Congenital immunodeficiency syndromes with cutaneous manifestations I.

Periodic synopsis This report reflects the best data available at the time the report was prepared, but caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report.

Congenital immunodeficiency syndromes with cutaneous manifestations I. Susan B. Mallory, MD,a and Amy S. Paller, MDb Little Rock, Arkansas, and Chicago, Illinois Congenital disorders of immunity are rare, particularly when compared with the growing number of infants and children with the acquired immunodeficiency syndrome (AIDS). However, the skin might be involved in primary immunodeficiency disorders as a site of infection, inflammation or specific cutaneous alterations that serve as a marker for the immunodeficiency. The purpose ofthis review is to provide a summary of some of the more common congenital genetic immunodeficiency syndromes, and to present updated information.

GENERAL 1. Textbook references A. Stiehm ER, Fulginiti VA. Immunologic disorders in infants and children. Philadelphia: WB B. C. D. E.

F.

Saunders, 1980. Excellent book, although dated. Dahl MV. Clinical immunodennatology. Chicago: Year Book, 1988. Roitt I. Essential immunology. 6th ed. Boston: Blackwell, 1988. Steele RW. Immunology for the practicing physician. Norwalk, Conn: Appleton-CenturyCrofts, 1983. Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases. Philadelphia: WB Saunders, 1987. Paller AS. Disorders of the immune system. In: Schachner LA, Hansen RC, eds. Pediatric der-

From the Departments of Dermatology and Pediatrics, University of Arkansas for Medical Sciences, Little Rock,' and Northwestern University School of Medicine, Chicago.b Reprint requests: Susan B. Mallory, MD, 51. Louis Children's Hospital, 400 S. Kingshighway Blvd., St. Louis, MO 63110.

16/1;:Z4366

matology. New York: Churchill Livingstone, 1988:93-137. II. Journal references A. Dwyer JM. Cutaneous manifestations of immunogenetic deficiency disorders. Birth Defects 1981;17:93-115. B. Stiehm ER, Chin TW, Haas A, et al. Infectious complications of the primary immunodeficiencies. Clin Immunol Immunopathol 1986;40:6986. C. Kersey JR, Shapiro RS, Filipovich All. Relationship of immunodeficiency to lymphoid malignancy. Pediatr Infect,Dis 1988;7:510-2. D. Buckley RH. ImmUnodeficiency diseases. JAMA 1987;258:2841-50. E. Good RA. Bone marrow transplantation symposium: bone marrow transplantation for immunodeficiency diseases. Am J Sci 1987; 294:68-74. F. Mensink EJBM, Schuurman RKB. Review article: immunodeficiency disease genes on the X chromosome. Disease Markers 1987;5:129-40. G. Jaret P. Our immune system. The wars within. Natl Goo June 1986:702-34. This article is an excellent review of basic immunology for the layman. The photographs and illustrations are superb. Although this article mainly talks about AIDS, it would be a good discussion for parents of children with primary ·immunodeficiencies. H. White CJ, Gallin JI. Phagocyte defects. Clin Immunollmmunopatho11986;40:50-61. Concise article with excellent tables. 1. Rosen PS, Cooper MD, Wedgwood RJP. The primary immunodeficiencies. N Engl J Med 1984;311:235-42,300-10. III. Key points A. Primary immunodeficiencies are usually associated with an undue susceptibility to infection.

Moo

1153

1154 Mallory and Paller

B. C. D. B.

Infections may be severe, frequent, complicated, prolonged, or unusual. Depending on the specific immune defect, certain infections classically occur. Patients with deficient cellular immunity usually have opportunistic viral, fungal, mycobacterial, and protozoan infections. Patients with antibody deficiencies primarily have bacterial infections particularly caused by gram-positive organisms. Disorders of phagocytosis and killing of organisms are associated with staphylococcal, gramnegative, and fungal infections. Patients with deficiencies of early complement components may have autoimmune disorders, especially lupus erythematosus, whereas patients with deficiencies of the alternate pathway complement components have recurrent neisserial infections.

ATAXIA-TELANGIECTASIA (LOUIS-BAR SYNDROME) I. Journal references A. Smith LL, Conerly SL. Ataxia-telangiectasia or Louis-Bar syndrome. J AM ACAD DERMATOL 1985;12:681-6. B. Cohen LB, Tanner DJ, Schaefer HG, et al. Common and uncommon cutaneous findings in patients with ataxia-telangiectasia. JAM ACAD DERMATOL 1984;10:431-8. C. McKinnon PJ. Ataxia-telangiectasia: an inherited disorder of ionizing-radiation sensitivity in man. Hum Genet 1987;75:197-208. D. Swift M, Reitnauer PJ, Morrell D, et al. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Moo 1987;316:1289-94. II. Key points A. Ataxia-telangiectasia is inherited as an autosomal recessive disorder characterized by (1) mucocutaneous telangiectases, (2) progressive cerebellar ataxia with degeneration ofPurkinje cells, (3) hypersensitivity of fibroblasts and lymphocytes to ionizing radiation, (4) increased incidence of cancer, (5) chromosomal rearrangements, (6) thymic hypoplasia with humoral (particularly 19Adeficiency) and cellular immunodeficiencies, (7) elevated serum levels of afetoprotein, (8) premature aging, and (9) endocrine disorders. B. The patient usually presents with ataxia in infancy, gradually becoming unable to walk. Telangiectases, most common on the bulbar conjunctivae and ears, usually de?eloped when children are between 2 and 6 years of age and become more numerous with time.

Journal of the American Academy of Dermatology

C. Other skin findings include sclerodermoid changes with loss of subcutaneous fat, gray hair, chronic seborrheic dermatitis, blepharitis, poikiloderma, eczema, vitiligo, cafe-au-lait macules, and acanthosis nigricans. Patients are more susceptible to viral infections, especially herpes simplex. D. Sinopulmonary infections with bronchiectasis are common. Pneumonia is the leading cause of death. B. Neurologic manifestations usually begin around 12 to 18 months of age with progressive ataxia. hypotonia, and dysarthria. Muscle atrophy, intention tremor, and parkinsonian-like facies develop. and a progressive decrease in intelligence may occur in one third of patients. F. Ophthalmic signs begin with telangiectases on the bulbar conjunctivae in 100% of persons, usually between the ages of 2 and 6 years. Bulbar telangiectases may be present at birth. Abnormal eye movements such as dysconjugate gaze, nystagmus, strabismus, and absence of optokinetic nystagmus develop. G. Other features include ovarian hypoplasia, testicular atrophy, gonadal dysfunction, abnormal carbohydrate metabolism. and mild hepatic dysfunction. H. Laboratory abnormalities include IgA and 19B deficiency, circulating anti-19A antibodies, defective cell-mediated immunity, anemia, lymphopenia, abnormal thymic development, and elevated levels of serum a-fetoprotein and carcinoembryonic antigen. The elevated levels of fetal proteins and poorly developed thymus suggest immaturity of mesodermal development and may be helpful for early diagnosis. I. Chromosomal breaks, especially on chromosomes 7 and 14, with defective DNA response to irradiation are common and may predispose these patients and family members to malignancies such as lymphoma, leukemia, Hodgkin's disease, and breast cancer, as well as others. Cultured fibroblasts are more sensitive to killing by ionizing radiation and radiomimetic chemicals such as bleomycin and may be more sensitive to UV light as well. J. Therapy is supportive with appropriate antibiotics. Avoidance of X irradiation and chemotherapy with radiomimetic agents is recommended. K. The gene for ataxia-telangiectasia has been • localized to the chromosome 11q22-23 region. CARTILAGE-HAIR HYPOPLASIA

I. Textbook reference A. Jones KL. Smith's recognizable patterns of hu-

Volume 23 Number 6, Part 1 December 1990

man malformation. 4th ed. Philadelphia: WB Saunders, 1988:334-5. II. Journal references A. Harris RE, Bachner RL, Gleiser S, et al. Cartilage hair hypoplasia, defective T-cell function, and Diamond-Blackfan anemia in an Amish child. Am J Med Genet 1981;8:291-7. B. Polmar SR, Pierce GF. Cartilage hair hypoplasia: immunological aspects and their clinical implications. Clin Immunol Immunopathol 1986; 40:87-93. C. Brennan TE, Pearson RW. Abnormal elastic tissue in cartilage-hair hypoplasia. Arch DermatoI1988;124:1411-4. III. Key points A. This syndrome, also called McKusick syndrome or metaphyseal chondrodysplasia (McKusick type), affects mainly old-order Amish or Finnish persons and is attributed to an autosomal recessive gene. B. Features include small stature, fine sparse light hair, relatively short limbs, mild bowing of legs at the ankles, short hands, small nails, lumbar lordosis, hyperextensible joints, soft doughy skin, and malabsorption. C. Limbs are disproportionately short. Head size is normal. Elbows cannot fully extend, but fingers are hyperextensible. D. Skeletalx:.ray films demonstrate irregularly scalloped metaphyses and a small pelvic inlet. E. Patients have a mild to severe deficiency of cellmediated immunity manifested by anergy. Antibody synthesis can be normal or moderately affected. Marked impairment of T-lymphocyte function is caused by an intrinsic defect in cell proliferation, including T cells, B cells, and fibroblasts. Proliferation-dependent mechanisms such as cell-mediated cytotoxicity and natural killer (NK)-like activity are impaired, whereas proliferation-independent NK activity is normal. F. No increased incidence of malignancy has been seen. Autoimmune hemolytic anemia, lymphopenia, thrombocytopenia, and DiamondBlackfan anemia have been described. Patients have an increased susceptibility to viral infections, such as varicella, poliomyelitis, rotavirus, and verrucae. CHEDIAK-HIGASlU SYNDROME I. Journal references A. Blume RS, Wolff SM. The Chediak-Higashi syndrome: studies in fOUf patients and review of the literature. Medicine 1972;51:247-80. Dated but excellent review. B. StegmaierOC, Schneider LA. Chediak-Higashi

Congenital immunodeficiency syndromes 1155 syndrome: dermatologic manifestations. Arch DermatolI965:91:1-9. C. Barak Y, Nir E. Chediak-Higashi syndrome. Am J Pediatr Hematol Oncol 1987;9:42-55. D. Boxer LA, Smolen !E. Neutrophil granule constituents and their release in health and disease. Hematol Oneal Clin North Am 1988;2:101-20. E. Nair MPN, Gray RH, Boxer LA, et al. Deficiency of inducible suppressor cell activity in the Chediak-Higashi syndrome. Am J Hematol 1987;26:55-66. II. Key points A. Inherited as an autosomal recessive disorder, Chediak-Higashisyndrome (CHS) is characterized by severe infections and pigment dilution of the skin and hair. B. Features include the following: 1. Frequent infections of skin, mucous membranes, and respiratory tract with both grampositive and gram-negative bacteria. Staphylococcus aureus, Streptococcus pyagenes, and S. pneumoniae are the most common organisms. 2. Pigment dilution of hair, skin, and eyes is due to an abnormal aggregation into giant melanosomes. Hair has a silvery sheen and shows clumped pigment granules on microscopic examination. 3. The eyes may show pigmentary dilution of the iris, nystagmus, photophobia, or strabismus. However, patients have normal visual activity. 4. Patients often have neurologic deterioration, resembling spinocerebellardeteriorationwith clumsiness, abnormal gait, dysesthesias, paresthesias, cranial nerve palsies, motor weakness, and sensory deficits. 5. Most patients who do not die of hemorrhage or infection have a fatal accelerated phase (lymphoproliferativedisorder) by 10 years of age, with hepatosplenomegaly, lymphadenopathy, pancytopenia, and infiltration of viscera by atypical cells. Recently, viruses, particularly the Epstein-Barr virus, have been implicated in triggering the accelerated phase. C. The diagnosis is made by finding giant abnormal lysosomal granules in circulating leukocytes, platelets, fixed melanocytes, and central nervous system neurons. The abnormal inclusions probably cause most ofthe leukocyte impairment and other cell functions. Other cell types with similar lysosomal defects include renal tubular cells, parietal gastric cells, hepatocytes, and fibroblasts. D. Patients alsodemonstrate neutropenia, depressed

Journal of the American Academy of Dermatology

1156 Mallory and Paller chemotaxis, depressed NK cell activity, reduced antibody-dependent cellular cytoxicity, and decreased bactericidal activity. E. Therapy is supportive with appropriate antibiotics. High-dose acyclovir, [-globulin, vincristine, or prednisone may be used in the lymphoproliferative phase. Cimetidine or high doses of ascorbic acid have been helpful in controlling the frequent infections in some patients. F. Bone marrow transplantation from an HLAcompatible donor before the accelerated phase is the treatment of choice and may be effective in prolonging life. CHRONIC GRANULOMATOUS DISEASE 1. Journal references A. Gatlin JI, Buescher ES, Seligmann BE, et' al. Recent advances in chronic granulomatous disease. Ann Intern Med 1983;99:657-74. B. Hitzig WH, Seger RA. Chronic granulomatous disease, a heterogeneous syndrome. Hum Genet 1983;64:207-15. C. Mouy R, Fischer A, Vilmer E, et al. Incidence, severity, and prevention of infections in chronic granulomatous disease. J Pediatr 1989;114:55560. D. ClarkRA, Malech HL, Gatlin n, et al. Genetic variants of chronic granulomatous disease: prevalence of deficiencies of two cytosolic components of the NADPH oxidase system. N Engl J Med 1989;321:647-52. E. Barton LL, Johnson CR. Discoid lupus erythematosus and X-linked chronic granulomatous disease. Pediatr DermatoI1986;3:376-9. II. Key points A. Chronic granulomatous disease (CGD) is a sexlinked disorder, which results in defects of bacterial and fungal killing by phagocytic cells. B. The main feature of CGD is the inability of polymorphonuclear leukocytes to generate oxidative metabolites, confirmed by a negative nitroblue tetrazolium test, impaired bacterial killing, absence of stimulated oxygenation, or by impaired chemiluminescence assays (testing the amount of light generated by phagocytic cells) with bacterial killing. C. Several biochemical abnormalities may account for this defect: absence of cytochrome b559, abnormal flavoproteins, low-affinity NADPH oxi· dase; or severe glucose-6-phosphate dehydrogenase deficiency. D. Recurrent infections begin in the first years of life, usually involving skin, lymph nodes, liver, lungs, bones, and gastrointestinal tract. Disseminated visceral granulomatous lesions result. E. Other features include eczematous dermatitis,

F.

G.

H.

I.

J.

cutaneous granulomas, persistent rhinitis, ulcerative stomatitis, blepharitis, keratoconjunctivitis, diarrhea, and abscesses of liver, spleen, lungs, bones, and perianal area. Sepsis and brain infection are rare. The most common organisms causing infection are S. aureus, Aspergillus. Serratia, Eschen'· chia, Pseudomonas, Proteus, Salmonella, and Candida. Aspergillus lung infections are associated with a high mortality rate. Several forms of COD have been demonstrated. Most male patients have the X-linked recessive form, with associated absence of cytochrome b559; however, autosomal recessive and autosomal dominant forms exist. Female carriers of X-linked CGD may have discoid lupus erythematosus, resulting from recurrent antigenic stimulation leading to antibody formation. Debridement of abscesses and antibiotics are the mainstay of therapy. Prophylactic antibiotics such as trimethoprim-sulfamethoxazole reduce infections but may not affect mortality. Bone marrow transplantation or transfusions with polymorphonuclear leukocytes maybe necessary in some patients. Dermatitis responds to topical corticosteroids, soaks, and oral antibiotics. Granulomatous lesions causing obstruction of vital structures may need systemic steroids to resolve.

HEREDITARY ANGIOEDEMA I. Journal references A. Guenther LC. Inherited disorders of complement. JAM ACAD DERMATOL 1983;9:815-39. B. Tappeiner G. Disease states in genetic complement deficiencies. Int J DermatolI982;21:17591. C. CoIten HR. Hereditary angioneurotic edema, 1887 to 1987. N Engl J Med 1987;317:43-5. D. Stoppa-Lyonnet D, Tosi M, Laurent J, et al. Altered C1inhibitor genes in type I hereditary angioedema. N Engl J Med 1987;317:1-6. E. Davis AE. Cl inhibitor and hereditary angioneurotic edema. AnnuRev ImmunolI988;6:595628. II. Key points A. Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a lack of quantitative or functional inhibitor of C1 esterase (Cl INH) leading to uninhibited C1, which results in uncontrolled cleavage of C4 and C2. B. The cause of the edema in the attacks is thought to be secondary to a kininlike cleavage product of C2, which increases capillary permeability. C. Nonpruritic swelling of the face, extremities, gastrointestinal tract, and upper respiratory tract

Volume 23 Number 6, Part 1 December 1990

is seen without typical urticaria. Symptoms be-

gin in childhood with localized nonpitting edema, which may be precipitated by direct trauma, anxiety, stress, menses, or infection. Abdominal pain may also occur. A potentially and not uncommon life-threatening manifestation is laryngeal edema. D. Autoimmune disorders, such as lupus erythematosus are more common, as seen in early complement component deficiencies. E. Types of HAE 1. Type 1 is characterized by low plasma concentrations of C1 INH. It is the more common form. and is due to a defective gene on chromosome 11. 2. Type 2 is less common. Normal or even elevated concentrations of a dysfunctional C1 INH are observed, probably because of a structural defect. F. Laboratory findings show the following: 1. Usually depressed C4, even during asymptomatic periods. This is a useful serum test. 2. Always depressed C2 during attacks. 3. C3 is usually normal during and between attacks. 4. CH so is a less sensitive test and may be normal or depressed. G. If C4 is low, the Cl INH should be measured. Levels less than 30% of normal or greater than 250% of normal are diagnostic. Patients with functionally inactive C1 INH need to have functional assays to detect dysfunction. H. Prophylactic therapy with antifibrinolytic agents (e.g., e-aminocaproic acid), or with androgens (e.g., danazol) may reduce the number of attacks. Fresh-frozen plasma during acute attacks may decrease the attack, but purified C 1 INH is more effective. The mortality rate is between 15% and 25%. I. Symptoms tend to diminish by the fifth or sixth decade of life, and the frequency of attacks decreases dramatically during pregnancy. DiGEORGE ANOMALY

I. Journal references A. Gidding SS, Minciotti AL, Langman CB. Unmasking of hypoparathyroidism in familial partial DiGeorge syndrome by challenge with disodium edetate. N Engl J Med 1988;319:1589-91. B. Thomas RA, Landing BH, Wells TR. Embryologic and other developmental considerations of thirty-eight possible variants of the DiGeorge anomaly. Am J Med Genet SuppI1987;3:43-66. C. Lammer EJ, Opitz JM. The DiGeorge anomaly as a developmental field defect. Am J Med Genet SupplI986;2:1l3-27.

Congenital immunodeficiency syndromes 1157 II. Key points A. The DiGeorge anomaly is defined as deficiency of the derivatives of the third branchial pouch (the thymus and inferior parathyroid glands) and/or deficiency of the derivatives of the fourth branchial pouch (superior parathyroid glands). This results in aplastic thymus and parathyroids and absence of circulating mature T cells. B. Embryonic neural crest cells participate in the development of the aortopulmonary and conotruncal septa, as well as the thymus and parathyroid glands. Manifestations range from the complete form with severe cardiac malformations and absence of affected glands to less severe forms with hypoplasia of parathyroid glands and thymus and no cardiac defect. C. Typical facial features demonstrate lateral displacement of the inner canthi, short down-slanting palpebral fissures, small ears with notched pinnae, micrognathia, hypertelorism, and short philtrum of the lip. D. Cardiac anomalies usually involve the aorta with interrupted aortic arch type B, truncus arteriosus, right aortic arch, and tetralogy of Fallot. E. Hypoparathyroidism, manifesting as hypocalcemia with or without tetany or seizures is seen. A T -lymphocyte defect results from thymic hypoplasia, which mayvary in severity. Lymphopenia, and increased susceptibility to infection, especially from Candida, cytomegalovirus, and Pneumocystis carinii, are common. B cell abnormalities are occasionally seen. F. EDTA infusion may unmask hypoparathyroidism in families with partial DiGeorge syndrome. G. DiGeorge syndrome may be inherited as an autosomal dominant trait, autosomal recessive, or sporadic. A deletion of the proximal long arm of chromosome 22 has been reported in some families. Concurrence with Zellweger syndrome and other syndromes that involve midline defects has been reported. H. Prognosis is variable and depends on severity. Fetal thymus gland transplantation, thymic epithelial transplantation, injections of thymic humoral factors, and bone marrow transplantation have met with variable success for more severe cases. Cardiac surgery can correct structural defects, and vitamin D therapy can control hypocalcemia in some cases. LEINER SYNDROME I. Textbook references A. Atherton DJ, Rook A. Leiner's disease. In: Rook A, Wilkinson DS, Ebling FJG, et aI, eds. Textbook of dermatology. 4th ed. Oxford: Blackwell, 1986:249-51.

1158 Mallory and Paller II. Journalreferen~ A. Glover MT, Atherton DJ, Levinsky RJ. Syndrome of erythroderma, failure to thrive, and diarrhea in infancy: a manifestation of immunodeficiency. Pediatrics 1988;81:66-72. B. Jacobs Je, Miller ME. Fatal familial Leiner's disease: a deficiency of the opsonic activity ofserum complement. Pediatrics 1972;49:225-32. C. Evans DIK, Holzel A, Macfarlane H. Yeast opsonizationdefect and immunoglobulin deficiency in severe infantile dermatitis (Leiner's disease). Arch Dis Child 1977;52:691-5. III. Key points A. The Leiner syndrome is a clinical disorder characterized by severe exfoliative erythroderma, se-

Journal of the American Academy of Dermatology

vere diarrhea, recurrent gram-negative and candidal infections, and failure to thrive in the first few months of life, often associated. with breastfeeding. If infants do not die of infections, their status tends to improve with time. B. It is now known that the Leiner syndrome represents the phenotype ofseveral immunodeficiency disorders. C. The variety of associated underlying defects include inadequate opsonization by polymorphonuclear leukocytes caused by dysfunctional C3 or C5, hyperimmunoglobulinemia E, hypogammaglobulinemia, or severe combined. immunodeficiency.

BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY are available to subscribers (only) for the 1990 issues from the Publisher at a cost of$55.oo ($68.00 international) for volume 22 (January-June) and volume 23 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name. volume number, and year stamped in gold on the spine, Payment must accompany all orders. Contact Mosby-Year Book. Inc,. Circulation Department, 11830 Westline Industrial Drive. St. Louis, MO 63146·3318, USA: phone (800) 325-4177, ext. 351.

Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.