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Background The hyper-IgE syndrome with recurrent infections is a rare immunodeficiency characterized by recurrent skin and pulmonary abscesses and extremely elevated levels of IgE in serum. Associated facial and skeletal features have been recognized, but their frequency is unknown, and the genetic basis of the hyper-IgE syndrome is poorly understood.
Methods We studied 30 patients with the hyper-IgE syndrome and 70 of their relatives. We took histories, reviewed records, performed physical and dental examinations, took anthropometric measurements, and conducted laboratory studies.
Results Nonimmunologic features of the hyper-IgE syndrome were present in all patients older than eight years. Seventy-two percent had the previously unrecognized feature of failure or delay of shedding of the primary teeth owing to lack of root resorption. Common findings among patients were recurrent fractures (in 57 percent of patients), hyperextensible joints (in 68 percent), and scoliosis (in 76 percent of patients 16 years of age or older). The classic triad of abscesses, pneumonia, and an elevated IgE level was identified in 77 percent of all patients and in 85 percent of those older than eight. In 6 of 23 adults (26 percent), IgE levels declined over time and came closer to or fell within the normal range. Autosomal dominant transmission of the hyper-IgE syndrome was found, but with variable expressivity. Of the 27 relatives at risk for inheriting the hyper-IgE syndrome, 10 were fully affected, 11 were unaffected, and 6 had combinations of mild immunologic, dental, and skeletal features of the hyper-IgE syndrome.
Conclusions The hyper-IgE syndrome is a multisystem disorder that affects the dentition, the skeleton, connective tissue, and the immune system. It is inherited as a single-locus autosomal dominant trait with variable expressivity.
.22,23,24,25 However, no specific defect in the immune system has been found in all patients. Several reports have pointed out findings apparently unrelated to the immune system,7,9,10,11 including characteristic facial features,3,5,6,8,26,27 hyperextensibility of joints,2 multiple bone fractures,28,29,30,31 and craniosynostosis.15,32,33,34 The genetic basis of the hyper-IgE syndrome is unclear; most cases are sporadic. A report of two sisters with parents unaffected by the hyper-IgE syndrome suggested autosomal recessive inheritance,35 but several pedigrees are more consistent with dominant inheritance.9,10,14,36,37 The hyper-IgE syndrome occurs in persons from diverse ethnic backgrounds and does not seem to be more common in any specific population.
A large cohort of patients with the hyper-IgE syndrome has been followed for more than two decades at the National Institutes of Health, providing an opportunity for the systematic assessment of the features of this syndrome, their incidence, and their development over time. We have found the hyper-IgE syndrome to be a multisystem disorder with variable expression of a specific group of dental, skeletal, and facial as well as immunologic abnormalities. Evaluation of the families in our cohort demonstrated autosomal dominant inheritance with variable expressivity. Recognition of the wide spectrum of phenotypes of the hyper-IgE syndrome will aid diagnosis, management, and genetic-linkage studies of this disorder.
Methods
Subjects
The 30 patients in our study had been given a diagnosis of the hyper-IgE syndrome on the basis of elevated serum IgE levels; eczematoid rashes; and unusual, severe, recurrent infections such as skin abscesses, candidiasis, and pneumatocele-forming pneumonias in the absence of any other underlying defect in the immune system. We studied these patients and 70 of their relatives under approved protocols at the Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland. Informed consent was obtained from all subjects or their parents. Some of the patients had been followed for up to 24 years; 14 patients had been followed for more than 10 years (a total of 291 patient-years). Thirteen of the cases were reported in 1983.6 In 1997, 26 patients were examined, of whom 2 have since died; we also reviewed records of 4 other National Institutes of Health patients, who had died before 1997. The current cohort consisted of 10 male and 20 female patients between 3 and 58 years of age (mean, 26.5) from diverse racial backgrounds (Table 1). Five families had more than one family member who was fully affected by the disorder.
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For all subjects, we took a complete history, reviewed medical records, performed physical examinations with anthropometric measurements, obtained chest radiographs, and performed laboratory measurements that included complete and differential blood counts and levels of IgE in serum. Patients underwent dental examination and radiography. The status of dental eruption, evaluated clinically, was compared with previously published standards that had been normalized for age.41 Radiographic assessment of the stage of tooth development was used to calculate dental-development age from standard tables.42
Statistical Analysis
Measurements of each patient's face and body were compared with published standards to determine the patient's z scores.38 Using the patients' z scores, we derived percentiles, mean z scores of the sample, and the significance of the z scores from the t function or the normal-distribution function. The t-test was used to assess the correlation between eosinophil counts and IgE levels and to evaluate the significance of the delay of tooth eruption for patients, as compared with normal tooth eruption.
Results
Dental Abnormalities
Seventy-two percent of the patients with the hyper-IgE syndrome who were older than eight years reported retained primary teeth, noneruption of permanent teeth, or double rows of teeth where permanent teeth erupted adjacent to primary teeth (Figure 1A and Figure 1B). Shedding of primary teeth, although delayed, did occur in some patients; however, most patients required extraction of eight or more retained primary teeth. The failure of primary teeth to exfoliate on time had not previously been found to be associated with the hyper-IgE syndrome.
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For teeth without predecessors (all deciduous teeth and permanent molars), eruption occurred on time. When primary teeth had been extracted in adolescence, permanent teeth erupted normally (Figure 1C, upper left quadrant of patient's mouth). We consistently found a reduced rate of resorption of the roots of primary teeth; retention of these teeth, in turn, prevented appropriate eruption of the permanent successors.
Abnormalities of the Head and Face
Distinctive facial characteristics of patients with the hyper-IgE syndrome were found to be universal by the age of 16 years (Table 1). Patients had facial asymmetry with a suggestion of hemihypertrophy; a prominent forehead; deep-set eyes; a broad nasal bridge; a wide, fleshy nasal tip; and mild prognathism (Figure 2). Facial skin was rough, with prominent pores. The interalar distance was compared with published standard values and with z scores for whites.38 The percentiles for the 20 patients with the hyper-IgE syndrome for whom interalar distance could be evaluated ranged from the 42nd to >99.9th percentile (Table 1); the mean interalar distance in these patients was above the 98th percentile (P<0.001). In the 24 patients whom we measured, head circumference also tended to be larger than normal (mean z score, 0.326; P=0.06). Craniosynostosis, which had been reported previously,32,33,34 was not seen in our patients. Height and other measurements were unremarkable. However, anomalies in midline facial development were observed: a high-arched palate in 71 percent of the patients, a cleft lip and palate in one patient (Patient 28), and midline sagittal clefts in the middle third of the tongue in Patients 9 and 13, who are sisters.
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Although bone fractures were known to occur frequently in patients with the hyper-IgE syndrome, their incidence was unknown.28,29,30,31 In our cohort, 57 percent of the patients had had at least three fractures, which occurred at all ages; the fractures were often due to unrecognized or minor trauma, such as having a diaper changed, carrying luggage, bearing the weight of a leg cast, standing in ocean waves, or line dancing. The fractures occurred in long bones, ribs, and pelvic bones. Some fractures prompted unwarranted investigations for possible child abuse, whereas others were initially unsuspected because of the absence of severe pain. In two patients with multiple fractures, values on densitometry of femoral, radial, and vertebral bones were consistently lower than normal; however, in three others, values were normal or nearly normal. Three of four additional patients without recurrent fractures also had low bone-density values.
Seventy-six percent of the patients with the hyper-IgE syndrome who were 16 or older had scoliosis with maximal curvature of 10 degrees or more, and 32 percent had curvature of 20 degrees or more (Table 1). In 10 patients, scoliosis was idiopathic. Seven others had scoliosis accompanied by leg-length discrepancy or received a diagnosis of scoliosis after undergoing thoracotomy for lung-cyst removal. In addition, two patients had congenital spinal abnormalities: a wedge-shaped L2 vertebra (Patient 10) and hemivertebrae at T3 to T5 (Patient 23). Four women required surgical stabilization of scoliosis between the ages of 17 and 23. Other skeletal abnormalities, each seen once, were occult spina bifida, bifid rib, and pseudarthrosis of the rib.
Hyperextensible joints, including fingers, wrists, shoulders, hips, and knees, were found in 68 percent of the patients, and three patients (Patients 7, 11, and 29) had genu valgum.
Immunologic Features and Infections
Eczema, abscesses, candidiasis, pneumonia, eosinophilia, and elevated serum levels of IgE were the most common manifestations of immune dysfunction in patients with the hyper-IgE syndrome (Table 1). Moderate-to-severe eczematoid rashes were universal in early life, but boils and pneumonia occurred less frequently in youth, particularly in children maintained on antibiotic prophylaxis. As is characteristic of hyper-IgE syndrome,43 pneumonia led to the formation of pneumatoceles in 77 percent of the patients.
Pathogens that were cultured from pulmonary specimens during the period from 1992 through 1997 are shown in Table 1. Acute pneumonia was caused most frequently by Staphylococcus aureus or Haemophilus influenzae; in contrast, superinfections of pneumatoceles were associated with Pseudomonas aeruginosa and Aspergillus fumigatus. Fifteen patients required thoracotomy for removal or drainage of infected pneumatoceles.
Other systemic infections were recurrent bacterial arthritis and staphylococcal osteomyelitis at fracture sites. Six patients (Patients 6, 12, 13, 16, 22, and 30) had episodes of bone pain; the findings on radioactive technetium scanning and magnetic resonance imaging were consistent with a diagnosis of osteomyelitis,44 but the cultures were negative. These patients received antibiotics, and the lesions resolved.
Chronic candidiasis of mucosal sites and nail beds affected 83 percent of the patients with the hyper-IgE syndrome, including children who had not yet had pneumonia or skin abscesses. Two patients had median rhomboid glossitis, which is a chronic form of candidiasis,45 and two had Pneumocystis carinii pneumonia. Tissue-invasive fungal infections also occurred. Patient 18 had a pulmonary cyst chronically colonized with aspergillus and died of a mycotic (A. fumigatus) aneurysm of the brain; Patient 13 had osteomyelitis of the femoral neck caused by yeast; Patient 23 had lymphatic and visceral candidiasis; and Patient 29 had invasive esophageal Cryptococcus neoformans infection.45
Substantial fluctuations in serum IgE levels were noted over time. The highest values recorded for each patient are shown with concurrent eosinophil counts in Table 1. IgE levels higher than 2000 IU per milliliter (4800 µg per liter)6,9,10 were documented in all but Patient 28, who enrolled at the age of 34 years with an IgE level of 1875 IU per milliliter (4500 µg per liter). An unexpected finding in six otherwise typical patients, each followed for more than five years, was a decline in the IgE level; IgE levels fell to less than 2000 IU per milliliter in five patients and fell to the normal range (less than 130 IU per milliliter [312 µg per liter]) in three of the five (Figure 3). Although eosinophil counts at least 2 SD above normal values were found in 93 percent of the patients, there was no correlation between the number of eosinophils and level of IgE in serum (r=0.27, P>0.05).
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Medical diagnoses not previously reported in patients with the hyper-IgE syndrome included apparently noninfectious vascular events in the central nervous system in three women. Patient 23 had an occlusion of the central retinal artery at the age of 18, and at the age of 34 a leaking berry aneurysm and bilateral aneurysms at the internal carotid bifurcations were diagnosed. Patient 13 had a left cerebral embolus at the age of 18 during an episode of transient cardiomyopathy, and Patient 30 had a thrombotic stroke of the left posterior inferior cerebellar artery at the age of 54. No consistent risk factors were identified in these patients.
Patient 25, who was uncharacteristically free of pneumonia, had double rows of eyelashes and lymphedema (this syndrome, distichiasis lymphedema syndrome, is frequently an autosomal dominant condition, but it was absent in other members of his family); Patient 28, a nonsmoker, died of squamous-cell carcinoma of the tongue at the age of 43. Patients 20, 22, and 30 died of respiratory failure, and Patient 12 died in an accident. Lupus erythematosus,46 autoimmune vasculitis,47 and lymphoma,48,49,50 all of which have been reported in the hyper-IgE syndrome, have not developed in any of the patients in our study.
Genetics of the Hyper-IgE Syndrome
Eleven of the patients with the hyper-IgE syndrome came from families that had more than one affected member (five families altogether) (Figure 4, Families A through E, solid symbols). Four pedigrees demonstrated parent-to-child transmission consistent with dominant inheritance; in Family A, transmission from father to son excluded X-chromosome linkage. Five of eight offspring of patients with the hyper-IgE syndrome were fully affected.
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Six other relatives of patients with the hyper-IgE syndrome had one or two immunologic features that are consistent with the hyper-IgE syndrome but are also common in the general population (e.g., moderate eczema, frequent respiratory infections, and eosinophilia); their genotypes were considered indeterminate (data not shown). The remaining relatives had no features consistent with the hyper-IgE syndrome and were judged unlikely to have a genotype for the syndrome. Under a model of single-locus autosomal dominant inheritance with varying expressivity, the persons represented in Figure 4 by a symbol marked with an asterisk would be at 50 percent risk for inheriting a genotype for the hyper-IgE syndrome, although grandparental origin could not be distinguished from origin from a new mutation in Families D and E. Of the 27 at-risk relatives, 10 were fully affected by the hyper-IgE syndrome, 11 had no features of the syndrome, and 6 had multiple immunologic, skeletal, or dental findings consistent with a phenotype of mild hyper-IgE syndrome.
Discussion
The hyper-IgE syndrome has been considered primarily an immunodeficiency disease because it causes frequent abscesses, persistent eczematoid rashes, and extreme elevations of IgE in serum. Our study shows that abnormalities in dentition, bones, and connective tissue are as common in the hyper-IgE syndrome as immunologic abnormalities and establishes that the hyper-IgE syndrome is a multisystem disorder.
The failure to shed primary teeth, not previously recognized as a feature of the hyper-IgE syndrome, occurred in 72 percent of patients old enough for evaluation. This characteristic contrasts with the early loss of primary teeth as a result of periodontal infection in other disorders of host defenses, most notably defects in leukocyte adhesion. Retention of individual primary teeth is not rare in the general population, but in our cohort the condition affected all primary teeth and caused impaction of the succedaneous teeth. Tooth development and the eruption of permanent molars occurred on time, suggesting impaired resorption of primary teeth rather than defective eruption. The latter has been implicated in cleidocranial dysplasia, which results from autosomal dominant mutations in the transcription factor CBFA1.51 Characteristics of cleidocranial dysplasia are alveolar bone abnormalities, impaired dental exfoliation, supernumerary teeth, and lack of cementum in roots.52 Cleidocranial dysplasia thus superficially resembles the hyper-IgE syndrome, but the dental and skeletal abnormalities of cleidocranial dysplasia — short stature, absent or hypoplastic clavicles, and depressed nasal bridge — are distinct, and cleidocranial dysplasia is not associated with immunologic dysfunction.
The factors that control physiologic dental-root resorption are undefined but may involve the activation of osteoclasts, macrophages, or both by cytokines, which also mediate local inflammation. We suspect that delayed resorption of the roots of primary teeth in the hyper-IgE syndrome may be a manifestation of the same defect that results in ineffective inflammatory responses and the formation of pneumatoceles.
Additional abnormalities of bone and connective tissue caused substantial morbidity in our patients with the hyper-IgE syndrome. Their unexpectedly frequent fractures may reflect a higher-than-normal level of cytokine-mediated bone resorption31; indeed, overexpression of interleukin-4 in mice causes osteoporosis.53 However, we documented fractures in subjects with normal bone density. Moreover, fracture sites commonly associated with osteoporosis are the vertebral bodies and femoral neck, but our patients' fractures were in the long bones, pelvis, and ribs. Whether bone fragility in the hyper-IgE syndrome is due to decreased mineralization or to other abnormalities remains to be determined.
More than three quarters of the patients with the hyper-IgE syndrome who were older than 11 years had 10 degrees or more of scoliosis, and one third had 20 degrees or more — far higher rates than are reported in unselected adolescents (of whom 1.5 percent had scoliosis of 10 degrees or more, and 0.5 percent had 20 degrees or more).54,55,56 More than half the cases of scoliosis in our patients were idiopathic, suggesting an intrinsic susceptibility to scoliosis in patients with the hyper-IgE syndrome. Generalized hyperextensibility of joints was recognized in the initial description of the disease,2 but the 68 percent incidence in our patients is higher than previously reported.
The unusual facial phenotype of the hyper-IgE syndrome had also been noted previously, in both early and recent reports.2,27 Our anthropometric evaluations confirmed strikingly large nasal interalar distance and suggested larger-than-average head circumference in addition to a specific combination of variations in craniofacial development that were independent of race and sex. Because of the associated developmental variations of the tongue, spine, and ribs and the high incidence of palatal elevation in our patients with the hyper-IgE syndrome, and because of reports of craniosynostosis in the literature,15,32,33,34 the hyper-IgE syndrome can be defined as a syndrome of congenital anomalies.
In our study, fluctuations in the patients' IgE levels and eosinophil counts were not correlated and were not related to infections or eczema; this finding had been suggested previously.57 We also saw no correlation between patients' IgE levels and their interleukin-4–receptor allotype,58 although such an association has been reported in persons with atopic dermatitis.59 In some of our patients, IgE levels fell over time. Although IgE levels exceeded 2000 IU per milliliter in our patients younger than 12, a normal IgE level should not exclude the presence of the hyper-IgE syndrome in an adult. Taken together, these data suggest that eosinophilia and IgE production are influenced by additional factors, beyond those that underlie the pathogenesis of the hyper-IgE syndrome.
Another autosomal dominant disorder with variably expressed anatomical and immunologic abnormalities is the DiGeorge velocardiofacial syndrome. The immunodeficiency associated with this syndrome is due to maldevelopment of the thymus; the prevalence of midline facial and congenital heart defects varies, even among affected members of the same family. Inherited deletions of chromosome 22q11 underlie most cases.60,61 Although the DiGeorge syndrome differs from the hyper-IgE syndrome in its specific manifestations, it exemplifies the potential for a genetic approach to provide a unified definition of a syndrome and to provide important information to patients and their families about the risk of recurrence in future offspring.
The hyper-IgE syndrome may be caused by the mutation of a single gene, mutations in different genes in different families (indicating genetic heterogeneity), or the deletion of contiguous genes in a short chromosomal region. Although most of our patients were female, large published series show equal distribution between the sexes.7,9 Because the genetic backgrounds of our patients were diverse and because survival of patients with this syndrome to reproductive age before the advent of antibiotics was unusual, a founder effect in the hyper-IgE syndrome is unlikely. Therefore the syndrome is expected to result from many independently arising mutations.
All the families in our study reported that there were no features compatible with the hyper-IgE syndrome in generations older than those shown in Figure 4. The apparently greater severity of cases in younger generations may suggest genetic anticipation, as associated with expansion of repetitive DNA motifs, but analysis of more families would be needed to substantiate this possibility. Characterization of the manner of inheritance and the extended phenotypic spectrum of the hyper-IgE syndrome now makes possible a search for genetic linkage and, ultimately, for the gene or genes in which defects produce this combination of immunologic, dental, and skeletal abnormalities.
An awareness of the diverse features of the hyper-IgE syndrome will facilitate the diagnosis of sporadic cases, make genetic counseling possible, and improve patient care.62 Patients benefit from aggressive antibiotic treatment to minimize infectious complications. They should also receive full evaluations for fractures after even minor trauma, should be monitored vigilantly and treated for scoliosis, and should have retained primary teeth removed.
Supported by a grant (GR1718/1-1) from Deutsche Forschungsgemeinschaft (to Dr. Grimbacher).
We are indebted to Marc Conte for help with data analysis and presentation, Alejandro Schaffer for statistical consultation, Dr. James Reynolds for bone densitometry, Drs. Rebecca Buckley and Max Muenke for helpful discussions, and all the patients and their families who joined in our research.
Source Information
From the Genetics and Molecular Biology Branch (B.G., J.M.P.) and the Genetic Disease Branch (F.G.), National Human Genome Research Institute; the Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (S.M.H., J.I.G., H.L.M., J.A.M.); the Department of Radiology, Warren Grant Magnuson Clinical Center (S.C.H.); and the Clinical Research Core, National Institute of Dental and Craniofacial Research (A.C.O.) — all at the National Institutes of Health, Bethesda, Md.
Address reprint requests to Dr. Puck at the Immunologic Genetics Section, GMBB/NHGRI, Bldg. 49, Rm. 3A14, 40 Convent Dr., Bethesda, MD 20892-4442, or at jpuck{at}nhgri.nih.gov.
References
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-globulin treatment for hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol 1995;95:771-774. [Medline]
subunit of the interleukin-4 receptor. N Engl J Med 1997;337:1720-1725.
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Related Letters:
Hyper-IgE Syndrome
Presotto F., Trentin L., Agostini C., Feingold M., Grimbacher B., Holland S. M., Puck J. M.
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Full Text
N Engl J Med 1999;
341:375-377, Jul 29, 1999.
Correspondence
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