Schimke Immunoosseous Dysplasia

A number sign (#) is used with this entry because of evidence that Schimke immunoosseous dysplasia (SIOD) is caused by homozygous or compound heterozygous mutation in the SMARCAL1 gene (606622) on chromosome 2q25.

Clinical Features

Schimke immunoosseous dysplasia 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.

Clinical Management

Petty et al. (2000) described successful bone marrow transplantation in a boy with Schimke immunoosseous dysplasia.

Molecular Genetics

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.

Genotype/Phenotype Correlations

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.