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Stiehm's Immune Deficiencies
Stiehm's Immune Deficiencies
Copyright
Contents
Contributors
Foreword
I - Approach to patients
1 - Common presentations and diagnostic approaches
Introduction
Prevalence and demographics
Registries
Prevalence
Age
Gender
Regional considerations
Approach concepts
Recurrent infections
Recurrent ``normal'' infections
Recurrent ``abnormal'' infections
Sentinel infections
Herpes simplex encephalitis
Epstein-Barr Virus
Cytomegalovirus
Human papilloma virus
Mycobacterial infections
Candidal infections
Aspergillus
Gram-negative rod infections
Cutaneous infections
Chronic diarrhea
Malignancies
Hematopoietic malignancies
Solid tumors
Genetics
Prognosis
Neutropenia
Short stature and infections
Immune deficiencies with skeletal dysplasia
Other syndromic immune deficiencies with short stature but without skeletal dysplasia
Immune deficiencies with short stature with defects in GH pathway
Immune deficiencies with short stature that belong to the group of impaired DNA damage response mechanisms
Conclusions
References
2 - Genetic syndromes with evidence of immune deficiency
Overview
Syndromes associated with growth deficiency
Syndromes associated with skeletal dysplasia
Short-limb skeletal dysplasia with combined immune deficiency (OMIM #200900)
MacDermot syndrome (OMIM #200900)
Kyphomelic dysplasia (OMIM #211350)
Spondylo-mesomelic-acrodysplasia
Short-limb skeletal dysplasia with humoral immune defect
Kenny-Caffey syndrome (OMIM #127000, 244460)
Immunoskeletal dysplasia with neurodevelopmental abnormalities (OMIM #617425)
Syndromes associated with proportionate short stature
Growth hormone deficiency with X-Linked agammaglobulinemia (OMIM #307200).
Growth hormone insensitivity with immune deficiency (OMIM #245590)
Mulvihill-Smith syndrome (OMIM #176690)
Mulibrey nanism (OMIM #253250)
Dubowitz syndrome (OMIM #223370)
Rubinstein-Taybi syndrome (OMIM #180849)
Smith-Lemli-Opitz syndrome (OMIM #270400)
Cornelia de Lange syndrome (OMIM #122470)
Sutor syndrome
Shokeir syndrome (OMIM #274190)
Toriello syndrome (OMIM #251190)
Stoll syndrome (OMIM #601347, #612541)
BILU syndrome (OMIM #609296)
Bernard syndrome (OMIM #609981)
Seckel syndrome (OMIM #210600)
Syndromes associated with cutaneous abnormalities
Griscelli syndrome, type 2 (OMIM #214450)
Incontinentia pigmenti (OMIM #308300)
Anhidrotic ectodermal dysplasia - immunodeficiency (EDA-ID) (OMIM #300291, 612312)
OLEDAID syndrome (OMIM #300301)
APLAID syndrome (OMIM #614878)
PLAID syndrome (OMIM #614878)
Dyskeratosis Congenita (OMIM #305000)
Acrodermatitis enteropathica (OMIM #201100)
Papillon-Lefevre syndrome (OMIM #245000)
Pignata syndrome (OMIM #601705)
Onychotrichodysplasia with neutropenia (OMIM #258360)
Xeroderma pigmentosum (OMIM #278700)
Trichothiodystrophy (OMIM #601675)
Hermansky-Pudlak Syndrome, type 2 (OMIM #608233)
Poikiloderma with neutropenia, clericuzio type (OMIM #604173)
p14 deficiency (OMIM #610798)
Jung syndrome (OMIM #146840)
Neutrophil chemotactic defect (OMIM #162820)
Davenport syndrome
Ipp-Gelfand syndrome
Syndromes associated with neurologic dysfunction
Myotonic dystrophy (OMIM #160900)
Arts syndrome (OMIM #301835)
Rambam-Hasharon syndrome (leukocyte adhesion deficiency type II) (OMIM #266265)
Microcephaly with immune defects (OMIM #251240)
Mousa syndrome (OMIM #271320)
Aguilar syndrome (OMIM #226850)
Adderson syndrome
Krawinkel syndrome
Roifman-Chitayat syndrome (OMIM #613328).
MECP2 duplication syndrome (OMIM #300260)
Inborn errors of metabolism associated with immune deficiency
Adenosine deaminase (ADA) deficiency (OMIM #102700)
Purine nucleoside phophorylase (PNP) deficiency (OMIM #164050)
5′-Nucleotidase elevation
Glycogen storage disease (GSD) Ib/Ic (OMIM #232220, 232240)
Galactosemia (OMIM #230400)
Barth syndrome (OMIM #302060)
Congenital disorders of glycosylation, type I
Branched-chain aminoacidurias
Lysinuric protein intolerance (OMIM #222700)
Orotic aciduria (OMIM #258900)
Alpha-mannosidosis (OMIM #248500)
Biotinidase deficiency (OMIM #253260)
Chondroitin-6-sulfaturia (OMIM #215250)
Miscellaneous genetic syndromes associated with immune deficiency
Timothy syndrome (OMIM #601005)
TIIAC syndrome (OMIM #614868)
Somech syndrome (OMIM #611926)
Thymic-renal-anal-lung dysplasia (OMIM #274265)
Hisama syndrome (OMIM #267430)
Frenkel-Russe syndrome (OMIM #267900)
PTEN hamartoma tumor syndrome (OMIM #158350)
Lichtenstein syndrome (OMIM #246550)
Beta-2 microglobulin deficiency (hypercatabolic hypoproteinemia) (OMIM #241600)
Schaller syndrome (OMIM #247800)
Turner-like phenotype
Well-recognized syndromes with immune deficiency as an occasional feature
Syndromes associated with chromosomal abnormalities of number or structure
Trisomy 21 (OMIM #190685)
Trisomy 8
Deletion of chromosome 22q11.2 (OMIM #188400)
Deletion of chromosome 17p11.2 (Smith-Magenis syndrome) (OMIM #182290)
Deletion of chromosome 10p13-p14 (OMIM #601362)
Partial deletions of chromosome 4p (Wolf-Hirschhorn syndrome) (OMIM #194190)
Turner syndrome
Jacobsen syndrome (OMIM #147791)
Partial deletions of chromosome 18
Other chromosomal rearrangements with reported immune deficiency
Conclusions
References.
3 - Key pathways in primary immune deficiencies
Introduction
NFκB pathway
NFκB activation and regulation
Antigen receptor signaling and the CBM complex
Innate immune receptor signaling
TNFR superfamily signaling
NFκB activation and cell death
NFκB pathway primary immune deficiency and autoinflammatory disease by category
Receptor proximal signaling molecules
IKK complex defects
NFκB family members
Ubiquitin modifiers
PI3 kinase signaling pathway
Phosphatidylinositol 3-kinase (PI3K) is the gateway where many signals converge
Tfh cells and germinal centers
Additional T cell effects
B cell effects
Overview of conditions associated with PI3Kδ activation
Recessive mutations
Summary of critical effects of an activated PI3Kδ
Innate interferon signaling pathway
Interferon induction
Interferon signaling
Disorders of interferon induction
Disorders of interferon signaling
Infection phenotypes
Inflammatory phenotypes
Summary
References
4 - Laboratory evaluation of primary immunodeficiency disorders
Introduction
Evaluating suspected defects in antibody response
Clinical indications
Methodology
Evaluating suspected T cell defects
Clinical indication
Methodology
Newborn screening for severe combined immune deficiency (SCID)
Clinical indication
Methodology
Evaluating suspected natural killer (NK) defects
Clinical indication
Methodology
Evaluating immune defects involving macrophage activation
Clinical indications
Methodology
Evaluating suspected toll like receptor (TLR) defects
Clinical indications
Methodology
Evaluating suspected phagocyte dysfunction syndromes
Clinical indications
Methodology
Evaluating suspected complement disorders
Clinical indications
Methodology
Conclusions
References.
5 - Genetics of primary immune deficiencies
Introduction
Genetic testing in the immunology clinic
The nomenclature of human gene variants
Definitions of types of variants
Modes of inheritance
Effects of mutations on protein function
Genetic testing
Approach to novel variants or variants of unknown significance
Conclusions
References
6 - Phenocopies of inborn errors of immunity
Introduction
Diseases associated with autoantibodies
AutoAb to IL-17A, IL-17F and/or IL-22/chronic mucocutaneous candidiasis
AutoAb to IFNγ/susceptibility to mycobacteria
AutoAb to IL-6/recurrent and severe bacterial skin infection
AutoAb to various cytokines/thymoma and Good syndrome
AutoAb to GM-CSF/pulmonary alveolar proteinosis
AutoAb to C1 inhibitor/acquired angioedema
Diseases associated with somatic mutations
Somatic mutation in TNFRSF6/autoimmune lymphoproliferative syndrome (ALPS-sFAS)
Somatic mutation in KRAS or NRAS/RAS-associated autoimmune leukoproliferative syndrome (RALD)
Somatic mutation in NLRP3/cryopyrinopathy
Somatic mutation in STAT3 or STAT5B (GOF)/large granular lymphocytosis
Somatic mutations in STAT5B (GOF)/hypereosinophilic syndrome
Conclusions
References
II - Specific disorders
7 - Severe combined immune deficiency
Introduction
T- B + severe combined immune deficiencies
X-linked severe combined immune deficiency
Definition
Genetics
Pathophysiology
Clinical presentation
Diagnosis
Management
Prognosis
Janus associated kinase-3 (JAK3) deficiency
Definition
Genetics
Pathophysiology
Clinical presentation
Diagnosis
Management
Prognosis
Interleukin-7 receptor α chain (IL7Rα) deficiency
Definition
Genetics
Pathophysiology
Clinical presentation
Diagnosis
Management
Prognosis.
Coronin 1A deficiency.
Stiehm's Immune Deficiencies
Stiehm's Immune Deficiencies
Copyright
Contents
Contributors
Foreword
I - Approach to patients
1 - Common presentations and diagnostic approaches
Introduction
Prevalence and demographics
Registries
Prevalence
Age
Gender
Regional considerations
Approach concepts
Recurrent infections
Recurrent ``normal'' infections
Recurrent ``abnormal'' infections
Sentinel infections
Herpes simplex encephalitis
Epstein-Barr Virus
Cytomegalovirus
Human papilloma virus
Mycobacterial infections
Candidal infections
Aspergillus
Gram-negative rod infections
Cutaneous infections
Chronic diarrhea
Malignancies
Hematopoietic malignancies
Solid tumors
Genetics
Prognosis
Neutropenia
Short stature and infections
Immune deficiencies with skeletal dysplasia
Other syndromic immune deficiencies with short stature but without skeletal dysplasia
Immune deficiencies with short stature with defects in GH pathway
Immune deficiencies with short stature that belong to the group of impaired DNA damage response mechanisms
Conclusions
References
2 - Genetic syndromes with evidence of immune deficiency
Overview
Syndromes associated with growth deficiency
Syndromes associated with skeletal dysplasia
Short-limb skeletal dysplasia with combined immune deficiency (OMIM #200900)
MacDermot syndrome (OMIM #200900)
Kyphomelic dysplasia (OMIM #211350)
Spondylo-mesomelic-acrodysplasia
Short-limb skeletal dysplasia with humoral immune defect
Kenny-Caffey syndrome (OMIM #127000, 244460)
Immunoskeletal dysplasia with neurodevelopmental abnormalities (OMIM #617425)
Syndromes associated with proportionate short stature
Growth hormone deficiency with X-Linked agammaglobulinemia (OMIM #307200).
Growth hormone insensitivity with immune deficiency (OMIM #245590)
Mulvihill-Smith syndrome (OMIM #176690)
Mulibrey nanism (OMIM #253250)
Dubowitz syndrome (OMIM #223370)
Rubinstein-Taybi syndrome (OMIM #180849)
Smith-Lemli-Opitz syndrome (OMIM #270400)
Cornelia de Lange syndrome (OMIM #122470)
Sutor syndrome
Shokeir syndrome (OMIM #274190)
Toriello syndrome (OMIM #251190)
Stoll syndrome (OMIM #601347, #612541)
BILU syndrome (OMIM #609296)
Bernard syndrome (OMIM #609981)
Seckel syndrome (OMIM #210600)
Syndromes associated with cutaneous abnormalities
Griscelli syndrome, type 2 (OMIM #214450)
Incontinentia pigmenti (OMIM #308300)
Anhidrotic ectodermal dysplasia - immunodeficiency (EDA-ID) (OMIM #300291, 612312)
OLEDAID syndrome (OMIM #300301)
APLAID syndrome (OMIM #614878)
PLAID syndrome (OMIM #614878)
Dyskeratosis Congenita (OMIM #305000)
Acrodermatitis enteropathica (OMIM #201100)
Papillon-Lefevre syndrome (OMIM #245000)
Pignata syndrome (OMIM #601705)
Onychotrichodysplasia with neutropenia (OMIM #258360)
Xeroderma pigmentosum (OMIM #278700)
Trichothiodystrophy (OMIM #601675)
Hermansky-Pudlak Syndrome, type 2 (OMIM #608233)
Poikiloderma with neutropenia, clericuzio type (OMIM #604173)
p14 deficiency (OMIM #610798)
Jung syndrome (OMIM #146840)
Neutrophil chemotactic defect (OMIM #162820)
Davenport syndrome
Ipp-Gelfand syndrome
Syndromes associated with neurologic dysfunction
Myotonic dystrophy (OMIM #160900)
Arts syndrome (OMIM #301835)
Rambam-Hasharon syndrome (leukocyte adhesion deficiency type II) (OMIM #266265)
Microcephaly with immune defects (OMIM #251240)
Mousa syndrome (OMIM #271320)
Aguilar syndrome (OMIM #226850)
Adderson syndrome
Krawinkel syndrome
Roifman-Chitayat syndrome (OMIM #613328).
MECP2 duplication syndrome (OMIM #300260)
Inborn errors of metabolism associated with immune deficiency
Adenosine deaminase (ADA) deficiency (OMIM #102700)
Purine nucleoside phophorylase (PNP) deficiency (OMIM #164050)
5′-Nucleotidase elevation
Glycogen storage disease (GSD) Ib/Ic (OMIM #232220, 232240)
Galactosemia (OMIM #230400)
Barth syndrome (OMIM #302060)
Congenital disorders of glycosylation, type I
Branched-chain aminoacidurias
Lysinuric protein intolerance (OMIM #222700)
Orotic aciduria (OMIM #258900)
Alpha-mannosidosis (OMIM #248500)
Biotinidase deficiency (OMIM #253260)
Chondroitin-6-sulfaturia (OMIM #215250)
Miscellaneous genetic syndromes associated with immune deficiency
Timothy syndrome (OMIM #601005)
TIIAC syndrome (OMIM #614868)
Somech syndrome (OMIM #611926)
Thymic-renal-anal-lung dysplasia (OMIM #274265)
Hisama syndrome (OMIM #267430)
Frenkel-Russe syndrome (OMIM #267900)
PTEN hamartoma tumor syndrome (OMIM #158350)
Lichtenstein syndrome (OMIM #246550)
Beta-2 microglobulin deficiency (hypercatabolic hypoproteinemia) (OMIM #241600)
Schaller syndrome (OMIM #247800)
Turner-like phenotype
Well-recognized syndromes with immune deficiency as an occasional feature
Syndromes associated with chromosomal abnormalities of number or structure
Trisomy 21 (OMIM #190685)
Trisomy 8
Deletion of chromosome 22q11.2 (OMIM #188400)
Deletion of chromosome 17p11.2 (Smith-Magenis syndrome) (OMIM #182290)
Deletion of chromosome 10p13-p14 (OMIM #601362)
Partial deletions of chromosome 4p (Wolf-Hirschhorn syndrome) (OMIM #194190)
Turner syndrome
Jacobsen syndrome (OMIM #147791)
Partial deletions of chromosome 18
Other chromosomal rearrangements with reported immune deficiency
Conclusions
References.
3 - Key pathways in primary immune deficiencies
Introduction
NFκB pathway
NFκB activation and regulation
Antigen receptor signaling and the CBM complex
Innate immune receptor signaling
TNFR superfamily signaling
NFκB activation and cell death
NFκB pathway primary immune deficiency and autoinflammatory disease by category
Receptor proximal signaling molecules
IKK complex defects
NFκB family members
Ubiquitin modifiers
PI3 kinase signaling pathway
Phosphatidylinositol 3-kinase (PI3K) is the gateway where many signals converge
Tfh cells and germinal centers
Additional T cell effects
B cell effects
Overview of conditions associated with PI3Kδ activation
Recessive mutations
Summary of critical effects of an activated PI3Kδ
Innate interferon signaling pathway
Interferon induction
Interferon signaling
Disorders of interferon induction
Disorders of interferon signaling
Infection phenotypes
Inflammatory phenotypes
Summary
References
4 - Laboratory evaluation of primary immunodeficiency disorders
Introduction
Evaluating suspected defects in antibody response
Clinical indications
Methodology
Evaluating suspected T cell defects
Clinical indication
Methodology
Newborn screening for severe combined immune deficiency (SCID)
Clinical indication
Methodology
Evaluating suspected natural killer (NK) defects
Clinical indication
Methodology
Evaluating immune defects involving macrophage activation
Clinical indications
Methodology
Evaluating suspected toll like receptor (TLR) defects
Clinical indications
Methodology
Evaluating suspected phagocyte dysfunction syndromes
Clinical indications
Methodology
Evaluating suspected complement disorders
Clinical indications
Methodology
Conclusions
References.
5 - Genetics of primary immune deficiencies
Introduction
Genetic testing in the immunology clinic
The nomenclature of human gene variants
Definitions of types of variants
Modes of inheritance
Effects of mutations on protein function
Genetic testing
Approach to novel variants or variants of unknown significance
Conclusions
References
6 - Phenocopies of inborn errors of immunity
Introduction
Diseases associated with autoantibodies
AutoAb to IL-17A, IL-17F and/or IL-22/chronic mucocutaneous candidiasis
AutoAb to IFNγ/susceptibility to mycobacteria
AutoAb to IL-6/recurrent and severe bacterial skin infection
AutoAb to various cytokines/thymoma and Good syndrome
AutoAb to GM-CSF/pulmonary alveolar proteinosis
AutoAb to C1 inhibitor/acquired angioedema
Diseases associated with somatic mutations
Somatic mutation in TNFRSF6/autoimmune lymphoproliferative syndrome (ALPS-sFAS)
Somatic mutation in KRAS or NRAS/RAS-associated autoimmune leukoproliferative syndrome (RALD)
Somatic mutation in NLRP3/cryopyrinopathy
Somatic mutation in STAT3 or STAT5B (GOF)/large granular lymphocytosis
Somatic mutations in STAT5B (GOF)/hypereosinophilic syndrome
Conclusions
References
II - Specific disorders
7 - Severe combined immune deficiency
Introduction
T- B + severe combined immune deficiencies
X-linked severe combined immune deficiency
Definition
Genetics
Pathophysiology
Clinical presentation
Diagnosis
Management
Prognosis
Janus associated kinase-3 (JAK3) deficiency
Definition
Genetics
Pathophysiology
Clinical presentation
Diagnosis
Management
Prognosis
Interleukin-7 receptor α chain (IL7Rα) deficiency
Definition
Genetics
Pathophysiology
Clinical presentation
Diagnosis
Management
Prognosis.
Coronin 1A deficiency.