Syndromic immunodeficiencies

INTRODUCTION — A number of conditions featuring immunodeficiency may also present with clinical problems that are not directly due to the immunologic deficit (table 1) [1-4]. These inborn errors of immunity, termed "syndromic immunodeficiencies," are in contrast to other primary immunodeficiencies, in which infection is the primary manifestation and the immune problem is well characterized [5]. A large variety of manifestations have been described in the different syndromic immunodeficiencies, and a number of organ systems may be involved. Some of these conditions feature metabolic derangements or chromosomal anomalies.

In this topic review, we focus on the more common syndromic immunodeficiencies in which immune defects are noted. A number of other syndromic immunodeficiencies are listed in the table (table 1). More complete delineation of syndromic immunodeficiencies, including rare conditions and those in which immune defects are only occasionally present, are available [1,2]. Some of these disorders are discussed in detail elsewhere. (See "Bloom syndrome" and "Nijmegen breakage syndrome".)

IMPORTANCE OF RECOGNIZING SYNDROMIC FEATURES — Recognition of a syndromic immunodeficiency is important in several respects [6]. For a patient with nonimmune-related anomalies who presents to the immunologist, it is critical to ascertain if the constellation of malformations is diagnostic for a specific syndrome. This may aid in giving an accurate prognosis for the immune defect. In addition, the diagnosis may alert the clinician to monitor for abnormalities in other organ systems. The prognosis for cognitive or motor development may also be impacted. Alternatively, if a child with one of these syndromes presents initially with nonimmune medical problems, then it is important to establish if an immune defect is present so that appropriate intervention can be undertaken. In addition, being able to establish the correct diagnosis may also have implications for the recurrence risk of future pregnancies of the patient or the patient's family and relatives.

CARTILAGE-HAIR HYPOPLASIA — Cartilage-hair hypoplasia (CHH) is a rare, autosomal recessive form of short-limb dwarfism (metaphyseal chondrodysplasia). Associated features may include fine, sparse hair; cellular and humoral immunodeficiencies; Hirschsprung disease; hematologic and skin malignancies; autoimmune disease; and bronchiectasis. CHH is caused by defects in the ribonuclease mitochondrial RNA-processing (RMRP) gene. This disorder is discussed in detail separately. (See "Cartilage-hair hypoplasia".)

ICF SYNDROME — The ICF syndrome is an autosomal recessive condition comprised of Immunodeficiency, Centromeric instability, and Facial anomalies [7].

Pathogenesis — Chromosomal methylation is defective in affected patients [8]. Mutations in the gene DNA methyltransferase 3 beta (DNMT3B), which encodes a DNA methyltransferase, are causative in approximately half of individuals with this syndrome [9,10]. However, other patients diagnosed with ICF do not have identified DNMT3B mutations [11,12]. Mutations in the zinc finger and BTB domain-containing 24 (ZBTB24) gene, which encodes a transcriptional repressor involved in DNA methylation, were identified in some of these patients [13]. There are not any apparent clinical differences between those patients with a DNMT3B mutation and those with a ZBTB24 mutation.

Clinical manifestations and laboratory abnormalities — Intellectual disability frequently occurs. Characteristic facial features include ocular hypertelorism, flat nasal bridge, epicanthal folds, and low-set ears.

Immunodeficiency is manifest by the development of sinopulmonary, gastrointestinal, and cutaneous infections. The immune defect may affect both immunoglobulin levels and T cell number and function. Generally, at least two immunoglobulin classes are affected in each patient, and agammaglobulinemia can occur [14,15]. T cell number and response to mitogen may be decreased [15,16].

Diagnosis — The centromeric instability most frequently involves chromosomes 1 and 16, often 9, and rarely 2 and 10 [14,17]. Deletions, breaks, interchanges between homologous and nonhomologous chromosomes, and multibranched configurations involving pericentric heterochromatin have been described. The ICF syndrome differs from other chromosome instability syndromes in that no hypersensitivity to clastogenic agents has been demonstrated, so the condition should not be considered a chromosome breakage syndrome.

The diagnosis should be considered in individuals with immunodeficiency and the characteristic facial appearance. Most patients have intellectual disability, although some patients have normal cognitive development [18].

Treatment — Treatment is supportive and is directed to the specific clinical and immunologic problems present in the individual. Allogeneic hematopoietic cell transplantation (HCT) in patients with severe disease corrects the immunodeficiency and improves growth [19]. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

Early diagnosis and intervention can improve outcome [20].

GRISCELLI SYNDROME — The Griscelli syndrome is an autosomal recessive syndrome that features hypopigmentation and may include immunodeficiency and/or neurologic deficits, depending upon the specific genetic defect.

Clinical manifestations and laboratory abnormalities — This condition is characterized by partial albinism, neutropenia and thrombocytopenia, and hemophagocytic lymphohistiocytosis [21-24]. Neurologic involvement may be progressive, possibly due to cerebral lymphohistiocytic infiltration [25,26].

Melanosomes accumulate in melanocytes, causing clumps of pigment in hair shafts. The absence of giant granules and the histologic characteristics of the hypopigmentation differentiate this condition from Chediak-Higashi syndrome. (See "Chediak-Higashi syndrome".)

The hemophagocytosis may be associated with a viral infection [27]. Neurologic complications may be caused by lymphohistiocytosis of the central nervous system.

Patients are susceptible to fungal, viral, and bacterial infections. The immune abnormalities may affect both the cellular and the humoral immune response, with neutropenia also being noted [23].

Diagnosis — Griscelli syndrome should be considered in infants with silvery-gray hair, hepatosplenomegaly, and immunodeficiency. Microscopic examination of the hair shaft can be used to confirm the diagnosis.

Pathogenesis — Several mutations have been found in affected patients:

●Mutations in myosin VA (MYO5A), which encodes an unconventional myosin, were detected in affected patients with neurologic symptoms who lacked the hemophagocytic syndrome and also lacked immunologic deficits [28,29]. This is referred to as type 1 Griscelli syndrome (GS1, MIM#214450).

●Mutations in RAB27A, member RAS oncogene family (RAB27A), which encodes a guanosine triphosphate (GTP)-binding protein of the Ras family, were identified in patients presenting primarily with the hemophagocytic syndrome and abnormal T cell and macrophage activation with variable neurologic involvement [29]. This is termed type 2 Griscelli syndrome (GS2, MIM#607624) [30].

●Type 3 Griscelli syndrome (GS3, MIM#609227) is characterized by partial albinism alone, without immune or neurologic complications, and this type can be due to a mutation in MYO5A or in the gene that encodes for melanophilin (MLPH) [31].

Treatment — Most patients with GS1 or GS2 die in childhood, usually secondary to severe neurologic sequelae or recurrent infection. Hematopoietic cell transplantation (HCT) is the only available curative therapy that has shown some success for patients with GS2 with hemophagocytic lymphohistiocytosis and immunodeficiency [26,32-35]. Patients with GS3 have a better prognosis since they lack immune and neurologic complications.

p14 DEFICIENCY — A syndrome of severe congenital neutropenia, short stature, cutaneous hypopigmentation, coarse facial features, and recurrent respiratory infections with Streptococcus pneumoniae has been described in four members of a single White family [36]. Deficiency of the endosomal adaptor protein p14 (also known as MAPBPIP, encoded by the late endosomal/lysosomal adaptor, MAPK and MTOR activator 2 [LAMTOR2] gene) was identified in all patients, and functional reconstitution of granule activity was achieved with p14 gene transfer [36]. Defects in cytotoxic T cell activity and abnormal B cell differentiation were also noted.

SCHIMKE IMMUNOOSSEOUS DYSPLASIA — Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive condition, which features skeletal, renal, and immune abnormalities.

Clinical manifestations and laboratory abnormalities — The principal features of SIOD include short stature (often with prenatal growth deficiency), spondyloepiphyseal dysplasia, defective cellular immunity, and progressive renal failure [37,38].

Additional specific abnormalities may be seen:

●Hyperpigmented macules are frequently present, especially on the trunk.

●Patients with short stature have disproportionate shortening of the trunk and lumbar lordosis. The vertebral bodies may be abnormally shaped, and epiphyseal changes are most frequently present in the proximal femur [38].

●Corneal opacities and other ophthalmologic abnormalities may be present.

●Patients eventually develop proteinuria and nephrotic syndrome, usually due to focal segmental glomerulosclerosis. This frequently progresses to end-stage kidney disease.

●Approximately 50 percent have an arteriopathy with cerebral infarcts and/or ischemia. Most patients have normal cognitive development, and those with developmental delay have only a mild delay.

Patients are prone to viral, fungal, and bacterial infections, with recurrent infections being noted in approximately one-half of patients. T cell deficiency with decreased CD4+ number, absent interleukin 7 receptor alpha chain (IL7RA) expression, and impaired T cell function are often present [38-41]. Humoral defects also occur. Lymphopenia is characteristic (94 percent), can be recurrent, and is often associated with other hematologic abnormalities, including pancytopenia.

Diagnosis — The diagnosis should be considered in patients with short stature and immunodeficiency. Renal function should be assessed if the diagnosis is suspected. Radiographs for the characteristic bony anomalies should be performed.

Pathogenesis — Mutations in the gene encoding the chromatin remodeling protein, SWI/SNF2-related matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), have been detected in affected patients [42]. The protein participates in DNA-nucleosome restructuring that occurs during gene regulation and DNA replication and recombination. Patients with defects in this gene have reduced thymic function that correlates with clinical phenotype [43]. Other genetic loci may also be involved since almost half of affected patients do not have detectable mutations in the coding region of SMARCAL1 [44].

Treatment — Thyroid, renal, and immune function should be monitored on a yearly basis. T cell number, subsets, and function should be assessed. Since humoral defects can also occur, evaluation for these abnormalities should be performed.

Renal transplants have been successfully used for those who progress to end-stage kidney disease [38] (see "Kidney transplantation in children: General principles"). Of note, transplanted kidneys generally do not show recurrence of the renal disease [45]. Hematopoietic cell transplantation (HCT) has been used to improve bone marrow function in severely affected cases, with one child showing markedly improved function at two years posttransplant [46]. However, HCT has not been successful for other patients [47].

ROIFMAN SYNDROME — Roifman syndrome is an autosomal recessive condition characterized by microcephaly, growth retardation, spondyloepiphyseal dysplasia, developmental delay, and retinal dystrophy.

Clinical manifestations and laboratory abnormalities — This condition is characterized by spondyloepiphyseal dysplasia, short stature, developmental delay, and a characteristic facial appearance [48-50]. Retinal dystrophy may also occur.

Patients may have recurrent infections with low specific antibody titers in response to infection. Reduced mitogenic response to Staphylococcus aureus Cowan antigen has been reported. T cell number and function are normal.

Diagnosis — The diagnosis should be considered in patients with developmental delay, disproportionate short stature, and immunodeficiency. Radiographs for spondyloepiphyseal dysplasia should be performed.

Pathogenesis — Compound heterozygous mutations in the RNA, U4atac small nuclear U12-dependent splicing (RNU4ATAC) gene have been identified in affected patients [51]. The mutations of this spliceosome component result in defects of minor intron splicing. Mutations in this gene have also been detected in patients with microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), which has different associated clinical features.

Treatment — Development should be monitored. Screening for retinal abnormalities can be performed. Since humoral immunity abnormalities frequently occur, assessment for these defects should be performed.

ROIFMAN-CHITAYAT SYNDROME — Roifman-Chitayat syndrome is an autosomal recessive condition characterized by combined immunodeficiency, developmental delay, optic nerve atrophy, and skeletal anomalies.

Clinical manifestations and laboratory abnormalities — Optic nerve atrophy, myoclonic seizures, skeletal anomalies (cone-shaped epiphyses, short metacarpals and metatarsals), and developmental delay were described in two sisters of consanguineous parents [52]. Facial features included hypoplastic supraorbital ridges, hypertelorism, a flat nasal bridge, a broad nasal root, and a square chin. Both patients had severe recurrent infections, including recurrent otitis media, and multiple episodes of bacterial and viral pneumonia (including S. pneumoniae septicemia). In addition, the older sister had persistent oral thrush, and the younger sister had parainfluenzae pneumonitis with bronchial lavage showing Pneumocystis jiroveci and Klebsiella aerogenes, prolonged rotavirus-associated diarrhea, and oral thrush.

Both sisters had hypogammaglobulinemia and inadequate response to immunizations, as well as decreased response to mitogens. The number and proportion of T cell subsets were normal to elevated, with reduced natural killer cell numbers and borderline low B cell numbers.

Diagnosis — The diagnosis should be considered in patients with developmental delay, skeletal anomalies, seizures, optic nerve atrophy, and combined immunodeficiency. Radiographs for the skeletal anomalies should be performed if other findings suggest the diagnosis.

Pathogenesis — Homozygous loss-of-function mutations resulting in protein truncation were detected in both phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD; encoding phosphatidylinositol 3 [PI3]-kinase p110 delta) and kinetochore-localized astrin (SPAG5) binding protein (KNSTRN; encoding small kinetochore-associated protein [SKAP]) [53]. The features present in the patients are probably due to contributions from abnormalities in both genes.

Treatment — Development should be monitored. Patients should be screened for optic nerve abnormalities and assessed for immunologic defects. Immune globulin replacement therapy may be indicated as it led to reduced frequency of infections in the older sister described above [52].

DELETION OF CHROMOSOME REGION 22Q11.2 (DiGEORGE SYNDROME) — Deletion of the 22q11.2 chromosome region is associated with the clinical conditions DiGeorge syndrome, velocardiofacial syndrome (VCFS), and (less commonly) Opitz G/BBB (oculogenitolaryngeal) syndrome. DiGeorge syndrome and VCFS are reviewed in more detail separately. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "Syndromes with craniofacial abnormalities".)

The Opitz G/BBB syndrome is characterized by ocular hypertelorism, hypospadias, and laryngoesophageal defects. Some patients diagnosed with Opitz G/BBB syndrome have deletions of 22q11, although mutations in a gene on chromosome Xp22, named midline 1 (MID1), have been identified in others [54]. It is likely that a relatively small proportion of patients with Opitz G/BBB have deletions of 22q11.

DELETIONS OF CHROMOSOME REGION 10p13-p14 — Deletions of the chromosome region 10p13-p14 are also associated with DiGeorge syndrome [55,56]. The deletions in these patients generally extend beyond the DiGeorge syndrome critical region to include the GATA-binding protein 3 (GATA3) gene [57]. This gene is also mutated in the syndrome of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome [58]. Patients with DiGeorge syndrome and 10p13-14 deletions more often have deafness than patients with underlying mutations in 22q11. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)

PARTIAL DELETIONS OF CHROMOSOME 4p (WOLF-HIRSCHHORN SYNDROME) — Deletions of chromosome 4p are associated with intellectual disability, growth deficiency, and immunodeficiencies. The critical region for the deletion is on chromosome 4p16.3. The deletion occurs de novo in approximately 87 percent of cases (approximately 80 percent involve the paternal chromosome) and, in the remainder of the cases, is due to a balanced translocation in one of the parents (most involve the maternal chromosome) [59-61].

Clinical manifestations, laboratory abnormalities, and pathogenesis — Affected patients often have prenatal and postnatal growth failure, intellectual disability, microcephaly, widely spaced eyes, and seizures. Hearing loss, optic coloboma, renal anomalies, structural brain anomalies, skeletal anomalies, abnormal tooth development, and congenital heart disease may also be present [62]. There is some correlation between deletion size and clinical severity [63].

Patients have frequent episodes of respiratory infections due in part to recurrent aspiration. Antibody deficiencies are also common. Immune defects include common variable immunodeficiency, immunoglobulin A (IgA) and immunoglobulin G2 (IgG2) subclass deficiency, IgA deficiency, and impaired polysaccharide responsiveness [64]. T cell immunity is normal. Immunodeficiency does not appear to correlate with deletion size.

The exact pathogenesis of Wolf-Hirschhorn syndrome (WHS) is unknown. Wolf-Hirschhorn syndrome candidate 1 (WHSC1) gene is deleted in all known cases of WHS. This gene encodes an H3K36me3-specific histone methyltransferase (HMTase) that plays a role in transcriptional regulation. One of the factors that WHSC1 modulates is Nkx2-5, a central transcriptional regulator of cardiac development. The interaction of WHSC1 with multiple different transcription factors may account for the variability in clinical phenotype [65].

Diagnosis — Many of the deletions are cytogenetically visible on a standard karyotype. In some cases, molecular techniques may be required for the diagnosis if the deletion is relatively small, such as fluorescence in situ hybridization (FISH) or array-based approaches.

Treatment — Treatment is supportive and directed to the specific clinical indications. Feeding difficulties are often present, and, if indicated, gastrostomy tube placement may be considered [66]. Audiologic screen, ophthalmologic evaluation, and careful cardiac exam may be performed. Developmental evaluation and appropriate intervention should be undertaken. Chromosome analysis of the parents should be performed.

BLOOM SYNDROME — Bloom syndrome, an autosomal recessive condition, is associated with short stature, a characteristic facial appearance, and increased risk of neoplasia. Bloom syndrome has been reported in a variety of ethnic groups, with an increased frequency in the Ashkenazi-Jewish population. This condition is discussed in detail separately. (See "Bloom syndrome".)

NIJMEGEN BREAKAGE SYNDROME — Nijmegen breakage syndrome, an autosomal recessive condition, is characterized by short stature and immune defects. The condition has been most frequently described in patients of Eastern European ancestry. This disorder is discussed in detail separately. (See "Nijmegen breakage syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

●Definition – A number of conditions featuring immunodeficiency may also present with clinical problems that are not directly due to the immunologic deficit (table 1). These inborn errors of immunity, termed "syndromic immunodeficiencies," are in contrast to other primary immunodeficiencies, in which infection is the primary manifestation and the immune problem is well characterized. (See 'Introduction' above.)

●ICF syndrome – The immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is an autosomal recessive condition caused by defective chromosomal methylation. Intellectual disability frequently occurs. Characteristic facial features include ocular hypertelorism, flat nasal bridge, epicanthal folds, and low-set ears. Immunodeficiency is manifest by the development of sinopulmonary, gastrointestinal, and cutaneous infections. (See 'ICF syndrome' above.)

●Griscelli syndrome type 2 – GS2 is an autosomal recessive condition characterized by partial albinism, neutropenia and thrombocytopenia, and hemophagocytic lymphohistiocytosis. Neurologic involvement may be progressive. Patients are susceptible to fungal, viral, and bacterial infections. (See 'Griscelli syndrome' above.)

●Schimke immunoosseous dysplasia – SIOD is an autosomal recessive condition with the principal features of short stature (often with prenatal growth deficiency), spondyloepiphyseal dysplasia, defective cellular immunity, and progressive renal failure. Patients are prone to viral, fungal, and bacterial infections. (See 'Schimke immunoosseous dysplasia' above.)

●Roifman syndrome – Roifman syndrome is an autosomal recessive condition characterized by microcephaly, growth retardation, spondyloepiphyseal dysplasia, developmental delay, and retinal dystrophy. (See 'Roifman syndrome' above.)

●Partial deletions of chromosome 4p – Partial deletions of chromosome 4p are associated with intellectual disability, growth deficiency, and immunodeficiencies. Patients have frequent episodes of respiratory infections due in part to recurrent aspiration. Antibody deficiencies are common, but T cell immunity is normal. (See 'Partial deletions of chromosome 4p (Wolf-Hirschhorn syndrome)' above.)

●Other syndromic immunodeficiencies – Syndromic immunodeficiencies that are discussed in other topic reviews include cartilage-hair hypoplasia (CHH); p14 deficiency; deletion of the 22q11.2 chromosome region that is associated with the clinical conditions DiGeorge syndrome, velocardiofacial syndrome (VCFS), and (less commonly) Opitz G/BBB syndrome; deletions of the chromosome region 10p13-p14 that are also associated with DiGeorge syndrome; Bloom syndrome; Nijmegen breakage syndrome, Wiskott-Aldrich syndrome, and ataxia-telangiectasia . (See "Cartilage-hair hypoplasia" and "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "Syndromes with craniofacial abnormalities", section on 'Velocardiofacial (Shprintzen) syndrome' and "Bloom syndrome" and "Nijmegen breakage syndrome" and "Wiskott-Aldrich syndrome" and "Ataxia-telangiectasia".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.