Chapter 143. Genetic Immunodeficiency Diseases

Primary immunodeficiency diseases are inherited disorders of the immune system that result in an increased susceptibility to infection and an increased morbidity and mortality. Many of these genetic immunodeficiency diseases may be associated with a variety of cutaneous abnormalities, and recognition of these clinical features may allow an early diagnosis of primary immunodeficiency. Cutaneous abnormalities may include cutaneous infections, atopic- or seborrheic-like dermatitis, macular erythemas, alopecia, poor wound healing, purpura, petechiae, telangiectasias, pigmentary dilution, cutaneous granulomas, extensive warts, angioedema, and lupus-like changes (Table 143-1). Other clinical features often include failure to thrive, visceral infection, autoimmune disorders, connective tissue/rheumatologic diseases, allergic reactions, and neoplasias.

Clinical Findings

Immunodeficiency should be suspected when patients have recurrent infections of increased duration or severity, particularly with unusual organisms. Incomplete clearing of infections, unexpected or severe complications of infection, or poor response to antibiotics may be associated.1 Affected infants often grow poorly (failure to thrive). The most common noncutaneous abnormalities are infections, diarrhea, vomiting, hepatosplenomegaly, arthritis, adenopathy or paucity of lymph nodes/tonsils, and hematologic abnormalities.

The classification of genetic immunodeficiency disorders includes (1) antibody deficiencies, (2) cellular deficiencies, (3) combined antibody and cellular deficiencies, (4) disorders of phagocytosis and cell killing, and (5) complement defects. The characteristic clinical signs of each group suggest that proper classification and laboratory tests may be used to confirm the diagnosis. The laboratory testing and clinical patterns of illness associated with each group of immunodeficiency disorders that allow their differential diagnosis are outlined in Table 143-2 and Fig. 143-1. The most important disorder in the differential diagnosis of all genetic immunodeficiency disorders is human immunodeficiency virus (HIV) infection. In addition to the lack of HIV antigen as detected by polymerase chain reaction in patients with genetic immunodeficiency, other features help to differentiate the disorders. Patients with HIV infection tend to show an inverted CD4/CD8 ratio and hypergammaglobulinemia, in contrast to the hypogammaglobulinemia of many patients with genetic immunodeficiency.

Agammaglobulinemia

Epidemiology

Agammaglobulinemia results from gene defects that prevent the assembly of a full B cell antigen receptor. X-linked agammaglobulinemia (XLA) is the most common cause of agammaglobulinemia and results from defects in a cytoplasmic tyrosine kinase, Bruton's tyrosine kinase (BTK). XLA is inherited in an X-linked fashion, and approximately 50% of affected boys have a family history of the disorder.2 Autosomal recessive agammaglobulinemia affects males and females equally and results from defects in the genes that encode for components of the pre-B cell and B cell receptors or in BLNK, a scaffold protein that assembles signaling molecules associated with the pre-B cell and B cell receptor.23

Etiology and Pathogenesis

Clinical Findings

Agammaglobulinemia is characterized by recurrent pyogenic infections that often begin between 3 and 18 months after birth, concurrent with the waning of maternal immunoglobulins (Ig). These patients have absent or barely detectable tonsils and cervical lymph nodes.5 Skin infections, especially furunculosis and impetigo, occur in 28% of patients and often surround body orifices. An atopic-like eczematous eruption that fails to improve with Ig therapy has been described in many affected children. Pyoderma gangrenosum and noninfectious cutaneous granulomas have been reported. Childhood exanthematous disorders are handled appropriately, but the infections may recur, owing to a failure to develop specific antibodies.

Recurrent otitis, sinusitis, bronchitis, and pneumonia are the earliest infectious manifestations and usually are caused by Pneumococci, Staphylococci, or Haemophilus. Untreated pulmonary infections may lead to progressive bronchiectasis and chronic pulmonary disease, seen in 45% of XLA patients over the age of 10.6 Patients can also suffer from chronic enteroviral infections and hearing loss from repeated otitis and sinusitis infections. Other common bacterial infections include conjunctivitis, osteomyelitis, septic arthritis, and meningitis. Protracted diarrhea may be due to infection, particularly with Giardia, Salmonella, Campylobacter, or Cryptosporidium spp. Three virus groups cause problems: (1) enterovirus, (2) hepatitis B virus, and (3) rotavirus. Patients have developed paralysis after administration of the live polio vaccine. A rheumatoid-like arthritis, characterized by chronic inflammation and swelling of the large joints, may develop in as many as one-third to one-half of boys with XLA and is often due to mycoplasmal infection (Ureaplasma urealyticum). Disseminated echovirus infection has caused meningoencephalitis and a dermatomyositis-like disorder with brawny edema, induration of the muscles with accompanying weakness, muscle contractures, and poikiloderma.

The diagnosis of agammaglobulinemia is made by serum concentrations of IgG, IgA, and IgM that are far below the 95% confidence limits for appropriate controls (usually less than 100 mg/dL total Ig) and by the virtual absence of B cells in the peripheral circulation (<1% of normal). Identification of a defect in one of the known genetic causes of agammaglobulinemia confirms the diagnosis and allows for genetic counseling and prenatal diagnosis.

Treatment, Prognosis, and Clinical Course

Early Ig replacement, intravenously (IVIG) or subcutaneously, and antibiotic use markedly reduces the risk of infections, although it may not be helpful in diminishing the risk and morbidity of chronic lung disease or chronic enterovirus infection.

Common Variable Immunodeficiency

Epidemiology

Etiology and Pathogenesis

Clinical Findings

CVI commonly presents in young adults, but 25% of cases are diagnosed before the age of 21 years.9 Patients have infections similar to those in patients with XLA, particularly sinopulmonary infections, but are less susceptible to enteroviral infections and more susceptible to Giardia infections. Many patients with CVI have liver disease and gastrointestinal (GI) disease, causing malabsorption syndromes. Noncaseating granulomas of skin (Fig. 143-2), lungs, liver, and spleen have been reported. Caseating granulomas of the skin and viscera, although rare, have also been described.11,12 Extensive warts can be a major problem in individuals with CVI (Fig. 143-3). Lymphoid tissues often are enlarged, and splenomegaly with hypersplenism is found in 25% of patients. Autoimmune disorders are especially frequent (11% to 22%),9,13 particularly autoimmune thrombocytopenia, autoimmune hemolytic anemia, rheumatoid arthritis, sicca syndrome, and pernicious anemia. Alopecia areata and lupus also have been described. In 10% to 20% of patients, at least one family member is also immunodeficient, particularly with CVI or IgA deficiency.14 The incidence of lymphoreticular malignancy and gastric carcinoma are markedly increased, particularly in the fifth and sixth decades of life.15

Laboratory Findings

Prognosis, Clinical Course, and Treatment

Immunoglobulin A Deficiency

Immunoglobulin M Deficiency

X-Linked Lymphoproliferative Disease (Duncan Disease)

Epidemiology

Pathogenesis

Clinical Findings

Prognosis, Clinical Course, and Treatment

Chronic Mucocutaneous Candidiasis

Epidemiology

Several clinical subtypes of chronic mucocutaneous candidiasis (CMC) have been defined (Table 143-3). They have varied clinical manifestations, variable immunodeficiency, and different forms of genetic inheritance. Patients with CMC may have childhood or mature onset, familial, or sporadic occurrence, and CMC may be present with or without endocrinopathy. Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED or autoimmune polyendocrine syndrome or APS, type 1) often have affected siblings. APECED and other familial forms of CMC are autosomal recessive. Autosomal dominant inheritance is seen in patients with associated keratitis.

Etiology and Pathogenesis

Clinical Findings

Patients with CMC have recurrent, progressive infections of the skin, nails, and mucous membranes most commonly due to Candida albicans.33,37 Depending on the subtype, the clinical presentation ranges from recurrent, recalcitrant thrush (Fig. 143-4) to mild erythematous scaling plaques (see eFig. 143-4.1) with a few dystrophic nails to severe generalized, crusted granulomatous plaques (Fig. 143-5). The cutaneous plaques occur most commonly in intertriginous areas, periorificial sites, and the scalp, but they may be generalized. The nails are thickened, brittle, and discolored, and the paronychial areas are often erythematous, swollen, and tender. Scalp infections may lead to scarring and alopecia. Although the oral mucosa is the most frequent site of mucosal alteration, esophageal, genital, and laryngeal mucosae may be affected. Strictures may be formed by candidal infection at these mucosal sites. Scrapings and cultures from cutaneous or mucosal lesions demonstrate candidal organisms.

Patients with CMC rarely develop systemic candidiasis, but 50% may develop recurrent or severe infections due to other organisms. In one study, 81% of patients with early-onset CMC also had infections with bacteria, fungi, and parasites, including bacterial septicemia.33 Concomitant dermatophyte infections may occur.

In patients with APECED, the candidal infections tend to begin by 5 years of age, although the endocrinologic dysfunction may not be apparent until 12–13 years of age (see Fig. 143-5). The most commonly associated endocrinopathies are hypoparathyroidism (88%) and hypoadrenocorticism (60%). One-third of patients have candidiasis, hypoparathyroidism, and defective adrenal function. Other associated endocrinopathies or autoimmune disorders include gonadal insufficiency (45%), alopecia areata (20%), pernicious anemia (16%), thyroid abnormalities (12%), chronic active hepatitis or juvenile cirrhosis (9%), vitiligo, diabetes mellitus, and hypopituitarism. Chronic diarrhea and malabsorption have been reported in 25% of patients and usually are associated with hypoparathyroidism. Some affected patients also have pulmonary fibrosis, dental enamel hypoplasia, and keratoconjunctivitis. The “ectodermal dysplasia” features are likely to be secondary to the candidal infections or autoimmunity.37 Patients with APECED often have autoimmune antibodies, including antithyroglobulin, antimicrosomal, antiadrenal, and antimelanocyte antibodies, and rheumatoid factor. Autoantibodies also have been found in patients with CMC who do not have clinical endocrinologic disease.

Prognosis, Clinical Course, and Treatment

Candidal lesions in patients with CMC generally respond to systemically administered azole antifungal agents (itraconazole, fluconazole) or terbinafine.38 Ketoconazole is no longer used because of the risk of hepatitis. Patients who are resistant usually respond to amphotericin B with or without flucytosine. Cutaneous granulomas often are less responsive despite clearance of infection. Recurrences are common, and the antifungal agents must be used intermittently. The drugs have no effect on the abnormal cell-mediated immunity. All patients with CMC should have an annual endocrine evaluation and patients with documented endocrinopathy or a family history of APECED should be monitored more closely. Patients who have a history of infections other than candidal should have further evaluation of their immune status.

Digeorge Syndrome

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Prognosis, Clinical Course, and Treatment

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Prognosis, Clinical Course, and Treatment

Hyperimmunoglobulin M Syndrome

Epidemiology

Pathogenesis

Clinical Findings

Prognosis, Clinical Course, and Treatment

Wiskott–Aldrich Syndrome

Epidemiology

Wiskott–Aldrich syndrome (WAS) is an X-linked recessive disorder with an incidence of approximately 4 per million male births.75

Pathogenesis

The defective gene is WASP, mapped to Xp11.22–11.23, which encodes WASp, a hematopoietic specific cytoplasmic protein that functions in signaling and cytoskeletal organization. WASp couples signals arising at the cell membrane with reorganization of the cellular cytoskeleton, resulting in cellular activation and promotion of cell motility. Mutations in WASp affect organization of the immunologic synapse and T-cell activation, T and B lymphocyte migration, and initiation of the primary antibody response.76 There is a strong phenotype–genotype correlation; classic WAS occurs when WASp is absent or truncated, while X-linked thrombocytopenia occurs when mutated WASp is expressed.77 The atopic dermatitis is likely associated with the observed skewing of CD4+ T cell differentiation towards Th2 cells with suppression of Th1 and regulatory T cells (Treg) differentiation.78 Given the expression of WASp on epidermal Langerhans cells, abnormal interactions of Langerhans cells with T cells and ability of Langerhans cells to move to the lymph node after antigen stimulation may be involved as well.

WAS patients have decreased function and number of both T- and B-lymphocytes, beginning in the first years of life.79 The lymphocytes of patients with WAS lack microvilli formed by actin bundles, resulting in defective chemotaxis and, in some patients, there is decreased expression of sialoglycoproteins (e.g., CD43 and others) on lymphocytes and platelets. Defects in humoral immunity include abnormal serum Ig and decreased antibody response to polysaccharide antigens. WAS patients also have defects in NK cell cytotoxicity, dendritic cell migration, and activation, and impaired macrophage chemotaxis.76

Clinical Findings

The classic triad of WAS is (1) hemorrhage due to thrombocytopenia and platelet dysfunction, (2) recurrent pyogenic infections, and (3) recalcitrant dermatitis, but this triad appears in only 25% of patients.80 The bleeding diathesis is the most common manifestation of mutations in WAS, present in 84% of patients79 and often manifests initially during the first weeks or months of life with bloody diarrhea. Epistaxis, hematemesis, hematuria, mucocutaneous petechiae, and intracranial hemorrhage also may occur. Recurrent bacterial infections begin in infancy as levels of placentally transmitted maternal antibodies diminish. These infections include furunculosis, conjunctivitis, otitis media and otitis externa, pansinusitis, pneumonia, meningitis, and septicemia. Infections with encapsulated bacteria such as Pneumococcus, Haemophilus influenzae, and Neisseria meningitidis predominate. Patients are also susceptible to infections due to herpes and other viruses and to Pneumocystis jiroveci.

The atopic dermatitis associated with WAS, which occurs in approximately 80% of patients,75 usually develops during the first few months of life and may be quite severe. The face, scalp, and flexural areas are the most severely involved, although patients commonly have widespread involvement with progressive lichenification. The eruption may be more exfoliative than that of atopic dermatitis in individuals without WAS, and excoriated areas frequently have serosanguineous crusts (Fig. 143-6). Secondary bacterial infection of eczematous lesions is common, as are eczema herpeticum (see eFig. 143-6.1) and molluscum contagiosum. IgE-mediated allergic problems, such as urticaria, food allergies, and asthma, are seen in addition to the atopic dermatitis.

As many as 40% of patients with WAS develop an autoimmune disorder.81 The most common are vasculitis (particularly involving the skin, GI tract, brain, and heart) in 20% of patients, autoimmune hemolytic anemia in 14%, and IgA nephropathy in up to 10% of patients.82 Other immune-mediated cutaneous manifestations are angioedema, dermatomyositis, pyoderma gangrenosum, and erythema nodosum.81 Hepatosplenomegaly is common, and lymphadenopathy, transient arthritis, and joint effusions are present occasionally.

The thrombocytopenia of WAS is persistent, and platelet counts may range from 1,000 to 80,000 platelets per μL. A platelet count of <70,000 is required for formal diagnostic criteria. The platelets are small, and platelet aggregation is defective. Levels of IgM and sometimes, IgG, are low, and isohemagglutinins are absent. IgA, IgE, and IgD levels usually are elevated. Eosinophilia, leukopenia, and lymphopenia are also seen. Delayed hypersensitivity skin-test reactivity is diminished, and patients fail to respond to polysaccharide antigens. WASp can be detected by flow cytometry using intracellular staining with an antibody to WASp and sequencing of the WASP gene can confirm the diagnosis of WAS or X-linked thrombocytopenia, which results also from mutations in the WASP gene that do not affect immune function.76 Mutation analysis allows for prenatal diagnosis.83

Prognosis, Clinical Course, and Treatment

Therapeutic interventions allow some patients with WAS to survive into adulthood; however, a significant proportion die before the age of 10 years due to infections secondary to hemorrhage, malignancies, or the complications of transplantation.75,84,85 Thirteen percent of patients with WAS develop lymphoreticular malignancies,80 especially non-Hodgkin lymphoma, with a predominance of extranodal and brain involvement. Development of autoimmune hemolytic anemia is a poor prognostic factor and associated with the development of lymphoid malignancies; overall 25% of patients with autoimmunity develop a malignancy.82 Ten percent of patients die from these malignancies, usually as adolescents or young adults.

Appropriate antibiotics, immunizations, and transfusions of platelets and plasma decrease the risk of fatal infections and hemorrhage. Ig replacement therapy is useful in some patients. Splenectomy has been advocated to ameliorate the bleeding abnormality in patients with recurrent severe hemorrhage, but this procedure increases the risk of infection from encapsulated bacterial organisms. Bone marrow or stem cell transplantation is the treatment of choice for patients with recurrent problems, especially significant autoimmunity. Full engraftment results in normal platelet number and function, normal immunologic status, and clearance of the dermatitis (T lymphocyte engraftment). The 5-year survival rate with HLA-matched sibling donors is 87%.80 Topical glucocorticoid preparations and Ig replacement may improve the dermatitis, and chronic administration of oral acyclovir is appropriate for patients with recurrent eczema herpeticum.

Severe Combined Immunodeficiency

Epidemiology

Pathogenesis

Clinical Findings

Infants with SCID usually fail to gain weight by 3–6 months of age, following the onset of recurrent sinopulmonary and skin infections. Persistent mucocutaneous candidiasis is often present at the time of diagnosis, and systemic candidal infections occur occasionally. Patients with SCID also may have chronic diarrhea and malabsorption caused by viral infections. P. jiroveci pneumonia (PCP) is often a presenting feature. Although bacterial infections usually respond to systemic antibiotics, viral infections tend to be fatal. Infants with SCID lack palpable lymphoid tissue despite recurrent infections.

In addition to cutaneous bacterial and candidal infections, the most common cutaneous eruptions are morbilliform or resemble seborrheic dermatitis. In some infants with SCID, biopsy sections show GVHD (see Chapter 28). GVHD may result from in utero exposure to maternal lymphocytes, from transfusion with nonirradiated blood products, or may follow transplantation. Patients with GVHD most commonly present acutely with morbilliform erythema, papular dermatitis, or diffuse erythroderma. The face, neck, palms, and soles are usually affected initially, before the eruption becomes generalized. Severe cases are complicated by diffuse bullae or toxic epidermal necrolysis. The clinical presentation of GVHD from maternal engraftment (without transplantation) is indistinguishable from the clinical presentation of GVHD from transplantation, but histopathologic features differ.98 Biopsy sections from GVHD secondary to maternal engraftment show psoriasiform hyperplasia with parakeratosis and variable spongiosis in contrast to the vacuolar interface pattern observed in conventional GVHD.98 Overall, 83% of SCID patients with maternal engraftment develop skin manifestations.98 Oral and genital ulcerations are also seen in SCID, particularly in Athabascan-speaking American Indian children with a defect in the Artemis gene.99 Patients with Omenn syndrome show erythroderma, hepatosplenomegaly and lymphadenopathy with eosinophilia and increased IgE production. B cells tend to be undetectable, and T cells, although often increased in number, are nonfunctional. Recently, Omenn syndrome has been shown to be a phenotype with several underlying genetic bases. Most patients have RAG1/RAG2 mutations, but the phenotype of Omenn syndrome has been described in patients with mutations in Artemis and IL7R.100–102 Two individuals with CHH and another with complete DGS also showed features of Omenn syndrome.103–104

Prognosis, Clinical Course, and Treatment

Ectodermal Dysplasia with Immunodeficiency

Epidemiology

X-linked recessive transmission is most common with an estimated incidence of 1:250,000 live male births.108 An autosomal dominant form of ectodermal dysplasia with immunodeficiency has also been described.109

Etiology and Pathogenesis

Several genetic disorders result from gene mutations in NEMO and lead to abnormal nuclear factor κB (NF-κB) signaling (see Section “Hypohidrotic Ectodermal Dysplasia” in Chapter 142, and Section “Incontinentia Pigmenti” in Chapter 73). One of these, hypohidrotic ectodermal dysplasia with immunodeficiency, results from hypomorphic mutations in the NEMO gene [also called ectodermal dysplasia, anhidrotic, with immunodeficiency (EDA-ID), or hyperimmunoglobulinemia M, immunodeficiency, X-linked with ectodermal dysplasia]. NF-κB is recognized as a DNA-binding factor,110 and its ability to transcribe genes is regulated by a cytoplasmic inhibitor, IKB. NF-κB signaling affects inflammation, apoptosis, development, and immunity.111,112 NF-κB activation requires phosphorylation of IKB by IKB kinase (IKK). IKK is composed of two catalytic components (IKKα and IKKβ) and a regulatory subunit, IKKγ or NEMO. NEMO has no catalytic function, but is the structural scaffold that supports the IKK complex.111 When NEMO is absent or defective, no functional IKK complex is formed and, as a result, NF-κB cannot translocate to the nucleus and activate gene transcription.

The hypomorphic mutations that cause EDA-ID allow early survival in males, in contrast to the large deletions in NEMO (usually of exons 4 to 10) that lead to incontinentia pigmenti in carrier females and fetal death in affected males (see Chapter 73). Female carriers of hypomorphic NEMO mutations often show mild features of incontinentia pigmenti, but may also express an incontinentia pigmenti phenotype with transient immunodeficiency.113 In boys with hypomorphic mutations of NEMO, the ectodermal dysplasia phenotype results from impaired NF-κB signaling.114 Immunodeficiency results from impaired NF-κB activation in response to Toll-like receptor (TRL), interleukin-1 receptor and tumor necrosis factor (TNF) α receptor signaling.115 Gain of function mutations in IκBα, the component of the inhibitor of NF-κB that is phosphorylated by IKK, lead to an autosomal dominant form of ectodermal dysplasia with a distinct immunologic phenotype,114 characterized by a profound T-cell deficiency,109 but normal natural killer (NK) cytotoxicity and responses to Mycobacteria. Mutations in NEMO have also been reported that cause immunodeficiency without the ectodermal dysplasia phenotype.116

Clinical Findings

Affected patients present with classic characteristics of hypohidrotic ectodermal dysplasia (Fig. 143-7). These include the characteristic facies, hypotrichosis or atrichia, hypohidrosis (leading to heat intolerance), hypodontia or anodontia with conical incisors, and associated dermatitis (see Chapter 142).66,108,116–118 A subset of patients has associated osteopetrosis and lymphedema in association with severe immunodeficiency. Boys with immunodeficiency from NEMO mutations without the features of hypohidrotic ectodermal dysplasia have also been described.119 In a recent analysis of 72 patients with NEMO mutations, only 77% had ectodermal dysplasia.120 Bacterial infections early in infancy are common, particularly sepsis, pneumonia, otitis, sinusitis, and lymphadenitis. Recurrent pneumonias may lead to bronchiectasis. Common pathogens include Streptococcus pneumoniae, H. influenzae, Klebsiella, Salmonella, and Pseudomonas. Infections with atypical Mycobacteria and viruses, including cytomegalovirus (systemic and GI involvement), herpes simplex virus, molluscum contagiosum, human papillomavirus, and Pneumocystis carinii, are also reported.66,108,117

The immunodeficiency is often severe, but its characteristics are variable with an apparent genotype–phenotype correlation that can be further identified by in vitro reconstitution of the mutations.119 Immune dysfunction includes impaired B-cell class switching with hypogammaglobulinemia (and often increased levels of IgM and/or IgA), impaired specific antibody production (particularly to polysaccharide antigens), deficient NK cell cytotoxicity, poor cytokine production in response to CD40 signaling and autoinflammation, especially of the gut.108,118,120 Biopsy of skin may show evidence of keratinocyte apoptosis, reflecting the dysfunction in NF-κB signaling, and must be differentiated from GVHD.

Treatment and Prognosis

There is an increased mortality with 36% of patients dying at a mean age of 6.4 years.120 Therapy is guided by the patient's clinical and immunologic phenotype. Ectodermal dysplasia is treated supportively (see Chapter 142). Patients with impaired antibody production may benefit from Ig replacement. All infections (bacterial and viral) should be treated aggressively with the appropriate antibiotics/antivirals. Prophylaxis for both P. jiroveci and Mycobacterium avium-intracellulare should be considered.108 Stem cell transplantation may lead to immune reconstitution.121 The mothers and sisters of these patients should be offered genetic testing for the NEMO mutation and counseling.

Ataxia-Telangiectasia

Epidemiology

Ataxia-telangiectasia [AT; Online Mendelian Inheritance in Man (OMIM) #208900], also called Louis–Bar syndrome, is an autosomal recessive disorder with an incidence of approximately 1:40,000 and a carrier rate of up to 1%. Carriers have an increased risk of breast cancer, hematologic malignancies,122 and ischemic heart disease, with a reduced life expectancy of approximately 8 years.123 These heterozygotes show an increased risk of chromosomal breaks after exposure to irradiation in vitro, suggesting that mammograms in known carriers of AT are contraindicated.

Etiology and Pathogenesis

Clinical Findings

Characteristic oculocutaneous telangiectasias begin near the ocular canthi and progress across the bulbar conjunctivae (Fig. 143-8). These telangiectasias usually appear when patients are 3–6 years of age; rarely have they been described at earlier ages. Cutaneous telangiectasias subsequently may develop on the malar prominences, ears, eyelids, anterior chest, and popliteal and antecubital fossae, and the dorsal aspects of the hands and feet (Fig. 143-9). The telangiectasias may be subtle and resemble fine petechiae, especially in the flexural areas. The development of telangiectasias may be related to sun exposure, because ocular, but not cutaneous, telangiectasias develop in affected dark-skinned children. The development of telangiectasias may relate, at least in part, to the sensitivity of some AT strains to ultraviolet (UV) light.127

Progeric changes of the skin, including xerosis and gray hair, occur in 90% of patients.128 During adolescence, the facial skin may become progressively more atrophic and sclerotic, causing a mask-like appearance. Occasionally, the ears, arms, and hands also become sclerodermatous. The hair may be diffusely gray by adolescence, and subcutaneous fat is generally lost in childhood. Recurrent severe impetigo often develops. Seborrheic dermatitis occurs in many patients, and the associated blepharitis may lead to a diagnosis of blepharoconjunctivitis rather than ocular telangiectasia. Mottled hyper- and hypopigmentation commonly occur and, together with the telangiectasias and atrophy, can resemble the poikiloderma of radiodermatitis, actinic damage, or scleroderma. Other pigmentary changes include café-au-lait spots that may be found in a dermatomal distribution,129 multiple ephelides, and vitiligo. Hypertrichosis of the arms and legs, alopecia areata, multiple warts, atopic dermatitis, keratosis pilaris, nummular eczema, and acanthosis nigricans have also been described in association with AT. Among the most common cutaneous manifestations are noninfectious cutaneous granulomas (Fig. 143-10).129 These persistent, atrophic, and often ulcerative lesions are often mistaken for other granulomatous processes, including sarcoidosis, necrobiosis lipoidica diabeticorum, granuloma annulare, and granulomatous dermatitis.

Usually, the progressive cerebellar ataxia first becomes apparent during infancy (median age, 1.2-years-old) with swaying of the head and trunk and apraxia of eye movements, often years before skin or conjunctival abnormalities develop. In childhood, dysarthric speech, drooling, choreoathetosis, and myoclonic jerks become prominent. The diagnosis of AT is usually made at a median age of 7 years, after appearance of the mucocutaneous telangiectasia. Patients usually require a wheelchair by their teenage years.

Recurrent bacterial and viral sinopulmonary infections occur in up to 80% of patients; these are the most common cause of death, which is usually from bronchiectasis and respiratory failure. Approximately 75% of patients with AT may have growth retardation and endocrine disorders, especially ovarian agenesis or testicular hypoplasia and insulin-resistant diabetes.

Neoplasia occurs in 40% of surviving adolescents or young adults, although lymphoid malignancy has been described as the presenting sign during infancy. Most common are lymphomas (especially B cell; 200-fold increased risk) and leukemia (especially T-cell chronic lymphocytic; 70-fold increased risk).130,131 Basal cell carcinomas have been reported in young adults.

Patients with AT tend to have both humoral and cellular immunologic abnormalities. Serum IgA and IgE are absent or deficient in 70 and up to 80% of patients, respectively. Circulating anti-IgA antibodies are common in AT patients with IgA deficiency. Approximately 60% of patients have selective IgG2 and IgG4 deficiencies. Defective cell-mediated immunity is found in 70% of patients, particularly lymphopenia and deficient in vitro responses to antigens and mitogens132; T cells bearing γ/δ receptors are increased in number, while CD4+ T cells tend to be reduced.

Virtually all patients have elevated levels of α-fetoprotein (which is particularly significant after 2 years of age), and many have detectable carcinoembryonic antigen. Patients with AT often have elevated hepatic transaminases (40% to 50%), and glucose intolerance. DNA is exquisitely sensitive to X-irradiation, and patients also show an increased rate of telomere shortening. Spontaneous chromosomal abnormalities (fragments, breaks, gaps, and translocations) occur 2–18 times more frequently in patients with AT than in normal individuals and mainly involve chromosomes 2, 7, and 14. Rearrangements of chromosomes 7 and 14, and especially 14:14 translocations, seem to predict the development of lymphoreticular malignancy including leukemia. The thymus is absent or hypoplastic, and the spleen may be reduced in size.

Among techniques to confirm diagnosis are an elevated serum α-fetoprotein level in children older than 8 months of age, analysis of radio-resistant DNA synthesis (which demonstrates an abnormal S phase checkpoint), radiosensitivity testing with the colony survival assay, immunoblotting for the ATM protein, assessment of ATM kinase activity, and molecular genetic testing.

Prognosis, Clinical Course, and Treatment

Therapy for AT is supportive and includes administration of antibiotics for infection, physiotherapy for pulmonary bronchiectasis, physical therapy to prevent contractures in patients with neurologic dysfunction, and sunscreens and sun avoidance to diminish actinic-like changes. Patients should be aggressively screened for malignancy, especially after the first decade of life. Intralesional injections of triamcinolone have helped to promote healing of the painful associated ulcerations, although the lesions do not clear completely with treatment. Autopsy findings indicate that approximately 50% of the patients die from pulmonary disease, the most common cause of death. Lymphoreticular malignancies, including lymphoid leukemia, are the second most common cause of death (15% of patients with AT). The remaining patients tend to die of both pulmonary disease and malignancy. Therapeutic radiation and radiomimetic chemotherapeutic agents, especially bleomycin, may lead to extensive tissue necrosis. The administration of small doses of other chemotherapeutic drugs and low-dose, fractionated radiation is the least harmful means of managing these malignancies. In a small subset of patients with milder AT, treatment with aminoglycosides increased ATM gene function.133 Death usually occurs by late childhood or early adolescence; the oldest surviving patient died at the age of 50 years. Prenatal diagnosis is currently best achieved by DNA analysis.

Patients with defects in phagocyte function or cell killing typically present during infancy or childhood with recurrent, unusual, and/or difficult to clear bacterial infections. Infections commonly seen include those of skin or mucosa, lung, lymph nodes, deep tissue abscesses, or childhood periodontitis. The most distinctive disorders of phagocytosis and cell killing are chronic granulomatous disease (CGD), leukocyte adhesion deficiencies, hyperimmunoglobulinemia E syndrome (HIES), and the silvery hair syndromes with immunodeficiency.134 However, several disorders with neutropenia, neutrophil dysfunction, or cytokine dysfunction also lead to a decreased ability to engulf and/or kill organisms. These are reviewed in Table 143-5.

Chronic Granulomatous Disease

Epidemiology

CGD is a heterogeneous group of X-linked and autosomal recessive disorders. Ninety percent of patients with the disorder are male, and the overall incidence is 1 in 200,000 to 250,000 persons. X-linked disease with deficiency of gp91phox occurs in 70% of affected individuals with signs and symptoms manifesting in the first year of life. Individuals with autosomal recessive disease (30%) present later in life with milder signs and symptoms; 56% of these patients have a deficiency of p47phox and deficiencies in p22phox and p67phox account for the remaining cases.135

Pathogenesis

CGD is caused by defects in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme complex responsible for the generation of superoxide.136 Normal bactericidal activity after phagocytosis requires the NADPH oxidase system, which consists of NADPH, an unusual phagocyte cytochrome b (b558), and cytosolic proteins. In patients with CGD, this membrane-associated NADPH oxidase system fails to produce superoxide and other toxic oxygen metabolites. Until recently, it was thought that the oxidative metabolites themselves were solely responsible for killing intracellular organisms. A new paradigm for NADPH oxidase-mediated microbial killing suggests that the oxidative molecules act as intracellular signaling molecules, activating the release of primary granule proteins neutrophil elastase and cathepsin G inside the phagocytic vacuole that in turn are necessary to kill microbes.137 Evidence supports a dual role for NADPH oxidase, as oxidative metabolites have direct microbicidal effects.138 and activate other microbicidal pathways.

In X-linked kindreds the CYBB gene encoding the gp91phox (phagocyte oxidase) subunit of cytochrome b558 is mutated. Patients with autosomal recessive CGD are deficient in NADPH oxidase cytosolic factors (p47phox or p67phox); occasionally, the p22phox (γ subunit of cytochrome b558), which contains a docking site for p47phox, is deficient. It is thought that cytochrome b558 is the membrane attachment site for these cytosolic factors that translocate from the cytosol to the plasma membrane, assembling oxidase components to allow activation of the NADPH oxidase.

The types of microbial organisms that cause infections in patients with CGD require intracellular killing and are usually catalase-positive. Only five organisms are responsible for the overwhelming majority of infections in CGD in North America and Europe: (1) Staphylococcus aureus, (2) Serratia marcescens, (3) Burkholderia cepacia, (4) Nocardia spp., and (5) Aspergillus spp.136 The intense humoral and granulomatous responses of CGD are thought to be compensatory in the robust but ineffectual response to organisms.

Clinical Findings

Pyodermas with associated regional lymphadenopathy and dermatitis, especially around the nares and ears, usually occur during infancy and sometimes even in affected neonates. Staphylococcal abscesses are found in 40% of patients, particularly of the perianal area. Purulent inflammatory reactions may develop at sites of lymph node drainage or minor cutaneous trauma and heal slowly with scarring. Patients with CGD often develop chronic inflammatory granulomas, most commonly of the lungs and liver. Cutaneous granulomas are nodular and often necrotic. Granulomas can occlude vital structures, especially of the GI and genitourinary systems. Intraoral ulcerations resembling aphthous stomatitis, chronic gingivitis, perioral ulcers, scalp folliculitis, and seborrheic dermatitis have also been described in many patients. Female carriers for X-linked CGD do not have the increased risk of infections but may have cutaneous lesions of discoid or systemic lupus erythematosus (SLE), Jessner lymphocytic infiltration of the skin, aphthous stomatitis, granulomatous cheilitis, photosensitivity, and/or Raynaud phenomenon.139

The lymph nodes, lungs, liver, spleen, and GI tract are the most frequent areas of noncutaneous involvement. Suppurative lymphadenitis with abscess and fistula formation usually affects cervical nodes. Pneumonia occurs in almost all affected children and may lead to abscess formation, cavitation, and empyema. Hepatosplenomegaly has been reported in 80% to 90% of patients; more than 30% of patients develop hepatic abscesses, and staphylococcal liver abscesses are almost pathognomonic to CGD.

Patients with bacterial and Nocardia spp. infections tend to be symptomatic and frequently have leukocytosis, anemia, and elevated sedimentation rate. In contrast, lack of fever, normal erythrocyte sedimentation rate, and few symptoms are more common in Aspergillus spp. infections. Thus, laboratory values within normal limits do not rule out infection in a CGD patient. Patients show an increased erythrocyte sedimentation rate, hypergammaglobulinemia, leukocytosis, and mild anemia; other immune function tests are otherwise usually normal.

The diagnosis of CGD is made on the basis of assays that rely on superoxide production. The dihydrorhodamine flow cytometry-based test is currently favored and can readily identify patients or carriers of X-linked disease140; the ferricytochrome c reduction assay is another quantitative measure of the respiratory burst. The screening test for CGD is the nitroblue tetrazolium (NBT) reduction assay, in which the yellow NBT becomes insoluble, oxidized form (blue formazan) when precipitated with normal oxidative metabolism. Quantitative NBT tests and chemiluminescence assays also may be performed. Immunoblot analysis confirms the absence of the glycoprotein 91phox (gp91phox) component; because deficiency of one component of cytochrome b558 leads to absence of the other, sequencing of the gp91phox or p22phox gene is necessary if absence is noted by immunoblot analysis. Immunoblots that show the absence of p47phox or p67phox can be diagnostic.

Biopsy of cutaneous granulomas shows histiocytic infiltrates associated with foreign body giant cells and accumulation of neutrophils with necrosis. Although the histopathologic features of lupus erythematosus-like skin lesions in CGD patients and carriers may resemble those of lupus patients, immunofluorescence examination of lesional skin is usually negative.

Prognosis, Clinical Course, and Treatment

Patients with X-linked CGD, p22phox CGD and p67phox CGD tend to have a more severe clinical course compared to patients with p47phox CGD. The mean age of diagnosis of X-linked CGD is 3 years of age, and of autosomal recessive forms 8 years of age. More than 90% of patients with non-p47phox CGD have undetectable levels of superoxide production.136 Some patients will develop severe infections as early as infancy while others will unexpectedly develop a serious infection typical of CGD later during childhood.

Small foci of localized inflammation may not be associated with fever and may be difficult to detect without vigorous investigation of the lungs, liver, and bones by routine screening radiographs, scans, or ultrasound. Cultures should be performed to identify the infectious agent, and invasive procedures may be necessary to obtain adequate tissue samples. Patients with evidence of infection should be treated empirically with broadspectrum parenteral antibiotics that cover S. aureus as well as Gram-negative organisms. Intravenous therapy should be continued for at least 10–14 days, followed by a several-week course of oral antibiotics. Surgical interventions (drainage, debridement) may be required for deeper infections (Table 143-6 Trimethoprim/sulfamethoxazole therapy decreases the incidence of bacterial infection without increasing the incidence of fungal infection. Itraconazole is an effective agent for prophylaxis for fungal infections.141 Prophylactic IFN-γ has been shown to decrease the number and severity of infections without increasing the incidence of chronic inflammatory complications in both X-linked and autosomal recessive CGD.142 Use of IFN-γ is not accompanied by any measurable improvement in NADPH oxidase activity; its clinical benefit is related to enhanced phagocyte function and killing by nonoxidative mechanisms.143 Leukocyte transfusions have been used for rapidly progressive, life-threatening infections. A recent study shows a survival rate of 90% after stem cell transplantation144 and, therefore, this procedure should be considered for patient with matched related or unrelated donors and for those that have severe, life-threatening infections despite appropriate medical care. Systemic glucocorticoids have been helpful for patients with obstructive visceral granulomas. Prenatal diagnosis has been performed by the NBT slide test and now can be based on molecular analysis.

The prophylactic administration of antibiotics and IFN-γ has reduced the mortality of CGD to about 2% per patient-year for autosomal CGD and 5% for X-linked CGD.135 The most common causes of death are pneumonia and/or sepsis due to Aspergillus or B. cepacia.

Leukocyte Adhesion Deficiencies

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Laboratory Abnormalities

Prognosis, Clinical Course, and Treatment

Hyperimmunoglobulinemia E Syndrome

Epidemiology

HIES is rare (incidence 1 in 106).148 It is found equally in males and females. Most cases are sporadic or consistent with an autosomal dominant inheritance. Autosomal recessive inheritance has also been described, but patients show different associated features.

Etiology and Pathogenesis

Three different gene defects have been identified in HIES. The most common is a dominant negative mutation in signal transducer and activator of transcription 3 (STAT3)149,150 and is associated with a severe reduction of Th17 cells.151 STAT3 signals downstream of IL-6, which together with TGF-β is important for the development of Th17 cells. Autosomal recessive HIES has been shown to result from mutation in TYK2 in a single patient152 and with defects in the dedicator of cytokinesis 8 (DOCK8), which encodes for a protein that is implicated in the regulation of the actin cytoskeleton.153,154 In all three types of HIES, there is an absence of Th17 cells, demonstrating the role of this T cell differentiation pathway in immunity to bacterial and fungal organisms. The pathogenesis of other features of HIES is not well known, but probably related to the lack of response or absence of Th17 cells and the resultant cytokine abnormalities.

Clinical Findings

The clinical presentation of individual patients with HIES may vary greatly. The neonatal or infantile rash of HIES is often a papulopustular eruption with prominent crusting distributed on the scalp, face, neck, axillae, and diaper area. The most consistent finding on skin biopsy is an eosinophilic spongiotic dermatitis, sometimes centered in the dermal follicles.155 In other infants, early candidal infections of the skin, mucosae, and nails and/or infantile atopic dermatitis are alternative presentations; in patients with the eosinophilic papulopustules, the atopic dermatitis commonly follows later in infancy. Superinfection of the dermatitis with S. aureus is very common,156 and patients show high levels of antistaphylococcal IgE antibodies. Staphylococcal skin infections include impetigo, furunculosis, paronychia, cellulitis, and characteristic “cold” abscesses (see Fig. 143-11) that do not demonstrate the anticipated degree of erythema, warmth, and purulence. The abscesses occur most commonly on the head and neck and in intertriginous areas.

Pulmonary bacterial pneumonia, abscesses, and empyema are the most frequent systemic infections and may result in pneumatoceles that serve as the nidus for bacterial or fungal superinfection. The most common infecting organisms are S. aureus and H. influenzae. Other than pneumonias, deep-seated infections, bacteremia, and sepsis are rare.148

Facial and skeletal abnormalities are common. Patients develop progressive coarsening of facial features (see Fig. 143-11), probably reflecting the skeletal defects, but the recurrent facial pustulation and lichenification from dermatitis may contribute. Distinctive facial features, including prominent forehead, a broad nasal bridge, and wide nasal tip are universally present by the age of 16 years. Dental anomalies include retention of primary teeth and lack of eruption of secondary teeth. Osteopenia is common, and 57% of patients have had at least three pathologic fractures, especially of the long bones, ribs, and pelvis. Scoliosis occurs in 63% of adult patients and hyperextensibility of joints in 68% of patients.148

By definition, serum IgE levels must be elevated, but normal levels of IgE increase markedly during childhood. Levels of >2,000 IU/mL are seen in adolescents and adults; considerably lower levels during infancy are seen, given that the upper limit of normal in infants <1-year-old is 12.7 IU/mL and by 5 years of age is 47.1 IU/mL; an IgE level tenfold above the 95th percentile for age is required for diagnosis. Eosinophilia of at least two standard deviations above normal (usually above 700 cells/μL) is also a clinical manifestation. The total white blood cell count is typically normal and often fails to elevate in the setting of acute infection. The most common clinical features and laboratory values of patients with sporadic or autosomal dominant HIES are summarized in Table 143-7.

Autosomal recessive disease is characterized by recurrent bacterial and viral infections, autoimmunity and devastating neurologic complications that are often fatal in childhood (see Fig. 143-12). Patients with autosomal recessive HIES show no tendency to form pneumatoceles and have no skeletal or dental abnormalities.157 Eosinophilia tends to be more severe (e.g., 17,500/μL).148 These patients have a global defect in T cell activation, which may explain their susceptibility to viral infections (including herpes and molluscum) in addition to bacterial and fungal infections.154

Prognosis, Clinical Course, and Treatment

Given the lack of correlation between serum levels of IgE, eosinophilia, and the susceptibility to severe infections, the clinical course is difficult to predict. Patients with autosomal recessive HIES have a more severe course related to the neurologic complications.157

Antistaphylococcal antibiotics are effective for most cutaneous infections in patients with HIE, and oral triazole antifungals treat the mucocutaneous candidiasis. The prophylactic use of antistaphylococcal antibiotics markedly reduces the incidence of skin abscesses and pneumonia. The cutaneous and pulmonary abscesses often require incision and drainage and may require partial lung resections. IVIG therapy has been used successfully. IVIG may influence IgE levels due to an increased Ig catabolism or neutralization of the IgE.148 Ascorbic acid and cimetidine have decreased the number of infections and the chemotactic defect in some patients. Isotretinoin has been reported to eliminate the recurrent staphylococcal abscesses in an isolated patient without any change in immunologic status. Cyclosporine A has also been used with good clinical and laboratory response.158,159 IFN-γ has shown inconsistent effects on IgE levels and infection susceptibility. Bone marrow transplant has been attempted in typical autosomal dominant HIES with limited success.

WHIM Syndrome

WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome is an immunodeficiency that is characterized by neutropenia, hypogammaglobulinemia, and a susceptibility to infection by human papilloma virus. The disorder results from defects in the chemokine receptor gene CXCR4,160 and thus mature neutrophils are not able to exit the bone marrow (myelokathexis). The susceptibility to human papilloma virus infections suggests an important role for CXCR4 in immunity to this virus.

Silvery Hair Syndromes: ChéDiak–Higashi and Griscelli Syndromes

The silvery hair syndromes comprise a group of autosomal recessive disorders in which a peculiar metallic sheen to hair and often skin is noted (see also Chapter 73). Of these, Chédiak–Higashi and Griscelli (type 2) syndromes have associated immunodeficiency (Table 143-8). Another syndrome with silvery hair, Elejalde syndrome, does not have associated immunodeficiency and may be allelic with the myosin 5a-deficient form of Griscelli syndrome (GS), with severe associated CNS dysfunction.

ChéDiak–Higashi Syndrome

Epidemiology

Chédiak–Higashi syndrome (CHS) is a rare autosomal recessive disorder. Parental consanguinity is often reported, and there are approximately 300 reported cases worldwide.

Etiology and Pathogenesis

CHS is caused by mutations in the LYST gene, located on chromosome lq42, which encodes a protein required for the final steps of vesicle trafficking and secretion.161,162 The LYST gene is expressed in lysosomes and other secretory organelles (melanosomes, cytolytic granules, and platelet dense granules). Characteristic giant granules are thought to result from altered granule maturation and fusion.163 Enlarged melanosomes are unable to be transferred to keratinocytes. NK cells and cytotoxic T lymphocytes do not release proteolytic enzymes necessary for target cell killing. Cytotoxic T lymphocyte-associated antigen is trapped in abnormally large vesicles rather than on the cell surface and thus may be unable to regulate T-cell activation, increasing the risk of lymphoproliferative disease.164 Platelet dense granules are delayed in secretion of storage pools required for normal coagulation. Diminished chemotaxis of neutrophils and monocytes and delayed intracellular microorganism killing are often associated.

Clinical Findings

Patients usually first show manifestations during infancy or early childhood. Pigment abnormalities occur in 75% of patients, particularly the silver sheen to the hair (Fig. 143-13A). Ocular hypopigmentation may cause photophobia, and strabismus and nystagmus are common. Visual acuity does not tend to be reduced. The skin is typically fair, but dark slate-colored areas of pigmentation and diffuse speckled hypopigmentation may be seen in the sun-exposed skin of dark-skinned individuals.165

Infections can be observed in the newborn period and continue through the lifetime of the patient. Infections most commonly involve the skin, lungs, and respiratory tract where microbes such as S. aureus, Streptococcus pyogenes, and Pneumococcus are prevalent. Deep ulcerations resembling pyoderma gangrenosum have been described.

Neurologic manifestations include muscle weakness, cranial and peripheral neuropathy and progressive neurologic deterioration. CHS patients have also been observed to exhibit a mild coagulation defect. Patients bruise easily, manifest petechiae, and have some mucosal bleeding, although platelet numbers remain normal.

The finding of large cytoplasmic granules in blood leukocytes is highly diagnostic. Hair shafts have evenly distributed small pigment granules (see Fig. 143-13B), in contrast to the irregular, large pigmentary clumping of GS (see Fig. 143-13C). Skin biopsy shows pigmentary dilution in both melanocytes and keratinocytes and electron microscopy reveals giant melanosomes.

Prognosis, Clinical Course, and Treatment

Hemophagocytic syndrome, an accelerated phase of the disease that resembles lymphoma, occurs by late childhood. Hemophagocytic syndrome is characterized by widespread visceral infiltration by atypical lymphoid and histiocytic cells. This lymphoma-like stage is precipitated by viruses, particularly by EBV infection. Hepatosplenomegaly lymphadenopathy pancytopenia, jaundice, fever, a leukemia-like gingivitis, and pseudomembranous sloughing of the buccal mucosa are common features.

The hemophagocytic syndrome associated with lymphohistiocytic proliferation of silvery hair syndromes needs to be distinguished from massive lymphoproliferation in other immunodeficiency disorders, particularly X-linked lymphoproliferative disorder (see Section “Antibody Deficiency Disorders”), familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, and immunodeficiency due to mutations in the IL-2R. Familial hemophagocytic lymphohistiocytosis is a group of autosomal recessive disorders with hemophagocytosis and absence of NK cell cytotoxicity that tends to be fatal without early stem cell transplantation.166 The condition can result either from mutations in the gene that encodes perforin, which is a critical intracellular granule protein of NK cells and cytotoxic T lymphocytes, or in UNC13D, which encodes Munc 13–4, a protein that allows secretion of cytolytic granules. Mutations in several genes can lead to autosomal recessive or dominant autoimmune lymphoproliferative syndrome, also known as Canale–Smith syndrome.102,167 These include the genes that encode Fas or CD95 (TNFRSF6), the cell surface apoptosis receptor, and its ligand (TNFSF6), and the caspase proteins 8 and 10, proteases in the cascade leading to apoptosis. This group of disorders features autoimmune disorders (cytopenias, leukocytoclastic vasculitis, lupus erythematosus) and an increased risk of lymphoma, and is associated with increased numbers of circulating CD4−/CD8− α/β T cells. Immunodeficiency with extensive lymphocytic infiltration of viscera is also a manifestation of autosomal recessive mutations in the α chain of the interleukin-2 receptor.168 Patients demonstrate bacterial, viral, and fungal infections because of early apoptosis of the developing thymic T lymphocytes.

The mean age of death for patients with Chédiak–Higashi syndrome is 6 years, usually from overwhelming infection or hemorrhage during the lymphoma-like accelerated phase. Prenatal diagnosis has been achieved by examination of hair from fetal scalp biopsies and of leukocytes from fetal blood samples.

The treatment of choice for patients with Chédiak–Higashi syndrome is early transplantation, which corrects the immunologic status but does not affect the pigment abnormality nor inhibit the development of neurologic disorders that grow increasingly worse with age. Acyclovir, high-dose intravenous γ-globulin, vincristine, cyclosporine, and prednisone have been used to control the accelerated phase, but it is usually fatal. Ascorbic acid corrects the microtubular defects in vitro but has no clinical ameliorative effects.169 Interferon has been demonstrated by some authors to partially restore NK cell function.170

Griscelli Syndrome

Epidemiology

The majority of affected patients with this autosomal recessive disorder are of Mediterranean or Middle Eastern origin and born into consanguineous families.

Etiology and Pathogenesis

Mutations in three genes may underlie GS. GS1 is caused by a mutation in the MYO5A gene that encodes myosin 5a, a motor protein responsible for intracellular organelle transport. MYO5A is abundantly expressed in brain tissue and is important for neurotransmitter secretion. It is not expressed in cytotoxic cells. GS2 is caused by a mutation in the RAB27A gene, which encodes Rab27a, a guanosine triphosphatase protein involved in the function of the intracellular-regulated secretory pathway. It is essential for T and NK lymphocyte cytotoxic granule release and cell death. This defective cytotoxic activity most likely leads to the uncontrolled activation of lymphocytes and macrophages in the hemophagocytic syndrome. Both MYO5A and RAB27A have been mapped to chromosome 15q21.1.171 A third type of Griscelli syndrome (GS3) is the result of a homozygous missense mutation in Slac2-a/mlph (melanophilin, mlph) or a deletion of the MYO5A F-exon. Melanophilin (also not expressed in cytotoxic cells) encodes a member of the Rab effector family and interacts with both myosin 5a (through the F-exon) and RAB27A to form a triprotein complex essential for the capture and local transport of melanosomes to the melanocytes (Fig. 143-14).171,172 All three genetic subtypes share the inability to construct this complex for melanosome transport, thus leading to the characteristic pigmentary abnormality of GS.

Clinical Findings

The pigmentary dilution of GS is often limited to the hair, characterized by a silver-gray sheen with a few cases of skin involvement. The hair shaft shows large uneven clusters of pigment (see Fig. 143-13C) and the skin shows pigmentary dilution in keratinocytes but accumulation of melanosomes in melanocytes. Electron microscopy reveals numerous stage IV melanosomes in epidermal melanocytes. In contrast to Chédiak–Higashi syndrome, smears of leukocytes do not show giant granules. The additional clinical features present in each subtype are dependent on the function and tissue expression of the defective protein. Patients with GS1 have a primary neurologic disorder that presents in infancy with hypotonia and developmental delay. Severe immune disorder characterized by hemophagocytic syndrome or an “accelerated phase of the disease” is seen in GS2. Hemophagocytic syndrome is characterized by infiltration of various organ systems by activated lymphocytes and macrophages. It develops at mean age of 36 months, and often is precipitated by a virus, particularly EBV. Patients have fever, hepatosplenomegaly, neurologic impairment, coagulopathy, and pancytopenia.173 Patients with GS3 present solely with the pigmentary abnormalities.

Prognosis, Clinical Course, and Treatment

GS has been uniformly fatal but now can be reversed by successful hematopoietic stem cell transplantation. Eighty-five percent of patients with GS2 have mutations in the RAB27A gene that lead to early protein truncation. They have the most severe form of the disease with early development of hemophagocytic syndrome and rapid progression. The median survival from the onset of the accelerated phase to death in these patients is 5 months. Most patients die by 5 years of age secondary to progressive CNS disease or recurrent infections.173 Missense mutations in the RAB27A gene show a milder phenotype with later age of hemophagocytic syndrome onset and a good response to chemotherapy treatment.174 Patients with GS1 do not develop hemophagocytic syndrome. Prenatal diagnosis has been achieved by examination of hair from fetal scalp biopsies and DNA from leukocytes of fetal blood samples.175

Epidemiology

Etiology and Pathogenesis

Clinical Features

Direct immunofluorescence may show deposition but is more likely to be negative than in lupus unrelated to C2 deficiency. Leukopenia has been described in 50% of affected individuals and rheumatoid factor in 40%. Although most individuals with MBL deficiency show no clinical manifestations, deficiency of MBL or its associated serum protease is also associated with an increased risk of SLE, and MBL deficiency has been described with dermatomyositis. In patients with SLE, having MBL deficiency is associated with a higher risk of bacterial complications. The risk of SLE is also increased in individuals with deficiencies in C3 or regulators of the complement pathway, such as factor H or factor I (C3b inactivator). Approximately 5% of individuals with deficiency of the late complement components have evidence of immune complex or autoimmune disease, and these manifestations have not been described with properdin deficiency.

Laboratory Abnormalities

Differential Diagnosis

Treatment

HAE is almost always inherited in an autosomal dominant fashion with a spontaneous mutation rate of 25% (for clinical features and management, see Chapter 38).190 It occurs in 1 in 150,000 persons and has no racial or ethnic predilection. Seventy-five percent of patients report a positive family history. There are three types of HAE. Type I is characterized by low antigenic levels of C1 INH and affects 85% of patients, whereas the remainder of patients have Type II, with low functional levels but normal/high antigenic levels of C1 INH.191 A third type of HAE does not show a deficiency of C1 INH.192 This type of HAE was previously thought to only affect women, although recently a family was described in which three male family members were affected.193 One family has been identified in which the disease is transmitted as an autosomal recessive trait due to a mutation in the promoter region of the gene.194