (606622.0001) and R586W (606622.0006), in patient tissues and cell lines, and observed that the mutations affected protein expression, stability, subcellular localization, chromatin binding, and ... Elizondo et al. (2009) characterized the effects of various SIOD-associated SMARCAL1 mutations, including E848X (606622.0001) and R586W (606622.0006), in patient tissues and cell lines, and observed that the mutations affected protein expression, stability, subcellular localization, chromatin binding, and enzymatic activity. In vivo analyses confirmed that disease severity is inversely proportional to overall SMARCAL1 activity.
Using genomewide linkage analysis and a positional cloning approach, Boerkoel et al. (2002) determined that mutations in SMARCAL1 (606622) are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, they observed that ... Using genomewide linkage analysis and a positional cloning approach, Boerkoel et al. (2002) determined that mutations in SMARCAL1 (606622) are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, they observed that affected individuals from 13 of 23 families with severe disease had 2 alleles with nonsense, frameshift, or splicing mutations (see 606622.0001-606622.0003), whereas affected individuals from all 3 of 3 families with milder disease had a missense mutation on each allele (see 606622.0004-606622.0006). These observations suggested that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease. Clewing et al. (2007) stated that 43 different mutations in the SMARCAL1 gene had been identified. In 4 SIOD patients with a presumed monoallelic, heterozygous mutation in the SMARCAL1 gene, the authors did not find expressed RNA and/or protein from the other allele, thus demonstrating that these 4 patients had biallelic SMARCAL1 mutations, though the second mutation could not be identified by conventional assays. - Heterogeneity Clewing et al. (2007) found that 30 of 72 unrelated patients with a clinical diagnosis of SIOD did not have SMARCAL1 coding mutations in either allele. Although the phenotype of mutation-negative patients was very similar to that of mutation-positive patients, the former showed decreased incidences of hyperpigmented macules, lymphopenia, glomerulosclerosis, and cerebral ischemic symptoms, as well as increased developmental delay, compared to the latter. Histologic examination of 2 mutation-negative patients showed a lack of premature atherosclerosis, brain ischemia, or pulmonary hypertension. Clewing et al. (2007) suggested that such patients may represent an endophenotype of SIOD and possibly locus heterogeneity. In 29 patients who fulfilled the diagnostic criteria for SIOD but who did not have detectable mutations in the SMARCAL1 gene, Baradaran-Heravi et al. (2008) analyzed the RMRP gene (157660), mutations in which are known to cause cartilage-hair hypoplasia (CHH; 250250), a disorder with the shared features of skeletal dysplasia, defective T-cell proliferation, and impaired lymphocytic production of and responsiveness to interleukin-2 (IL2; 147680). The authors detected no mutations in the RMRP gene in these patients and concluded that diagnostic criteria for SIOD effectively distinguish between SIOD and CHH, and that RMRP mutations do not cause SIOD.
Schimke immunoosseous dysplasia (SIOD) is diagnosed on the basis of clinical findings. The clinical diagnosis of SIOD is suspected in individuals with the following:...
DiagnosisClinical DiagnosisSchimke 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 TestingGene. 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 testingTable 1. Summary of Molecular Genetic Testing Used in Schimke Immunoosseous DysplasiaView in own windowGene SymbolTest Method Mutations Detected Mutation Detection Frequency by Test Method 1Test AvailabilitySMARCAL1Sequence analysisSequence variants 2~90% Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Testing StrategyTo 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.Genetically Related (Allelic) DisordersTo date, mutations of SMARCAL1 have not been identified in any other disorders.
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. ...
Natural HistorySchimke 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. Table 2. Frequency of Disease Features in Individuals with SIOD with Biallelic SMARCAL1 MutationsView in own windowFeatureNumber of Affected Individuals with FeatureTotal Individuals with SIODPhysical featuresBroad and low nasal bridge37 (65%)57Bulbous nasal tip43 (80%)54Microdontia11 (39%)28Pigmented macules44 (76%)58Unusual hair30 (63%)48Short neck45 (83%)54Short trunk47 (82%)57Lumbar lordosis41 (75%)55Protruded abdomen44 (80%)55Corneal opacities9 (16%)57DevelopmentSchooling delay6 (23%)26Developmental delay14 (26%)54GrowthIUGR31 (72%)43Decreased postnatal growth rate/short stature59 (98%)60EndocrineAbnormal TFTs21 (44%)48SkeletonOvoid flat vertebrae42 (79%)53Hypoplastic pelvis34 (68%)50Abnormal femoral heads43 (84%)51HematologyT-cell deficiency38 (83%)46Lymphopenia46 (81%)57Neutropenia21 (41%)51Thrombocytopenia17 (31%)55Anemia30 (59%)51KidneyProteinuria or nephropathy57 (98%)58FSGS34 (79%)43VasculatureHeadaches22 (49%)45TIAs24 (45%)53Strokes22 (45%)49MiscellaneousNon-Hodgkin lymphoma 13 (5%)60IUGR = intrauterine growth retardation TFT = thyroid function testFSGS = focal segmental glomerulosclerosis TIA = transient ischemic attack1. EBV-positive and negative non-Hodgkin lymphomaPhysical 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].
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]....
Genotype-Phenotype CorrelationsOngoing 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].
The differential diagnosis of Schimke immunoosseous dysplasia (SIOD) depends on the presenting features of the individual....
Differential DiagnosisThe 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 DefectsView in own windowSyndromeImmune Cell DefectOMIM NumberAssociated with nephrotic syndromeConorenal syndrome266920Nail-patella syndrome 161200Schimke immunoosseous dysplasiaT cell242900Braegger syndrome B cellAssociated with immune defectsSkeletal dysplasia with combined immune deficiencyT & B cell200900Cartilage-hair hypoplasiaT & B cell250250Short-limbed skeletal dysplasia with humoral immune deficiencyB cellSchimke immunoosseous dysplasiaT cell242900Roifman syndromeB cell300258Kenny-Caffey syndromeT cell & phagocytes127000, 244460Sanjad-Sakati syndromeT cell & phagocytes241410Immunodeficiency-centromeric instability-facial anomalies syndrome B cell242860MacDermot syndromeT cell, B cell, & phagocytesSpondylo-mesomelic-acrodysplasiaT & B cellsRamaan syndromeT & B cellsThe 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Schimke immunoosseous dysplasia (SIOD), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 thrombocytopeniaOrthopedic 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 ManifestationsRenal 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 ComplicationsBecause 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.SurveillanceThe following are appropriate:Regular monitoring of the hips Annual monitoring of renal, immune, and hematologic status Agents/Circumstances to AvoidHypertension. 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 InvestigationCombined 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.OtherIndividuals 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].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSMARCAL12q35SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1Resource of Asian Primary Immunodeficiency Diseases (RAPID) SMARCAL1 homepage - Mendelian genesSMARCAL1Data 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) View in own window 242900IMMUNOOSSEOUS DYSPLASIA, SCHIMKE TYPE 606622SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A-LIKE PROTEIN 1; SMARCAL1Normal 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, submitted]. Also, as a modulator of DNA structure SMARCAL1 regulates gene expression [Baradaran-Heravi et al 2012; Morimoto et al, submitted-a]. 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).