LAUSR

An 18-month-old white boy presented with non-bloody diarrhea and pallor and one week of cough and nasal congestion. On examination, he was hypertensive (115/99) and tachycardic (140 bpm). Pertinent labs included normocytic hemolytic anemia with hemoglobin (Hb) 5.7 g/dL, mean corpuscular volume (MCV) 84 fL, thrombocytopenia (platelet count 153 × 103/μL, nadir of 127 × 1,000/μL), serum creatinine 1.3 mg/dL, lactate dehydrogenase (LDH) 3,800 U/L, markedly increased schistocytes (> 6/hpf), undetectable haptoglobin levels (< 10 mg/dL), microscopic hematuria (20–30 red blood cells (RBCs)/hpf), and proteinuria (3 +). Further studies demonstrated a negative direct Coombs test, normal levels of complement C3 and C4, and normal activity of disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (Table 1). Stool PCR was negative for pathogens associated with diarrhea + hemolytic uremic syndrome (HUS) including Shiga toxin-producing E. coli, Shigella, Salmonella, Campylobacter, Vibrio and Y. enterocolitica. Infectious workup was notable for leukocytosis 22 × 103/μL, elevated erythrocyte sedimentation rate (ESR) 92 mm/h, negative blood culture, negative respiratory viral panel, and negative chest X-ray. Given the concern for atypical hemolytic uremic syndrome (aHUS), empiric eculizumab therapy was initiated with a 600 mg loading dose administered within 24 h of presentation, while awaiting the thrombotic microangiopathy (TMA) profile per the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [7]. Given the trend of worsening hematologic parameters, worsening renal function (stage 3 AKI) and hypertension, eculizumab was given to treat his thrombotic microangiopathy. Complement analysis (drawn prior to administration of eculizumab) showed elevated levels of factor Bb at 7.92 mcg/mL (1.32–4.18) and C5a at 18.66 ng/mL (2.74–16.33) (Table 1). The patient’s hematologic and renal function parameters improved while eculizumab therapy was continued (Fig. 1). Serial peripheral blood smears showed improvement of schistocytosis. An aHUS gene panel later demonstrated two heterozygous mutations in diacylglycerol kinase epsilon (DGKE), including the known truncating allele c.966G > A, p.322Trp* [1] and one novel c.171del, p.Ser58fs. The genes in this panel included C3, CFB, CFH, CFHR1, CFHR3, CFHR5, CFI, DGKE, MCP, THBD, MLPA, CFHR1/CFHR3 deletion. This patient did not carry at-risk haplotypes in CFH, CD46 and s. In reviewing the Human Gene Mutation Database (HGMD) Biobase, the c.171del allele is a novel mutation that results in a frameshift mutation with likely premature protein termination. Parental segregation was notable for the mother being heterozygous for c.966G > A, wild type for c.171del and the father being heterozygous for c.171 del, wild type for c.966G > A. The patient was discharged on eculizumab infusions every two weeks, prophylactic penicillin, antihypertensives (labetalol and amlodipine), and enalapril for its antihypertensive and antiproteinuric effects. After one month, antihypertensive medications were weaned, except enalapril which was continued for proteinuria (urine protein-to-creatinine ratio of 1.5–2.5 mg/mg). He continues on antibiotic prophylaxis and was fully vaccinated for pneumococcus * Jillian K. Warejko [email protected]