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European Journal of Pediatrics
Eur J Pediatr. 2010 July; 169(7): 801–811.
Published online 2009 December 15. doi:  10.1007/s00431-009-1115-9
PMCID: PMC2876264

Schimke immunoosseous dysplasia: defining skeletal features


Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.

Electronic supplementary material

The online version of this article (doi:10.1007/s00431-009-1115-9) contains supplementary material, which is available to authorized users.

Keywords: Genocopy, Immunodeficiency, Proteinuria, Skeletal dysplasia, Locus heterogeneity, Schimke immunoosseous dysplasia


The osteochondrodysplasias are a heterogeneous group of inherited disorders of skeletal growth and development [28]. Among these, the spondyloepiphyseal dysplasias (SEDs) are characterized by primary involvement of the vertebrae and proximal epiphyseal centers resulting in a short-trunk disproportionate dwarfism [16, 26]. The radiographic findings, which are frequently age dependent, commonly include flattened vertebrae (platyspondyly) and dysplastic femoral epiphyses.

Schimke immunoosseous dysplasia (SIOD; OMIM #242900) is an autosomal recessive, pleiotropic disorder with distinct spondyloepiphyseal abnormalities [27]. Nonskeletal manifestations include mild facial anomalies [3, 23], T cell immunodeficiency [3, 27], nephrotic syndrome [3, 10, 11, 24, 27], hypothyroidism [3], migraine-like headaches [15], cerebral ischemia [10, 25], and enteropathy [13, 14, 17, 18].

SIOD is caused by biallelic loss-of-function mutations in SMARCAL1 (OMIM #606622) [4]. SMARCAL1 encodes a protein homologous to the sucrose nonfermenting type 2 family of chromatin-remodeling proteins [8, 19]; it functions as a DNA annealing helicase [30]. However, in our experience, nearly half of patients with manifestations of SIOD do not have identifiable mutations in the coding exons of SMARCAL1 or detectable alterations of SMARCAL1 mRNA or protein [7] suggesting a close phenotypic overlap with other conditions or genetic heterogeneity.

Despite the clinical similarity of these patients, we hypothesized that individuals with and without SMARCAL1 mutations are distinguishable by the type of bone dysplasia. Therefore, we analyzed detailed clinical and radiographic information from a series of 33 SIOD patients with or without detectable SMARCAL1 mutations.

Materials and methods

Human subjects

Patients referred to this study gave informed consent approved by the Institutional Review Board of the Hospital for Sick Children (Toronto, ON, Canada), Baylor College of Medicine (Houston, TX, USA), or the University of British Columbia (Vancouver, BC, Canada).

Analysis of clinical features

The clinical data for patients were obtained from questionnaires completed by the referring physician as well as medical records and summaries provided by that physician. The data obtained for patients with and without SMARCAL1 mutations were tabulated and then summed to allow comparison of the features of patients in each group. If a feature was not reported for a patient, then that patient was excluded from the denominator. Statistically significant differences between the groups were determined by the Fisher’s exact test. Also, to subgroup patients according to disease severity, each patient’s signs and symptoms were scored as previously described [12].

Analysis of skeletal radiographs

All radiographs were reviewed independently by Jürgen Spranger and Cornelius F. Boerkoel.


Since we had previously found that only about half of patients clinically diagnosed with SIOD have detectable SMARCAL1 mutations, we sought to identify skeletal radiographic features distinguishing these two groups of patients [7]. Identification of such features would be useful for guiding molecular diagnosis as well as for characterization of other genetic causes of SIOD. To this end, we assembled detailed clinical and skeletal radiographic data on 33 patients, 11 without SMARCAL1 mutations and 22 with biallelic SMARCAL1 mutations.

Phenotypic comparisons

The 22 patients with and 11 without detectable SMARCAL1 mutations have very similar clinical features (Table 1; Supplementary Tables 1 and 2) and similar disease severity scores, which we calculated as previously described [7]. Those with SMARCAL1 mutations have slightly more neurological complications, but these are insufficient to distinguish between the two groups of patients. Given the inadequacy of clinical features for distinguishing those with and without SMARCAL1 mutations, we looked for distinguishing radiographic features.

Table 1
Features of SIOD patients with and without SMARCAL1 mutations

Radiographic findings

As previously described [26], the spondyloepiphyseal dysplasia of SIOD is most prominent in the spine, pelvis, and capital femoral epiphyses (Fig. 1). The hands and other long bones are essentially normal.

Fig. 1
Typical bony features of SIOD. a Lateral spine radiograph of a 5-year-old child showing dorsally flattened, pear-shaped vertebral bodies. b Lateral skull radiograph of a 5-year-old child showing the typical widening of the sella. c Posteroanterior hand ...

Spine findings among patients with SMARCAL1 mutations

The vertebral bodies are ovoid, dorsally flattened and without segmentation defects at all ages (Figs. 2 and and3).3). The spinal changes between 4 and 6 years of age show dorsally flattened, pear-shaped vertebral bodies. By 7–11 years of age, there is more generalized vertebral flattening with slightly irregular upper and lower plates (see SD114, Fig. 2). There is variable expressivity as only mild abnormalities are observed in some patients (see SD112, Fig. 2). By adulthood, all have clear signs of progressive osteopenia with compressed vertebral bodies and vertebral bone density similar to that of the soft tissue (Figs. 1 and and2).2). Peculiarly, SD27 also has diffuse calcification of her discs (Figs. 2 and and33).

Fig. 2
Lateral spine radiographs of patients with identified SMARCAL1 mutations at different ages. The vertebral bodies are flattened at all ages and pear-shaped between 4 and 6 years. There is generalized vertebral flattening with slightly irregular ...
Fig. 3
Anterior–posterior spine radiographs of patients with identified SMARCAL1 mutations at different ages show various degrees of platyspondyly. SD27 had diffuse disc calcification; the significance of this is uncertain

Pelvis and capital femoral epiphyseal findings among patients with SMARCAL1 mutations

Nearly consistently at all ages, the pelvis and femora are notable for small, laterally displaced capital femoral epiphyses, hypoplastic basilar ilia with upslanting and poorly formed acetabula (Fig. 4). The femoral dysplasia progresses to premature coxarthrosis requiring prosthetic therapy (SD27, Fig. 4).

Fig. 4
Hip radiographs of patients with identified SMARCAL1 mutations at different ages. The femora generally have small, laterally displaced capital epiphyses, but normal epiphyseal ossification may occur (e.g., SD78, SD 112). By adulthood, the femoral dysplasia ...

The severity of these skeletal changes varies among the patients. For example, the proximal femoral pathology ranges from coxa valga with well-preserved capital femoral epiphyses and a normal pelvis (SD78, Fig. 4) to short femoral necks with a peculiar lip-like medial protrusion and markedly hypoplastic lower ilia (SD121, Fig. 4).

Skull findings among patients with SMARCAL1 mutations

No bony abnormalities have been reported in the skull of SIOD patients before. However, of five skull radiographs, three (SD44, SD61, SD114) show a markedly wide sella turcica, one (SD120) a depression of the anterior portion of the sella, and one (SD79) a normal sella turcica (Fig. 5).

Fig. 5
Skull and hand radiographs of patients with identified SMARCAL1 mutations at different ages. Note the marked widening of the sella in SD44, SD61, and SD79 and mild widening of the sella in SD120. No bony abnormalities are observed in the hands

Hand and feet findings among patients with SMARCAL1 mutations

Although one SIOD individual has been referred to us with preaxial hexadactyly (C. F. Boerkoel, unpublished data), no others have been reported with bony abnormalities of the hands or feet [26]. Consistent with this, the hand and feet radiographs from the patients in this study do not show bony abnormalities (Fig. 5).

Skeletal findings among patients without detectable SMARCAL1 mutations

Among the patients without detectable SMARCAL1 mutations, three (SD87, SD95, SD55) have skeletal abnormalities typical of SIOD (Fig. 6). Two (SD80, SD85) have a mild spondyloepiphyseal dysplasia consistent with SIOD (Fig. 6), similar to that of patient SD112 (Figs. 2, ,3,3, and and4).4). One (SD54) has a typical SIOD-type spondyloepiphyseal dysplasia and severe scoliosis and anterior hypoplasia of L2; these latter changes, which have not been observed among SIOD patients with a SMARCAL1 mutation, may be secondary to an unrelated muscular hypotonia.

Fig. 6
Lateral spine and hip radiographs of SIOD patients without detectable SMARCAL1 mutations at different ages. Note the similarity of bony features to those with SMARCAL1 mutations. SD54 had kyphoscoliosis and anterior hypoplasia of L2, which may have been ...

Patients distinct from SIOD

Radiographs from four patients diagnosed with SIOD but without a detectable SMARCAL1 mutation do not show the skeletal features consistent with SIOD. The radiographs of one (SD89) show enchondromata in the tubular and flat bones and flattened vertebral bodies with irregular areas of increased and decreased mineralization (data not shown); these findings are most consistent with a form of spondyloenchondrodysplasia [21]. The radiographs from three (SD81, SD52a, SD52b) have no signs of SED.


The characteristic skeletal features of SIOD patients with SMARCAL1 mutations are (1) ovoid and flattened vertebral bodies without segmentation defects, (2) small, laterally displaced capital femoral epiphyses, hypoplastic basilar ilia, and upslanting and poorly formed acetabula, and (3) possibly a wide sella. The flattening of the vertebrae and the abnormalities of the hips usually worsen with age and do so to a degree independent of the severity of other features of SIOD. Also, during later childhood, adolescence, and early adulthood, many individuals with SIOD develop coxarthrosis and vertebral osteopenia.

A wide sella turcica has not been reported among SIOD patients previously. If additional studies confirm the findings in this small number of patients, then this will be an additional marker for the clinical diagnosis of SIOD. The wide sella turcica does not reflect anterior pituitary or adenohypophysis dysfunction since in the three patients tested, all had normal growth hormone and thyroid stimulating hormone levels. Also, prior reviews of anterior pituitary function in SIOD patients have not identified a functional pituitary defect [3].

One reason the wide sella turcica may not have been noted previously is the high degree of intra- and interfamilial variability of SIOD [2, 7]. This is reinforced by our findings that not all SIOD patients with SMARCAL1 mutations had each of the typical skeletal findings. Additionally, we found that there was even variability among tissues within the same person since the severity of vertebral flattening did not predict the severity of hip dysplasia or vice versa.

Relevant to our question of whether the clinical skeletal radiographs can guide molecular testing, our results show that none of the patients without SED had detectable SMARCAL1 mutations. Therefore, testing for SMARCAL1 mutations in this group may not be indicated although studies with more patients are needed to confirm this. On the other hand, for individuals with radiographic findings of SED, there were no distinguishing radiographic or clinical features to suggest who would or would not have detectable SMARCAL1 mutations. Therefore, all patients with SED and the other clinical signs of SIOD should be tested for SMARCAL1 mutations.

The known molecular mechanism underlying SIOD is a generalized disturbance of genomic structure arising secondary to loss of SMARCAL1 DNA strand annealing [31]. This disturbance disrupts both DNA replication [1, 6, 9, 20, 29, 31] and RNA transcription (Baradaran-Heravi et al., submitted for publication; Morimoto et al., submitted for publication). Since cell proliferation and RNA transcription are quantitative traits affected by environment, stochastics, and genetic background [5, 22], the variability among patients and tissues can be accounted for by the combined impact of environment, stochastics, and genetic variation.

The similar clinical and radiographic features of individuals with and without SMARCAL1 mutations also suggest that SIOD could be induced by some environmental conditions or by mutations in genes other than SMARCAL1. Evidence supporting genetic heterogeneity as opposed to environmental factors includes the recurrence of disease in siblings, the absence of disease in parents, and the geographic dispersal of patients. Of interest for human biology, this suggests that although SMARCAL1 is the only identified annealing helicase in humans [30], other enzymes with redundant or similar function may exist or that SMARCAL1 deficiency mimics that of another global modulator of chromatin structure. Assessments of these possibilities as well as delineation of the physiologic mechanism leading to the skeletal abnormalities will require studies in model organisms.

Besides being unable to distinguish SIOD patients with and without SMARCAL1 mutations, skeletal radiographs also do not differentiate SIOD from many other spondyloepiphyseal dysplasias. The differential diagnosis of SIOD includes other forms of spondyloepiphyseal and spondyloepimetaphyseal dysplasia listed in group 11 of the International Nosology [28]. These are distinguished from SIOD by their different clinical presentation and by the absence of the characteristic extraskeletal features such as facial dysmorphism, skin changes, T cell deficiency, and renal failure. Thus, the skeletal features are not pathognomonic of SIOD.

In summary, we further define the radiographic features of SIOD and show that SED is a feature common to all individuals with SIOD and SMARCAL1 mutations. However, among SIOD patients with SED, no radiographic features distinguish those with SMARCAL1 mutations from those without SMARCAL1 mutations. Understanding of the clinical variability of this disorder as well as other possible genetic causes requires further elucidation of the molecular mechanisms underlying SIOD.

Electronic supplementary material

Supplementary Table 1(25K, doc)

Features of SIOD patients with biallelic SMARCAL1 mutations. (DOC 25kb)

Supplementary Table 2(21K, doc)

Features of SIOD patients without SMARCAL1 mutations. (DOC 20kb)


The authors thank Drs. Alireza Baradaran-Heravi, Jan M. Friedman, and Judith Hall for critical review of this manuscript. This work was supported in part by grants from the Child & Family Research Institute (C. F. Boerkoel) and the Michael Smith Foundation for Health Research (C. F. Boerkoel).

Conflict of interest The authors declare no conflicts of interest.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


Deoxyribonucleic acid
Messenger ribonucleic acid
Schimke immunoosseous dysplasia database
Spondyloepiphyseal dysplasia
Schimke immunoosseous dysplasia
swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1
Sucrose nonfermenting type 2
Transient ischemic attack


Hunter, Lücke, and Spranger contributed equally to this work.


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