|Year : 2015 | Volume
| Issue : 5 | Page : 987-991
|Schimke immune-osseous dysplasia: A case report
Ashraf Bakr1, Riham Eid1, Amr Sarhan1, Ayman Hammad1, Ahmed Mahmoud El-Refaey1, Atef El-Mougy1, Mohammed Magdy Zedan1, Fatma ElHusseini2
1 Department of Pediatric Nephrology, Mansoura University Children's Hospital, Mansoura, Egypt
2 Department of Pathology, Mansoura University Children's Hospital, Mansoura, Egypt
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|Date of Web Publication||7-Sep-2015|
| Abstract|| |
Schimke immune-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondylo-epiphyseal dysplasia (SED), progressive renal insufficiency beginning as steroid-resistant nephrotic syndrome (SRNS) and defective cellular immunity. This article reports a case from Egypt with a mild form of SIOD. A 14.5-year-old male patient presented with disproportionate short stature, SRNS (focal and segmental glomerulosclerosis), laboratory evidence of cellular immune deficiency and radiologic characteristics of SED. He died at the age of 16.5 years with bone marrow failure and severe pneumonia. To the best of our knowledge, this is the first case of SIOD to be reported from Egypt.
|How to cite this article:|
Bakr A, Eid R, Sarhan A, Hammad A, El-Refaey AM, El-Mougy A, Zedan MM, ElHusseini F. Schimke immune-osseous dysplasia: A case report. Saudi J Kidney Dis Transpl 2015;26:987-91
|How to cite this URL:|
Bakr A, Eid R, Sarhan A, Hammad A, El-Refaey AM, El-Mougy A, Zedan MM, ElHusseini F. Schimke immune-osseous dysplasia: A case report. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 Sep 17];26:987-91. Available from: http://www.sjkdt.org/text.asp?2015/26/5/987/164585
| Introduction|| |
Schimke immune-osseous dysplasia (SIOD) is an inherited multisystem disorder characterized by spondylo-epiphyseal dysplasia (SED) resulting in disproportionate short stature, nephropathy and T-cell deficiency. The prevalence of SIOD in North America is estimated to be one in one to three million people.  SIOD involves a spectrum that ranges from an infantile or severe early-onset form, with death early in life, to a juvenile or milder later-onset form with survival into adulthood, if renal disease is appropriately treated.  Dialysis and renal transplantation are the only effective treatments for progressive renal failure. There are no effective therapies for growth failure, blood cytopenias and cerebral ischemia. 
| Case Report|| |
The proband is the first child of consanguineous (4 th degree) Egyptian parents. Both parents and the two younger sisters have normal stature and are healthy. The proband was born at 32 weeks of gestation by induced vaginal delivery following prenatal ultrasound diagnosis of oligo-hydraminos and decreased fetal movement. Birth weight was 1800 g (50 th centile) while head circumference and length at birth were not available. Post-natal development was unremarkable except for poor growth rate. The patient received all his compulsory vaccines as scheduled, without complications. There was no significant history of recurrent infections or hospital admissions.
He was referred to our hospital at the age of 14.5 years because of short stature and puffy eyelids. Height, weight and head circumference were below the 3 rd centile (according to growth parameters in Egyptian children)  , upper segment/lower segment was 0.7 and the ratio of sitting height/leg length was 0.8. He had a triangular face, a broad nasal bridge, short trunk, syndactyly of the second and third toes of both right and left feet and hyperpigmented macules over the trunk, neck and upper limb. The Tanner staging was prepubertal. Intelligence quotient was assessed by the Stanford Binnet Intelligence Scale, and revealed mild mental retardation (68%).
At presentation, the patient had puffy eyelids and pitting edema of both lower limbs and there was no shifting dullness. Ophthalmologic examination was normal; there was no retinitis pigmentosa.
The 24-h urinary protein was 63 mg/m 2 /hr. The serum albumin was 2.2 g/dL, creatinine was 0.8 mg/dL, serum activated calcium (Ca 3 ) was 1.39 g/L and cholesterol was 303 mg/dL. The corrected serum calcium was 7 mg/dL, serum phosphorus was 5.3 mg/dL and intact parathyroid hormone was <3 pg/mL. The hemoglobin was 13.4 g/dL, white blood cell (WBC) count was 7.600 × 10 3 /μL and platelets were 287 ×10 3 /μL. The thyroid profile revealed T3 of 2.4 ng/mL, T4 of 8.3 ng/dL, thyroid-stimulating hormone of 1.5 IU/mL and free T4 of 0.7 ng/dL. Sex hormones showed pre-pubertal levels. The growth hormone provocation test revealed deficiency.
Abdominal ultrasound did not reveal any abnormality. Bone survey revealed delayedbone age, generalized osteopenia, J-shaped sella and relative cephalo-facial disproportion, shallow acetabulum on both sides with narrow pelvis, bilateral small femoral heads and flattening of lumbar vertebrae; this picture is suggestive of mild SED [Figure 1] and [Figure 2]. Magnetic resonance imaging (MRI) of the brain did not reveal any abnormalities. Genetic study was unfortunately not performed due to non-availability. The patient was diagnosed to have nephrotic syndrome and was started on full-dose steroid induction (60 mg/m 2 /day).
|Figure 1: Plain X-ray of the spine showing flattening of the lumbar veretebrae.|
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|Figure 2: X-ray of the hips showing shallow acetabulum, narrow pelvis and small femoral head.|
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Five days after hospital admission, the patient developed severe hypertension and serial focal fits; computed tomography of the brain revealed ischemic changes in the right high parietal region. The hypertension and seizures were controlled with valproic acid (20 mg/kg/ day), captopril (2 mg/kg/day) and losartan (1.5 mg/kg/day); atorvastatin and cholestyramine were used for hyperlipidemia.
Following full-dose steroid induction (60 mg/m 2 /day) for four weeks, there was no clinical or laboratory remission and renal biopsy revealed focal and segmental glomerulosclerosis (FSGS). Cyclosporine was started and continued for two years, but with poor compliance, interrupted follow-up, partial remission, poorly controlled blood pressure and stable kidney functions. Second renal biopsy was performed in January 2013, which revealed FSGS. Immunofluorescence was negative for IgA, IgG, IgM and C3. However, by the time the biopsy report was available, the patient developed pneumonia and all immunesuppressive therapies were discontinued.
Few days after the second renal biopsy, the patient presented with right-sided heart failure, chest X-ray showed cardiomegaly, echocardiography revealed moderate pulmonary hypertension and severe tricuspid regurgitation and right and left ventricular hypertrophy. Blood pressure was controlled with oral medications.
Later, in January 2013, the patient developed progressive thrombocytopenia followed by lymphocytopenia and immune hemolytic anemia and frequent blood transfusions had to be administered. No organomegaly or lymphadenopathy was noted. Serum IgM was 8.9 g/L, IgG was 0.86 g/L and IgA was 1.44 g/L (all normal for age). Hemoglobin was 5.6 g/dL, corrected reticulocyte count was 3.2%, Coombs' test was positive, WBCs were 2.7 × 10  /μL (lymphocytes 12%), platelets were 63 × 10 / μL, CD4 was <10% and CD8 was <10% of the total T-Lymphocytes; the CD4/CD8 ratio was 1.6 (consistent with cellular immune deficiency). Screening for human immune deficiency virus was negative. Bone marrow aspiration revealed normo-cellular bone marrow with increased fat spaces; erythroid series showed erythroid hyperplasia.
In February 2013, the patient developed extensive pneumonia with rapid deterioration of general condition, poor response to antibiotics, oxygen therapy and mechanical ventilation for one day, after which he passed away at the age of 16.5 years.
| Discussion|| |
SIOD is suspected in individuals with disproportionate short stature, dysmorphism, hyperpigmented macules, SED, progressive steroid-resistant nephropathy and T-cell deficiency.  There are two forms of SIOD, severe or infantile and mild or juvenile. Patients with the severe form have an early onset of symptoms, including intrauterine growth retardation, nephropathy, neurologic symptoms (such as transient ischemic attack, seizures and stroke) and short life span.  Patients who survive beyond 15-16 years have the mild form and do not suffer from hypothyroidism, recurrent infections, bone marrow failure and neurological symptoms. 
Patients with SIOD frequently have steroidresistant nephrotic syndrome (SRNS) (98% of cases), with the typical renal pathology being FSGS, and develop end-stage renal disease in a short time.  However, minimal change nephrotic syndrome, nephronophthisis, mesangial proliferative glomerulonephritis  and membranous nephropathy  have also been reported.
Growth failure in SIOD patients is not a result of chronic kidney disease (CKD). Lucke et al compared the anthropometric measurements of eight SIOD patients with 304 patients with CKD. The most marked difference observed was that in non-SIOD CKD, the median leg length was significantly more reduced than trunk length, while in persons with SIOD, the reduction in trunk length was significantly more than the leg length. Therefore, a sitting height/leg-length ratio of <0.83 is suggestive of SIOD in persons with CKD. 
About 50% of individuals with SIOD have symptoms suggestive of atherosclerosis. Vascular changes observed included focal intimal lipid deposition, focal myo-intimal proliferation, macrophage invasion, foam cells, fibrous transformation and calcium deposits. ,,
T-cell deficiency causes lymphocytopenia in approximately 80% of affected individuals. The B-cell count is usually normal to slightly elevated.  A child with severe SIOD and rituximab-resistant Evans syndrome (ES) preceding bone marrow failure was first reported in 2011.  Our patient developed hematological manifestations two months before death, which started as thrombocytopenia followed by lymphocytopenia, hemolytic anemia and, finally, neutropenia. Bone marrow examination revealed early bone marrow failure.
Only 50-60% of individuals with SIOD have identifiable mutations in SMARCAL1, suggesting that mutations in other unidentified genes can also cause SIOD. The SMARCAL1 gene is located on chromosome 2q34-q36 and encodes HARP and SNF2 sub-family member.  The expression of SMARCAL1 in affected tissues and the non-recurrence of disease in grafted organs lead one to hypothesize a cell autonomous function for SMARCAL1.  Patients with the severe form have at least one null allele (non-sense, frame shift, deletion mutations of SMARCAL1) while patients with the mild form usually have mis-sense mutation. However, correlations of genotype to phenotype have shown that genotype does not predict disease severity or outcome, either within or among families. ,,,,
The differential diagnosis of SIOD includes the following syndromes: (a) Cono-renal syndrome, which is a rare association of coneshaped epiphyses and chronic renal disease, retinitis pigmentosa and abnormality of proximal femur;  (b) nail patella syndrome, which is an autosomal dominant condition affecting the nails, skeletal system, kidneys and eyes; skeletal features include absent or hypoplastic patellae, patellar dislocations, elbow abnormalities, talipes and iliac horns on X-ray; kidney involvement may lead to renal failure and there is also a risk of glaucoma  and (c) Braegger syndrome, which is characterized by humoral immunodeficiency with facial dysmorphology, mental retardation, limb anomalies and nephrotic syndrome. 
The combination of abnormalities of the immune and skeletal systems is also present in other osteo-chondro-dysplasias, including cartilage-hair hypoplasia. Also, progressive renal disease and skeletal dysplasia are features of asphyxating thoracic dysplasia; however, the presence of the immune, skeletal, and renal abnormalities is specific to immuno-osseous dysplasia. 
Dialysis and renal transplantation are the only effective treatment modalities; there is no increased risk of recurrence of nephropathy or atherosclerosis post-transplantation.  The optimal immunosuppressive therapy that should be used following renal transplantation remains unresolved. With conventional immunosuppressive regimens, some patients with SIOD have reportedly developed severe disseminated cutaneous papilloma virus infections or Epstein Barr virus-associated lymphoproliferative disease. 
The mean age of death of SIOD patients is 9.2 years. The principal 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%), lymphoproliferative disease (9%) and acute restrictive lung disease (3%). 
| Conclusion|| |
We report a case of SIOD from Egypt. We wish to emphasize that SIOD is to be considered in children with growth retardation, SRNS and bone abnormalities and that inherited nephrotic syndrome may present at late childhood or even adolescence. Patients suspected to have SIOD, even before development of the full picture, should be closely monitored for proteinuria, hypertension, cellular immunity and opportunistic infections, especially with the need to start immune suppressive therapy for nephrotic syndrome.
| Acknowledgment|| |
The authors would like to thank Dr. Naglaa Salah El-Deen, Radiologist, for radiological assessment of patient's imagings and Dr. Maha Magdy for collecting patient's data and providing medical care to the patient.
| Disclosure|| |
All the authors have declared no competing interest. Neither this manuscript nor one with substantially similar content under our authorship has been published or is being considered for publication elsewhere, and all the data collected during the study is presented in this manuscript and no data from the study has been or will be published separately.
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Pediatric Nephrology and Dialysis Unit, Mansoura University Children's Hospital, 35516 Mansoura
[Figure 1], [Figure 2]
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