Sandbox:Ali

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2]

Classification

Immunodeficiency disorders are classified into two types:

• Primary immunodeficiency
• Secondary immunodeficiency

Primary immunodeficiency:

Primary immunodeficiency disorders
Phagocyte cell defects	Decreased number Functional Defects	Schwachman-Diamond Syndrome G6PC3 deficiency Cohen Syndrome Barth Syndrome Glycogen Storage Disease Type 1b Clericuzio Syndrome VPS45 deficiency P14/LAMTOR2 deficiency JAGN1 deficiency 3-methylglutaconic aciduria SMARCD2 deficiency WDR1 deficiency HYOU1 deficiency Elastase deficiency HAX1 deficiency(Kostmann Disease) GFI1 deficiency G-CSF receptor deficiency X-linked neutropenia /mylodysplasia WAS GOF Neutropenia with combined immune deficiency Cystic Fibrosis Papillion-Lefèvre Localized juvenile peridontitis B-Actin Leukocyte adhesion deficiency GATA2 def (MonoMac sd) Specific granule deficiency Pulmonary alveolar proteinosis Chronic Granulomatous Disease Rac 2 def G6PD def Class 1
Defects in Intrinsic and Innate immunity	Predisposition to bacterial infections

Algorithms

Immunodeficiency affecting cellular and humoral immunity

CD19 NL: SCID T-ve B+ve

CD19 ↓: SCID T-ve B-ve

SCID T-ve B+ve NK-ve

SCID T-ve B+ve NK+ve

SCID T-ve B-ve NK-ve

SCID T-ve B-ve NK+ve

yc deficiency

IL7Ra .

ADA def

Microcephaly present

Microcephaly absent

JAK-3 def

CD3D, CD3E, CD247

Reticular dysgenesis

DNA Ligase IV def

RAG1/2 def

CD45 def

XLF def

DCLRE1C def

Coronin-1A def

DNA PKcs def

Winged helix def

Combined Immunodeficiency Diseases with associated or syndromic features

Combined Immunodeficiency Diseases with associated or syndromic features

Congenital thromocytopenia

DNA Repair Defects

Immuno-osseous dysplasias

Thymic Defects with additional congenital anomalies

Hyper-IgE syndromes(HIES)

Dyskeratosis congenita (DKC)

Defects of Vitamin B12 and Folate metabolism

Anhidrotic Ectodermodysplasia with ID

Others

Wiskott Aldrich Syndrome

Ataxia telangiectasia

Cartilage Hair Hypoplasia

DiDeorge Syndrome

Job Syndrome

Dyskeratosis congenita

Transcobalmin 2 deficiency

NEMO deficiency

Purine nucleoside phosphorylase deficiency

XL thrombocytopenia

Nijmegen breakage Syndrome

Schimke Syndrome

TBX1 deficiency

Comel Netherton Syndrome

COATS plus syndrome

Deficiency causing hereditary folate malabsorption

EDA-ID due to IKBA GOF mutation

ID with multiple intestinal atresias

WIP deficiency

Bloom syndrome

MYSM1 deficiency

Chromosome 10p13-p14 deletion Syndrome

PGM3 deficiency

SAMD9

Methylene-tetrahydrofolate-dehydrogenase 1 deficiency

Hepatic veno-occlusive disease with immunodeficiency

ARPC1B deficiency

PMS2 deficiency

MOPD1 deficiency

CHARGE Syndrome

SAMD9L

Vici Syndrome

Immunodeficiency with centromeric instability and facial anomalies(ICF1, ICF2, ICF3, ICF4)

EXTL3 deficiency

HOIL1 deficiency, HOIP1 deficiency

MCM4 deficiency

Calcium Channel Defects(ORAI-1 deficiency, STIM1 deficiency)

RNF168 deficiency

Hennekam-lymphangiectasia-lymphedema syndrome

POLE1 deficiency

STAT5b deficiency

POLE2 deficiency

Kabuki Syndrome

NSMCE3 deficiency

ERCC6L2(Hebo deficiency)

Ligase 1 deficiency

GINS1 deficiency

Phenocopies of PID

Phenocopies of PID

Associated with Somatic Mutations

Associated with Auto-Antibodies

ALPS-SFAS

Chronic mucocutaneous candidiasis

RALD(RAS-associated autoimmune leukoproliferative disease)

Adult-onset immunodeficiency with susceptibility to mycobacteria

Cryopyrinopathy(Muckle-Wells Syndrome)

Recurrentt skin infections

Hypereosinophilic syndrome due to somatic mutations in STAT5b

Pulmonary alveolar proteinosis

Acquired angiooedema

Atypical Hemolytic Uremic Syndrome

Thymoma with hypogammaglobulinemia

Predominantly Antibody deficiencies

Predominantly Antibody deficiencies, a: Hypogammaglobulinemia

Serum immunoglobulin assays : IgG, IgA, IgM, IgE

IgG, IgA, and/or IgM ↓↓ → B Lymphocyte (CD19+) enumeration (CMF)

B absent

B >1%

X-Linked Agammaglobulinemia

Common Variable Immunodeficiency Phenotype

CD19 deficiency

µ heavy chain Def

CVID with no gene defect specified

CD20 deficiency

Igα def

PIK3CD mutation(GOF),PIK3R1 deficiency(LOF)

CD21 deficiency

Igβ def

PTEN deficiency(LOF)

TRNT1 deficiency

BLNK def

CD81 deficiency

NFKB1 deficiency

λ5 def

TACI deficiency

NFKB2 deficiency

PI3KR1 def

BAFF receptor deficiency

IKAROS deficiency

E47 transcription factor def

TWEAK deficiency

ATP6AP1 deficiency

Mannosyl-oligosaccharide glucosidase deficiency (MOGS)

TTC37 deficiency

IRF2BP2 deficiency

Predominantly Antibody deficiencies. b:Other antibody deficiencies

Serum Immunolobulin Assays: IgG, IgA, IgM, IgE

Severe Reduction in Serum IgG and IgA with NI/elevated IgM and Normal Numbers of B cells: Hyper IgM Syndromes

Isotype, Light Chain, or Functional Deficiencies with Generally NI Numbers of B cells

High B cell numbers due to constitutive NF-kB activation

AID deficiency

Selective IgA deficiency

CARD11 Gain of Function

UNG deficiency

Transient hypogammaglobuliemia of infancy

INO80

IgG subclass deficiency with IgA deficiency

MSH6

Isolated IgG subclass deficiency

Specific antibody deficiency with normal Ig levels and normal B cells

Ig heavy chain muations and deletions

Kappa chain deficiency

Selective IgM deficiency

Congenital defects of phagocyte number

Congenital defects of phagocyte number

Syndrome associated

No syndrome associated

Shwachman-Diamond syndrome

Elastase deficiency (SCN1)

G6PC3 deficiency (SCN4)

HAX1 deficiency (Kostmann Disease) (SCN3)

Glycogen storage disease type 1b

GFI 1 deficiency (SCN2)

Cohen syndrome

X-linked neutropenia/myelodysplasia WAS GOF

Barth Syndrome

G-CSF receptor deficiency

Clericuzio syndrome (poikiloderma with neutropenia)

Neutropenia with combined immune deficiency

VPS45 deficiency(SCN5)

P14/LAMTOR2 deficiency

JAGN1 deficiency

methylglutacoic aciduria

SMARCD2 deficiency

WDR1 deficiency

HYOU1 deficiency

Congenital defects of phagocyte function

Congenital defects of phagocyte function

Syndrome associated

No Syndrome associated;DHR assay(or NBT test)?

Cystic Fibrosis

Normal

Abnormal

Papillion-Lefèvre

GATA2 def (MonoMac syndrome

CGD

Localized juvenile periodontitis

Specific granule deficiency

Rac 2 deficiency

B-Actin

Pulmonary alveolar proteinosis

G6PD def Class 1

Leukocyte adhesion deficiency

Auto-inflammatory disorders

Auto-inflammatory disorders

Recurrent inflammation

Systemic inflammation with urticaria rash

Others

Sterile inflammation (skin/bone/joints)

Type 1 Interferonopathies

Familial Mediterranean Fever

Familial Cold Autoinflammatory Syndrome (CAPS)

CANDLE syndrome

Predominant on the bone/joints

Predominant on the skin

Aicardi-Goutieres syndrome

Mevalonate kinase deficiency

Muckle Wells syndrome

COPA defect

Pyogenic sterile arthritis, pyoderma gangrenosum, acne(PAPA) syndrome, hyperzincemia and hypercalprotectinemia

Blau syndrome

Spondyloenchondro-dysplasia with immune dysregulation

TNF receptor-associated periodic syndrome; TRAPS

Neonatal onset multisystem inflammatory disease

NLRC4-MAS(Macrophage activating syndrome)

Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia

CAMPS

STING-associated vasculopathy, infantile onset

PLAID (PLCg2 associated antibody deficiency and immune dysregulation), or APLAID

DIRA (Deficiency of the interleukin 1 receptor antagonist)

DITRA

ADA2 deficiency

NLRP1 deficiency

Cherubism

ADAM17 deficiency

XL reticulate pigmentary disorder

A20 haploinsufficiency

SLC29A3 mutation

USP18 deficiency

Otulipenia/ORAS

AP153 deficiency

Diseases	History and Symptoms			Physical Examination			Laboratory Findings			Other Findings
	Abdominal Pain	Rectal Bleeding	Fatigue	Abdominal Tenderness	Hyperpigmentation	Anemia	Gene(s)	Gastrointestinal Tumors	Cancers
Hereditary Non–Polyposis Colon Cancer	–	+	+	+/–	–	+	MLH1 MSH2 MSH3 MSH6 PMS1 PMS2	Adenoma+	Endometrium Stomach Kidneys Ureter Ovaries	Sebaceous adenoma
Carney Syndrome	–	–	–	–	Facial+ Mucosal+	–	PRKAR1A		Thyroid Sertoli Cell	Myxoma of skin Myxoma of heart
Familial Adenomatous Polyposis	+	+	+	+/–	–	+	APC gene MUTYH gene	Adenoma+++	Colon Brain Thyroid	Desmoid tumor Osteoma
Peutz–Jeghers syndrome	+	+	+	+	+	+	STK11 (LBK1) gene	Adenoma+ Hamartoma+++	Breast Lung Pancreas Ovaries Sertoli cells Uterine
Juvenile Polyposis Syndrome	+		+	–	–	–	SMAD4 BMPR1A	Adenoma+  Hamartoma+++	Colon
Cowden Syndrome	–	–	–	–	Axillary+ Inguinal+ Facial+	–	PTEN	Adenoma+  Hamartoma+++	Breast Thyroid Endometrium	Trichilemmoma Skin hamartoma Hyperplastic polyp Macrocephaly Breast fibrosis

Differential Diagnosis	Similar Features	Differentiating Features
Familial adenomatous polyposis	Familial inheritance, increased risk of colorectal cancer, extra-colonic tumors, and genetic mutations	Autosomal recessive, 100+ polyps and age under 40, centinel tumors are differently located than hereditary nonpolyposis colorectal cancer, such as: multiple osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and APC is the gene affected
Juvenile polyposis	Familial inheritance, autosomal dominant, increased risk of colorectal cancer, extra-colonic tumors, and genetic mutations	Gastrointestinal hamartomatous polyps, on physical exam lip pigmentation is common, and STK11 is the gene affected
Cowden syndrome	Familial inheritance, rare autosomal dominant, increased risk of colorectal cancer, and genetic mutations	Intestinal hamartomatous polyps, physical exam may show macrocephaly, and PTEN is the gene affected