Brief Clinical Report

Hemophagocytic Lymphohistiocytosis in a PatientWith Deletion of 22q11.2

Maurizio Arico,1 Alberto Bettinelli,2 Rita Maccario,1 Rita Clementi,1 Grazia Bossi,1 andCesare Danesino3*1Clinica Pediatrica, IRCCS Policlinico S. Matteo, Pavia, Italy2II Clinica Pediatrica, Istituti Clinici di Perfezionamento, Universita di Milano, Milan, Italy3Biologia Generale e Genetica Medica, Universita di Pavia, Pavia, Italy

We report on a new patient with deletion of22q11 associated with hemophagocytic lym-phohistiocytosis and a fatal outcome. Shehad minor facial anomalies and cardiac mal-formation corresponding to those describedin del (22q11) syndrome, normal T and B cellfunction and NK activity; bone marrow as-piration showed active erythrophagocyto-sis. Our case in addition to two other chil-dren reported previously suggest that sucha rare association between lymphocyte-macrophage activation and deletion of22q11 may be more frequent than previouslyrecognized. Am. J. Med. Genet. 87:329–330,1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: histiocytosis; velo-cardio-facial syndrome

INTRODUCTION

Deletion of 22q11.2 is a relatively common chromo-some abnormality [Thomas and Graham, 1997]. Thespectrum of clinical manifestations is wide and in-cludes a number of immunological defects [Dallapiccolaet al., 1996; Ryan et al., 1997]. Hemophagocytic lym-phohistiocytosis (HLH) is a rare condition that may beobserved in childhood either as an autosomal recessivedisorder, usually with very early onset [Arico et al.,1996] or as an apparently sporadic condition, some-times associated with an infection. Common pathogenshave been reported in such patients, including the Ep-

stein-Barr virus (EBV) [Arico et al., 1996; Imashuku etal., 1999].

We report on a patient with HLH and a deletion of22q11.2. The possibility of this uncommon and severecomplication should be taken into account when caringfor del (22q) patients who are at risk for immune de-rangement.

CLINICAL REPORT

The patient was a girl born to nonconsanguineousIraqi parents; her birth weight was 2500 g at 38 weeks.Pregnancy was uneventful. Family history failed to dis-close any relevant medical problem; an older sister isreported to be healthy at the age of 18 years. A diag-nosis of tetralogy of Fallot with agenesis of the pulmo-nary valve was made at the age of 3 months and cor-rected surgically. The subsequent clinical course wasuneventful. At the age of 5 3/12 years she developedrecurrent episodes of mucosal bleeding (oral, nasal)and petechiae. On admission to our hospital she was asmall child (height, weight and cranial circumference<3rd centile) with hypertelorism, high nasal bridge,short philtrum, thin lips with down-turned mouth cor-ners; slender fingers; normal lung function; a heartmurmur with normal cardiac function; a slightly en-larged liver and grossly enlarged spleen, palpable atthe umbilical line. No bone abnormalities were evident;fundoscopy showed an embryotoxon. There were noneurological deficits. Psychological evaluation was in-complete because of her insufficient knowledge of theItalian language. Blood count showed moderate micro-cytic (65 fl) anemia (8.2 g/dL), ferritin 15.9 mg/dL, re-ticulocytes 150,000/mm3, with thrombocytopenia(52,000/mm3), leukocyte count 8500/mm3 with monocy-tosis (1955/mm3). Triglycerides were 113 mg/dL andfibrinogen 201 mg/dL. Moderate hypoparathyroidismwas noted (calcium 8.12 mg/dL, phosphoremia 4.79 mg/dL, parathyroid hormone 9 pg/mL, n.v. 10–71). Screen-ing for infectious disease showed the presence of cyto-megalovirus and EBV specific IgG antibodies. Bonemarrow aspiration showed normal cells and an in-

Contract grant sponsor: Telethon; Contract grant numbers:E755, C30; Contract grant sponsor: IRCCS Policlinico S. Matteo;Contract grant number: 390RCR9701.

*Correspondence to: Prof. Cesare Danesino, Biologia Generalee Genetica Medica, C.P. 217, 27100 Pavia, Italy.E-mail cidi@ipv36.unipv.it

Received 22 April 1999; Accepted 27 August 1999

American Journal of Medical Genetics 87:329–330 (1999)

© 1999 Wiley-Liss, Inc.

creased number of monocytes with active erythropha-gocytosis (Fig. 1). Immune function tests showed thefollowing: IgG 2280 mg/dL (n.v. 528–1959), IgA 211mg/dL (n.v. 37–257), IgM 1680 mg/dL (n.v. 25–493);lymphocyte subsets: CD3+ 89%, CD4+ 62% (1755/mm3), CD8+ 18%, CD56+ 8%. Bone age was 3 years atchronologic age 5.3 years. Brain CT scan showed anarachnoid cyst in the right frontotemporal lobe. Thepresence of minor anomalies, heart malformation, andmoderate hypoparathyroidism suggested a diagnosis ofvelo-cardio-facial syndrome and prompted a chromo-some analysis with fluorescence in situ hybridizationusing the DiGeorge region probe D22S75, whichshowed a deletion at band 22q11.2.

The child was treated with dexamethasone and in-travenous immunonoglobulins with clinical improve-ment. One month after treatment started she againdeveloped fever, splenomegaly, anemia, and thrombo-cytopenia. Steroid dose was increased, and i.v. immu-noglobulins were given with moderate transient im-provement. During the following weeks the child hadpersistent fever and cytopenia. Three months later,during another acute phase of her disease, she under-went reevaluation, showing fever, cytopenia, hemo-phagocytosis, hypertriglyceridemia, and hypofibrino-genemia. Based on such findings a diagnosis of HLHwas made. Based on lack of familial occurrence and ofparental consanguinity, and normal natural killer lym-phocytotoxic activity, she was considered to have a sec-ondary form of HLH, likely associated with recent EBVinfection. The child was treated with etoposide anddexamethasone according to the HLH-94 treatmentprotocol [Henter et al., 1997]. Despite initial clinicalresponse the disease course was rapidly fatal and thechild died at age 6 2/12 years.

DISCUSSION

The diagnostic criteria for HLH diagnosis were es-tablished by the FHL study group of the HistiocyteSociety [Henter et al., 1991]. Clinical (fever and spleno-megaly), laboratory (cytopenia affecting at least two

lineages, hypertriglyceridemia and/or hypofibrinogen-emia) and histopathologic (hemophagocytosis in bonemarrow or spleen or lymph nodes without evidence ofmalignancy) criteria are required for the diagnosis ofHLH. Immune system derangement with T-cell andmonocyte hyperactivation, hypercytokinemia, and a se-lective deficiency of cellular cytotoxicity have been re-ported as potentially related to HLH pathogenesis[Arico et al., 1988; Burgio et al., 1990]. In addition tothe clinical picture of velo-cardio-facial syndrome, ourpatient also fits the diagnostic criteria for HLH.

The present case is the third one in which a 22q11deletion caused a clinical picture of histiocytic hyper-activation. Langerhans cell histiocytosis (LCH), an his-tiocytic disorder well distinguished from HLH, hasbeen reported with partial DiGeorge syndrome in anewborn infant [Levendoglu-Tugal et al., 1996]. Re-cently, in another patient with del (22q11) [Touraine etal., 1999] HLH was diagnosed, although active hemo-phagocytosis could not be documented. In our patienthistiocytic hyperactivation resulted in typical HLH. Wecannot exclude a random association of either form ofhistiocytosis with the deletion of 22q11. Yet, in view ofthe rarity of these conditions, estimated to occuraround 1:50,000 (for HLH) and 1:20,000 (for LCH), theprobability that this chromosomal aberration causes orpredisposes for histiocytic activation should be kept inmind and further cases with this association should bereported.

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Fig.1. Bone marrow aspirate smear showing activated macrophagesengaged in phagocytosis of erythrocytes and leukocytes. May GrumwaldGiemsa.

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