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Macrophage Activation Syndrome Mimicking Life-Threatening Infection in a Patient With Variable Immunodeficiency, Centromeric Instability, and Facial Anomalies

Posted on: Sunday, 24 October 2004, 02:00 CDT

To the Editor.-

ICF syndrome is a rare autosomal recessive disease characterized by variable immunodeficiency, centromeric instability, and facial anomalies.1,2 In most ICF cases reported, mutations in the DNA methyltransferase 3B gene are implicated.1,2 Negative selection breakdown and peripheral B cell maturation blockage contribute to agammaglobulinemia in ICF syndrome.3 The consequences of immunodepression are a higher frequency of infections such as recurrent and prolonged respiratory infections and infections of the skin and digestive system, which can be frequently lethal, leading to premature death of affected patients.4

Macrophage activation syndrome (MAS) is a serious complication of childhood systemic inflammatory disorders that is caused by excessive activation and proliferation of T lymphocytes and macrophages.5 Although the clinical and biological diagnosis criteria of MAS are well established,6 early diagnosis remains difficult.

We report the case of a young girl with ICF syndrome who presented with MAS mimicking life-threatening septicemia who responded well to corticoids.

S.A. is a young girl in whom the diagnosis of ICF syndrome was made at the age of 2 years. She presented with recurrent infections, facial anomalies, and cytogenetic abnormalities. No DNA methyltransferase 3B mutations were found in this patient (patient 4 in ref 3).

At 5 years old, she presented with a high-grade fever, hepatomegaly, and diffuse edema. Her infectious disease work-up was negative. Because of her medical history, antibiotherapy with teicoplanin, imipenem, and amphotericin B was initiated. Over 20 days, she developed cardiovascular collapse and respiratory distress and was transferred into the pediatric intensive care unit of our hospital. Broad-spectrum antibiotherapy and systemic antifungal therapy were maintained. Cardiovascular support and artificial ventilation were started, but the situation became critical. MAS was suspected because of the association of fever, hepatosplenomegaly, and pancytopenia (platelet count: 115.10^sup 9^ per L; hemoglobin: 73 g/L [hemoglobinemia]; white blood cell count: 3.8 10^sup 9^ per L). Additional laboratory studies showed hypertriglyceridemia (triglycerides: 3.5 mmol/L) and hypofibrinogenemia (fibrinogen: 1.5 g/L), a lactate dehydrogenase level of 1800 IU/L, and a C-reactive protein level of 222 mg/mL). Testing on bone marrow aspirates were performed, and typical hemophagocytosis was found. Therefore, based on the guidelines from the FHL Study Group of the Histiocyte Society,6 the diagnosis of MAS was made. Corticotherapy was initiated at the dose of 10 mg/kg per day, and evolution was favorable within 3 days. She left the intensive care unit after 3 days and was discharged from the hospital after 2 weeks. Six months later, she did not show any relapse.

MAS bears close resemblance to secondary hemophagocytic lymphohistiocytosis, which can be met in a diverse group of diseases including infections, neoplasms, hematologic conditions, and rheumatic or autoimmune disorders.7 Whether the association of MAS and ICF is fortuitous or MAS is a feature of the underlying syndrome remains to be confirmed by additional reports. Nevertheless, although this is the first case of MAS in children with ICF, it could represent an underestimated complication in children with this disease. Physicians should be alert that MAS is a potentially lethal complication among patients with ICF.

Letters to the Editor reflect the viewpoints of the writers and do not represent the official position of the journal or of the American Academy of Pediatrics. Letters on any topic, including the contents of PEDIATRICS, are welcome from all members of the profession. For instructions on submitting Letters to the Editor, please see the Instructions for Authors in this issue or visit the journal's Web site.

REFERENCES

1. Xu GL, Bestor TH, Bourc'his D, et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 1999;402:187-191

2. Erlich M. ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin Immunol. 2003;109:17-28

3. Blanco-Betancourt CE, Monda A, Milili M, et al. Defective B- cell-negative selection and terminal differentiation in the ICF syndrome. Blood. 2004; 103:2683-2690

4. Haas OA. Centromeric heterochromatin instability of chromosomes 1, 9, and 16 in variable immunodeficiency syndrome-a virus-induced phenomenon? Hum Genet. 1990;85:244-246

5. Ramanan AV, Schneider R. Macrophage activation syndrome- what's in a name! J Rheumatol. 2003;30:2513-2516

6. Renter JI, Blinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18:29-33

7. Athreya BH. Is macrophage activation syndrome a new entity? Clin Exp Rheumatol. 2002;20:121-123

doi:10.1542/peds.2004-1271

NICOLAS ANDR, MD, PHD

Dpartement Multidisciplinaire de Pdiatrie and Oncologie Pdiatrique

Hpital Pour Enfants de "La Timone"

Marseille 13005, France

BERTRAND ROQUELAURE, MD

MATHILDE CAILLEZ, MD

Dpartement Multidisciplinaire de Pdiatrie

Hpital Pour Enfants de "La Timone"

Marseille 13005, France

MARIANNE CHRESTIAN, MD

Service d'Anatomie Pathologique et de Neuropathologie

Hpital de la Timone

Marseille 13005, France

ANNE MONCLA, MD, PHD

Centre de Gntique Mdicale

Hpital Pour Enfants de "La Timone"

Marseille 13288, France

CARLA BLANCO-BETANCOURT, PHD

CLAUDINE SCHIFF, PHD

Centre d'Immunologie de Marseille-Luminy

Marseille 13288, France

Copyright American Academy of Pediatrics Oct 2004

Source: Pediatrics

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