Correspondence

Hyper-IgE Syndrome

N Engl J Med 1999; 341:375-377July 29, 1999

Article

To the Editor:

Grimbacher et al. (March 4 issue)1 described in detail 30 patients with hyper-IgE syndrome. Recently, a 29-year-old Italian woman was admitted to our hospital because of acute back pain due to spontaneous fracture of the L3 vertebral body. She had a history of chronic generalized eczematoid lesions, diffuse microlymphadenopathy, bronchial asthma, rhinosinusal polyps, migraine-like headache, and recurrent vaginal candidiasis. During childhood, she had had frequent skin infections and recurrent pneumonitis. Additional findings included hypoplasia of the right mandibular condylus, cleft of the posterior arch of the S1 vertebra, bilateral keratoconus, ovarian and renal cysts, and fibroadenoma of the breast. Physical examination showed facial traits strongly resembling those described by Grimbacher et al. Laboratory analyses revealed high levels of total IgE (peak, 38,600 IU per milliliter) and mild eosinophilia (peak eosinophil count, 1100 per cubic millimeter), with a normal white-cell count. The patient had a younger brother with eczematous dermatitis and high levels of IgE (3100 IU per milliliter).

Immunophenotypic analysis of peripheral-blood lymphocytes demonstrated a 64 percent increase in CD4+ T cells. Since lymphokine-producing CD4+ T cells may influence IgE synthesis by releasing lymphokines, we evaluated cytokine expression by peripheral-blood T cells. Lymphokine-producing CD4+ T cells can be subdivided into two broad categories, called T_H1 and T_H2, according to their pattern of lymphokine production. T_H1 cells secrete interleukin-2, interferon-γ, and tumor necrosis factor β; they inhibit cytokine secretion by T_H2 lymphocytes and IgE synthesis through the release of interferon-γ. In contrast, T_H2 lymphocytes produce interleukin-4, interleukin-5, interleukin-6, interleukin-9, and interleukin-10; inhibit proliferation of T_H1 cells; and favor IgE synthesis and eosinophil activation.2 In our patient, intracellular study of T_H1- and T_H2-related cytokines revealed a T_H0 profile with expression of both interleukin-4 and interferon-γ (Figure 1AFigure 1Southern Blot Analysis of T-Cell–Receptor β Genes (Panel A) and Flow-Cytometric Analysis of Intracellular Cytokine Expression by CD4+ T Cells (Panel B). and Figure 1B) but not interleukin-2. The expression of interleukin-4 was limited to CD4+ T lymphocytes. Because of the restricted pattern of cytokine expression, T-cell–receptor genes were analyzed. As shown in Figure 1A and Figure 1B, rearrangement bands were seen, indicating the presence of at least one T-cell clonal population.

On the basis of these findings, we speculate that the hyper-IgE syndrome might be related to a disruption of the T-cell compartment that has evolved into a clonal expansion and accumulation of T cells with a T_H0 profile. Finally, our data suggest that immunophenotyping and molecular study of peripheral-blood lymphocytes should be performed in patients with this syndrome to understand the immunopathogenic mechanisms involved and possibly to design future treatment strategies.

Fabio Presotto, M.D.
Livio Trentin, M.D.
Carlo Agostini, M.D.
Padua University, School of Medicine, 35128 Padua, Italy

2 References

1. 1

   Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections -- an autosomal dominant multisystem disorder. N Engl J Med 1999;340:692-702
   Full Text | Web of Science | Medline

2. 2

   Romagnani S. The Th1/Th2 paradigm. Immunol Today 1997;18:263-266
   CrossRef | Medline

To the Editor:

Grimbacher et al. describe what they consider the “characteristic facial appearance” of patients with the hyper-IgE syndrome. For years, dysmorphologists and geneticists have debated and pondered what constitutes a “characteristic” facial appearance. Twenty-five years ago a colleague and I reported normal values for selected facial features,1 and more reports were subsequently published.2-4 These data are available but are frequently not used. Grimbacher et al. substantiated their clinical impression of increased interalar distances by comparing their measurements with published standard values, but the majority of the other facial characteristics mentioned were not documented.

An increasing array of newer techniques that can provide anthropometric measurements are now available, such as magnetic resonance imaging, stereoscopic imaging, computed tomography, and ultrasonography. It is not always practical to use these methods in clinical practice; however, if findings are to be published, these techniques can help substantiate an author's impression of a characteristic facial appearance. Granted, not all facial features can be adequately measured.

I also want to stress the importance of the clinician's ability to diagnose what we used to term a “facial gestalt” — that is, a pattern of clinically observed, physical facial findings that is derived from the sum of its parts and that culminates in a distinctive and characteristic appearance or image. In Grimbacher's photographs of the patients with the hyper-IgE syndrome, despite the lack of many specific measurements, the facial gestalt of the patients appears to be characteristic. However, my clinical impressions have been wrong before, which is why we need anthropometric measurements.

Murray Feingold, M.D.
National Birth Defects Center, Waltham, MA 02451

4 References

1. 1

   Feingold M, Bossert WH. Normal values for selected physical parameters: an aid to syndrome delineation. Birth Defects Orig Artic Ser 1974;10:1-16
   Medline

2. 2

   Saksena SS, Bader P, Bixler D. Facial dysmorphology, roentgenographic measurements, and clinical genetics. J Craniofac Genet Dev Biol 1989;9:29-43
   Medline

3. 3

   Allanson JE. Objective techniques for craniofacial assessment: what are the choices? Am J Med Genet 1997;70:1-5
   CrossRef | Web of Science | Medline

4. 4

   Ward RE, Jamison PL, Farkas LG. Craniofacial variability index: a simple measure of normal and abnormal variation in the head and face. Am J Med Genet 1998;80:232-240
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: As stated in our article, the hyper-IgE syndrome in nonfamilial cases is diagnosed on the basis of skin abscesses, pneumonia with formation of pneumatoceles, and recurrent eczematoid rashes, as well as extreme elevations in serum IgE levels. The woman described by Presotto et al. may have hyper-IgE syndrome, although from the limited information given and in the absence of boils or pneumatoceles, she would not meet our criteria for an affected proband, nor would a brother with isolated IgE elevation be considered to have a hyper-IgE genotype. Moreover, it is not clear whether this woman's clonal T cells or CD4+ cells producing interleukin-4 and interferon-γ, described at a single point in time, would be continuously present. The specific primary immunologic defect in the hyper-IgE syndrome has remained elusive, despite more than 30 years of immunologic investigations. A wide array of lymphocyte abnormalities and cytokines has been noted, but these findings have not been present in all patients or at all times. For this reason, we have elected to pursue a genetic-linkage strategy; identification of a gene that, when mutated, results in hyper-IgE syndrome may be the most efficient way to understand the syndrome's primary cause.

Feingold stresses the importance of anthropometric measurements in the definition of syndromic phenotypes. We performed a series of external measurements of the body, head, and face, including height, weight, arm span, head circumference, inner and outer canthal distances, interpupillary distance, interalar distance, and lengths of the nose, philtrum, ears, hands, palms, and feet. These were compared with population standards and are available on request. For brevity, we reported only the measurements for which the values for our patients with hyper-IgE syndrome differed from population means: interalar distance and head circumference. We did not confirm the increased outer canthal distance reported for such patients by Borges et al.1 Further measurements, such as quantitation of asymmetry by methods requiring exposure to radiation, sedation of young children, or substantial expense, were not undertaken in this study in part because the “facial gestalt” assessment was so highly reproducible by independent observers who viewed our subjects.

Bodo Grimbacher, M.D.
National Human Genome Research Institute

Steven M. Holland, M.D.
National Institute of Allergy and Infectious Diseases

Jennifer M. Puck, M.D.
National Human Genome Research Institute, Bethesda, MD 20892

1 References

1. 1

   Borges WG, Hensley T, Carey JC, Petrak BA, Hill HR. The face of Job. J Pediatr 1998;133:303-305
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Fabio Di Stefano, Nicola Verna, Mario Di Gioacchino. (2007) Cavitary legionella pneumonia in a patient with immunodeficiency due to Hyper-IgE syndrome. Journal of Infection 54:3, e121-e123
   CrossRef