A severily affected case with Schimke immuno osseous dysplasia

Abstract

To the Editor Schimke immuno osseous dysplasia SIOD; MIM 242900 is a multi system syndrome with autosomal recessive inheritance caused by a rare mutation in chromatin remodeling protein SMARCAL 1 characterized by disproportional short stature with truncal shortness due to spondyloepiphysial dysplasia steroid resistant nephrotic syndrome progressing to end stage renal failure ESRD recurrent infections caused by cellular immune deficiency and typical phenotypic characteristics 1 2 Ischemic attacks in the brain migraine ectodernal abnormalities and hypothroidism are observed frequently in SIOD 2 3 In this article a patient who was referred with a clinical picture of steroid resistant nephrotic syndrome in the early childhood and who was diagnosed as SIOD with growth failure and typical phenotypic characteristics was presented Treatment administered to this patient who rapidly progressed to ESRD and underwent peritoneal dialysis PD and developed treatment resistant migraine attacks and severe recurrent ischemic attacks in the brain was summarized A three year old female patient was referred to our clinic because of swelling in the eyelids abdomen and legs Her personal medical history revealed that she was born from the 3rd pregnancy of a 24 year old mother as the first living baby by cesarean section at the 34th gestational week which was performed because of oligohydramniosis and intrauterine growth failure determined in the 6th month of pregnancy with a birth weight of 1780 g and a height of 46 cm The family recognized that her body weight and height were retarded compared to her peers after she was 1 5 years of age The mother and the father were double cousins On physical examination the height was found to be compatible with 4 SD and the body weight was found to be compatible with 2 4 SD The blood pressure was found to be compatible with the 95th percentile Brown discolorations with a diameter of 3 8 cm were found on the whole body especially on the groins and trunk The hair was fine the nose root was prominent and the nose had a bulleous structure Her teeth were small her neck was short and the antero posterior diameter of her chest was increased Picture 1a b Abdominal ascites and pretibial edema were present A diagnosis of nephrotic syndrome was made in the patient who had hypoalbuminemia and hyperlipidemia Since she did not respond to oral prednisolone treatment renal biopsy was performed and a diagnosis of focal segmental glomerulosclerosis FSGS was made Since no response to cyclosporine A and steroid treatment could be obtained immunsuppressive treatment was discontinued at the end of 6 months and the patient was followed up with angiotensin converting enzyme inhibitor angiotensin receptor blocker and statin treatment ESRD developed 15 months after the first diagnosis and the patient was included in PD program The patient rsquo;s blood pressure was maintained in normal ranges with dual antihypertensive drug therapy 4 months after peritoneal dialysis was started the patient developed headaches which were pulsative lasted for a few hours and recurred during the day recurring 3 4 times a day which responded to oral analgesics initially but did not respond to treatment later and gradually became more severe One month after this she presented to the emergency department with left central facial paralysis and weakness in the left lower and upper extremity An area of acute ischemia was observed in the right half of the brain on diffusion magnetic resonance MR imaging Picture 2 Low molecular weight heparin acetyl salicylic acid and levetiracetam treatment was started and the neurologic findings started to improve from the second day of treatment 5 days after the attack neurologic examination was found to be normal Digital angiographic imaging revealed 20 50 narrowing in the first segments of the anterior and middle cerebral arteries bilaterlly At this time a diagnosis of SIOD was considered in pediatric genetic consultation with the clinical findings DNA sample was planned to be obtained for molecular diagnosis Our patient had most of the dysmorphic and phenotypic characteristics described in the literature for SIOD Direct graphies revealed flattening in the vertebrae and hypoplastic pelvis Picture 3a b Total lymphocyte count was found to be 570 mm3 10 6 and CD3 34 CD3 CD4 25 and CD3 CD8 9 were found to be low but a severe clinical picture of infection was not observed The patient was discharged with levetiracetam and acetyl salicylic acid Three weeks later she presented to our hospital with acute ischemic attack in the brain It was learned that migraine type headache attacks continued at this time In the period following the second attack levetiracetam was changed with sodium valproate and enoxaparine was started again 10 days later a third ischemic attack developed and severe headaches continued After the dose of valproic acid was increased to 20 mg kg day a marked improvement was observed in migraine attacks While our patient was being followed up with this treatment without any neurologic findings she was lost following the stroke attack she had 3 months later In 50 60 of the patients with Schimke immuno osseous dysplasia a mutation in SMARCAL1 has been found 4 While some of the patients have early onset and severe disease some others have a late onset and milder disease However some early onset patients reach their mid twenties and clinical variance has been shown even in siblings 5 6 Failure to establish a relation between genotype and phenotype and clinical variance have been explained by affection of mutation in SMARCAL1 by environmental genetic and epigenetic variables and occurence of the clinical picture in patients in whom no mutation can be found has been explained by non allelic heterogeneity 7 However no difference could be found between the patients in whom mutation could be found and could not be found in terms of clinical and radiologic characteristics 8 In Schimke immuno osseous dysplasia the disease is due to ESRD recurrent infections and cerebrovascular complications The patients frequently have steroid resistant nephrotic syndrome and the typical renal pathology is FSGS and results in ESRD in a short time 9 Although a decrease in proteinuria has been found with immunosuppressive drugs in some patients the disease is resistant to treatment 3 9 In our patient FSGS did not respond to immunosupressive drugs progressed to ESRD rapidly and requirement for dialysis occured High blood pressure in our patient was controlled with enalapril and amlodipine Interestingly it was reported that glomerulosclerosis did not recur after renal transplantation in this patient 9 10 In approximately half of the patients with Schimke immuno osseous dysplasia cerebrovascular events including transient ischemic attacks and stroke and severe migraine attacks are observed 11 In some patients heath intolerance and increase in cerebrovascular events in summer have been reported 12 Our patient had all her ischemic attacks in August and September but she had no heath intolerance It has been reported that diffuse and progressive atherosclerosis is the basic cause of cerebrovascular events in patients with Schimke immuno osseous dysplasia 7 10 Although hypertension hyperlipidemia proteinuria and ESRD which were also found in our patient are significant risk factors for atherosclerosis symptoms of cerebrovascular ischemia have been observed in patients with SIOD even before renal disease started 13 In fact it is difficult to explain cerebral vascular narrowing reaching a ratio of 50 related to atherosclerosis with traditional risk factors in a 5 year old patient In addition progression of systemic hypertension and vascular disease without recurrence of glomerulosclerosis after renal transplantation suggested that other causes accelerated atherosclerosis Morimoto et al 13 showed elastin mRNA and protein levels decreased as a result of dysfunction of SMARCAL1 and thus defect in elestogenesis which has a critical role for vascular structure was the cause of progressive arteriosclerosis in SIOD On the other hand the reason of migrain attacks have not been explained yet Kılıç et al 11 suggested that migraine attacks may occur because of an intrinsic neuroimmune and neurovascular disorder caused by dysfunction in SMARCAL1 gene The drugs tried until the present time have not shown a significant effect in treatment of migraine We observed that migraine attacks improved to a great extent with sodium valproate in our patient at the time when we could not obtain a response with analgesics and levetiracetam Conclusively SIOD should be considered especially in patients with steroid resistant nephrotic syndrome displaying disproportionate growth failure and other common and life threatening findings should be investigated Sodium valproate may be en efficient option in patients with migraine attacks Cengiz Candan1 Yüksel Yılmaz2 Yasemin Alanay3 Pınar Turhan4 Fatma Candan5 Müferet Ergüven6 1SB İstanbul Medeniyet University Göztepe Education and Research Hospital Pediatric Nephrology İstanbul Turkey 2Association of Cardiac Health and Brain Health Pediatric Neurology İstanbul Turkey 3Acıbadem University Medical Faculty Pediatric Genetic Unit İstanbul Turkey 4SB İstanbul Medeniyet University Göztepe Education and Research Hospital Pediatric Nephrology Unit İstanbul Turkey 5SB İstanbul Medeniyet University Göztepe Education and Research Hospital Neurology Clinic İstanbul Turkey 6SB İstanbul Medeniyet University Göztepe Education and Research Hospital Department of Pediatrics İstanbul Turkey References 1 Boerkoel CF Takashima H John J Yan J Stankiewicz P Rosenbarker L Andr eacute; JL Bogdanovic R Burguet A Cockfield S Cordeiro I Fründ S Illies F Joseph M Kaitila I Lama G Loirat C McLeod DR Milford DV Petty EM Rodrigo F Saraiva JM Schmidt B Smith GC Spranger J Stein A Thiele H Tizard J Weksberg R Lupski JR Stockton DW Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno osseous dysplasia Nat Genet 2002; 30: 215 220 2 Saraiva JM Dinis A Resende C Faria E Gomes C Correia AJ Gil J da Fonseca N Schimke immuno osseous dysplasia: case report and review of 25 patients J Med Genet 1999; 36: 786 789 3 Boerkoel CF O 39;Neill S Andr eacute; JL Benke PJ Bogdanov iacute;ć R Bulla M Burguet A Cockfield S Cordeiro I Ehrich JH Fründ S Geary DF Ieshima A Illies F Joseph MW Kaitila I Lama G Leheup B Ludman MD McLeod DR Medeira A Milford DV Orm auml;l auml; T Rener Primec Z Santava A Santos HG Schmidt B Smith GC Spranger J Zupancic N Weksberg R Manifestations and treatment of Schimke immuno osseous dysplasia: 14 new cases and a review of the literature Eur J Pediatr 2000; 159: 1 7 4 Clewing JM Fryssira H Goodman D Smithson SF Sloan EA Lou S Huang Y Choi K Lücke T Alpay H Andr eacute; JL Asakura Y Biebuyck Gouge N Bogdanovic R Bonneau D Cancrini C Cochat P Cockfield S Collard L Cordeiro I Cormier Daire V Cransberg K Cutka K Deschenes G Ehrich JH Fründ S Georgaki H Guillen Navarro E Hinkelmann B Kanariou M Kasap B Kilic SS Lama G Lamfers P Loirat C Majore S Milford D Morin D Ozdemir N Pontz BF Proesmans W Psoni S Reichenbach H Reif S Rusu C Saraiva JM Sakallioglu O Schmidt B Shoemaker L Sigaudy S Smith G Sotsiou F Stajic N Stein A Stray Pedersen A Taha D Taque S Tizard J Tsimaratos M Wong NA Boerkoel CF Schimke immunoosseous dysplasia: suggestions of genetic diversity Hum Mutat 2007; 28: 273 283 5 Lou S Lamfers P McGuire N Boerkoel CF Longevity in Schimke immuno osseous dysplasia J Med Genet 2002; 39: 922 925 6 Dekel B Metsuyanim S Goldstein N Pode Shakked N Kovalski Y Cohen Y Davidovits M Anikster Y Schimke immuno osseous dysplasia: expression of SMARCAL1 in blood and kidney provides novel insight into disease phenotype Pediatr Res 2008; 63: 398 403 7 Clewing JM Antalfy BC Lücke T Najafian B Marwedel KM Hori A Powel RM Do AF Najera L SantaCruz K Hicks MJ Armstrong DL Boerkoel CF Schimke immuno osseous dysplasia: a clinicopathological correlation J Med Genet 2007; 44: 122 130 8 Hunter KB Lücke T Spranger J Smithson SF Alpay H Andr eacute; JL Asakura Y Bogdanovic R Bonneau D Cairns R Cransberg K Fründ S Fryssira H Goodman D Helmke K Hinkelmann B Lama G Lamfers P Loirat C Majore S Mayfield C Pontz BF Rusu C Saraiva JM Schmidt B Shoemaker L Sigaudy S Stajic N Taha D Boerkoel CF Schimke immunoosseous dysplasia: defining skeletal features Eur J Pediatr 2010; 169: 801 811 9 Zivicnjak M Franke D Zenker M Hoyer J Lücke T Pape L Ehrich JH SMARCAL1 mutations: a cause of prepubertal idiopathic steroid resistant nephrotic syndrome Pediatr Res 2009; 65: 564 568 10 Lücke T Marwedel KM Kanzelmeyer NK Hori A Offner G Kreipe HH Ehrich JH Das AM Generalized atherosclerosis sparing the transplanted kidney in Schimke disease Pediatr Nephrol 2004; 19: 672 675 11 Kilic SS Donmez O Sloan EA Elizondo LI Huang C Andr eacute; JL Bogdanovic R Cockfield S Cordeiro I Deschenes G Fründ S Kaitila I Lama G Lamfers P Lücke T Milford DV Najera L Rodrigo F Saraiva JM Schmidt B Smith GC Stajic N Stein A Taha D Wand D Armstrong D Boerkoel CF Association of migraine like headaches with Schimke immuno osseous dysplasia Am J Med Genet 2005; 135: 206 210 12 Alireza Baradaran Heravi Kyoung Sang Cho Bas Tolhuis Mrinmoy Sanyal Olena Morozova Marie Morimoto Leah I Elizondo Darren Bridgewater Joanna Lubieniecka Kimberly Beirnes Clara Myung Danny Leung Hok Khim Fam Kunho Choi Yan Huang Kira Y Dionis Jonathan Zonana Kory Keller Peter Stenzel Christy Mayfield Thomas Lücke Arend Bokenkamp Marco A Marra Maarten van Lohuizen David B Lewis Chad Shaw Cornelius F Boerkoel Schimke immuno osseous dysplasia: a disorder of interacting genetic and environmental influences on gene expression Hum Mol Genet 2012; 21: 2572 87 13 Morimoto M Yu Z Stenzel P Clewing JM Najafian B Mayfield C Hendson G Weinkauf JG Gormley AK Parham DM Ponniah U Andr eacute; JL Asakura Y Basiratnia M Bogdanović R Bokenkamp A Bonneau D Buck A Charrow J Cochat P Cordeiro I Deschenes G Fenkçi MS Frange P Fründ S Fryssira H Guillen Navarro E Keller K Kirmani S Kobelka C Lamfers P Levtchenko E Lewis DB Massella L McLeod DR Milford DV Nobili F Saraiva JM Semerci CN Shoemaker L Stajić N Stein A Taha D Wand D Zonana J Lücke T Boerkoel CF Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno osseous dysplasia? Orphanet J Rare Dis 2012; 7 1 : 70

Keywords

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Şiddetli seyirli Schimke immün kemik displazili olgu sunumu

Öz

Schimke immün-kemik displazisi (SIOD, MIM 242900), otozomal çekinik geçişli, nadir görülen kromatin remodeling proteindeki (SMARCAL 1) mutasyonun yol açtığı spondiloepifizyel displazi nedenli gövde kısalığı ile giden orantısız boy kısalığı, son dönem böbrek yetersizliğine (SDBY) ilerleyen steroide dirençli nefrotik sendrom, hücresel immün yetersizliğe bağlı tekrarlayan enfeksiyonlar ve tipik fenotipik özellikleri ile belirgin çok sistemli bir sendromdur (1,2). Beyinde iskemik ataklar, migren, ektodermal anormallikler, hipotiroidizm SIOD’da sık görülen bulgulardır (2,3). Bu yazıda erken çocukluk döneminde steroide yanıtsız nefrotik sendrom kliniği ile başvuran, büyüme geriliği ve tipik fenotipik özellikleri ile SIOD tanısı alan bir olgu sunulmuştur. Hızla SDBY’ye ilerleyerek periton diyalizi (PD) uygulanırken, tedaviye dirençli migren atakları ve beyinde yineleyen şiddetli iskemik ataklar geliştiren olguda uygulanan tedavi özetlenmiştir. 

Anahtar Kelimeler

• Schimke
• immün
• kemik displazili