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Chapter 50 Disorders of Phagocyte Function 705

Clinical Manifestations prevent superinfection by fungal and gram-negative organisms.
Intravenous Ig infusions have shown some success in the management
The clinical manifestations of HIES are at times dramatic. Onset is of HIES. Attention should also be paid to blood pressure and other
generally in the first 2 months of life and is manifested by chronic vascular complications. Although a role for hematopoietic stem cell
dermatitis. By 5 years of age, patients have a history of recurrent transplantation in AD HIES is unclear, two children with STAT3
skin abscesses, pneumonias, chronic otitis media, and sinusitis. mutations who underwent transplantation for non-Hodgkin lym-
As patients grow older, recurrent staphylococcal pneumonia is phoma are alive 10 and 14 years later with resolution of all immu-
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a common problem and can be complicated by the formation of nologic and nonimmunologic features of HIES. Patients with AR
pneumatoceles. Septic arthritis, cellulitis, and osteomyelitis are also HIES may need prophylaxis for viral infections, and hematopoietic
observed and are usually caused by S. aureus, although other bacterial stem cell transplant probably should be considered. 20
pathogens have also been found. Patients can have chronic muco-
cutaneous candidiasis and occasionally exhibit keratoconjunctivitis,
sometimes complicated by corneal scarring. One feature noted in Miscellaneous Chemotactic Disorders
the majority of patients by the time they reach the teenage years is
the presence of coarse facial features (broad nasal bridge, prominent It is extremely rare to have primary defects in neutrophil actin
nose). Dental and bone abnormalities are also common features of polymerization as a cause of abnormal chemotaxis and recurrent
2,3
HIES. Delayed or failure to shed primary teeth occur in the major- infections. In one case, neutrophils had diminished actin polymer-
ity. Hyperextensible joints and scoliosis are frequent. Osteopenia ization, chemotaxis, and phagocytosis of serum-opsonized particles.
of unknown etiology is observed in most patients, and there is an Family members had decreased CD11b/CD18 expression and a
increased risk of fractures to the long bones and vertebral bodies partial decrease in actin polymerization, which suggested that this
even in the absence of osteopenia. Vascular disease, including aneu- disorder might be a variant of LAD I; however, no similar cases have
rysms, tortuosity of middle-sized arteries, and hypertension is also otherwise been described. An apparent AR disorder of actin polym-
frequently seen. erization has been described in a male infant of Tongan descent who
Patients with the AR form of HIES, the majority of whom have presented with severe skin infections, recurrent pulmonary infiltrates,
defects of DOCK8, which is also referred to as DOCK8 immunodefi- thrombocytopenia, and invasive Candida tropicalis infection. Neutro-
ciency syndrome, also have recurrent sinopulmonary infections, skin phil actin polymerization was markedly abnormal and associated with
abscesses, and dermatitis, with the latter often the first symptom and increased expression of an actin-binding protein. Finally, a heterozy-
developing in infancy. Unlike AD HIES, patients with DOCK8 gous point mutation in β-actin affecting binding to actin-regulatory
defects can develop asthma; severe allergies, including to foods, and proteins was discovered in a female patient with recurrent infections,
chronic cutaneous viral infections with human papillomavirus, mol- photosensitivity, and mental retardation. Neutrophils had a marked
luscum contagiosum virus, and herpes family viruses is a distinctive impairment in chemotaxis and in the formyl peptide-induced respira-
feature seen in approximately 90% of patients. These patients are also tory burst.
at high risk for a variety of malignancies in late childhood to early A new syndrome of severe neutrophil dysfunction caused by a
adulthood, believed to be caused by loss of immune surveillance for dominant-negative mutation in Rac2, a small GTPase expressed in
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tumors. AR HIES patients do not have the nonimmunologic blood cells that acts in many signal transduction pathways, was
skeletal and dental abnormalities characteristic of AD HIES. recently described in an infant boy born to unrelated parents. (see
3
Dinauer and Newburger ). This baby presented with rapidly progres-
sive and deep-seated soft tissue infections, along with neutrophilia
Diagnosis and poor formation of pus but normal expression of β2 integrins
and fucosylated proteins. Neutrophils had marked defects in actin
The diagnosis of HIES should be entertained in any child or young polymerization, chemotaxis, degranulation, and the respiratory
adult who has the above-described clinical picture or simply a history burst in response to chemoattractants. Neutrophil responses to other
of recurrent infections. The hallmark laboratory finding is a marked agonists were normal, suggesting that the dominant negative Rac2
elevation of serum immunoglobulin E (IgE), almost always greater mutation produces a selective intracellular signaling defect.
than 2500 IU/mL. Levels can be as high as 150,000 IU/mL. Most Localized juvenile periodontitis (LJP) is a heterogeneous disor-
patients also have peripheral eosinophilia. However, there is no cor- der of unknown etiology characterized by chronic and recurrent
relation of clinical disease activity with the level of either IgE or periodontal infections and severe alveolar bone loss with onset at
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peripheral eosinophilia. Atopic dermatitis is the major differential the time of puberty. Many patients with LJP have been reported
diagnosis because comparably high serum levels of IgE can be seen to have defective neutrophil chemotaxis in vitro. At present, it
in patients in this disorder, as well as superficial skin infections. The appears that LJP is an acquired disorder in some patients and a
severe and recurrent nature of the staphylococcal furuncles and genetic disorder in others. It may also be a combination of both in
pneumonias usually seen in HIES can help distinguish these patients certain patients because they may inherit an unusual sensitivity to
from those with atopic dermatitis. Patients with other primary the chemotactic inhibitors released by certain periodontal micro-
immunodeficiency syndromes may also manifest elevated IgE levels. organisms. The diagnosis of the disorder is made on the basis of
Scoring criteria predictive of STAT3 mutations, including recurrent severe periodontal disease and destructive alveolar bone loss involv-
pneumonia, pathologic bone fractures, and lack of Th17 cells, are ing the first molars and incisors developing during adolescence. It
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helpful. DNA testing should be used to make a definitive is important to note that many qualitative and quantitative neu-
diagnosis. trophil disorders are also associated with severe periodontal disease.
Therefore, the differential diagnosis should include neutropenia
(both chronic and cyclic), LAD, CGD, and Chediak-Higashi syn-
Therapy drome (CHS).
One of the most consistently observed chemotactic abnormalities
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The therapy for AD HIES is largely supportive. Prophylactic anti- is seen in neonatal neutrophils. These cells exhibit impaired chemo-
biotics (e.g., dicloxacillin or TMP-SMX) can be effective in prevent- taxis in vitro in response to a wide variety of chemotactic factors. It
ing S. aureus infections. Dermatitis can be treated with topical appears as though this abnormality is caused, at least in part, by
steroids. Bathing in diluted bleach can diminish colonization by S. defects in cellular adhesion as a result of diminished mobilization of
aureus. Prophylactic antifungals can be helpful in patients with intracellular adhesion-promoting molecules to the cell surface. Defec-
chronic mucocutaneous candidiasis. Intravenous antibiotics are used tive neutrophil chemotaxis can be seen in normal neonates between
for deep-seated infections or for resistant cutaneous infections. Surgi- birth and 5 days of age. In severely ill infants, the defect may persist
cal resection of persistent pneumatoceles is sometimes indicated to for a longer time.