LETTER TO THE EDITOR

A diagnostic dilemma in AL(L)PS

Cariosa Lee-Brennan & Maeve O’Reilly & Owen Smith &

John Quinn & Philip Murphy & Mary Keogan

Received: 4 June 2013 /Accepted: 10 June 2013# Springer-Verlag Berlin Heidelberg 2013

Dear Editor,An 18-month-old female infant presented to the paediatrichaematology service in 1985 with lymphadenopathy,hepatosplenomegaly, anaemia (Hb 6.3 g/dL, range 11.7–14 g/dL) and thrombocytopenia (17×109, range 150–400×109). Bone marrow and lymph node examinations werereported as ‘reactive’. Karyotyping was normal. Viral, auto-immune and metabolic screens were negative. Following aperiod of observation and external review, during which timeher marrow blast count rose to 9 %, the decision was made toproceed with Medical Research Council protocol for acutelymphoblastic leukaemia, with complete normalisation of pe-ripheral blood counts and regression of spleen size for theduration of treatment (1986–1988). Her subsequent diseasecourse included recurrent sinus and respiratory tract infec-tions, fluctuating cytopenias, chronic lymphadenopathy andan elective splenectomy in the setting of massive splenomeg-aly. She developed severe autoimmune haemolytic anaemia,requiring intense immunosuppression and ultimately plasmaexchange followed by recurrent invasive pneumococcalsepticaemia on ages 14, 16 and 18 years. She was referred for

immunological assessment in 2009 when a biopsy of anepitrochlear lymph node revealed paracortical T cell zone ex-pansion with evidence of clonal T cell rearrangements, subse-quently confirmed on bone marrow biopsy. CT images ofthorax, abdomen and pelvis showed no evidence of lymphoma.On review, it emerged that her father, paternal aunt and firstcousin all had a previous diagnosis of lymphoma. Screening forautoimmune lymphoproliferative syndrome (ALPS) confirmedthe presence of double negative (DN) αβT cells (18 %,normal<1.5%) andFasL 1.5 ng/mL (normal range<0.2 ng/mL).Genetic testing demonstrated heterozygous nonsense mutationin exon 9 of the Fas gene confirming the diagnosis. Her fatherwas found to have the same mutation.

She failed to respond to the meningococcal vaccine and toboth conjugated and unconjugated pneumococcal vaccines.She had a low IgG (IgG 4.6, range 6–15 g/L) and absentIgG2 with an elevated IgA (IgA 5.65, range 0.7–4.0 g/L) andnormal IgM (IgM 1.0, range 0.5–2.3 g/L). Hypogamma-globulinaemia, recurring infection and failure to respondto vaccination is consistent with common variable im-mune deficiency which has been reported in associationwith ALPS [1]. At age 28, she presented with left handand forearm swelling following minor trauma. C4 wasundetectable (<0.0167 g/L, range 0.14–0.54 g/L). Both C3and C1 inhibitor levels were reduced at 0.55 g/L (range0.75–1.65 g/L) and 0.38 mg/L (range 150–350 mg/L),respectively. C1q levels were 44 mg/L (normal range 50–250 mg/L). Based on the history, reduced C4, C1 inhibitorand C1q levels, a diagnosis of acquired C1 inhibitor deficiencywas made.

The diagnostic criteria for ALPS are elevated CD3+

TCRαβ+ CD4− CD8− DNT cells ≥1.5 % of the total lym-phocytes along with chronic non-malignant, non-infectious

C. Lee-Brennan :M. KeoganDepartment of Immunology, Beaumont Hospital, Beaumont,Dublin 9, Ireland

M. O’Reilly (*) : J. Quinn : P. MurphyDepartment of Haematology, Beaumont Hospital, Beaumont,Dublin 9, Irelande-mail: maeveannoreilly@yahoo.co.uk

O. SmithDepartment of Paediatric Haematology, Our Lady’s Children’sHospital Crumlin, Dublin 12, Ireland

Ann HematolDOI 10.1007/s00277-013-1823-0

lymphadenopathy or splenomegaly [2]. The clinical featurescan be misinterpreted as evidence of lymphoid malignancy.Our case highlights the difficulty in diagnosing ALPS andthe need for a high index of suspicion. When this patientoriginally presented, the genetic basis for ALPS had not yetbeen established. Acquired C1 inhibitor deficiency due toautoantibodies against C1 inhibitor has been described inlymphoproliferative disease and SLE, but has not previouslybeen described in ALPS [3].

Conflict of interest The authors declare that they have no conflict ofinterest.

References

1. Campagnoli MF, Garbarini L, Quarello P, Garelli E, Carando A,Baravalle V, Doria A, Biava A, Chiocchetti A, Rosolen A, DufourC, Dianzani U, Ramenghi U (2006) The broad spectrum ofautoimmune lymphoproliferative disease: molecular bases, clin-ical features and long-term follow-up in 31 patients. Haematologica91:538–541

2. Oliviera JB, Blessing JJ, Dianzani U, Fleisher TA, Jaffe EF,Lenardo MJ, Rieux-Lacat F, Siegal RM, Su HC, Teachey DM(2010) Revised diagnostic criteria and classification for theautoimmune lymphoproliferative syndrome (ALPS): report fromthe 2009 NIH International workshop. Blood 116:e35–e40

3. Cicardi M, Zanichelli A (2010) Acquired angioedema. AllergyAsthma Clin Immunol 6(1):14

Ann Hematol