and E. Richard Stiehm2
(1)
Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA
(2)
Department of Pediatric Immunology/Allergy/Rheumatology, Mattel Children’s Hospital at UCLA, UCLA Medical Center, Los Angeles, CA, USA
Keywords
ImmunodeficiencyImmunologic deficiency syndromesGenetic syndromesCongenital anomaliesImmune systemChromosome disordersInborn genetic disorders10.1 Introduction
In most primary immunodeficiencies, frequent infections and complications arising from defective immune function are the predominant clinical manifestations. Most individuals will have no phenotypic abnormalities except for those related to the immunodeficiency. In contrast, in syndromic immunodeficiencies, abnormalities in other organ systems in addition to the immune defects are significant manifestations. Many of these conditions are recognizable genetic syndromes [152].
In syndromic immunodeficiencies, the immunodeficiency may not present as the major clinical problem, and the immune abnormality may be characterized only after the underlying syndrome has been diagnosed. In addition, in some of these conditions, the immune defect may be present in only a subset of the patients. A number of genetic disorders, such as Wiskott-Aldrich syndrome and ataxia-telangiectasia, have been categorized as primary immunodeficiencies [3], but may also be considered as syndromic immunodeficiencies since such conditions have both characteristic organ dysfunction and/or dysmorphology unrelated to the immune system as well as a consistent, well-defined immunodeficiency (Table 10.1).
Table 10.1
Syndromic primary immunodeficiency diseases
Name | Gene | Extra-immune features |
|---|---|---|
1. ADA deficiency | ADA | Costochondral junction cupping/flaring |
2. Omenn syndrome | RAG1/RAG2/ARTEMIS | Erythematous dermatitis, hemophagocytosis |
3. DNA ligase IV deficiency | LIG4 | Growth failure, developmental delay |
4. NHEJ1 deficiency | NHEJ1 | Microcephaly, growth failure |
5. PNP deficiency | PNP | Neurologic findings, hemolytic anemia |
6. WHN deficiency | WHN | Congenital alopecia, nail dystrophy |
7. Wiskott-Aldrich syndrome | WASP | Severe eczematous dermatitis, thrombocytopenia, bloody diarrhea |
8. Ataxia-telangiectasia | ATM | Progressive cerebellar ataxia, telangiectasias |
9. Ataxia-like syndrome | MRE11 | Ataxia, chromosomal radiosensitivity |
10. Nijmegen breakage syndrome | NBS1 | Microcephaly, mental retardation, prenatal onset short stature, bird-like facies |
11. Bloom syndomre | RECQL3 | Short stature, sensitivity to sunlight |
12. DiGeorge syndrome | Chr 22q11/10p | Aortic arch anomalies, hypocalcemia, thymic hypoplasia, cleft palate |
13. Chediak-Higashi syndrome | LYST | Partial albinism, giant cytoplasmic granules in leukocytes |
14. Griscelli syndrome type 2 | RAB27A | Partial albinism, lymphohistiocytosis, episodic thrombocytopenia |
15. Leukocyte adhesion deficiency type 2 | FUCT1 | Severe mental retardation, seizures, growth failure, congenital disorder of glycosylation |
16. Papillon-Lefèvre syndrome | CTSC | Palmar/plantar hyperkeratosis; precocious periodontal disease, furunculosis, pyoderma |
17. Shwachman-Diamond syndrome | SBDS | Metaphyseal dysplasia, exocrine pancreatic insufficiency |
18. Anhidrotic ectodermal dysplasia with immunodeficiency (X-linked) | NEMO | Alopecia, hypo/anhydrosis, tooth anomalies |
19. Anhidrotic ectodermal dysplasia with | NFKBIA | Alopecia, hypo/anhydrosis, tooth anomalies immunodeficiency (autosomal) |
20. WHIM syndrome | CXCR4 | Warts, hypogammaglobulinemia, infection, myelokathexis |
21. Cartilage-hair hypoplasia | RMRP | Metaphyseal dysplasia, mild leg bowing, fine/sparse hair; severe varicella infection |
22. Schimke immunoosseous dysplasia | SMARCAL1 | Spondyloepiphyseal dysplasia, progressive nephropathy, pigmentary skin changes |
23. p14 deficiency | MAPBPIP | Hypopigmented skin, short stature, coarse facial features |
24. ICF syndrome | DNMT3B | Immunodeficiency, centromere instability, facial abnormalities |
25. Netherton syndrome | SPINK5 | Trichorrhexis invaginata (bamboo hair), dermatitis |
Syndromic immunodeficiencies may arise from several diverse processes, including single-gene mutations, defective embryogenesis, metabolic derangements, chromosomal abnormalities, or teratogenic disorders. Recognition of the extra-immune and immune defects will facilitate accurate diagnosis of the underlying syndrome as well as clinical management. In this chapter, we delineate syndromic immunodeficiencies that are associated with recognizable genetic syndromes. We will provide an overview of the clinical manifestations and genetic aspects of each syndrome and delineate the specific associated immune defects. While the primary immunodeficiencies will be briefly discussed, the focus of this report will be on syndromic immunodeficiencies that are not classified as primary immunodeficiencies and for which there has been recent progress in characterization of the genetic, immune, or phenotypic features. Syndromic immunodeficiencies associated with growth deficiency (disproportionate or proportionate), gastrointestinal dysfunction, cutaneous abnormalities, neurologic dysfunction, inborn errors of metabolism, chromosome instability and/or defective DNA repair, and chromosomal abnormalities of number or structure will be discussed.
Thus, a number of genetic conditions feature immunodeficiency in conjunction with other organ system involvement. This co-occurrence could arise from several different underlying mechanisms. First, the mutated gene could be directly involved in the function, regulation, or development of both the immune and non-immune systems, resulting in abnormalities of both organ systems. Second, a contiguous gene deletion could affect different genes that are located close to each other on the same chromosome. In this case, one gene critical in the function of the immune system and a second gene important for the function of the other organ system would both be altered. Third, insults during a critical window in embryological development could affect more than one organ system if both were developing at that time. Fourth, abnormalities in bone or thymic development could affect development of immune cells by providing an inhospitable environment. Last, exposure to toxic metabolites could disrupt the immune response and activity.
Recognition of an underlying syndrome is critical for optimal clinical care so that both the immune system and the other involved organ systems can be properly treated or even diagnosed before clinical symptoms arise. For a child with a recognizable genetic syndrome that is associated with immunodeficiency, it is important to establish if the immune defect is present so appropriate treatment can be undertaken. Monitoring for laboratory or clinical evidence of immunodeficiency would also be beneficial even if the patient does not currently show symptoms of the immunodeficiency since it could develop later. Alternatively, for a child with an immune defect and other anomalies, it is vital to determine if the other malformations fit into a recognizable pattern. This will aid in giving accurate prognosis for the immunodeficiency and other involved organ systems, including cognitive development. In addition, ascertainment of the underlying diagnosis may have implications for the medical care and genetic counseling for other family members.
There are additional conditions that feature both immunodeficiency and other organ system involvement that are not presented in this chapter. We have chosen to focus on those conditions which are relatively more common and in which both the immune defect and the extra-immune manifestations are present in a substantial proportion of patients. The inheritance pattern of each condition and the chromosomal location of the disease-related genes, when known, are indicated in the tables. Online Mendelian Inheritance in Man (OMIM) [171] numbers are indicated within parentheses in the text.
10.2 Syndromes Associated with Growth Deficiency
Several immunodeficiency states are associated with growth deficiency (Table 10.2). The growth deficiency may be due to a skeletal dysplasia, in which there is an abnormality of bone formation. Many skeletal dysplasias are associated with disproportionate short stature (the limbs and trunk are not proportional to each other). Forms of short stature that are not associated with skeletal abnormalities usually show proportionate growth failure. In this case, the overall height is small, but the various body parts are commensurate with one another. Short-limb skeletal dysplasia is a form of disproportionate short stature that affects the limbs more than the trunk.
Table 10.2
Syndromic immunodeficiencies associated with growth deficiency
Name | Inheritance (Chromosome) | Associated features | Immune defect | Frequency of ID |
|---|---|---|---|---|
Disproportionate short stature | ||||
1. Cartilage-hair hypoplasia | AR (9p13) | McKusick type metaphyseal dysplasia, mild leg bowing, fine/sparse hair; varicella and other infections, increased risk for lymphoma/basal cell carcinoma | T, B | ++++ |
2. Schimke immunoosseous dysplasia | AR 2q34-q36 | Spondyloepiphyseal dysplasia, progressive nephropathy, episodic lymphopenia, pigmentary skin changes | T | ++++ |
3. Short-limb skeletal dysplasia with immunodeficiency | AR | Short-limb skeletal dysplasia, metaphyseal dysplasia, may be associated with adenosine deaminase deficiency or Omenn syndrome; heterogeneous | T, B | ++++ |
4. Roifman syndrome | ?XL | Spondyloepiphyseal dysplasia, retinal dystrophy | B | ++++ |
5. SPENCD1 syndrome | AR (19p13) | Radiolucencies in vertebral bodies and long bone metaphyses | T | ++++ |
Proportionate short stature | ||||
6. Growth hormone pathway defects (including STAT5b) | Various | Defects in growth hormone synthesis or sensitivity deficiency; sinopulmonary infections | B, T, NK | + |
7. Kabuki syndrome | ?AD | Long palpebral fissures, prominent eyelashes, skeletal anomalies, congenital heart disease; increased risk of autoimmune diseases | B | +++ |
8. CHARGE association | ? | Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness | T | + |
9. Rubinstein-Taybi syndrome | AD (16p13) | Broad thumbs and halluces, prominent nasal septum below ala nasi, cryptorchidism, mental retardation | T | + |
10. Mulvihill-Smith syndrome | ?AD | Prenatal growth deficiency, microcephaly, small face, premature aging, multiple nevi, mental retardation | T, B | ++++ |
11. Cornelia de Lange syndrome | AD (various) | Growth and psychomotor retardation, synophrys, limb anomalies, congenital heart disease | T, B | +++ |
12. Smith-Magenis syndrome | AD (17p11.2) | Growth and psychomotor retardation, sleep disturbances, characteristic facial appearance | B | ++ |
13. Bernard syndrome | AR (8q11) | Growth failure, microcephaly, glucocorticoid deficiency | NK | ++++ (1 kindred) |
Primary Immunodeficiencies Associated with Disproportionate Short Stature
10.2.1 Cartilage-Hair Hypoplasia
Cartilage-Hair Hypoplasia (CHH, OMIM#250250), a recognized primary immunodeficiency, is characterized by short-limb dwarfism, fine sparse hair, and a cellular immune defect. Varicella infections can be severe. Metaphyseal dysplasia (flared, scalloped, and sclerotic metaphyseal ends) most frequently affects the lower extremities. There is significant variability in the phenotype, and some individuals have normal hair and some may have normal immune function. The condition is caused by mutations in the RMRP gene, which encodes a mitochondrial RNA-processing endoribonuclease [186]. Please see Sect. 2.11 for more details.
10.2.2 Schimke Immunoosseous Dysplasia
This condition (OMIM#242900) is associated with short stature with exaggerated lumbar lordosis, spondyloepiphyseal dysplasia, defective cellular immunity, and progressive renal failure [16, 194]. Patients develop proteinuria and may progress to end-stage renal disease, and an arteriopathy with cerebral infarcts and/or ischemia may be seen. Mutations in the gene encoding the chromatin remodeling protein SMARCAL1 have been detected in affected patients [17]. Patients are prone to viral and bacterial infections and demonstrate decreases in CD4 T cell number, mitogen-induced proliferation, and delayed cutaneous hypersensitivity responses, and immunoglobulin levels are often abnormal [16]. Please see Sect. 2.11 for more details.
Other Immunodeficiencies Associated with Disproportionate Short Stature
10.2.3 Short-Limb Skeletal Dysplasia with Combined Immunodeficiency
The conditions (OMIM#200900) in which short-limb skeletal dysplasia is associated with combined immunodeficiency are etiologically heterogeneous [221]. While some of these patients have adenosine deaminase deficiency, other patients have more severe metaphyseal changes than are typically found in adenosine deaminase deficiency. Short-limb skeletal dysplasia may also be seen in association with Omenn syndrome, a fatal disorder characterized by eosinophilia, skin eruptions, and reticuloendotheliosis. Please see Sect. 2.4 for more details on Omenn syndrome. Both adenosine deaminase deficiency and Omenn syndrome are classified as primary immunodeficiencies.
10.2.4 Roifman Syndrome
This condition (OMIM#300258) is characterized by microcephaly, growth retardation, spondyloepiphyseal dysplasia, developmental delay, and retinal dystrophy [46, 190]. They had low/absent antibody titers in response to infection, decreased isohemagglutinins, and decreased mitogenic response to Staphylococcus aureus Cowan A. T cell number and function were normal. There was epiphyseal dysplasia of the hips and long bones and vertebral anomalies. Because all reported patients have been male, X-linked recessive inheritance has been suggested.
10.2.5 SPENCDI Syndrome
Spondyloenchondrodysplasia (SPENCD, vertebral dysplasia with enchondroma-like lesions in the long bones) with immune dysregulation (SPENCDI) has been associated with autoimmune conditions, neurologic deficits, combined immunodeficiency (low specific antibody titers, T-cell mitogenic response, and CD4 T cell count), and recurrent infections (OMIM#607944) [183, 191]. This syndrome is due to mutations in the ACP5 gene, encoding an acid phosphatase [20, 129].
Syndromic Immunodeficiencies Associated with Proportionate Short Stature
10.2.6 Growth Hormone Pathway Defects (Including STAT5b)
Patients with defects in the growth hormone pathway as well as immunodeficiency have been described. In patients with growth hormone deficiency (GHD) with X-linked agammaglobulinemia (XLA) (OMIM#307200), individuals have recurrent sinopulmonary infections, short stature, and decreased growth hormone levels without other endocrinologic abnormalities [68]. Both B cell number and immunoglobulin levels are greatly decreased or absent, consistent with XLA. T cell number and function are normal. Mutations in the gene BTK, the gene associated with isolated XLA, have been detected in some but not all patients with GHD and XLA [1, 57, 207]. Please see Sect. 3.2 for more details.
Additional immune defects reported in association with isolated GHD include combined immunodeficiency [139, 213], decreased NK activity [111], and hypogammaglobulinemia [166]. However, the vast majority of children with GHD do not display an increased susceptibility to infection [31, 206].
Some patients with growth hormone insensitivity were found to have a mutation in the STAT5B gene, which is involved in both the growth hormone and IL-2 signaling pathways. Immune defects have included decreased regulatory T cells, T cell lymphopenia, low NK and γδT cells, and decreased proliferation to mitogen [11, 118]. These patients may have recurrent skin and respiratory infections, and T cell lymphopenia, decreased regulatory T cells, low NK and CD4 T cell numbers, and decreased proliferation to mitogens have been noted [11, 118].
10.2.7 Kabuki Syndrome
This syndrome (OMIM#147920) features short stature, congenital heart disease, developmental delay, skeletal anomalies, and cleft palate [163]. The distinctive facial features include long palpebral fissures with eversion of the lower lateral eyelid, prominent eyelashes, and abnormal ears. Frequent infections occur in approximately 60 % of patients [30]. Hypogammaglobulinemia, including decreased IgG and very low IgA, is a common manifestation [95]. Autoimmune conditions, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and hypothyroidism, have also been reported [108, 151] and may reflect the underlying immune dysfunction. Most patients have a mutation in MLL2 [88, 162], and a few patients have a KDM6A mutation [130, 153]. Both genes encode proteins involved in histone modification.
10.2.8 CHARGE Association
The abnormalities that comprise the CHARGE association (OMIM#214800) include coloboma, heart defects, atresia of the choanae, retardation of growth and development, genital hypoplasia, and ear anomalies and/or deafness [172, 214]. Some patients with CHARGE syndrome have mutations in CHD7, which encodes the chromodomain helicase DNA-binding protein-7 [104, 230] or in SEMA3E, encoding sempahorin-3E [126] Some patients with CHARGE association also have DiGeorge sequence. T cell defects can range from severe to mild, and isolated low Ig levels have also been reported [239].
10.2.9 Rubinstein-Taybi Syndrome
Rubinstein-Taybi syndrome (OMIM#180849) is characterized by broad thumbs and great toes, characteristic facial features, short stature, mental retardation, and cardiac abnormalities. There is an increased susceptibility to infection. Decreased T cell number, impaired delayed cutaneous hypersensitivity response [187], lymphopenia, thymic hypoplasia [112], poor response to pneumococcal vaccine [227], and a deficit in polysaccharide antibody response [160] have been reported. Microdeletions and truncating mutations in the gene encoding CREB-binding protein (CBP), a histone acetyltransferase, are associated [176, 196]. Mutations in the gene EP300, which also encodes a transcriptional coactivator, have also been detected [189].
10.2.10 Mulvihill-Smith Syndrome
This disorder (OMIM#176690) is characterized by pre- and postnatal growth retardation, multiple pigmented nevi, microcephaly, reduced facial fat, genitourinary anomalies, and a high-pitched voice [45, 157]. Infectious complications are common, and the immunodeficiency is often progressive. Impaired T cell response to mitogen, decreased CD4 count, and/or low Ig levels have been described [9, 45, 66, 165].
10.2.11 Cornelia de Lange Syndrome
This autosomal dominant condition (OMIM#122470) is characterized by pre- and post-natal growth failure, mental retardation, upper limb defects, congenital heart disease, and characteristic facial features (including synophrys, long eyelashes, ptosis). Chronic respiratory infections, pneumonia, and sinusitis commonly occur, and infections and sepsis may account for 13 % of deaths [197]. Hypogammaglobulinemia was detected in 9 of 27 patients, and there was a significantly decreased percentage of regulatory T cells and T follicular helper cells [106]. Five different genes have been reported in association with Cornelia de Lange syndrome, with mutations in the gene encoding NIPBL being the most common [47, 122, 216]. All of the identified genes (NIPBL, SMC1A, SMC3, RAD21, HDAC8) play a role in the cohesin complex, which is important for chromosome segregation in mitosis. In immune cells, cohesin may also play a role in transcriptional regulation and V(D)J recombination [198].
10.2.12 Smith-Magenis Syndrome
This autosomal dominant condition (OMIM#182290) is associated with mental retardation, sleep abnormalities, and cardiac and renal abnormalities, and a characteristic facial appearance (including midface hypoplasia, prognathism). Low serum immunoglobulin levels have been reported in 23 % [82], and chronic ear infections are reported in the majority of patients [13]. Approximately 90 % of patients have an interstitial deletion in chromosome region 17p11.2, and a few patients have mutations in the RAI1 gene (retinoic acid–inducible 1), which lies within the associated 17p11.2 region [13, 200]. The gene encoding TACI (transmembrane activator and CAML interactor) is in the commonly deleted region, and TACI is important for B cell differentiation and maturation. Patients with Smith-Magenis syndrome with a TACI deletion had reduced TACI expression, and patients with the lowest TACI expression had significantly decreased antibody response to pneumococcal vaccine [29]. Thus, it is likely that deletion of one copy of TACI contributes to the humoral immunity abnormalities. Of note, mutations in TACI have also been found in 8–10 % of patients with common variable immunodeficiency (CVID) [25, 192].
10.2.13 Bernard Syndrome
This condition is associated with pre- and post-natal growth failure, microcephaly, glucocorticoid deficiency, and hypoglycemia (OMIM#609981) [10]. DNA repair defects have also been noted [24]. Patients have less than 5 % of normal NK cell number and have recurrent respiratory infections. Mutations in MCM4, encoding a protein involved in DNA replication, were reported [77, 99].
10.3 Syndromes Associated with Gastrointestinal Dysfunction
Gastrointestinal abnormalities may lead to malnutrition and secondarily result in an immunodeficient state. However, in the syndromes described herein, the immunodeficiency precedes nutritional deprivation and thus is likely to be intrinsic to each condition (Table 10.3).
Table 10.3
Syndromic immunodeficiencies associated with specific organ dysfunction
Name | Inheritance (Chromosome) | Associated features | Immune defect | Frequency of ID |
|---|---|---|---|---|
Gastrointestinal | ||||
1. Shwachman-Diamond syndrome | AR (7q11) | Metaphyseal dysplasia, exocrine pancreatic insufficiency, cyclic neutropenia; hematologic malignancy | B, Ph | ++++ |
2. Familial intestinal polyatresia | AR (2p21) | Multiple atresias from pylorus to rectum | T, B | ++ |
3. Trichohepatoenteric syndrome | AR (5q15, 6p21) | Severe infantile diarrhea, hepatic cirrhosis, Trichorrhexis nodosa, characteristic facies | B, Ph | ++++ |
Dermatologic – primary immunodeficiencies | ||||
1. Wiskott-Aldrich syndrome | XL (Xp11) | Severe eczematous dermatitis, thrombocytopenia, bloody diarrhea, recurrent infection; lymphoreticular malignancy; autoimmune disease | T, B | ++++ |
2. Chediak-Higashi syndrome | AR (1q42) | Partial abinism, leukopenia, neuropathy, giant cytoplasmic granules in leukocytes; bacterial infections (especially Staphylococcus, Streptococcus) | Ph, NK | ++++ |
3. Griscelli syndrome, type 2 | AR (15q21) | Partial albinism, frequent pyogenic infections, lympho-histiocytosis, episodic thrombocytopenia | T, B, NK, Ph | ++++ |
4. Hermansky Pudlak syndrome, type 2 | AR (5q14) | Oculocutaneous albinism, platelet defects, congenital neutropenia | T, NK, Ph | ++++ |
5. p14 deficiency | AR (1q22) | Hypopigmented skin, short stature, coarse facies | T, B, Ph | ++++ |
6. Vici syndrome | AR (18q) | Agenesis corpus callosum, cataracts, seizures, cutaneous hypopigmentation, cleft lip/palate, cerebellar hypoplasia | T, B, Ph | ++++ |
7. Omenn syndrome | AR (11p13) | Erythematous dermatitis, eosinophilia, lymphadenopathy, hemophagocytosis; severe combined immune deficiency | T, B | ++++ |
8. WHN deficiency | AR (17q11-q12) | Congenital alopecia, nail dystrophy | T | ++++ (2 sibs) |
9. Papillon-Lefèvre syndrome | AR (11q14) | Palmar/plantar hyperkeratosis; precocious periodontal disease, furunculosis, pyoderma | Ph | + |
10. WHIM syndrome | AD | Warts, hypogammaglobulinemia, infection, myelokathexis | T, B, Ph | ++++ |
11. Hypohidrotic/anhidrotic ectodermal dysplasia | XL, AD (Xq28, 14q13) | Alopecia, hypo/anhidrosis, tooth anomalies; with immunodeficiency, hypogammaglobulinemia | T, B | ++++ |
12. Poikiloderma with neutropenia | AR (16q21) | Poikiloderma, progressive erythematous rash, telangiectasias | Ph | ++++ |
13. Dyskeratosis congenita | XL, AR, AD (Xq28) | Atrophy and pigmentation of skin, nail dystrophy, leukoplakia of oral mucosa; risk of cancer of the mouth, anus, skin | T, B, Ph | ++ |
14. Netherton syndrome | AR (5q32) | Trichorrhexis invaginata (bamboo hair), ichthyosiform dermatitis, atopic diathesis; skin infections | T, B, Ph | ++ |
Dermatologic – other syndromic immunodeficiencies | ||||
15. Incontinentia pigmenti | XL (Xq28) | Erythematous vesiculobullous eruptions, CNS involvement, swirling macules of hyperpigmentation | T, B, Ph | + |
16. OLEDAID syndrome | XL (Xq28) | Anhidrotic ectodermal dysplasia, osteopetrosis, lymphedema | B | ++++ (2 cases) |
17. Acrodermatitis enteropathica | AR (8q24) | Vesiculobullous dermatitis, alopecia, diarrhea; due to zinc deficiency, may be associated with opportunistic infections | T, B, Ph | ++ |
18. Keratitis-Ichthyosis-Deafness (KID) syndrome | AD (13q12) | Hypervascular keratitis, ichthyosis, sensorineural hearing loss, corneal defects | T, B, Ph | ++ |
19. PLAID and APLAID syndromes | Cutaneous abnormalities; other organ involvment and autoimmunity in APLAID | B, NK | ++++ | |
20. Epidermodysplasia verruciformis | AR (various), AD, XL | Warts, increased skin cancer risk, papillomavirus infection | T | ++++ |
Neurologic | ||||
1. Høyeraal-Hreidarsson syndrome | XL, AR (Xq28, 20q13) | Cerebellar hypoplasia, absent corpus callosum, microcephaly, growth failure, pancytopenia; fungal sepsis | T, B, Ph | ++++ |
2. Cohen syndrome | AR (8q22-q23) | Prominent central incisors, hypotonia, obesity; gingivitis, periodontitis, skin infections | Ph | ++ |
3. Myotonic dystrophy | AD (19q13, 3q) | Myotonia, muscle wasting, cataract, hypogonadism, cardiac arrhythmia; due to triplet repeat expansion | B | ++ |
Primary Immunodeficiencies Associated with Gastrointestinal Dysfunction
10.3.1 Shwachman-Diamond Syndrome
This autosomal recessive syndrome (OMIM#260400) presents with pancreatic insufficiency, neutropenia, and metaphyseal dysostosis resulting in short stature. Neutropenia (which may be intermittent or cyclic) occurs in 88 %, and leukopenia and/or pancytopenia may arise [138, 203]. The condition is caused by mutations in SBDS, which is involved in ribosomal function [19]. Please see Sect. 4.14 for more details.
Other Syndromic Immunodeficiencies Associated with Gastrointestinal Dysfunction
10.3.2 Familial Intestinal Polyatresia
Multiple atretic lesions are found throughout the gastrointestinal tract in this condition (OMIM#243150). Severe combined immunodeficiency and other immune defects (e.g., hypogammaglobulinemia, T cell lymphopenia, and marked lymphoid depletion in the thymus and peripheral lymphoid tissues) have been described in some affected patients [5, 35, 204], as well as in some cases of duodenal atresia [155]. Adenosine deaminase activity is normal. The recurrent infections were not due to the intestinal problems since they occurred while the patients still had good nutritional status. Mutations in the tetratricopeptide repeat (TPR) domain 7A gene TTC7A were detected in children with autosomal recessive multiple intestinal atresia [28, 193].
10.3.3 Trichohepatoenteric Syndrome
This condition (OMIM#222470) is characterized by severe infantile diarrhea, dysmorphic features (hypertelorism, prominent forehead, flat/broad nose), hepatic cirrhosis, and the hair abnormality of trichorrhexis nodosa. Immune defects may include poor response to vaccination with negative skin tests [78], pancytopenia [127], and hypogammaglobulinemia [63]. Severe infection, including sepsis, pneumonia, and CMV hepatitis, often occurs. Cardiac defects, developmental delay, and large platelets with thrombocytosis may be present [91]. Mutations in TTC37, which encodes an uncharacterized tetratricopeptide repeat protein, thespin, have been detected [220].
Another trichohepatoenteric syndome also associated with severe diarrhea in infancy, trichorrhexis nodosa of the hair, and immunodeficiency (low immunoglobulin levels and poor response to vaccines) is caused by mutations in SKIV2L, which encodes a cytoplasmic exosome cofactor [64].
10.4 Syndromes Associated with Cutaneous Abnormalities
While dermatitis or skin infection often occur in immune deficient patients, some immunodeficiency syndromes present with primarily cutaneous manifestations (Table 10.3). Some of these conditions present with alterations in pigmentation.
Primary Immunodeficiencies Associated with Cutaneous Abnormalities
10.4.1 Wiskott-Aldrich Syndrome
This well-defined X-linked primary immunodeficiency (OMIM#301000) is characterized by chronic eczema, thrombocytopenia (with small, defective platelets), and bloody diarrhea. Recurrent and life-threatening infections are a leading cause of death [210]. Abnormal humoral immune responses are typical. The disease phenotype is very variable. Mutations in the WAS gene, encoding WAS protein (WASP), have been detected [49]. A patient with features of Wiskott-Aldrich syndrome had mutations in WIPF1, which encodes WASP interacting protein (WIP) [128]. Please see Sect. 9.14 for more details.
10.4.2 Chediak-Higashi Syndrome
Chediak-Higashi syndrome (OMIM214500) presents with recurrent bacterial infections (especially with S. aureus and streptococci), partial oculocutaneous albinism, prolonged bleeding time, nystagmus, and neuropathy. Most patients eventually develop a distinctive lymphoproliferative disorder characterized by generalized lymphohistiocytic infiltrates, which are difficult to treat. The defective gene, LYST, encodes a regulator of lysosomal trafficking [159]. Please see Sect. 5.4 for more details.
10.4.3 Griscelli Syndrome, Type 2
This is an autosomal recessive syndrome of partial albinism, neutropenia and thrombocytopenia, and lymphohistiocytosis (OMIM#214450) [56, 84, 141]. Melanosomes accumulate in melanocytes, resulting in large clumps of pigment in hair shafts. Most patients suffer from recurrent and severe fungal, viral, and bacterial infections. T cell dysfunction, hypogammaglobulinemia, and neutropenia have been reported [56]. Mutations in the RAB27A gene, which encodes a GTP-binding protein of the Ras family, were detected in affected individuals [149]. A genetically distinct form of Griscelli syndrome that is not associated with immune deficits has also been described (type 1) [149, 175]. Please see Sect. 5.5 for more details.
10.4.4 Hermansky-Pudlak Syndrome, Type 2
This autosomal recessive condition (OMIM#608233) is characterized by platelet defects leading to a hemorrhagic diathesis and oculocutaneous albinism. Microcephaly, abnormal hair, nystagmus, and mild mental retardation may also occur [121]. Congenital neutropenia is a distinguishing feature of Type 2 compared to other forms of Hermansky-Pudlak syndrome. Recurrent bacterial infections often occur. Defective cytotoxic T cell activity [33], decreases in NK cell number and activity [69, 105], and lymphohistiocytosis have also been described [61]. Mutations in the gene encoding the beta-3A subunit of the AP3 complex (AP3B1) have been described [48]. Please see Sect. 5.6 for more details.
10.4.5 p14 Deficiency
A syndrome of hypopigmented skin, short stature, coarse facial features, and recurrent respiratory infections was described in four members of a kindred who had consistently low neutrophil counts (OMIM#610798) [18]. Decreased CD8 cytotoxic T cell activity and abnormal B cell differentiation were also present. Deficiency of the endosomal adaptor protein p14 (the MAPBPIP gene) was identified, and functional reconstitution of granule activity was achieved with p14 gene transfer [18]. Please see Sect. 5.7 for more details.
10.4.6 Vici Syndrome
This autosomal recessive syndrome features agenesis of the corpus callosum, bilateral cataracts, seizures, cleft lip/palate, cerebellar hypoplasia, and cutaneous hypopigmentation (OMIM#242840). Patients often suffer from recurrent respiratory and other infections and chronic mucocutaneous candidiasis. The immune deficiency is variable, and defects may include decreases in T cell number, response to mitogen, and delayed type hypersensitivity; hypogammaglobulinemia; or leukopenia [67]. The condition is due to mutations in the EPG5 gene, which plays a role in regulation of autophagy [43]. Please see Sect. 5.7 for more details.
10.4.7 Omenn Syndrome
This autosomal recessive form of familial histiocytic reticulocytosis (OMIM#267700) presents with an erythematous skin rash, eosinophilia, reticulosis, hepatosplenomegaly, protracted diarrhea, alopecia, and lymphadenopathy. A characteristic severe combined immunodeficiency leads to failure-to-thrive, recurrent infection, and premature death. Mutations in genes encoding either of three proteins that play a role in V(D)J recombination, RAG1, RAG2, or Artemis (DCLRE1C) cause Omenn syndrome with SCID [58, 226]. Additional genes are associated with familial hemophagocytic lymphohistiocytosis (PRF1, UNC13D, STX11, STXBP2) [143]. Please see Sect. 2.4 for more details.
10.4.8 WHN Deficiency
Siblings with congenital alopecia, nail dystrophy, and T cell dysfunction (OMIM#601705) [178] were found to have a mutation in the gene WHN (FOXN1), or winged-helix nude [70]. Mutations in the mouse ortholog cause the “nude” phenotype of abnormal hair growth and abnormal thymus development [161]. Please see Sect. 2.10 for more details.
10.4.9 Papillon-Lefèvre Syndrome
This is an autosomal recessive disorder associated with palmar-plantar hyperkeratosis and severe periodontal disease leading to loss of both primary and permanent teeth (OMIM#245000). Approximately 17 % of cases are associated with infections other than periodontal disease, most frequently furunculosis and pyoderma [222]. Neutrophil chemotaxis and random movement are both decreased. Mutations in the gene encoding cathepsin C (CTSC) have been demonstrated [89, 90]. Please see Sect. 4.11 for more details.
10.4.10 WHIM Syndrome
WHIM syndrome (OMIM#193670) is associated with multiple warts, hypogammaglobulinemia, infection, and myelokathexis (bone marrow retention of neutrophils) [80, 235]. Neutrophil count is reduced, B cell number and IgG and IgA levels are mildly decreased, and depressed T cell number and diminished response to mitogens and skin tests have been noted. Mutations in the gene encoding the chemokine receptor CXCR4 were detected [93]. Please see Sect. 6.8 for more details.
10.4.11 Hypohidrotic/Anhidrotic Ectodermal Dysplasia
A subset of patients with the form of ectodermal dysplasia associated with diminished or absent sweat glands, thin and sparse hair, and hypodontia also has immune defects (HED-ID, OMIM#300291). The subset with immune defects is genetically distinct from those forms without immune defects. The most common immune defect is hypogammaglobulinemia [53, 246]. The X-linked recessive form is due to mutations in the NEMO gene, which is involved in NF-κB regulation [53, 246]. Mutations in this gene have also been described in incontinenia pigmenti and OLEDAID syndrome (see below) An autosomal form of HED-ID with T cell defects and abnormal immunoglobulin levels has been described [148]. The condition is due to mutations in the NFKBIA gene, which encodes an inhibitor of NF-κB [38].
HED can also occur with X-linked hyper-IgM immune deficiency (XHM) that is genetically distinct from isolated XHM. Patients with ectodermal dysplasia (ED) and XHM have normal CD40L expression on T cells. Two patients with XHM-ED and decreased IgG levels had a mutation in the NEMO gene [100]. Please see Sect. 6.2 for more details.
10.4.12 Poikiloderma with Neutropenia
This disorder (OMIM#604173) is characterized by a progressive erythematous rash which begins in infancy and the development of telangiectasias [34]. Neutropenia and neutrophil dysfunction are variably present, and recurrent pneumonias often occur. The condition is caused by mutations in the USB1 (C16ORF57) gene, encoding U6 snRNA biogenesis 1 [231].
10.4.13 Dyskeratosis Congenita
Dyskeratosis congenita (OMIM#305000) is an X-linked disorder marked by reticulate skin pigmentation, nail dystrophy, leukoplakia of the oral mucosa, aplastic anemia, and an increased risk of malignancy. Progressive bone marrow failure develops in most patients and is the major cause of early mortality. Neutropenia occurs in the majority of the patients, and both humoral and cellular immune responses may be defective [54, 205]. Thymic aplasia was reported in two patients [218]. The gene causing dyskeratosis congenita (DKC1) codes for a protein that is predicted to function in ribosome formation [92]. Mutations in this gene also cause Høyeraal-Hreidarsson syndrome (see below). Please see Sect. 9.17 for more details.
10.4.14 Netherton Syndrome
The triad of trichorrhexis (brittle “bamboo” hair), ichthyosiform erythroderma, and atopic diathesis make up the Netherton syndrome (OMIM#256500), an autosomal recessive disorder. Recurrent infections occur in 28 %, most commonly involving the skin [83, 209]. IgG abnormalities (both hypo- and hyper-IgG) are present in 12–14 %. Impairment of delayed cutaneous hypersensitivity response, mitogen response, and neutrophil phagocytosis can occur. Immunoglobulin supplementation can result in clinical improvement [184]. Mutations in the gene SPINK5, which encodes a serine protease inhibitor, have been detected in affected patients [27]. Please see Sect. 9.16 for more details.
Other Syndromic Immunodeficiencies Associated with Cutaneous Abnormalities
10.4.15 Incontinentia Pigmenti
Linear erythematous vesiculobullous lesions that evolve into hyperpigmented swirling macules on the trunk and proximal extremities are typical findings for this X-linked dominant neurocutaneous disorder with fetal lethality in most affected males (OMIM#308300). Other findings include mental retardation, seizures, alopecia, ocular abnormalities, nail dystrophy, and malformed teeth. In a review of 77 cases, 13 % had significant infection, and 4 died of infectious causes [50]. No consistent immunologic abnormality has been detected, but decreased neutrophil chemotaxis and impaired proliferative response to phytohemagglutinin have been described [101, 150]. Another girl had transient immunodeficiency that resolved, likely due to progressive selection against cells carrying an active mutated X chromosome [144]. Mutations in the gene encoding IKKγ, also termed NEMO, cause incontinentia pigmenti [201]. The protein is involved in the regulation of the transcriptional regulator nuclear factor-κB (NF-κB). Interestingly, mutations in this gene cause other forms of ectodermal dysplasia associated with immune defects: hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID), a primary immunodeficiency, and OLEDAID syndrome (see below).
10.4.16 OLEDAID Syndrome
Two male patients with osteopetrosis, lymphedema, ectodermal dysplasia, anhidrotic type, and immune deficiency (OLEDAID, OMIM#300301), were born from mothers with mild incontinentia pigmenti [53]. Both had multiple infections and died from infectious causes. The inflammatory response was poor, and isohemagglutinin titers and titers to Pneumococcus (despite documented infection) were decreased. Both patients had a mutation in NEMO [53]. Overall, four X-linked clinical syndromes are associated with mutations in NEMO (incontinentia pigmenti (IP), HED-ID, OLEDAID, XHM-ED).
10.4.17 Acrodermatitis Enteropathica
Acrodermatitis enteropathica (OMIM#201100) is an autosomal recessive disorder characterized by diarrhea, dermatitis, and alopecia is due to inadequate zinc metabolism. Severe infection with opportunistic pathogens occurs frequently and recurrent infection occurs in 30 % [224]. Decreased response to phytohemagglutinin and abnormal delayed cutaneous hypersensitivity skin response is typical [168]. Hypogammaglobulinemia and defective chemotaxis of neutrophils and monocytes are variably present [224, 234]. Both the clinical and immunological abnormalities resolve after normalization of serum zinc levels. Mutations in the gene encoding the intestinal zinc transporter SLC39A4 have been detected [125].
10.4.18 Keratitis Ichthyosis Deafness (KID) Syndrome
This autosomal dominant ectodermal dysplasia is characterized by hypervascular keratitis, ichthyosis, severe sensorineural hearing loss, and corneal defects (OMIM#148210). Susceptibility to bacterial, viral and fungal infections has been reported, including death in infancy from infectious complications. No consistent immune defect has been identified, although impaired delayed type hypersensitivity response to Candida, increased IgE levels, and neutrophil chemotactic defects have been reported [76]. KID syndrome is caused by heterozygous mutation in the gene encoding the gap junction protein connexin-26, GJB2 [185, 223].
10.4.19 PLAID and APLAID Syndromes
PLAID is associated with PLCG2-associated antibody deficiency, and immune dysregulation, and APLAID has the additional feature of autoinflammation. Cutaneous manifestations are present in both (PLAID, cold-induced urticaria; APLAID, recurrent blisters), and APLAID may have involvement of the joints, lung, intestines, and eye. In both conditions, there may be B cell and NK abnormalities. These syndromes are caused by mutations in PLCG2, encoding phospholipase Cγ2, which plays a role in immune function [170, 243].
10.4.20 Epidermodysplasia Verruciformis
This condition (OMIM#226400) is characterized by disseminated and persistent warts and pityriasis versicolor–like macules. The skin lesions are due to papillomavirus infection, though affected individuals do not display increased susceptibility to bacterial, other viral, or fungal infections or to genital papillomavirus infections. There is an increased risk for non-melanoma skin cancer, which is associated with HPV5 infection. Decreased T cell number and abnormal delayed-type hypersensitivity and mitogen response have been reported, as well as a significant increase of memory CD4+ and effector memory CD8+ T cells and an increase of skin-homing CD4+ T-cell subsets, though the findings are not consistent [40]. In most individuals, the condition is caused by mutations in either of 2 adjacent genes: TMC6 or TMC8 [182], which encode transmembrane proteins that play a role in maintaining cellular zinc homeostasis. A small number of patients have been identified with a mutation in the RHOH (ras homolog gene family member H) or serine-threonine kinase 4 (STK4, or MST1) gene [39, 41]. These genes are associated with autosomal recessive transmission. Potential X-linked [6] and autosomal dominant [147] forms have also been reported.
10.5 Syndromes Associated with Neurologic Dysfunction
Neurological abnormalities ranging from structural abnormalities to epilepsy or ataxia have been reported in association with immunodeficiency (Table 10.3).
10.5.1 Høyeraal-Hreidarsson Syndrome
A syndrome of X-linked cerebellar hypoplasia, psychomotor retardation, microcephaly, growth failure, and progressive pancytopenia has been reported in several affected males (OMIM#300240). Decreased IgG [96] and death from fungal sepsis [12, 97] have been described. Progressive combined deficiency has been noted in other patients [116, 212]. This condition is caused by mutations in the DKC1 gene, the same gene that is mutated in dyskeratosis congenita [116]. Other patients have a mutation in RTEL1, which encodes a DNA helicase that is involved in telomere regulation [233]. RTEL1 mutations may be more specific for Høyeraal-Hreidarsson syndrome as they have been identified in patients with this diagnosis but not in patients with only standard features of dyskeratosis congenital [233]. Please see Sect. 9.9 for more details.
10.5.2 Cohen Syndrome
Cohen syndrome (OMIM#216550) is an autosomal recessive condition featuring hypotonia, microcephaly, mental retardation, short stature, obesity, and characteristic facies with short philtrum, prominent upper central incisors, and prominent nasal root. Neutropenia is mild to moderate, intermittent, and not generally associated with severe infection, although gingivitis, periodontitis, and cutaneous infections are common [4, 113, 114, 169]. Mutations in the COH1 (VPS13B) gene have been identified [119].
10.5.3 Myotonic Dystrophy
This autosomal dominant condition (OMIM#160900) is a multisystem disorder, characterized by difficulty in relaxing a contracted muscle. Muscle weakness and wasting, cataracts, hypogonadism, and cardiac conduction defects are also frequent manifestations. Cognitive function may deteriorate in adults. In the congenital form, there is severe hypotonia and respiratory insufficiency.
Most cases of myotonic dystrophy are due to a trinucleotide repeat expansion in the 3′ untranslated region of the DMPK gene (type 1), which encodes the dystrophia myotonica protein kinase [21, 72, 140]. In general, the size of the expansion correlates with the severity of the disease and the age of onset. Myotonic dystrophy, type 2, is associated with an expansion in a CCTG repeat in intron one of the ZNF9 gene [132].
10.6 Inborn Errors of Metabolism Associated with Immunodeficiency
For most of these syndromes, it is unknown if the immunological deficit is due to block of a metabolic process important for immune function or if the buildup of toxic metabolites adversely affects immune cells (Table 10.4). Most of the immunological abnormalities appear to be secondary to the metabolic derangement since correction of the metabolic defect usually restores immune function.
Table 10.4
Inborn errors of metabolism associated with immunodeficiency
Name | Inheritance (Chromosome) | Associated features | Immune defect | Frequency of ID |
|---|---|---|---|---|
Primary immunodeficiencies | ||||
1. Adenosine deaminase deficiency | AR (20q13) | Severe combined immunodeficiency, cupping and flaring of costochondral junctions | T, B | ++++ |
2. Purine nucleoside phosphorylase deficiency | AR (14q13) | Severe immunodeficiency, neurological findings, hemolytic anemia; viral/fungal infections | T | ++++ |
3. Leukocyte adhesion deficiency, type 2 | AR (11p11) | Severe mental retardation, seizures, growth failure, abnormal facies, congenital disorder of glycosylation IIc | Ph | ++++ |
4. Glycogen storage disease Ib/Ic | AR (11q23) | Hypoglycemia, glucose-6-phosphate transport defect; perianal abscesses; inflammatory bowel disease | Ph | +++ |
5. Barth syndrome | XL (Xq28) | Endocardial fibroelastosis, myopathy, abnormal mitochondria, 3-methylglutaconicaciduria | Ph | ++++ |
Other syndromic immunodeficiencies | ||||
6. Congenital disorders of glycosylation | Various Types Ia, Ig, Ik | Decreased glycosylation, hypotonia, poor growth, other organ systems may be involved depending on the type | B, Ph | ++ |
7. Galactosemia | AR (9p13, 17q24) | Hepatomegaly, hypoglycemia, jaundice, feeding difficulties; risk for E. coli sepsis | Ph | + |
8. Brached chain amino acidemias | AR (various) | Methylmalonic, propionic, and isovaleric acidemias; acidosis, vomiting, ketosis | T, B, Ph | +++ |
9. Lysinuric protein intolerance | AR (14q11) | Dibasic aminoaciduria, hepatomegaly, failure to thrive; severe varicella infection | T, B, Ph, NK | +++ |
ID immunodeficiency, T T cell defect, B B cell defect, Ph Phagocyte defect, NK NK cell defect. Frequency of ID: + = less than 5 % of reported cases with documented ID; ++ = 5–30 %; +++ = 30–65 %; ++++ = >65 %. AR autosomal recessive, AD autosomal dominant, XL X-linked
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