Table 2.
NP Associated With Immunodeficiency/Immune Dysregulation Disorders
| Associated With Pigmentary Disorders/Vesicular Trafficking | ||||||
|---|---|---|---|---|---|---|
| Disease | Gene | Inheritance | Clinical/Immunological Features | Postulated Mechanism | ||
| Chediak-Higashi syndrome | LYST/CHS | AR | Oculocutaneous albinism, neurodegeneration, deficient cytotoxic cell function | ↓ Survival of myeloid progenitors | ||
| Griscelli syndrome type 2 | RAB27 A | AR | Oculocutaneous albinism/deficient cytotoxic cell function | ↓ Survival of myeloid progenitors | ||
| Hermansky-Pudlak syndrome type 2 | AP3B1 | AR | Oculocutaneous albinism, hemorrhagic diathesis/deficient cytotoxic cell function | ↓ Survival of myeloid progenitors | ||
| P14 deficiency | LAMTOR2 | AR | Short stature, skin hypo-pigmentation, high B-cell counts | ↓ Survival of myeloid progenitors | ||
| Syndromic neutropenias | ||||||
| Cohen syndrome | VPS13 B | AR | Microcephaly, retinopathy, developmental delay | ↓ Survival of myeloid progenitors | ||
| Pearson syndrome | Mitochondrial deletion | Mitochondrial DNA inheritance | ↓ Survival of myeloid progenitors | |||
| Clericuzio NP | C16orf57/USB1 | AR | Poikiloderma | ↓ Survival of myeloid progenitors | ||
| Charcot-Marie-Tooth disease type II | DNM2 | AD | Myopathy, axonal neuropathy. Congenital cataract |
↓ Survival of myeloid progenitors | ||
| Neutropenia plus additional immunodeficiency | ||||||
| Wiskott-Aldrich syndrome | WAS | XL missense mutation in GTPase binding WASp | NP, low IgM, high IgA, progressive T-cell reduction | ↓ Survival of myeloid elements | ||
| WHIM | CXCR4 (gain of function) | AD | Warts, hypogammaglobulinemia, infections, myelokathexis | Low egress of cells from BM | ||
| Cartilage-hair hypoplasia | RMRP | AR | Short stature and limbs, malabsorption and celiac disease, mild anemia | ↓ Survival of myeloid elements | ||
| Reticular dysgenesis | AK2 | AR | SCID-like, inner ear hearing loss | ↓ Survival of myeloid elements | ||
| GINS1 deficiency | GINS1 | AR | Growth retardation, low CD8 T-cell counts, very low NK cells | ↓ Survival of myeloid elements | ||
| WDR1 deficiency | WDR1 | AR | Stomatitis | ↓ Survival of myeloid elements | ||
| MST1 deficiency | STK4 | AR | Recurrent infections (papilloma virus), EBV-driven lymphoproliferation, lymphoma, congenital heart disease, autoimmune cytopenia, progressive T-cell lymphopenia, NP, often intermittent | Unknown | ||
| IRAK4 deficiency | IRAK4 | AR | Invasive bacterial infections, NP, often intermittent | Defective development of myeloid precursors | ||
| MyD88 deficiency | MYD88 | AR | Invasive bacterial infections, NP often intermittent | Defective development of myeloid precursors | ||
| X-linked agammaglobulinemia | BTK | XL | Absent B cells and low antibody levels, NP usually seen in patients not yet on Ig therapy | Unknown | ||
| X-linked hyper-IgM syndrome | CD40 L | X-linked | Thrombocytopenia, hemolytic anemia, biliary/liver disease, low IgG and IgA levels, poor Ig class-switching, NP (often intermittent) | Defective development of myeloid precursors | ||
| CD40 hyper-IgM syndrome | CD40 | AR | Gastrointestinal/liver/biliary disease, low IgG and IgA levels, poor Ig class-switching, NP (often intermittent) | Defective development of myeloid precursors | ||
| ADA deficiency | ADA | AR | Decreased NK cells, neurological features, hearing impairment, lung and liver manifestations | Unknown/↑ peripheral destruction | ||
| ADA2 | CECR1 | AR | Vasculitis, autoimmunity | Unknown/↑ peripheral destruction | ||
| CVID | RAG, TNFRSF13B TACI, BAFFR, LRBA, CTLA4 | AR/AD | Recurrent infections, GI symptoms, low IgG/IgA/IgM, progressive lymphopenia, intermittent NP | Unknown/↑ peripheral destruction | ||
| PI3K-D | PI3KCD, gain of function | AD | Infections/autoimmunity | Unknown/↑ peripheral destruction | ||
| PNP | PNP deficiency | AR | Ataxic diplegia and defective cellular immunity | Unknown/↑ peripheral destruction | ||
| Myelodysplastic conditions | ||||||
| GATA-2 deficiency | GATA2 | AD | Broad phenotype with progressive loss of B and NK cells, warts, AML | Defective development of myeloid precursors | ||
| Schwachman-Diamond syndrome | SBDS, DNAJC21, SRP54, ELF1 | AR | Growth failure, fat malabsorption | Defective development of myeloid precursors | ||
| Telomeropathies | DXC1, NPH2, TERC, TERT, RTEL1, TINF2, DKC1, PARN, CTC1 | AR/AD | Growth retardation, cutaneous pigmentation, nail hypoplasia | Defective development of myeloid precursors | ||
| Mirage syndrome SAMD9 | SAMD9L | AD | Ataxia, growth failure, adrenal insufficiency | Defective development of myeloid precursors | ||
| Familial platelet disorder | RUNX1, ETV6, ANKRD26 | AR/AD | Thrombocytopenia, predisposition to AML | Defective development of myeloid precursors | ||
| DNA repair | MECOM, ERCC6L2, LIG4 | AR/AD | MECOM-associated syndrome with skeletal/cardiac phenotypes | Defective development of myeloid precursors | ||
| Congenital anemia | GATA1, RPS19, ALAS2, RPL5, RPL35 A, RPL11, RPS10, RPS24, RPS17 | X-linked/AR/AD | Anemia, prominent | Defective development of myeloid precursors | ||
| Myelodysplasia, mechanism not known | MYSM1, PRF1, SRP72, STIM1, DDX41, ATR | AR/AD | BM failure alone | Defective hemopoiesis/↑ peripheral destruction | ||
AD = autosomal dominant; AR = autosomal recessive; AML = acute myeloid leukemia; BM = bone marrow; EBV = Epstein Barr virus; GI = gastrointestinal; Ig = immunoglobulin; NK = natural killer; SCID = severe combined immunodeficiency; MECOM = MDS1 and EVI1 complex locus.
Adapted from Sullivan. J Allergy Clin Immunol. 2019;143:96–100.