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Schimke immuno-osseous dysplasia: A clinicopathological correlation

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J Marietta Clewing
J Marietta Clewing
J Marietta Clewing
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Barbara C Antalfy
Barbara C Antalfy
Barbara C Antalfy
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T Lucke
T Lucke
T Lucke
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Behzad Najafian at University of Washington Seattle
Behzad Najafian
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Abstract and Figures

Schimke immuno-osseous dysplasia (SIOD) is a fatal autosomal recessive disorder caused by loss-of-function mutations in swi/snf-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1). Analysis of detailed autopsies to correlate clinical and pathological findings in two men severely affected with SIOD. As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified. Clinically unexpected findings included a paucity of B cells in the peripheral lymphoid organs, emperipolesis-like (penetration of one cell by another) abnormalities in the adenohypophysis, fatty infiltration of the cardiac right ventricular wall, pulmonary emphysema, testicular hypoplasia with atrophy and azospermia, and clustering of small cerebral vessels. A regulatory role for the SMARCAL1 protein in the proliferation of chondrocytes, lymphocytes and spermatozoa, as well as in the development or maintenance of cardiomyocytes and in vascular homoeostasis, is suggested. Additional clinical management guidelines are recommended as this study has shown that patients with SIOD may be at risk of pulmonary hypertension, combined immunodeficiency, subcortical ischaemic dementia and cardiac dysfunction.
Bone and renal histopathology. Bone: (A-C) haematoxylin and eosin (H&E) staining of the proximal femoral growth plate of SD600. (A) The growth plate is thin and disorganised, with chondrocyte hypoplasia and poorly formed columns. CZ, calcification zone; HZ, hypertrophic zone; PZ, proliferative zone; RZ, resting zone. (B) Poorly formed columns of chondrocytes in the PZ and HZ. This is a high-power view of the region outlined in panel A. (C) The calcification zone has few chondrocytes and small lacunae (arrowhead). The ossified bone has thin trabeculae (*). Kidney: (D) Renal cortex from SD600 showing the glomerulosclerosis (inset, bar = 40 mm; periodic acid-Schiff stain). (E) Renal cortex exhibiting onion skinning of vascular smooth muscle (SD840, H&E stain). (F) Renal cortex from the allograft of SD600 showing normal glomeruli (inset, bar = 40 mm; H&E stain).
Bone and renal histopathology. Bone: (A-C) haematoxylin and eosin (H&E) staining of the proximal femoral growth plate of SD600. (A) The growth plate is thin and disorganised, with chondrocyte hypoplasia and poorly formed columns. CZ, calcification zone; HZ, hypertrophic zone; PZ, proliferative zone; RZ, resting zone. (B) Poorly formed columns of chondrocytes in the PZ and HZ. This is a high-power view of the region outlined in panel A. (C) The calcification zone has few chondrocytes and small lacunae (arrowhead). The ossified bone has thin trabeculae (*). Kidney: (D) Renal cortex from SD600 showing the glomerulosclerosis (inset, bar = 40 mm; periodic acid-Schiff stain). (E) Renal cortex exhibiting onion skinning of vascular smooth muscle (SD840, H&E stain). (F) Renal cortex from the allograft of SD600 showing normal glomeruli (inset, bar = 40 mm; H&E stain).
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Summary of the patients' clinical signs and symptoms
Summary of the patients' clinical signs and symptoms
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Peripheral lymphoid organ immunohistochemistry. (A,B) The thymus from SD600 has fewer CD4 + (A, anti-OPD4) than CD8 + cells (B, anti-CD8). (C,D) A hilar lymph node from SD600 showing depletion of follicular B (C, arrows, anti-CD20) and T cells and aberrant T cell localisation (D, arrows, antiCD3). (E,F) Decreased number of B (E, arrow, anti-CD20) and T cells (F, arrow, anti-CD3) in splenic tissue from SD600.
Peripheral lymphoid organ immunohistochemistry. (A,B) The thymus from SD600 has fewer CD4 + (A, anti-OPD4) than CD8 + cells (B, anti-CD8). (C,D) A hilar lymph node from SD600 showing depletion of follicular B (C, arrows, anti-CD20) and T cells and aberrant T cell localisation (D, arrows, antiCD3). (E,F) Decreased number of B (E, arrow, anti-CD20) and T cells (F, arrow, anti-CD3) in splenic tissue from SD600.
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Summary of gross pathology and organ weights
Summary of gross pathology and organ weights
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Histopathology and immunohistochemistry of the arterial vasculature. (A) Pulmonary artery from SD840 showing foam cells in the intima (inset, bar = 100 mm; haematoxylin and eosin (H&E) stain). (B) Focal myointimal proliferation (arrows) within a pulmonary artery wall (SD840, anti-smooth muscle actin). (C) Macrophage invasion of a pulmonary artery atherosclerotic plaque (SD840, anti-KP-1). The region of maximal macrophage infiltration is shown by the arrowheads. (D) Myocardial infarction of the left cardiac ventricular tissue (SD840, H&E stain). (E) Muscular hyperplasia in the wall of a small pulmonary artery (SD840, H&E stain). (F) Diffuse thickening, splitting and fraying of the internal elastic layer (arrowheads) of the basilar artery (SD600, Verhoeff Van Giesson stain. Inset, bar = 100 mm). (G) Cerebral white matter showing an arteriole with a thickened wall, hyaline deposits and surrounding filamentous connective tissue (SD600, H&E stain). (H) Clustering of small intracerebral blood vessels (SD840, anti-smooth muscle actin).
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Histopathology and immunohistochemistry of the arterial vasculature. (A) Pulmonary artery from SD840 showing foam cells in the intima (inset, bar = 100 mm; haematoxylin and eosin (H&E) stain). (B) Focal myointimal proliferation (arrows) within a pulmonary artery wall (SD840, anti-smooth muscle actin). (C) Macrophage invasion of a pulmonary artery atherosclerotic plaque (SD840, anti-KP-1). The region of maximal macrophage infiltration is shown by the arrowheads. (D) Myocardial infarction of the left cardiac ventricular tissue (SD840, H&E stain). (E) Muscular hyperplasia in the wall of a small pulmonary artery (SD840, H&E stain). (F) Diffuse thickening, splitting and fraying of the internal elastic layer (arrowheads) of the basilar artery (SD600, Verhoeff Van Giesson stain. Inset, bar = 100 mm). (G) Cerebral white matter showing an arteriole with a thickened wall, hyaline deposits and surrounding filamentous connective tissue (SD600, H&E stain). (H) Clustering of small intracerebral blood vessels (SD840, anti-smooth muscle actin).
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... Biallelic loss-of-function mutations in the SMARCAL1 gene are responsible for Schimke Immunoosseous Dysplasia (SIOD, MIM 242900), an autosomal recessive disorder characterized by severe growth defects and premature death 4,5 . SIOD is a multisystemic disease affecting various organs. ...
... Its primary clinical features include defective chondrogenesis, skeletal dysplasia, renal failure, and immunodeficiency. Notably, about half of SIOD patients experience cardiovascular complications, including transient ischemic attacks, stroke, and myocardial infarction, which are presumed to be associated with cerebral and coronary ischemia [5][6][7] . ...
... Furthermore, hyperlipidemia is frequently observed in individuals with SIOD, in certain reported cases, exceptionally elevated levels of blood total cholesterol (TC) and triglyceride (TG) have been documented (e.g., TC, up to 915 mg/dl; TG, 215 mg/dl; and low-density lipoprotein cholesterol (LDL-C), 220 mg/dl) 8,9 . In specific tissues, there have been reports of fat accumulation, such as extensive adipose deposition found between myocytes within the hearts of SIOD patients 5 . The leading cause of premature atherosclerosis is likely hyperlipidemia, although the mechanisms underlying its development remain poorly understood. ...
Chromatin regulator SMARCAL1 modulates cellular lipid metabolism
Article
Full-text available
  • Dec 2023
Biallelic mutations of the chromatin regulator SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), characterized by severe growth defects and premature mortality. Atherosclerosis and hyperlipidemia are common among SIOD patients, yet their onset and progression are poorly understood. Using an integrative approach involving proteomics, mouse models, and population genetics, we investigated SMARCAL1’s role. We found that SmarcAL1 interacts with angiopoietin-like 3 (Angptl3), a key regulator of lipoprotein metabolism. In vitro and in vivo analyses demonstrate SmarcAL1’s vital role in maintaining cellular lipid homeostasis. The observed translocation of SmarcAL1 to cytoplasmic peroxisomes suggests a potential regulatory role in lipid metabolism through gene expression. SmarcAL1 gene inactivation reduces the expression of key genes in cellular lipid catabolism. Population genetics investigations highlight significant associations between SMARCAL1 genetic variations and body mass index, along with lipid-related traits. This study underscores SMARCAL1’s pivotal role in cellular lipid metabolism, likely contributing to the observed lipid phenotypes in SIOD patients.
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... MMA has been reported as an association with microcephalic osteodysplastic primordial dwarfism (MOPDII), Seckel syndrome, and Schimke immunoosseous dysplasia. [69][70][71] A common factor in these DNA repair-related syndromes is the occurrence of intrauterine growth retardation, short stature, and microcephaly. All of these syndromes fall under primordial dwarfism, where growth is restricted very early in embryonic development and continues to be so postnatally. ...
The mechanobiological theory: a unifying hypothesis on the pathogenesis of moyamoya disease based on a systematic review
Article
Full-text available
  • Sep 2021
  • Neurosurg Focus
OBJECTIVE Moyamoya angiopathy (MMA) affects the distal internal carotid artery and is designated as moyamoya disease (MMD) when predisposing conditions are absent, or moyamoya syndrome (MMS) when it occurs secondary to other causes. The authors aimed to investigate the reason for this anatomical site predilection of MMA. There is compelling evidence to suggest that MMA is a phenomenon that occurs due to stereotyped mechanobiological processes. Literature regarding MMD and MMS was systematically reviewed to decipher a common pattern relating to the development of MMA. METHODS A systematic review was conducted to understand the pathogenesis of MMA in accordance with PRISMA guidelines. PubMed MEDLINE and Scopus were searched using “moyamoya” and “pathogenesis” as common keywords and specific keywords related to six identified key factors. Additionally, a literature search was performed for MMS using “moyamoya” and “pathogenesis” combined with reported associations. A progressive search of the literature was also performed using the keywords “matrix metalloprotease,” “tissue inhibitor of matrix metalloprotease,” “endothelial cell,” “smooth muscle cell,” “cytokines,” “endothelin,” and “transforming growth factor” to infer the missing links in molecular pathogenesis of MMA. Studies conforming to the inclusion criteria were reviewed. RESULTS The literature search yielded 44 published articles on MMD by using keywords classified under the six key factors, namely arterial tortuosity, vascular angles, wall shear stress, molecular factors, blood rheology/viscosity, and blood vessel wall strength, and 477 published articles on MMS associations. Information obtained from 51 articles that matched the inclusion criteria and additional information derived from the progressive search mentioned above were used to connect the key factors to derive a network pattern of pathogenesis. CONCLUSIONS Based on the available literature, the authors have proposed a unifying theory for the pathogenesis of MMA. The moyamoya phenomenon appears to be the culmination of an interplay of vascular anatomy, hemodynamics, rheology, blood vessel wall strength, and a plethora of intricately linked mechanobiological molecular mediators that ultimately results in the mechanical process of occlusion of the blood vessel, stimulating angiogenesis and collateral blood supply in an attempt to perfuse the compromised brain.
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... Schimke Immuno-Osseous Dysplasia (SIOD, OMIM 242900) is an autosomal recessive disorder, which is caused by compound heterozygous or homozygous variants in chromatin remodeling enzyme SMARCAL1 (encoding SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin, Subfamily A Like 1) [134][135][136] . SMARCAL1 regulates transcription through chromatin remodeling during development and later in life. ...
What can clinical immunology learn from inborn errors of epigenetic regulators?
Article
  • Feb 2021
  • J ALLERGY CLIN IMMUN
The epigenome is at the interface between environmental factors and the genome, regulating gene transcription, DNA repair and replication. Epigenetic modifications play a crucial role in establishing and maintaining cell identity and are especially crucial for neurology, musculoskeletal integrity, and the function of the immune system. Mutations in genes encoding for the components of the epigenetic machinery lead to the development of distinct disorders, especially involving the central nervous system and host defense. In this review, we focus on the role of epigenetic modifications for the function of the immune system. By studying the immune phenotype of patients with monogenic mutations in components of the epigenetic machinery (Inborn Errors of Epigenetic regulators, IEE), we demonstrate the importance of DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and mRNA processing for immunity. Moreover, we give a short overview on therapeutic strategies targeting the epigenome.
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... Epistatic relationships identified by genome-wide genetic interaction screens in SMARCAL1-or ZRANB3-deficient cells may potentially uncover new factors that promote fork reversal and/or identify biological pathways relevant to the suppression of multisystem developmental diseases, such as SIOD and diabetes. Furthermore, these same screens may also identify buffering interactions from which we could infer potential therapies to ameliorate disease symptoms, such as T-cell immunodeficiency in SIOD [275]. The identification of synthetic lethal partners of SNF2-family members may also provide supporting rationale for precision medicine in cancer treatment. ...
Time for remodeling: SNF2-family DNA translocases in replication fork metabolism and human disease
Article
  • Aug 2020
Over the course of DNA replication, DNA lesions, transcriptional intermediates and protein-DNA complexes can impair the progression of replication forks, thus resulting in replication stress. Failure to maintain replication fork integrity in response to replication stress leads to genomic instability and predisposes to the development of cancer and other genetic disorders. Multiple DNA damage and repair pathways have evolved to allow completion of DNA replication following replication stress, thus preserving genomic integrity. One of the processes commonly induced in response to replication stress is fork reversal, which consists in the remodeling of stalled replication forks into four-way DNA junctions. In normal conditions, fork reversal slows down replication fork progression to ensure accurate repair of DNA lesions and facilitates replication fork restart once the DNA lesions have been removed. However, in certain pathological situations, such as the deficiency of DNA repair factors that protect regressed forks from nuclease-mediated degradation, fork reversal can cause genomic instability. In this review, we describe the complex molecular mechanisms regulating fork reversal, with a focus on the role of the SNF2-family fork remodelers SMARCAL1, ZRANB3 and HLTF, and highlight the implications of fork reversal for tumorigenesis and cancer therapy.
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Schimke immunoosseous dysplasia: a multisystem disorder
Article
Full-text available
  • May 2023
Schimke immunoosseous dysplasia is an autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, lymphopenia with defective cellular immunity, and renal insufficiency. It is caused by a biallelic mutation in SMARCAL 1 gene. In this study, we described clinical and genetic diagnosis of a 5 years old girl who presented to our centre with short stature and repeated infections in the past. She had one episode of stroke in the past due to infarction and she was diagnosed with hypertension 1 year back. Last admission in the hospital, she had new stroke episode and found to have steroid resistant nephrotic syndrome.
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Moyamoya syndrome in Schimke immuno-osseous dysplasia: A case report
Article
Full-text available
  • Jan 2022
Introduction. Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive multisystem disorder associated with biallelic mutations of the SMARCAL1 gene. Vascular central nervous system complications in the form of Moyamoya syndrome (MMS) have been reported as a comorbidity in nearly half of the cases clinically presenting with severe migraine-like headaches, transient ischemic attacks (TIA) and ischaemic or haemorrhagic infarctions. We present an illustrative case of infantile form of SIOD with MMS, with a review of the latest diagnostic possibilities, as well as current diagnostic and therapeutic dilemmas in managing SIOD. Case report. We report the case of a female patient with the infantile form of SIOD. The proband was born small for gestational age in the 34th gestation week with characteristic dysmorphic features. Genetic testing found a biallelic, nonsense mutation c.2542G>T in the SMARCAL1 gene. She presented early with TIA, seizures and recurrent ischemic strokes. Magnetic resonance imaging (MRI) confirmed the presence of progressive brain atrophy with bilateral occlusion/stenosis of middle (MCA) and anterior (ACA) cerebral arteries and a smoke like collateral vessel appearance consistent with a Moyamoya syndrome. Conclusion. Patients with SIOD may present with progressive cerebral vascular changes and clinical neurologic deterioration early in the course of disease. In such patients early diagnosis and preventive revascularization surgery are of paramount importance. In diagnosing Moyamoya syndrome MRI angiography can be an appropriate substitute for a standard invasive cerebral angiography.
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Different phenotypes of Schimke immuno-osseous dysplasia (SIOD) in two sisters with the same mutation in the SMARCAL1 gene: case reports
Article
  • Feb 2022
Background Schimke immuno-osseous dysplasia (SIOD) is a very rare autosomal recessive genetic disease caused by mutations in the SMARCAL1 gene. It is characterized by spondyloepiphyseal dysplasia, T-cell immunodeficiency, hypercromic nevi, hypercholesterolemia and steroid-resistant nephrotic syndrome with progressive renal failure to end-stage kidney disease. Case presentation We report two cases of SIOD in sisters, diagnosed after the debut of nephrotic syndrome. Both had a personal history of short stature, acetabular hip dysplasia and hypercholesterolemia. The first case, a 6 year-old girl, presented peripheral refractory edema, severe arterial hypertension and progressive decrease of the glomerular filtration rate. Steroid-resistance of nephrotic syndrome was confirmed, treated with tacrolimus without response. Renal function worsened over the following 4 months, so haemodialysis was started. Her sister, a 5 years-old girl, had steroid-resistant nephrotic syndrome, who is currently with normal blood pressure and normal renal function under enalapril treatment. In view of the suspicion of SIOD, the genetic studies were carried out, revealing the same mutation in homozygosis. Conclusions SIOD has a variable expression with multi-systemic involvement with a short life expectancy. The early diagnosis is important, which can encourage the early start of treatment and anticipation of complications that may be life-threatening.
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Combined immunodeficiencies with associated or syndromic features
Chapter
  • Jan 2021
Combined immune deficiencies (CIDs) are a heterogeneous group of inherited immune disorders characterized by impaired development, function, or both of T lymphocytes, with variable B cell defects. Among CIDs, a group of disorders is associated with syndromic features. The term CID syndromes apply to disorders in which other clinical features are present in addition to immunodeficiency. CID with associated or syndromic features comprises nine major categories including congenital thrombocytopenia, DNA repair defects, immunoosseous dysplasias (IODs), thymic defects with additional congenital anomalies, hyper-immunoglobulin E syndromes, dyskeratosis congenital, defects of vitamin B12 and folate metabolism, anhidrotic epidermodysplasia with ID and others. Most patients belonging to this group of primary immunodeficiency disorders manifest severe infections caused by opportunistic organisms, chronic diarrhea, failure to thrive, and recurrent and chronic respiratory infections. These patients present with less severe complications in the first year of life than severe CID patients, as evidence of immunodeficiency may be initially absent, whereas other clinical complications are present. Because syndromic CID can present initially with nonimmunologic manifestation, the various medical specialists involved in these cases should be aware of the signs and symptoms of this PID category.
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Primary Immunodeficiency and Thrombocytopenia
Article
  • Jan 2021
Primary immunodeficiency (PID) or Inborn errors of immunity (IEI) refers to a heterogeneous group of disorders characterized by immune system impairment. Although patients with IEI manifest highly variable symptoms, the most common clinical manifestations are recurrent infections, autoimmunity and malignancies. Some patients present hematological abnormality including thrombocytopenia due to different pathogenic mechanisms. This review focuses on primary and secondary thrombocytopenia as a complication, which can occur in IEI. Based on the International Union of Immunological Societies phenotypic classification for IEI, the several innate and adaptive immunodeficiency disorders can lead to thrombocytopenia. This review, for the first time, describes manifestation, mechanism and therapeutic modalities for thrombocytopenia in different classes of IEI.
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Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707-710
Article
Full-text available
  • Oct 1996
STROKE is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent sub-cortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuro-imaging1,2. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries3. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis4. We have previously mapped the mutant gene to chromosome 19 (ref. 5). Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.
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Longevity in Schimke immuno-osseous dysplasia
Article
  • Dec 2002
  • J MED GENET
Schimke immuno-osseous dysplasia (SIOD) is characterised by autosomal recessive inheritance, spondyloepiphyseal dysplasia causing growth retardation, defective cellular immunity, progressive nephropathy leading to renal failure, hyperpigmented macules, and dysmorphic facial features.1–16 Half of SIOD patients also have hypothyroidism, half episodic cerebral ischaemia, and a tenth bone marrow failure.3 SIOD is caused by mutations in SMARCAL1 (SWI/SNF2 related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1).17 SNF2 related proteins participate in the DNA nucleosome restructuring which commonly occurs during gene regulation and DNA replication, recombination, methylation, and repair.18,19 Generally SIOD patients surviving past 15-16 years have milder and fewer symptoms than patients dying at younger ages. These older patients do not suffer from hypothyroidism, recurrent infections, bone marrow failure, or central nervous system symptoms such as migraine headaches, transient ischaemic attacks, or strokes but do have spondyloepiphyseal dysplasia, renal disease, and T cell deficiency.3 These older patients have had two SMARCAL1 alleles with missense mutations, whereas most patients dying at younger ages have had at least one null allele.17 Based on this, we had hypothesised that patients surviving into adulthood have two hypomorphic alleles of SMARCAL1 as opposed to null alleles. Here we review the longevity of 38 patients and the causes of death for 22 patients on whom we have collected detailed clinical data. We also describe a 20 year old woman who has had severe clinical symptoms of SIOD and has two SMARCAL1 null alleles; this suggests that prolonged survival of severely affected patients with SMARCAL1 null alleles is possible. ### Human subjects Patients referred to this study gave informed consent approved by the Institutional Review Board of Baylor College of Medicine (Houston, TX, USA) or the Hospital for Sick Children (Toronto, ON, Canada). We isolated DNA from peripheral blood. Clinical data, collected …
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Association of spondylo-epiphyseal dysplasia with nephrotic syndrome
Article
  • Jan 1990
The association of a spondylo-epiphyseal dysplasia and growth failure with the nephrotic syndrome was found in three boys. Renal biopsy performed on two revealed focal and segmental glomerulosclerosis. The nephrotic syndrome occurred at the age of 3–7 years, leading to end-stage renal failure in all patients. Growth failure persisted after successful renal transplantation. This association may represent a distinct disease entity.
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Schimke immuno-osseous dysplasia: A newly recognized multisystem disease
Article
  • Aug 1991
  • J Pediatr
On the basis of five cases personally observed and one previously reported, we describe a disorder characterized by skeletal dysplasia, rapidly progressive nephropathy, episodes of lymphopenia, and pigmentary skin changes. Defects of T-cell function were compatible with an autoimmune process. The disorder is probably of genetic origin and inherited as an autosomal recessive trait.
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Steroid resistant nephrotic syndrome associated with spondyloepiphyseal dysplasia, transient ischemic attacks and lymphopenia
Article
  • Mar 1995
  • CLIN NEPHROL
Focal segmental glomerulosclerosis, nephrotic syndrome and chronic renal failure were associated with spondyloepiphyseal dysplasia, growth failure, lymphopenia and transient ischemic attacks leading to severe neurological symptoms in three children. Two boys and one girl developed the full syndrome at the age of 5, 6 and 10 years. Positron emission tomography revealed perfusion defects of both cerebral and cerebellar arteries. A variant of the disease was found in two other children who had a nephrotic syndrome and terminal renal failure with only mild spondyloepiphyseal dysplasia, impaired growth and a normal cerebral function. It is concluded that there may be a close association between focal segmental glomerulosclerosis and spondyloepiphyseal dysplasias.
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Spondyloepiphyseal dysplasia tarda and nephrotic syndrome in three siblings
Article
  • Feb 1995
The association of a spondyloepiphyseal dysplasia tarda (SED-T) with the nephrotic syndrome (NS) was found in three siblings. They have counsaguineous (first cousins) healthy parents. Patient 1 was a boy who was admitted to hospital for oedema at the age of 8 years; NS was diagnosed, renal biopsy revealed mesangioproliferative glomerulonephritis. After 4 years he developed end-stage renal failure and died whilst on haemodialysis. Combined therapy with cyclophosphamide and prednisone was of no benefit. At the age of 11 years his height was 122 cm (< 3rd percentile -3.2 SD); he had a short neck, broad and prominent chest and a short wide trunk. Patient 2, another male, had non-nephrotic proteinuria in a 24-h urinary sample at the age of 11 years; this was confirmed in a later analysis; mild lymphopenia and a reduction of helper T cell (OKT4)/suppressor T cell (OKT8) ratio was also detected. At 22 years of age he was admitted to hospital with end-stage renal failure. He was on haemodialysis for a few months until his mother donated a kidney. At the age of 22 years his height was 157 cm (< 3rd percentile), he had a short trunk with the thoracic cage increased in anteroposterior diameter and shoulder elevation. Roentgenograms revealed a disostosis of the spinal column and pelvis and a slight lombar platyspondylia. Patient 3, a girl, was admitted to hospital at 12.5 years for pain and restricted mobility of the right hip. X-rays showed deep acetabula and short femoral necks and mild dysplastic changes, especially in the right hip.(ABSTRACT TRUNCATED AT 250 WORDS)
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Juvenile variant of Schimke immunoosseous dysplasia
Article
  • Feb 1994
We report on a 16-year-old girl with spondyloepiphyseal dysplasia, nephrotic syndrome, lymphopenia, and signs of defective cellular immunity. The manifestations are very similar to those reported by Spranger et al. [1991: J. Pediatr 119: 64-72] as Schimke immunoosseous dysplasia, except for age of onset. In Schimke immunoosseous dysplasia, growth retardations as an initial symptom is noted in early childhood and about 1 year after onset of progressive proteinuria. In our case the skeletal abnormality was noted at age 10 years as dislocation of the hip joints and the diagnosis of nephrotic syndrome was made at age 16 years. The findings strongly suggest that our patient has a juvenile variant of Schimke immunoosseous dysplasia.
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Schimke immuno-osseous dysplasia: Case report and review
Article
  • Oct 1993
We report on a patient with Schimke immunoosseous dysplasia, an autosomal recessive disorder, and review nine patients from the literature. Manifestations include spondyloepiphyseal dysplasia, lymphopenia, signs of defective cellular immunity, and progressive renal disease. This is the first patient known to have the additional findings of thrombocytopenia and microdontia.
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