To the Editor:
Recently, Goulet et al. (1) described 47 children with a “syndrome of intractable diarrhea with persistent villous atrophy in early childhood.” These children all had life-threatening diarrhea leading to dependency on total parenteral nutrition from an early age onward. Six of eight patients in a subgroup with abnormal phenotype (group IIa, phenotypic diarrhea) had been reported before (2). These patients with phenotypic diarrhea were small for gestational age and showed facial dysmorphism; hypertelorism; woolly, easily removable hair with trichorrhexis nodosa; and moderate to severe intestinal villous atrophy. A variable degree of immunodeficiency was present in all cases with decreased antigen-induced T-cell proliferation in vivo (skin tests), decreased specific antibody production, and hyperimmunoglobulinemia. Immunoglobulin (Ig)A monoclonal gammopathy was found in three of them.
We present a boy now aged 3 years with the described abnormal phenotype (Fig. 1), mild mental retardation, and intractable diarrhea starting in the fifth week of life. He was born small for his age (1345 g) at 35 weeks of gestation. He underwent successful operation for tetralogy of Fallot. Because of persistent diarrhea and failure to thrive, he received parenteral nutrition for long periods, leading to increased growth rate in weight but limited catch-up in length. Intravenous immunoglobulin replacement therapy was administered because of the frequent infectious complications and low specific antibody responses. Recurrent episodes of Enterococcus faecalis sepsis were finally successfully prevented using prolonged oral prophylaxis with low-dose amoxicillin. Chromosomal analysis showed a normal 46, XY karyotype. Gut enterocyte autoantibodies were not detectable (kindly evaluated by R. Mirakian, London). Analysis of an enteral biopsy specimen showed only moderate villous atrophy with variable mononuclear cellularity of the lamina propria, which improved when his condition was better. Colonoscopy revealed areas with mucosal atrophy and some pseudopolyps. His hair, although scanty and fuzzy in appearance, showed no trichorrhexis nodosa and normal amino acid chromatography (kindly evaluated by C. Bodemer, Paris). Clinically however, this patient fits the group IIa phenotypic diarrhea classification, as was confirmed by our consultation with the group of Goulet et al.
Immunologic investigations showed no abnormalities in cell-mediated immunity: The relative frequencies and absolute counts of lymphocyte subpopulations and the proliferation of T lymphocytes, determined by in vitro stimulation with mitogens and antigens, were normal. However, humoral immunity was disturbed. IgG was low (3 g/l), but increased spontaneously when the patient's condition improved (5–8 g/l). Specific antibody production after booster immunization with tetanus toxoid was low (increase from 0.05 to 0.31 IU/ml). Pneumococcal vaccination at the age of 2.5 years elicited only a response against pneumococcus type 3 (increase from 1 to 32 U/ml). The spectrum of serum immunoglobulins after zone electrophoresis showed oligoclonal gammopathy in IgM, IgG (IgG1K), and IgA (IgA1K and IgA2K;Fig. 2). The restricted immunoglobulin heterogeneity improved with his improving condition (Fig. 2, lane 2) and further normalized when intravenous IgG therapy was begun (Fig. 2, lane 3). X-linked hyper IgM and CATCH-22 syndromes were unlikely because of normal CD40L expression after in vitro activation of T lymphocytes and absence of deletions on chromosome 22, respectively.
In clonal gammopathy, plasma cells derived from one (monoclonal) or a few (oligoclonal) specific B lymphocytes produce large amounts of an immunoglobulin molecule, detected as bands in zone-electrophoresis. This clonal gammopathy in patients without a B-cell malignancy is a manifestation of immune dysregulation caused by impaired T-lymphocyte function and has been described in congenital immunodeficiency diseases (3,4), in acquired conditions such as human immunodeficiency virus infection (4), and after bone marrow transplantation (5,6). Continuous immune stimulation by recurrent infections may also play a role (4). Clonal gammopathy is not necessarily monoclonal, as in the patients described by Girault et al., (2) but frequently appears to be oligoclonal, as is shown in our patient. The pathogenesis of intractable diarrhea syndrome, as in phenotypic diarrhea, is not yet clear. A genetic defect, an antenatal infection with postnatal consequences, or a postnatal event are all possible. The immunologic abnormalities found in subgroup IIa of these patients seem to be an integral part of their disease.
*† Esther de Vries
* Diana M. Visser
† Jacques J.M. van Dongen
* Corrie J.W.F.M. Jacobs
* J. Hans Hoekstra
‡ Maarten J. D. van Tol
1. Goulet OJ, Brousse N, Canioni D, Walker–Smith JA, Schmitz J, Phillips AD. Syndrome of intractable diarrhea with persistent villous atrophy in early childhood: A clinicopathological survey of 47 cases. J Pediatr Gastroenterol Nutr 1998; 26:151–61.
2. Girault D, Goulet O, LeDeist F, et al. Intractable infant diarrhea associated with phenotypic abnormalities and immunodeficiency. J Pediatr 1994; 125:36–42.
3. Radl J. Age-related monoclonal gammopathies: Clinical lessons from the aging C57BL mouse. Immunol Today 1990; 11:234–6.
4. Gerritsen EJA, Vossen JMJJ, van Tol MJD, Jol-van der Zijde CM, van der Weijden–Ragas CPM, Radl J. Monoclonal gammopathies in children. J Clin Immunol 1989; 4:296–305.
5. Fischer AM, Simon F, LeDeist F, Blanche S, Griscelli C, Fischer A. Prospective study of the occurrence of monoclonal gammapathies following bone marrow transplantation in young children. Transplantation 1990; 49:731–5.
6. Gerritsen EJA, van Tol MJD, Lankester AC, et al. Immunoglobulin levels and monoclonal gammopathies in children after bone marrow transplantation. Blood 1993; 82:3493–502.