Schimke Immuno-osseous dysplasia. Abi Cheung RCH Immunology Fellow

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1 Schimke Immuno-osseous dysplasia Abi Cheung RCH Immunology Fellow

2 2 y/o M Referred to Immunology March 2014 after diagnosis by microarray (del 2q35) Deletes exons 13 & 14 of SMARCAL1 a/w Schimke Immunoosseous dysplasia Investigated in context of: Prematurity ex-25 weeks with IUGR. Associated ROP & grade I intraventricular haemorrhage Dysmorphic features Solitary right kidney with nephrotic range proteinuria & hypertension Bicuspid aortic valve & trivial mitral stenosis Skeletal dysplasia & short stature (weight & height < 3 rd centile) Developmental delay Family history: parents 4 th cousins, great-grandfathers 1 st cousins. Older brother born at 26/40, died at 5 months unclear cause 3 y/o older sister well Infection history: ~ 2 URTI, 1-2 gastroenteritis per year. Intermittent episodes of herpes stomatitis Had vaccinations including live vaccines without problem

3 Immunology Work-up Lymphopenia (1.55 x 10 9 ) Reduced T cells with reduced CD4 and CD8 T cells Reduced naïve CD4 and CD8 T cells. Lymphocyte proliferation to PHA essentially normal Lymphocyte proliferation to anti-cd3 reduced. Mild decrease in non-switched memory B cells. Normal Immunoglobulin G, A, M and E levels. Haemophilus influenzae and tetanus antibodies were normal. Poor antibody response to non-prevenar serotypes in Pneumovax-23.

4 Progress Commenced on bactrim prophylaxis Progressive decline in T cell function Decreasing numbers of T cells Decreasing naïve T cells Decreasing lymphocyte proliferation to PHA & anti-cd3 Clinically, developing increasing infections Chest infections, HSV stomatitis Commenced on subcutaneous immunoglobulin in March 2015 with subsequent reduction in frequency of infections Bone Marrow Transplant decided not to proceed No good donors High risk of mortality

5 Clinical Deterioration December 2015: presented with tachypnoea after 1 week history of diarrhoea Acute kidney injury: creatinine rise to 378 (baseline 50) Conservative management with electrolyte correction & antihypertensives Improvement with creatinine 165 on discharge Jan 2016: presented with acute WOB & fever Chest infection & pericardial effusion Declining renal function over next few months until he presented in June with respiratory distress & seizures. End-of-life care provided in hospital

6 Genetics Autosomal recessive Mutation in gene encoding SMARCAL1 Located 2q35 Prevalence unknown, estimated 1:1,000,000 SMARCAL-1 protein encodes a chromatin remodelling enzyme Participates in gene regulation DNA replication & recombination Genotype does not predict disease severity or outcome

7 Clinical Manifestations Growth failure Short stature (99%) short neck & trunk with lumbar lordosis & protruding abdomen Spondyloepiphyseal dysplasia (75%) Ovoid & mildly flattened vertebral bodies Small deformed capital femoral epiphyses Shallow dysplastic acetabular fossae Characteristic facial features depressed nasal bridge (65%), broad nasal tip (78%) Hyperpigmented macules (70%) Renal: 99% proteinuria Progressive steroid-resistant nephropathy (83%) Generally evolves into ESRD CNS migraines, cerebral ischaemic events Development

8 Immunological Findings T-cell deficiency (76%) Both CD4 & CD8 cells reduced, CD4/CD8 ratio normal T cells predominantly of a memory surface phenotype B cells usually normal to slightly elevated IgG normal in 70% of patients Lack of interleukin 7 receptor alpha expression on T cells T cells do not respond to IL7 Reduced TRECs and TCR rearrangements 20% have features of autoimmune disease Levels of T-cell recombination events in SIOD patients

9 Prognosis & management options Variable severity Mean age of death is 11 years Causes of death include: Infection (23%) stroke (13%) pulmonary hypertension & CCF (13%) renal failure (11%) Largely supportive treatment Antibiotic prophylaxis Antivirals Renal transplantation effectively treats nephropathy (does not recur)

10 HSCT N Pre-BMT Disease Age at BMT Graft Conditioning GVHD prophylaxis/ treatment Outcome 1 34/40, IUGR -Recurrent infections SED, pancytopenia, TIA, neprhotic syndrome with ESRD 10.5 y Haplotype matched Busulphan Thiothepa Cyclophosphamide ATG Cyclosporin A Dexamethasone Sequential kidney &BMT D22: acute skin GVHD D63: adenovirus infection complicated by rotavirus & G neg sepsis D92:pulmonary aspergillosus D100: Death due to cardiopulmonary arrest 2 34/40, IUGR & FTT. Nephrotic syndrome, neutropenia, T-cell deficiency 6y Haplotype matched Busulfan Cyclophosphamide Tacrolimus, MTx, methylprednisolone, MMF, ATG, anti-cd2 D26: acute skin & GI-GVHD D210: haemodialysis D600: renal transplantation Now 21 y/o with good BM & renal fxn 3 36/40, IUGR, SED, T-cell deficiency, nephrotic syndrome 9.5 y Matched 7/8 HLA loci Fludarabine Mephalan Rabbit ATG Tacrolimus, MMF D0: HTN, seizures, PRES D44: acute GVHD, EBV D84: Pancreatitis D105: death due to pulmonary oedema & tamponade 4 FTT, T-cell deficiency, nephrotic syndrome 5.5y Matched 10/10 HLA loci Busulfan Cyclophospamide ATG, CSA D1: pneumococcal sepsis D9: passed away due to pulmonary embolism 5 30/40, IUGR Pancytopenia, recurrent infections, nephrotic syndrome, polyneuropathy, TIA & seizures, diffuse cortical atrophy 4.5 y Haplotypematched Radiation therapy, Fludarabine, cyclophosphamide, Rabbit ATG Rituximab D30: reactivation of CMV infection D31: sepsis with enterococcus faecium D49: b/l nystagmus, hypotension, severe oxygen desaturation & epistaxis D55: death due to complications of cerebral haemorrhagic-ischaemic regions

11 Summary SIOD is a multi-system disorder Wide variable phenotype Poor prognosis with limited treatment options. HSCT (+/- renal transplantation) may be option of treatment but high mortality from reported literature

12 References Morimoto et al. Schimke Immunoosseous Dysplasia. Gene Reviews Update 2016 Sanyal et al. Lack of IL7Ra expression in T cells is a hallmark of T-cell immunodeficiency in SIOD. Clinical Immunology 161 (2015) Lev et al. Molecular assessment of thymic capacities in patients with SIOD. Clinical Immunology (2009) 133, Baradaran-Hervai et al. Bone marrow transplantation in SIOD