Recent advances and controversies in inborn errors of immunity presenting in the newborn period

Severe combined immune deficiency

Severe combined immune deficiency (SCID) is a group of rare genetic disorders with an absence of T, B, and/or natural killer (NK) cells, predisposing the infant to early life-threatening infections and death within the first 2 years of life. This condition is classified based on the presence or absence of T, B, and NK cellular phenotypes: T ^– B ⁺ NK ⁺ , T ^– B ⁺ NK ⁻ , T ^– B ^– NK ⁺ , or T ^– B ⁻ NK ⁻ .

Combined immune deficiencies less profound than SCID

Clinical phenotypes of CID are less profound and more variable than SCID. Hypomorphic mutations of the genes that cause SCID such as RAG1/2 may lead to a CID phenotype with partial defects in T, B, and/or NK cell function. ^, Major histocompatibility complex (MHC) I or II deficiencies are characterized by isolated low CD8 or CD4 numbers presenting with failure to thrive and recurrent respiratory and/or gastrointestinal infections. Zeta-chain associated protein kinase 70 kDa (ZAP-70) deficiency with defective T-cell receptor signaling results in poor cellular proliferation to mitogens with normal CD3 and CD4 but low CD8 numbers, and it may present with immune dysregulation.

Dedicator of cytokinesis 8 (DOCK8) deficiency presents with low T, B, and NK cell numbers, early-onset severe atopic disease (eczema, food allergies), refractory viral infections (human papillomavirus, herpes simplex virus [HSV], varicella zoster virus, molluscum), eosinophilia, and elevated immunoglobulin E (IgE). DOCK2 deficiency presents with early invasive herpes viruses and bacterial infections with defective NK cell function with normal number. ^,

CD40 ligand deficiency (X-linked) or CD40 deficiency (AR), previously classified as hyper-IgM syndromes, present with sinopulmonary and/or gastrointestinal infections with pyogenic bacteria, opportunistic infections ( PJP pneumonia, Cryptosporidium cholangitis), neutropenia with perirectal abscesses and oral ulcers, and immune phenotype showing normal to high IgM; low to absent IgG, IgA, and IgE; and defects in T-cell proliferation with normal to low T-cell numbers. ^, Caspase recruitment domain family member 11 (CARD11) deficiency presents with severe susceptibility to bacterial and opportunistic infections and is characterized by normal numbers of T and B lymphocytes, increased number of transitional B cells, T-cell dysfunction, and hypo- to agammaglobulinemia.

CID with associated or syndromic features

Conditions that affect cellular and humoral immunity often involve other organ systems. Representative examples that may present in the newborn period are listed below. CID due to thymic defects with additional congenital anomalies includes 22q11.2 deletion syndrome (DiGeorge syndrome [DGS]); CHARGE syndrome (an acronym for coloboma, heart defects, atresia of the choanae, retarded growth, genital abnormalities, and ear abnormalities); forkhead box N1 ( FOXN1 ) deficiency/haploinsufficiency; paired box 1 ( PAX1 ) deficiency; embryopathy associated with infants born to diabetic mothers; and Jacobsen syndrome.

DGS (22q11.2 deletion syndrome) results from defective development of the pharyngeal pouch system. It is characterized by congenital conotruncal cardiac anomalies, facial dysmorphism, hypocalcemia due to hypoparathyroidism, and varying degrees of thymic output ranging from athymia to normal thymic function. The majority of infants with DGS have heterozygous deletions in chromosome 22q11.2, but genetic deletions in chromosomes 10p13 and 17p13, as well as diabetic embryopathy, may present with similar phenotypes. ^, The inheritance of 22q11.2 deletion is autosomal dominant, but most cases result from de novo microdeletions. TBX1 has been identified as a candidate gene deleted in this region possibly responsible for the clinical phenotype of DGS. The 22q11.2 deletion is relatively common, affecting 1 in 5000 births and 1 in 1000 fetuses. ^, Infants with DGS may present with neonatal tetany and seizures due to hypocalcemia resulting from hypoparathyroidism. Speech abnormalities due to velopharyngeal insufficiency, developmental and language delay, learning disabilities, and neuropsychiatric problems including schizophrenia are common. The majority of patients with DGS have mild thymic hypoplasia (termed partial DGS), and their T-cell numbers and function improve over time, but autoimmunity is common. Approximately 0.5% to 1% of DGS cases have complete athymia with absent T cells (naïve T cells < 50 cells/µL, termed complete DGS). Some develop atypical phenotype with oligoclonal T-cell expansion, rash, and lymphadenopathy resembling Omenn syndrome or autologous GVHD.

CHARGE syndrome is associated with mutations in the chromodomain helicase DNA-binding protein 7 ( CHD7 ) gene on chromosome 8q12 or semaphorin-3E gene ( SEMA3E ) on chromosome 7q21. Patients characteristically present with coloboma of the eyes, choanal atresia, heart anomalies, central nervous system abnormalities, developmental/growth retardation, and genital and ear malformations. Infants with CHARGE syndrome may present with thymic hypoplasia or aplasia.

In FOXN1 deficiency, loss of FOXN1 function results in thymic agenesis and premature thymic involution. This condition is inherited autosomal recessive, and patients may present at birth with alopecia totalis, nail dystrophy, and severe T-cell immunodeficiency. Infants with FOXN1 haploinsufficiency may present with thymic hypoplasia with recurrent viral and bacterial respiratory tract infections in infancy, but T-cell lymphopenia can normalize by adulthood.

PAX1 deficiency, inherited autosomal dominant (AD), results in aberrant development of thymic epithelial cells, as well as other pharyngeal pouch tissues, leading to T-cell lymphopenia and orofaciocervical syndrome characterized by facial dysmorphism (long face, narrow mandible), shoulder girdle abnormalities, hearing loss, and mild intellectual disability.

Jacobsen syndrome is a rare syndrome that occurs due to partial deletion of the long arm of chromosome 11. Most common clinical features include pre- and postnatal growth retardation, characteristic facial dysmorphism, and thrombocytopenia/platelet dysfunction (Paris–Trousseau syndrome). Cognitive function may range from normal intelligence to moderate intellectual disability. Patients may present with recurrent otitis media, sinusitis, and upper and/or lower respiratory tract infections. Patients with Jacobsen syndrome may present with a combined immunodeficiency phenotype, with low memory B cells, impaired response to S. pneumoniae polysaccharide vaccine, and low T- and NK-cell numbers for age.

Wiskott–Aldrich syndrome (WAS) is a CID with associated congenital thrombocytopenia. Inherited X-linked, classical presentation of WAS includes eczema, thrombocytopenia (small platelets with poor aggregation), and immunodeficiency, with increased risk for autoimmunity and lymphoid malignancies. The immunoglobulin profile is characteristic, with elevated IgA and IgE levels and low IgM levels. The most common complication of WAS in infancy is hemorrhage, a major cause of morbidity and mortality. There is an increased susceptibility to severe disseminated infections with herpesviruses and encapsulated bacteria. Diagnosis is confirmed with genetic mutations in the WASP (Wiskott–Aldrich syndrome protein) gene. Hypomorphic mutations of the WASP gene results in a milder variant with isolated X-linked thrombocytopenia, and transactivating mutations cause X-linked neutropenia and myelodysplasia. Infants with WAS may experience an accelerated phase, presenting as hemophagocytic lymphohistiocytosis.

Ataxia telangiectasia is an autosomal recessive disorder caused by mutations in the DNA repair enzyme ATM (ataxia telangiectasia mutated) gene. Patients with ataxia telangiectasia present with ataxia and ocular telangiectasia, with an increased risk of infections and malignancy that is rarely evident in the newborn period. However, the enzyme defect can also cause thymic hypoplasia, resulting in low T-cell receptor excision circle (TREC) levels and abnormal SCID newborn screen. Levels of α-fetoprotein are typically increased, as are the proportion of γδ T cells. Radiation sensitivity increases the risk for lymphoreticular malignancies.

Trichohepatoenteric syndrome is a rare condition of neonatal enteropathy characterized by intractable diarrhea, woolly hair, intrauterine growth restriction, facial dysmorphism, and short stature. Infants may also present with liver cirrhosis, platelet abnormalities, and immunodeficiency. The immune phenotype is variable and may include hypogammaglobulinemia, low antibody responses, and variably low switched-memory B cells. It is inherited autosomal recessive, with mutations in either TTC37 or SKIV2L . Inherited AR TTC7A mutation is responsible for the condition. Infants present with multiple intestinal atresias and thymic structural abnormalities leading to bacterial, fungal, and viral infections. It is often identified prenatally with intrauterine polyhydramnios and early demise, and some present with a SCID phenotype. Immunological phenotype is heterogeneous with normal B cells in general, accompanied by markedly decreased immunoglobulins due to intestinal losses, and normal to absent T cells with variable T cell function.

Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by primary immunodeficiency with terminal hepatic lobular vascular occlusion and hepatic fibrosis, which may present as hepatomegaly or liver failure. It is inherited autosomal recessive due to mutations/variants in the SP110 gene, and the onset of disease occurs prior to 6 months of age. Infants are susceptible to bacterial and opportunistic infections including PJP , mucocutaneous candidiasis, or disseminated viral infections. Immune phenotyping shows serum IgG, IgA, and IgM levels low for age; low memory B cells; absent lymph node germinal centers; and defective T-cell memory with normal T-cell numbers and normal proliferative response to mitogens.

Cartilage hair hypoplasia is a condition of immuno-osseous dysplasia that results from mutation of the RNAse mitochondrial ribonucleoprotein (RMRP) gene. It is characterized by short-limbed dwarfism, metaphyseal dysplasia, sparse hair, increased risk for malignancies, and bone marrow failure with varying degrees of immunodeficiency ranging from SCID to normal thymic function. Cartilage hair hypoplasia presenting with SCID requires hematopoietic stem cell transplantation (HSCT), which corrects immunodeficiency and autoimmunity but not musculoskeletal or growth findings. Bowel function should be closely monitored during the first year of life, as Hirschsprung’s disease is common. Other rare immune-osseous dysplasias that may present in early infancy include MYSM1 deficiency, microcephalic osteodysplastic primordial dwarfism type 1, and immunoskeletal dysplasia with neurodevelopmental abnormalities.

Dyskeratosis congenita (DC) is characterized by a triad of nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Patients with DC are predisposed to development of bone marrow failure, leukemia, and cancers. Immune phenotypes vary, but lymphopenia with low B-cell numbers and decreased T-cell function occur frequently. Disease onset in infancy is associated with more severe immunologic and somatic features, especially severe enteropathy. The inheritance pattern varies, and most present with mild phenotype.

The classical presentation of Comel–Netherton syndrome includes a triad of congenital ichthyosiform erythema, “bamboo hair” ( trichorrhexis invaginata ), and atopy. This condition is inherited autosomal recessive due to mutations in the serine protease inhibitor of the serine protease inhibitor Kazal-type 5 gene ( SPINK5 ). Infants typically present in infancy with generalized scaling erythroderma, failure to thrive, and bacterial infections, and they may experience life-threatening hypernatremic dehydration from water loss through the dysfunctional skin barrier. These infants generally have elevated IgE and IgA with decreased memory B cells.

The inherited X-linked NF-κB essential modulator (NEMO) deficiency syndrome is characterized by anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) due to abnormal development of ectodermal tissue. Hypomorphic mutations in the inhibitor of nuclear factor kappa B kinase regulatory subunit gamma ( IKBKG ) gene encoding NEMO protein lead to EDA-ID, and loss-of-function mutations of IKBKG lead to X-linked incontinentia pigmenti, usually lethal in male fetuses. Typical presentation includes conical teeth, sparse scalp hair, frontal bossing, absence of sweat glands, and early severe and multiple bacterial infections with pyogenic bacteria ( S. aureus , S. pneumoniae , or H. influenzae ) or atypical mycobacteria. Immune function varies with a range of T-, B-, and NK-cell dysfunction, but low memory B cells and impaired T-cell receptor activation is common. Infants may present with eczematous dermatitis at birth, and life expectancy depends on the degree of immune deficiency.

Predominantly antibody deficiencies

Antibody deficiencies are characterized by bacterial sinopulmonary infections, meningitis, and sepsis, as well as persistent enteroviral infections of the gastrointestinal tract or central nervous system. Antibody deficiencies are difficult to recognize in the newborn period due to passively acquired maternal IgG antibodies through the placenta and the low IgA levels that are characteristic of normal newborns. Maternal antibodies can be detected through the first 18 months of life. Immunoglobulin deficiency generally becomes apparent after 6 months of age but may be detected earlier, especially in preterm infants.

Congenital X-linked agammaglobulinemia (XLA) is the most common form and results from mutations in the gene encoding B-cell–specific src-associated tyrosine kinase (Bruton’s tyrosine kinase [BTK]). Without BTK, B-cell development stops in the pre-B-cell stage, leading to absent B cells in the blood, which can be detected by flow cytometry. ^, T-cell number and function are normal. Newborn infants with XLA may present with overwhelming enteroviral sepsis. Rarely, autosomal recessive forms of congenital agammaglobulinemia may present similarly and occur due to a defect in the µ heavy chain, Igα, Igβ, BLNK, or λ5.

Hyper-IgM (HIGM) syndromes are antibody deficiency disorders that involve defects in immunoglobulin class switch recombination, characterized by isolated normal or elevated levels of IgM with low or absent levels of immunoglobulin isotypes IgG, IgA, and IgE. Defects in CD40L and CD40 were classified in this category, but they have recently been reclassified as combined immunodeficiency, as T-cell deficiency is also involved. Currently, genetic mutations in AID , UNG , INO80 , and MSH6 , which are all rare, fall under this classification. Infants with HIGM suffer recurrent or severe bacterial infections and have enlarged lymph nodes and germinal centers.

Transient hypogammaglobulinemia of infancy (THI) is defined by IgG levels greater than 2 standard deviations below the age-appropriate range in infants over 6 months of age. The IgG levels are typically less than 400 mg/dL, and IgA and IgM levels may also be low. The ability of these infants to make specific antibodies is frequently near normal range, and most infants with THI are not susceptible to infection, so the question remains as to whether THI is a true immunodeficiency or an extension of the physiologic nadir that occurs as maternally transferred antibody wanes and the infant begins to produce its own antibodies. ^, Infants with THI may present with chronic or recurrent respiratory infections, with ear and sinus infections being the most common. Increased risk of infection in THI does not decrease with the use of intravenous immunoglobulin. Most children with THI develop age-appropriate IgG levels by age 3.