ICF Syndrome (Immunodeficiency, Centromeric Instability and Facial Anomalies), Types 1–4

Literature and regulatory information update: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and definition

Immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is an autosomal recessive inborn error of immunity whose definition rests on a triad: immunoglobulin deficiency despite the presence of circulating B lymphocytes, rearrangements of the heterochromatin adjacent to the centromeres of chromosomes 1, 16 and, less often, 9, visible in mitogen-stimulated lymphocytes, and mild facial dysmorphism [20, 26]. The first published observation dates from 1979, when Tiepolo and colleagues described, in a 12-year-old boy with combined IgA and IgE deficiency, instability of the centromeric region of chromosome 1 and multibranched configurations formed by arms of chromosomes 1, 9 and 16 in cultured lymphocytes, without abnormalities in fibroblasts or in the parents' lymphocytes [27]. In 1988, Maraschio and colleagues studied a 4-year-old girl, compared her with the previous patient and with four published cases and proposed the acronym ICF for the association between combined immunodeficiency, centromeric heterochromatin instability and facial anomalies, postulating a defect in the condensation of that heterochromatin [26]. The instability does not occur in the centromere proper, but in the constitutive juxtacentromeric heterochromatin (qh regions) of the long arms of chromosomes 1, 9 and 16, formed mainly by classical satellites 2 and 3, regions that are hypomethylated in all ICF cell populations examined [20, 28]. In the International System for Human Cytogenomic Nomenclature (ISCN), the letter «h» designates constitutive heterochromatin, as in 16qh+ [29]. A 2026 review dates the initial description to 1978 [16].

1.2. Milestones of the molecular discovery

Until the mid-1990s only 14 to 15 patients had been described, and it was already known that the classical satellite DNA of these patients had an altered methylation pattern [30, 31]. In 1998, homozygosity mapping in three consanguineous families localised the locus to a 9 cM region in 20q11–q13, between the markers D20S477 and D20S850 [32]. In 1999, three independent groups linked the disease to the de novo DNA methyltransferase gene DNMT3B: Xu and colleagues identified biallelic variants in five unrelated patients, noting that classical satellites 2 and 3, normally heavily methylated, were almost completely demethylated in all tissues, which made ICF the first known genetic disease with a constitutive abnormality of genomic methylation [33]; Hansen and colleagues described the first natural mutations in a mammalian DNA methyltransferase, including a three-amino-acid insertion created by a new splice acceptor site [34]; and Okano and colleagues demonstrated, in the mouse, that Dnmt3a and Dnmt3b are indispensable for de novo methylation and development, with Dnmt3b responsible for methylation of the centromeric satellites [35]. In 2000 it became clear that only some patients had DNMT3B variants (9 of 14 in one series) and that there was genetic heterogeneity [36]. In 2005 two types of patient were distinguished: both with hypomethylation of the classical satellites, but the second without DNMT3B variants and with additional hypomethylation of the centromeric α satellite [37]; in the same year it was estimated that almost 40% of published patients had no DNMT3B variant [5]. The following reviews gave similar proportions: biallelic variants in the coding region of DNMT3B in 57% of 35 patients analysed, with α satellite hypomethylation in 9 of 9 patients without a variant and in 0 of 5 with a variant [20], and DNMT3B variants in 19 of 34 patients studied in the 2008 review, with no phenotypic difference between patients with and without a variant [38]. The second gene, ZBTB24, was identified in 2011 by homozygosity mapping and exome sequencing [39], and the genes CDCA7 and HELLS were described in 2015 in ten patients until then without a genetic explanation [40].

1.3. Nomenclature and classification

The nomenclature in force distinguishes four types according to the gene: ICF1 (DNMT3B), ICF2 (ZBTB24), ICF3 (CDCA7) and ICF4 (HELLS); patients with the phenotype and no variant identified in the four genes are historically designated ICFX [14, 16, 17]. Before 2011, «ICF2» designated all patients without a DNMT3B variant, so reading older articles requires attention to this usage [37, 39]. A patient with biallelic UHRF1 variants and an atypical picture, without immunodeficiency, was described as an atypical form, not included among the four official types [41, 42]. Orphanet uses a single code for the whole syndrome (ORPHA:2268) [2]. The 2024 classification of the International Union of Immunological Societies (IUIS) places the four types in the table of combined immunodeficiencies with syndromic features, in the subgroup of DNA repair defects, alongside ataxia-telangiectasia, Nijmegen breakage syndrome, Bloom syndrome and PMS2 deficiency; for the four genes, the table records decreased or normal T lymphocytes, sometimes decreased response to PHA, decreased or normal B lymphocytes, hypo- or agammaglobulinaemia with variable antibody deficiency, facial dysmorphism, macroglossia, developmental delay, bacterial and opportunistic infections, malabsorption, cytopenias, neoplasms and multiradial configurations of chromosomes 1, 9 and 16 [21]. ClinGen classifies the relationship of DNMT3B and ZBTB24 with the disease as definitive and that of HELLS (June 2025) and CDCA7 (April 2026) as moderate, reflecting the small number of families described for these two genes [13]. The 2017 Oxford handbook presents only ICF1 and ICF2, with the type 2 gene spelled «ZBT2B4», a misprint for ZBTB24 [43].

1.4. The syndrome as a class

ICF syndrome is a syndromic class: the four types share hypogammaglobulinaemia with B lymphocytes, hypomethylation of the pericentromeric satellites with the characteristic chromosomal instability and facial dysmorphism, and they differ in aspects that have practical consequences, such as the severity of the humoral defect, the frequency of intellectual disability, the methylation pattern and the predisposition to Epstein-Barr virus (EBV)-associated lymphomas [14, 16, 17]. Digenic facioscapulohumeral muscular dystrophy due to a heterozygous DNMT3B variant (FSHD4) is an allelic disease of ICF1, whose importance for ICF1 families lies mainly in counselling [24, 25].

2. Molecular Genetics and Pathophysiology

2.1. The four genes and the common pathway

DNMT3B encodes one of the two de novo DNA methyltransferases (with DNMT3A) that establish CpG methylation patterns during embryogenesis and haematopoietic differentiation, with a preference for pericentromeric satellite repeats; the protein has the chromatin-reading domains ADD (ATRX-Dnmt3-Dnmt3L) and PWWP in the N-terminal region and a C-terminal catalytic S-adenosylmethionine-dependent methyltransferase domain with conserved motifs [7, 16]. DNMT3B also keeps the D4Z4 macrosatellite and the DUX4 retrogene silenced in somatic cells, which explains the allelic muscular disease [7, 25]. ZBTB24 encodes a transcription factor with a BTB domain (amino acids 10–133), an A-T hook that binds DNA (amino acids 159–171) and eight C2H2 zinc fingers (amino acids 294–512), belonging to a family of more than 40 ZBTB proteins with roles in haematopoietic differentiation, such as BCL6 [39]. The gene is ubiquitously expressed, with maximum levels in naïve B lymphocytes [16]. The link between ICF2 and ICF3 is direct: ZBTB24 binds the CDCA7 promoter and activates its transcription; in the mouse, loss of Zbtb24 reduces Cdca7 more than any other transcript, and patients with nonsense ZBTB24 variants have reduced CDCA7 levels [44]. CDCA7 encodes a MYC-regulated nuclear protein whose C-terminal 4-CXXC zinc finger domain recognises hemimethylated CpGs in nucleosomes and recruits the remodeller HELLS to pericentromeric heterochromatin [7, 16]. HELLS (also designated LSH or SMARCA6) encodes an ATP-dependent chromatin remodeller of the SNF2 family, which promotes de novo methylation of repetitive sequences, recruits DNA methyltransferases and histone deacetylases, silences transposable elements, participates in homologous recombination of double-strand breaks in heterochromatin and is required for lymphoid expansion [7].

2.2. Establishment and maintenance of methylation: three patterns

The molecular feature common to the four types is hypomethylation of classical satellites 2 and 3 (hSATII and hSATIII) of the pericentromeric regions of chromosomes 1, 9 and 16 [42, 45]. Transient depletion of HELLS, CDCA7 and ZBTB24, but not of DNMT3B, reduces methylation of the centromeric repeats in mouse embryonic fibroblasts, which indicates that DNMT3B acts in establishing methylation during development and that ZBTB24 and CDCA7 act in its maintenance, with HELLS possibly performing both roles [40]. Unoki distinguishes three patterns: DNMT3B variants impair establishment after implantation and produce pericentromeric and subtelomeric hypomethylation; ZBTB24, CDCA7 and HELLS variants impair replication-uncoupled maintenance in regions that require remodelling by the CDCA7–HELLS complex (heterochromatin, B compartment, late replication), including the pericentromeric and centromeric but not the subtelomeric regions; and UHRF1 variants impair both coupled and uncoupled maintenance, with pericentromeric, centromeric and subtelomeric hypomethylation [42]. The genomic methylation profile separates ICF1 from ICF2, ICF3 and ICF4: these three affect CpG-poor regions with heterochromatin features, including clusters of monoallelically expressed genes involved in neuronal development, a finding consistent with the higher frequency of intellectual disability in these subgroups [45]. Subtelomeric hypomethylation, increased transcription of the telomeric RNA TERRA, accelerated telomere shortening and early senescence of fibroblasts are exclusive to ICF1; in ICF2–4 subtelomeric methylation and telomere length are normal [46]. The additional hypomethylation of the centromeric α satellite, initially used to separate «two types» of patient, corresponds to the non-DNMT3B genotypes [37, 39]. Despite the importance of these regions, the overall reduction in 5-methylcytosine in ICF tissues is only about 7% [20]. Other hypomethylated regions described include the NBL2 and D4Z4 macrosatellites, Alu sequences, PGK1 and other X-chromosome sequences, and imprinted genes such as H19 [16, 39].

2.3. From hypomethylation to chromosomal instability

Pericentromeric heterochromatin, normally compact and cohesive, decondenses when it loses methylation, which allows aberrant recombination between repeats of different chromosomes, breaks and multibranched configurations [16]. In HEK293 cell lines with the ICF genes inactivated, aberrant transcription of hSATII from the hypomethylated regions generates DNA:RNA hybrids (R-loops) that cause double-strand breaks; the cells grow more slowly and show more apoptosis, enlarged nuclei and numerous, bulky centrosomes [42]. ICF lymphoblastoid lines show decondensation of 1qh and 16qh as early as interphase, increased colocalisation of these regions, anaphase bridges, fragmentation of chromosomes 1 and 16 and micronuclei containing material from these chromosomes [20]. The classical cytogenetic descriptions, summarised in OMIM, include despiralisation, chromatid and chromosome breaks, somatic pairing and homologous and non-homologous exchanges of the heterochromatin of chromosomes 1, 9 and 16, generally restricted to lymphocytes, with nuclear protrusions and micronuclei and without the major abnormalities in fibroblasts; classical satellites also exist in the distal region of Yq, where no abnormalities have been described [1]. Cell specificity is marked: the abnormalities predominate in stimulated lymphocytes and are scarce in bone marrow and in fibroblasts of many patients, and normal chorionic villus cultures, also hypomethylated in these regions because of their extraembryonic origin, rarely show rearrangements at early passages [1, 20].

2.4. From methylation to immunodeficiency

Patients have naïve B lymphocytes, but no memory B cells or plasma cells in peripheral blood [42]. Circulating B lymphocytes have an immature phenotype and undergo increased apoptosis when activated, although class-switch recombination stimulated in vitro by CD40 and IL-4 was normal in an old study [14]. In recent years, CDCA7, HELLS and ZBTB24 have been implicated in the classical non-homologous end joining (NHEJ) pathway: CDCA7 interacts with Ku80 and with DNA-dependent protein kinase, the CDCA7–HELLS complex facilitates Ku80 access to breaks, and ZBTB24 stimulates PARP1 auto-PARylation, protects poly-ADP-ribose chains from degradation and promotes assembly of the DNA ligase 4–XRCC4 complex [42]. Because class-switch recombination depends on NHEJ, these defects partly explain the lack of IgG and IgA: the mouse with haematopoietic inactivation of Hells has low IgG and normal IgM, and ICF2 patients have almost normal unswitched and decreased switched memory B cells, with intact V(D)J recombination and AID induction [42]. The simultaneous reduction of IgM, IgG and IgA observed in many patients is not explained by class switching alone: in the mouse with haematopoietic inactivation of Zbtb24, the Il5ra promoter becomes hypomethylated, overexpression of the IL-5 receptor increases CD19 phosphorylation and the animals respond poorly to T-independent type 2 antigens (such as bacterial capsular polysaccharides), with a reduction in plasma cells and in all immunoglobulin classes, and respond excessively to T-dependent antigens [7, 42]. The patients' naïve B lymphocytes have long VHCDR3 regions, potentially autoreactive [42]. Class-switch recombination defects are documented mainly in ICF2, with few data in ICF1 [16]. In ICF1, lymphoblastoid lines show altered expression of immunoglobulin signalling genes, decreased CD27 through hypermethylation of its promoter and alternative splicing of CD45 [42]. HELLS is also required for T cell-dependent B responses and for persistence of germinal centres, which may explain the low IgG in the four types [42].

The T compartment is also involved. In a subgroup of patients there is lymphopenia, inversion of the CD4/CD8 ratio through reduction of CD4 cells and increased apoptosis after mitogen stimulation; regulatory T lymphocytes (Treg) and recent thymic emigrants are decreased and effector memory CD4 T cells and circulating T follicular helper cells (cTFH) are increased in most patients studied [42, 47]; in the Turkish cohort, follicular regulatory T lymphocytes were also reduced and there was a shift towards a Th2 profile [47]. Expansion of T lymphocytes after stimulation with PHA and IL-2 is significantly lower in ICF1 and ICF2 patients than in controls and relatives (P=0.028), which suggests an intrinsic T defect [14]. CD19 activation, the imbalance between T subsets and activation of innate immunity by aberrant satellite RNA (demonstrated in zebrafish lacking Zbtb24) are the mechanisms proposed for the autoimmune manifestations [42].

2.5. Animal models and compatibility with life

The murine models reproduce the disease only in part: mice with Dnmt3b missense mutations equivalent to those of ICF1 have hypomethylation of repeats, low weight and craniofacial anomalies, but have no B defect, and show massive thymocyte apoptosis after birth [14, 39]. Complete inactivation of Dnmt3b is lethal between E14.5 and E16.5, with defects including ventricular septal defect, which is consistent with the cardiac malformations of some patients [14]. Loss of Zbtb24 is lethal in early embryogenesis and loss of Hells is lethal in the perinatal period, whereas patients with biallelic null variants in ZBTB24 (including complete deletion of the locus) and in HELLS survive [22, 40, 42]. In ICF1, by contrast, no patient is homozygous for nonsense alleles and N-terminal truncating variants appear in compound heterozygosity with catalytic domain missense variants, which suggests that total absence of DNMT3B is incompatible with human life and that the causal variants leave residual activity [16, 20, 36].

2.6. Variant spectrum and genotype-phenotype correlations

In ICF1, most variants are missense in or near the catalytic domain, affecting residues conserved in the ten motifs of the cytosine-C5-methyltransferases; a recurrent intronic variant, NM_006892.4:c.2421-11G>A, creates a new splice acceptor site and inserts amino acids with a termination codon (historically described as p.E806_R807insSTP) [8, 14, 20]. Some missense variants have a known structural effect (numbering of protein NP_008823.1): p.(His814Arg), p.(Asp817Gly) and p.(Val818Met) prevent homodimer formation; p.(Arg823Gly) reduces affinity for DNA; p.(Leu656Pro), p.(Leu656Thr) and p.(Arg670Gln) disturb assembly of the DNMT3B–DNMT3B complex [16]. The variant p.(Ser270Pro) lies in the PWWP domain [16]. An ICF1 patient with a mild picture was homozygous for NM_006892.4:c.2308A>G, p.(Lys770Glu) [8, 14]. In ICF2, most variants are nonsense or frameshift, many in homozygosity, without a hotspot [14, 39]; the known pathogenic missense variants lay in the zinc fingers, where they impair CDCA7 activation and localisation to heterochromatin [48, 49], until the description, in 2026, of missense variants in the BTB domain (NM_014797.3:c.127G>C, p.(Val43Leu), homozygous, and c.175A>G, p.(Ser59Gly), previously described in compound heterozygosity) that destabilise the protein and act as loss of function; the patient homozygous for p.(Val43Leu) had severe infections in the first year, developmental delay, an abnormal face and a methylation profile identical to that of ICF2 patients [8, 48]. A homozygous deletion of exons 1–5 of ZBTB24 (NG_029388.1:g.2831_18995del) has also been described [50]. The original ICF3 variants were homozygous missense variants near the first two motifs of the 4-CXXC domain of CDCA7 [40], and the ICF4 variants include a missense variant in the helicase domain, splicing variants, frameshift deletions, an in-frame deletion of Leu801 and two nonsense variants in compound heterozygosity [40]. A functional assay with a luciferase reporter and chromatin immunoprecipitation allows classification of ZBTB24 missense variants of uncertain significance; applied to two published variants, it indicated that they were probably not causal, and showed that rare gnomAD variants in the C2H2 zinc fingers have loss of function, that is, they correspond to carriers [51].

The following table presents published variants, normalised in VariantValidator (GRCh38) with the MANE Select transcript.

The CDCA7 variants published in recent series (c.1114C>T and c.1077delC in the transplant cohort; c.695delC in a Chinese series) were described without a transcript; in the MANE transcript, c.1114C>T would correspond to a termination codon and c.695del to a frameshift different from the one described, so they cannot be safely normalised from the publications [8, 17, 62].

Genotype-phenotype correlations come mainly from the European registry of 44 patients: the humoral defect is generally more marked in ICF1 (all patients with data had IgA deficiency), the B and T compartments are involved in both types and intellectual disability is significantly more frequent in ICF2 (13/13 versus 9/20 in ICF1; P=0.001) [14]. The only ICF2 patient with two ZBTB24 missense variants had normal IgG and IgA, which suggests that truncating alleles produce more severe deficiencies [14]; in a review of 39 patients with ZBTB24 variants, low IgG and IgA and Candida and Pneumocystis infections were more frequent with truncating variants [61]. In ICF1, the four patients who developed neutropenia, thrombocytopenia and T lymphopenia in the second decade had variants in the same region, presumed to destabilise the protein [14]. Predisposition to EBV-associated lymphomas and haemophagocytic lymphohistiocytosis, as well as natural killer (NK) cell dysfunction, is concentrated in ICF2 [17, 65]. A meta-analysis of all published cases found 79% of patients to be male in ICF2, a bias absent in ICF1 and still unexplained [22]. Expressivity is variable even within families: three siblings with the same ZBTB24 variant ranged from late-onset combined immunodeficiency with severe respiratory infections and recurrent shingles to asymptomatic selective antibody deficiency [55]. Penetrance in homozygotes or compound heterozygotes is complete for the cellular phenotype, but clinical immunodeficiency is not universal, as shown by an ICF2 patient with low IgM and no infections [66].

2.7. Allelic disease: facioscapulohumeral dystrophy due to DNMT3B

Heterozygous DNMT3B variants may derepress the D4Z4 repeat and increase the penetrance of facioscapulohumeral muscular dystrophy (FSHD) when they coexist with a permissive 4qA haplotype; OMIM classifies this entity as digenic FSHD4, with onset described between 30 and 63 years and incomplete penetrance [24, 25]. In ICF1 patients, D4Z4 hypomethylation is severe (Delta1 between −35% and −46%), and some heterozygous parents have reduced values (−19% to −26%), similar to those of patients with FSHD; about half the carriers in these families did not have a permissive chromosome 4, and those who did had repeats much larger than those typical of FSHD [25]. Fibroblasts from ICF1 patients transdifferentiated into muscle produced small amounts of DUX4, and a 15-year-old patient with an 11-unit repeat on a permissive chromosome might still be too young to manifest weakness; the short life expectancy of ICF1 patients may conceal this phenotype [25]. The immunological treatment of ICF does not apply to the muscular form [7].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and their limitations

Knowledge of the natural history rests on small series and reviews of published cases: the review by Hagleitner and colleagues (45 patients with proven centromeric instability, 2008), the European registry analysed by Weemaes and colleagues (66 patients registered, 44 with molecular study: 23 ICF1, 13 ICF2 and 8 ICFX, 2013), the French (9 patients), Japanese (11) and Turkish (12) national cohorts, the systematic review by Kiaee and colleagues (48 studies, 118 patients, 2021) and the international cohort of 18 transplanted patients from the inborn errors working party of the European Society for Immunodeficiencies and the European Society for Blood and Marrow Transplantation (EBMT/ESID, 2024) [14, 15, 17, 38, 47, 67, 68]. These series bring together patients from different decades, with varying degrees of treatment, and have publication bias towards severe cases; the denominators vary from feature to feature according to the data available.

3.2. Immune system: humoral deficiency

Hypo- or agammaglobulinaemia is the central immunological finding: it was present in 39 of 44 patients in the 2008 review [38]. In the European registry, all ICF1 patients but one had hypo- or agammaglobulinaemia (agammaglobulinaemia, defined as IgG <2.5 g/L, in at least 14), all 20 with data had IgA deficiency and only three had normal IgM; in ICF2, one patient (the only one with two missense variants) had normal IgG and IgA, and of the remaining 12 half had hypogammaglobulinaemia and half agammaglobulinaemia, with (sub)normal IgA in seven, (sub)normal IgM in seven and both normal in four [14]. The median IgA, IgG and IgM levels were greatly reduced in the four types in the systematic review [15]. The total number of B lymphocytes is usually normal, but memory B cells are absent: all nine French patients lacked CD19+CD27+ memory B cells, a finding proposed as a major diagnostic criterion of ICF1 and ICF2 [67], and in the transplant cohort switched memory B cells were ≤1% in the three patients assessed [17]. Total B lymphocytes may, however, be low: in 4 of the Japanese patients and in at least a third of the 39 patients with ZBTB24 variants reviewed in 2020, all with a reduction of at least one isotype [61, 68]. Mass cytometry of an ICF2 patient showed a reduction in NK cells and switched memory B cells and low IgG4 and IgM, with T lymphocytes and myeloid cells at normal frequency [69]. The deficiency may be partial or vary over a lifetime: there are patients with IgG subclass deficiency only [20], an Iranian boy had low IgG and IgM in childhood and IgA and IgM deficiency at 10 years [70], and an ICFX patient with isolated IgM deficiency progressed to agammaglobulinaemia during JC virus encephalitis [14]. Vaccine responses are inadequate [17, 55].

3.3. Immune system: cellular compartment and evolution with age

In young children, CD3+, CD4+ and CD8+ lymphocytes are usually normal in ICF1 and ICF2 [14]. The immunodeficiency is, however, progressive: in the European registry, four ICF1 patients developed, in the second decade, neutropenia and thrombocytopenia with a decrease in B and T lymphocytes, one of them with a hypoplastic marrow [14]; in three ICF2 siblings followed over time there was gradual depletion of B and CD4 lymphocytes, with transition from a disease resembling common variable immunodeficiency (CVID) to late-onset combined immunodeficiency in one of them [55]; and the first description of combined immunodeficiency appearing with age was made in ICF2 [71]. In the Japanese cohort, mitogen proliferation was decreased in three of six patients, memory B cells were low in seven of nine, CD3 cells were low in three, the CD4/CD8 ratio was inverted in five, CD31+ recent thymic emigrants were low in two and T-cell receptor excision circles (TREC) were undetectable in two; ICF2 patients had fewer B and NK lymphocytes and more T lymphocytes than ICF1 patients [68]. In the Turkish cohort, T proliferation and CD25 induction were decreased in all patients, especially in CD8 cells, and gastrointestinal involvement correlated negatively with CD3, CD4 and NK counts [47]. In the transplant cohort, T counts were normal for age in 12 of 16 evaluable patients, and the two cases of T lymphopenia without immunosuppressive treatment occurred in ICF3 patients aged 5.5 and 15 years; NK cells were normal in 80% [17]. An ICF1 patient homozygous for NM_006892.4:c.1753G>A, p.(Ala585Thr), had normal TREC and KREC and normal repertoires at presentation and progressively lost CD4 lymphocytes [60]. NK abnormalities and NK dysfunction have been described mainly in ICF2 [17, 65, 69]. In a Turkish study of five patients, CD3, CD4, CD8 and CD19 lymphocytes were normal in the three ICF3 patients (except CD19 in one) and low in the two ICF2 patients, and expression of the transcription factors of the Th1, Th17 and Treg subsets was decreased relative to controls [63].

3.4. Infections

Recurrent infections are the usual mode of presentation, generally in the first or second year of life: almost all patients have severe respiratory infections and more than half have recurrent gastrointestinal infections, with otitis, sepsis, pericarditis and oral candidiasis also described [20]. In the European registry, bronchopneumonia occurred in 16 of 16 ICF1 patients assessed, 5 of 7 ICF2 and 3 ICFX; otitis in 8 of 13 ICF1 and 2 of 6 ICF2; sepsis in 5 ICF1, 1 ICF2 and 1 ICFX; candidiasis in 4, 2 and 2; and Pneumocystis jirovecii pneumonia (PJP) in 2 patients of each group [14]. The systematic review found sepsis and fungal infections to be more frequent in ICF1 [15]. Opportunistic infections occur even with normal T counts and indicate a functional T defect: in the transplant cohort, two thirds (12/18) had opportunistic infections (PJP, EBV, cytomegalovirus or adenovirus viraemia, severe candidiasis) and a third (6/18) had bronchiectasis before transplantation [17, 38]; in the French cohort, three of nine patients had bronchiectasis [67]. In the review of 39 patients with ZBTB24 variants, respiratory infections and facial anomalies were present in more than 80% [61]. Severe and fatal viral infections have been described: rubella pneumonitis in a 6-year-old girl [72], influenza, persistent EBV infection and progressive multifocal leukoencephalopathy due to JC virus in an adult [68, 73], enterovirus encephalitis with severe sequelae [17], Pseudomonas aeruginosa meningitis [56, 59] and cytomegalovirus pneumonitis in infancy [65]. In the transplant cohort, viral gastrointestinal infections (norovirus, astrovirus, sapovirus) were frequent [17].

3.5. Digestive system and growth

Chronic diarrhoea, enteropathy and failure to thrive weigh on the prognosis. In the European registry, diarrhoea occurred in 7 of 14 ICF1 patients, 2 of 6 ICF2 and 2 of 3 ICFX, and failure to thrive in 8, 3 and 2 patients [14]. In the transplant cohort, 13 of 18 patients (72%) had diarrhoea and/or failure to thrive, three needed a nasogastric tube or parenteral nutrition, and enteropathy was recorded in 4 of 5 evaluable ICF1 patients, 4 of 4 ICF3 and 2 of 2 ICF4, but in only 1 of 4 ICF2; enteropathy with or without failure to thrive was the second indication for transplantation (56%) [17]. In the Turkish cohort, seven of twelve patients had gastrointestinal involvement [47]. Resolution of the enteropathy after transplantation indicates that the cause is immunological and not intrinsic to the gut [17]. Granulomatous hepatitis (ICF2), macronodular cirrhosis after treatment of acute lymphoblastic leukaemia (ICF1) and cirrhosis of unknown cause in an adult have been described [14, 19, 61]. Low birth weight (below the 10th centile) occurred in 9 of 20 ICF1 patients, 4 of 6 ICF2 and 4 of 5 ICFX, and prematurity in 3 of 20, 1 of 7 and 0 of 5 [14]; intrauterine growth restriction and short stature are frequent [20, 74].

3.6. Face and malformations

Facial dysmorphism is mild, variable and almost constant: it was present in 41 of 42 patients in 2008 and in 21 of 22 ICF1, 13 of 13 ICF2 and 7 of 7 ICFX in 2013, with a single ICF1 patient having a normal face even in adulthood [14, 38]. The following table transcribes the frequencies from the European registry.

Source: European registry, 44 genetically studied patients; the denominators correspond to the patients with data for each feature [14].

The congenital malformations of ICF1 included cardiac defects in three patients (two ventricular septal defects and one atrial septal defect), cleft lip, clinodactyly and syndactyly, choanal stenosis, hip dislocation and horseshoe kidney, and one case of congenital hypothyroidism; in ICF2 there was one atrial septal defect and one dilatation of the ascending aorta [14]. The 2025 North American practice parameter adds inguinal hernia, hypospadias and cleft palate [23]. Other findings described are café-au-lait or hyperpigmented patches, bifid nipples, scleral telangiectasias, a protuberant abdomen with thin limbs [20, 66], scoliosis [70], bilateral vesicoureteric reflux with renal failure and dialysis [58], a bronchopulmonary collateral artery [59] and, in the ICF3 patient previously labelled as IHRDIP, the son of consanguineous Turkish parents, intrauterine growth restriction, microcephaly, ischiadic hypoplasia, renal dysgenesis, polydactyly, conductive deafness, strabismus, hypospadias, cryptorchidism and, later, scoliosis, tapetoretinal degeneration and intellectual disability [4, 5]. The three Lebanese siblings with ICF2 had a round face, high palate, retrognathia, everted lower lip, head circumference between the 5th and 15th centiles and height below the 5th centile [3, 54].

3.7. Neurodevelopment and nervous system

Motor and speech delay is the rule and intellectual disability is variable: it was present in about a third of patients in the older series and in all ICF2 patients of the European registry, against about half of the ICF1 patients [14, 20]. The systematic review confirmed intellectual disability and prematurity as more frequent in ICF2 [15]. Neurological deficits (ataxic gait, hypotonia) have been described in about a fifth of patients, and in one case psychomotor delay normalised at 36 months [20]. The brain malformations described include hypoplasia of the corpus callosum, macrocephaly, cortical atrophy (four patients), focal cortical heterotopia and a large arachnoid cyst [14, 66]. There are patients with normal intelligence, including a Japanese patient who died of a viral infection and a man diagnosed at 42 years [19, 68].

3.8. Immune dysregulation and autoimmunity

Autoimmunity was considered rare, but is probably underestimated: it is estimated at 10–20% of patients [42]. In the French cohort, two ICF1 patients had autoimmune hepatitis, nephritis and thyroiditis, and a patient with severe autoimmunity and pancytopenia was transplanted [67]; in ICF2, granulomatous hepatitis and nephritis have been described [61, 71]; and in the transplant cohort a third (6/18) had immune dysregulation — cytopenias of one to three lineages, enteropathy or colitis, hepatitis, renal and skin disease — often without detectable autoantibodies and with T-cell infiltrates in the tissues [17]. Refractory thrombocytopenia in an ICF1 infant, pauciarticular arthritis and macrophage activation syndrome have been described [56, 75, 76].

3.9. Haematological diseases and neoplasms

Neoplasms are infrequent in absolute terms (the overall prevalence of cancer described in the syndrome is low), but they carry weight in mortality [16]: in the European registry there were one angiosarcoma and one acute lymphoblastic leukaemia in ICF1 and one Hodgkin lymphoma in ICF2 [14]. Fatal metastatic hepatic angiosarcoma was the first non-haematological neoplasm described [76], and a 7-year-old boy presented with classical Hodgkin lymphoma with invasion of the brachial plexus [77]. In the transplant cohort, two ICF2 patients had B-cell lymphoma (one EBV-associated and one diffuse large B-cell lymphoma), another ICF2 patient had EBV-associated haemophagocytic lymphohistiocytosis and an ICF1 patient had transfusion-dependent myelodysplastic syndrome [17]. Fatal vasculitis associated with chronic active EBV infection has also been described in ICF2 [78]. Progressive cytopenia with a hypoplastic marrow and myelodysplasia constitute a risk specific to ICF1 in the second decade [14, 17].

3.10. Particularities by type

ICF1 is the most frequent type and tends to be diagnosed earlier, because the humoral defect is more severe and infections occur earlier; it is associated with sepsis, fungal infections, failure to thrive and, in the second decade, with cytopenias and myelodysplasia [14–16]. ICF2 is associated with intellectual disability in practically all patients, with immunoglobulin class deficiencies that are sometimes less extreme, with male predominance, NK dysfunction and EBV-associated lymphomas and lymphohistiocytosis; the mortality described for ICF2 is 20% [14, 17, 22, 55]. ICF3 and ICF4 have fewer patients described; enteropathy was constant in the transplanted patients of these types, and there was T lymphopenia in two ICF3 patients [17]. Of the five initial ICF4 patients, four had recurrent infections, all had facial anomalies, three had psychomotor delay and one died at 1.2 years [6].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

ICF syndrome should be considered in any infant or child with recurrent or severe respiratory or gastrointestinal infections and hypogammaglobulinaemia with B lymphocytes present, especially if there is mild facial dysmorphism (hypertelorism, flat nasal bridge, epicanthus, low-set ears, macroglossia), developmental delay, low birth weight or failure to thrive, or parental consanguinity [20, 23, 56]. The combination of hypogammaglobulinaemia with an abnormal face should prompt examination of the face of every patient with hypogammaglobulinaemia [31, 61]. In populations with high consanguinity the suspicion should be greater [53, 56]. The general approach to the patient with recurrent infections includes a three-generation pedigree, extended on the maternal side, recording unexplained infant deaths or deaths from infection, neoplasms and haematological diseases, the history of infections (type, age, agents, opportunistic or fungal infections) and of vaccines received, including BCG, and examination of growth, skin, lymph nodes, tonsils, liver and spleen [43]. In the investigation of failure to thrive, the Oxford handbook includes lymphocyte subsets and immunoglobulins to exclude an inborn error of immunity [79].

4.2. Warning signs

The following are warning signs of combined, and not merely humoral, immunodeficiency: Pneumocystis pneumonia, persistent cytomegalovirus, EBV or adenovirus viraemia, severe candidiasis, prolonged viral gastrointestinal infections and viral encephalitis [17, 68]. In a patient diagnosed with CVID, onset in early childhood, an abnormal face, developmental delay, opportunistic infections, enteropathy or cytopenias should prompt reconsideration of the diagnosis: six of the eleven Japanese patients were labelled as CVID before being reclassified as ICF, and the IUIS notes that a small minority of patients with ICF present to the immunologist with hypogammaglobulinaemia and normal or reduced B lymphocytes [21, 61, 68]. Neutropenia and thrombocytopenia with lymphopenia in an older child with ICF1 suggest progression to marrow failure or myelodysplasia [14, 17]. Lymphadenopathy, masses, prolonged fever or hepatosplenomegaly, especially in ICF2, raise suspicion of EBV-associated lymphoma or lymphohistiocytosis [17, 65].

4.3. Urgent situations

Sepsis, pneumonia with hypoxaemia (including PJP), meningitis and encephalitis are the causes of death described and require immediate treatment and broad microbiological investigation [14, 23, 52]. A 28-year-old woman with undiagnosed ICF2, cognitively able and with a history of strabismus and trichiasis surgery at 3 years and a pleural effusion 13 years earlier, presented with fever, shock, coma, pancytopenia, herpetic lesions and purpura, followed by repeated septic shocks due to Klebsiella pneumoniae, Acinetobacter baumannii and Haemophilus influenzae, with Aspergillus flavus in bronchoalveolar lavage; the diagnosis arose from the combination of almost absent B lymphocytes (0.14%), greatly reduced NK cells, expanded CD8 cells and an abnormal face (round face, broad flat nasal bridge, low-set ears), and the exome confirmed the homozygous variant ZBTB24 NM_014797.3:c.1123C>T, p.(Gln375*); she recovered with antibiotics and immunoglobulin and was well after one year [18]. Also in adulthood, the disease may present with bronchiectasis and infections since childhood without a diagnosis, as in a British man of Indo-Caribbean origin, the son of non-consanguineous parents, born 3.5 weeks before term, with a slightly tapered face, without malformations or cognitive impairment, with IgG, IgA and IgM deficiency with normal lymphocytes and T proliferation and several failed diagnostic attempts in childhood, diagnosed at 42 years when a karyotype showed instability of chromosomes 1 and 16 [19].

4.4. Newborn screening

Newborn screening by TREC quantification on a dried blood spot detects severe combined immunodeficiency (T lymphocytes <300/µL at birth) with a presumed sensitivity of 100%, but does not identify most ICF patients [80]. In a study of archived Guthrie cards from 22 children born between 2006 and 2018 in Berlin-Brandenburg and transplanted for inborn errors of immunity, two of three ICF patients had TREC above the threshold at birth, although all had had a severe course that would have justified earlier transplantation: naïve T lymphocytes may be present at birth and decrease with age [17, 80]. A normal TREC result does not exclude the syndrome. The siblings of known patients are the group in which neonatal diagnosis has been possible, through family history [17].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

The ESID Registry criteria for probable clinical diagnosis, intended for patients without a genetic diagnosis, require immunodeficiency (variable hypogammaglobulinaemia, variably reduced T, B and NK lymphocytes, bacterial and opportunistic infections), the craniofacial abnormalities (microcephaly, hypertelorism, epicanthus, flat face, micrognathia, macroglossia, tongue protrusion, small upturned nose) and centromeric instability of chromosomes 1, 9 and 16 with increased somatic recombination and multibranched or multiradial configurations, plus at least two of the following: short stature, variable intellectual disability, malabsorption or diarrhoea, sinusitis and upper and lower respiratory infections [74]. For Ehrlich and colleagues, the three invariable features are immunodeficiency despite the presence of B lymphocytes, the characteristic rearrangements of chromosomes 1 and/or 16 with breakpoints in 1qh and 16qh in mitogen-stimulated lymphocytes, and hypomethylation of classical satellites 2 and 3 [20]. The Orphanet definition adds the absence of CD19+CD27+ memory B cells with normal total B and T counts [2], and the French cohort proposed this absence as a major criterion [67].

5.2. Immunological assessment

The initial assessment of a patient with suspected antibody deficiency includes quantification of immunoglobulins (IgG, IgA, IgM and IgG subclasses), specific responses to protein and polysaccharide vaccines, lymphocyte immunophenotyping and exclusion of secondary causes [7, 23]. The North American practice parameter uses as serotype-specific protective thresholds against pneumococcus 1.3 µg/mL after a polysaccharide vaccine and 0.35 µg/mL after a conjugate vaccine [23]. In ICF, immunophenotyping should include naïve and memory B subsets (CD19+CD27+, switched memory B cells), naïve and memory T subsets, recent thymic emigrants and NK cells, supplemented by mitogen proliferation tests, because the T defect is mainly functional [7, 17, 47, 68]. The full blood count with film and, in the presence of cytopenias, bone marrow examination, assessment of growth, nutrition and enteropathy, and chest imaging and microbiology for bronchiectasis form part of the assessment [7, 43].

5.3. Cytogenetics: the characteristic test

Cytogenetic analysis to assess centromeric instability is the specific test recommended for ICF syndrome in the 2025 practice parameter [23]. In metaphases from PHA-stimulated (or Phytolacca mitogen-stimulated) peripheral blood cultures, whole-arm deletions and pericentromeric breaks of chromosomes 1 and 16 (sometimes 9), multibranched chromosomes with three or more arms (up to ten) of chromosomes 1 and/or 16 joined near the centromere, isochromosomes and occasional translocations, and stretching (decondensation) of 1qh and 16qh are observed; in most patients chromosome 1 is more affected than chromosome 16, rearrangements of 9qh are less frequent and those of chromosomes 2 and 10 rare [20, 23]. A culture of 72 to 92 hours maximises the frequency of the rearrangements; 20 G-banded metaphases usually suffice, but examining 50 is preferable to increase the probability of seeing the specific multiradial figures [20]. The frequency of abnormal metaphases varies: 30–40% of cells in the Lebanese ICF2 siblings, 56% in a patient whose diagnosis had been missed in an earlier cytogenetic study, and only 7% stretching and 1% multiradials in a girl without a DNMT3B variant [3, 77, 81].

The limits of the test are important. The typical configurations are not reported in a routine karyotype if the laboratory is not informed of the suspicion, and a normal routine karyotype does not exclude the disease [7, 77]. Bone marrow and fibroblasts show little or no recombination in many patients and should not be used for diagnosis [20]. The frequency of sister chromatid exchanges is not increased, which distinguishes ICF from Bloom syndrome [20]. Cytogenetics confirms the syndrome, but not the type: the same picture occurs in the four genotypes, and assigning the type requires molecular confirmation [7]. Heterozygotes usually have normal chromosomes, although a carrier of a DNMT3B variant showed a low frequency of multibranched figures [20, 25]. Chromosome analysis also helps to interpret variants of uncertain significance in DNMT3B [82].

5.4. Methylation study

Hypomethylation of pericentromeric satellites 2 and 3, demonstrable by Southern blot with methylation-sensitive enzymes or by genomic methods, supports the diagnosis; additional hypomethylation of the α satellite points to the non-DNMT3B genotypes [7, 37, 40]. In the non-DNMT3B forms the hypomethylation involves a small fraction of the genome and is not always demonstrable, so a normal result does not exclude ICF4 [7]. Hypomethylation and expression of the germline genes MAEL and SYCE1 in uncultured whole blood are robust biomarkers of ICF1, used to diagnose a newborn in a family with an affected child [83], and the genomic methylation profile distinguishes ICF1 from ICF2, ICF3 and ICF4 [45]. Subtelomeric methylation is reduced only in ICF1 [46].

5.5. Molecular tests

Sequencing of the four genes, in an inborn errors of immunity panel or by exome or genome, confirms the diagnosis and defines the type [23, 43]. Most variants are single-nucleotide changes or small insertions and deletions, but there are multi-exon and whole-gene deletions in ZBTB24, which require copy number analysis [22, 50], and deep intronic or splicing variants in DNMT3B and HELLS [14, 40]. The report should state the gene, the transcript with its version (for example NM_006892.4 for DNMT3B, NM_014797.3 for ZBTB24, NM_031942.5 for CDCA7 and NM_018063.5 for HELLS), the HGVS nomenclature, the zygosity and the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [8]. In compound heterozygosity, analysis of the parents confirms that the variants are on different alleles; in one ICF4 family the mother had only one of the two variants, and in one ICF1 patient one of the variants was de novo [1, 40]. Missense variants of uncertain significance in ZBTB24 can be classified with the transcriptional activation functional assay [51], and cytogenetics and methylation provide functional evidence for variants in the remaining genes [45, 82]. A fraction of patients with the phenotype remain without a genetic explanation (8 of 44 in the European registry, before the discovery of CDCA7 and HELLS), which indicates that at least one further gene may exist [14, 40]. When the molecular study is not performed immediately, the Oxford handbook recommends storing a DNA sample for future use [43]. The proportion of patients with a detected variant is not a measure of clinical sensitivity: the series are small and many older patients were never genotyped.

5.6. Practical algorithm

5.7. Prenatal and preimplantation diagnosis

When the proband's two variants are known, prenatal diagnosis is performed by molecular study on chorionic villus biopsy [43, 85] and preimplantation genetic diagnosis is technically possible on the same principle. Karyotyping should not be used on prenatal material: about 2% of metaphases from normal chorionic villus cultures on day eight show decondensation of 1qh or 16qh and, less often, breaks or tri- and quadriradial figures, and high-passage cultures of normal villi or amniotic fluid show abnormalities similar to those of ICF; short amniotic fluid cultures are less subject to these artefacts, but DNA study is possible only when the affected relative's variants are known [20]. Historically, diagnoses were made by fetal blood sampling in the second trimester and by linkage analysis with the marker D20S850 on a biopsy at 12 weeks [20, 86].

6. Differential Diagnosis

The differential is organised along two axes: the other causes of hypogammaglobulinaemia or combined immunodeficiency in children and the other syndromes with spontaneous chromosomal instability and immunodeficiency [20, 43, 87]. The table summarises the distinguishing features and the test that discriminates each entity.

The agammaglobulinaemias are distinguished from ICF by the absence of B lymphocytes, whereas ICF has naïve B lymphocytes in normal numbers; CVID is the most frequent incorrect diagnosis, because it shares hypogammaglobulinaemia with B cells present, and the reclassification of six of the eleven Japanese patients, previously labelled as CVID, illustrates the importance of a targeted karyotype and of sequencing in the face of early onset, dysmorphism or opportunistic infections [21, 61, 68]. SCID presents earlier and with profound T lymphopenia, detectable by newborn screening, unlike ICF, which may have normal TREC at birth [43, 80]; however, ICF1 may present as SCID in infancy [57]. Among the chromosomal instability disorders, ICF is distinguished by the location of the abnormalities (heterochromatin of 1qh, 16qh and 9qh) and by the absence of an increase in sister chromatid exchanges, whereas ataxia-telangiectasia and Nijmegen syndrome show rearrangements at the antigen receptor loci of chromosomes 7 and 14 and radiosensitivity, Bloom syndrome has greatly increased sister chromatid exchanges and Fanconi anaemia has breaks induced by cross-linking agents [20, 87]. Cell cycle checkpoints are normal in ICF, unlike in ataxia-telangiectasia and Nijmegen syndrome [20]. The 2025 practice parameter groups DNMT3B and ZBTB24 with the DNA repair defects and recommends, for this group, serum alpha-fetoprotein after 6 months and assessment of lymphocyte radiosensitivity by flow cytometry [23]. The inborn errors of folate and cobalamin metabolism (transcobalamin deficiency, MTHFD1 deficiency, hereditary folate malabsorption) and PNP deficiency enter the differential of the infant with hypogammaglobulinaemia or combined immunodeficiency, failure to thrive and developmental delay, because they have treatment or biochemical markers of their own: megaloblastic anaemia, raised homocysteine and a response to cobalamin or folinic acid point to the former, and low uric acid and enzyme activity to the latter; in transcobalamin deficiency, folic acid should never be given alone, because of the risk of neurological deterioration [89, 90]. IHRDIP syndrome (ischiadic hypoplasia, renal dysgenesis, immunodeficiency, polydactyly) is not a distinct entity: the patient who defined it had the hypomethylation and instability of ICF and was later shown to have CDCA7 variants [4, 5].

7. Treatments and Risk Management Strategies

7.1. Principles and evidence base

There is no guideline specific to ICF syndrome; the recommendations derive from the general guidelines for inborn errors of immunity and combined immunodeficiency, applied to a disease now understood as a progressive combined immunodeficiency, and from retrospective series [17, 23, 68, 84]. The specific evidence is observational: there are no randomised trials, and the outcome data come from the European registry, the national cohorts, the systematic review and the EBMT/ESID transplant cohort [7, 14, 15, 17]. Treatment has three components: immunoglobulin replacement, prophylaxis and aggressive treatment of infections with nutritional support, and haematopoietic stem cell transplantation as the only curative treatment of the immunodeficiency [7, 17]. The Japanese cohort concluded that these patients should be managed as having combined immunodeficiency and not merely antibody deficiency [68].

7.2. Immunoglobulin replacement

The 2025 practice parameter of the Joint Task Force on Practice Parameters (JTFPP), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the Clinical Immunology Society (CIS) recommends immunoglobulin replacement in all inborn errors of immunity with IgG antibody deficiency (strong recommendation, high certainty), with an initial dose of 400–600 mg/kg per month — intravenously every 3–4 weeks or, subcutaneously, divided into weekly or fortnightly administrations — and adjustment to the clinical response and to weight changes above 5% (strong, moderate) [23]. It recommends keeping serum IgG above 800 mg/dL (strong, high), on the basis of a meta-analysis in which the incidence of pneumonia fell by 27% for each 100 mg/dL increase in trough IgG and was five times higher with a trough of 500 mg/dL than with 1000 mg/dL (0.113 versus 0.023 cases per patient-year), with no additional benefit above 1000 mg/dL; the target should be individualised according to the «biological trough» above which the patient remains free of infections [23]. The therapy is continuous (strong, low) and requires monitoring of IgG, full blood count and biochemistry, with IgG every 6–12 months in the stable patient and monthly if there are intercurrent infections, pregnancy, protein losses (such as enteropathy), immunosuppression, weight change or poor adherence [23].

In ICF syndrome, immunoglobulin reduces the frequency and severity of infections in most patients; in the Netherlands, the target described in 2006 was a serum IgG of 5 g/L in children, and early introduction, possible in siblings diagnosed at birth, may prevent gastrointestinal symptoms in some [20]. The 2008 review and OMIM emphasise that early diagnosis is critical because immunoglobulin introduced early improves the course of the disease [1, 38]. All patients in the French, Japanese, Turkish and transplant cohorts received immunoglobulin, and in the transplant cohort trough IgG was within the normal range for age when measured [17, 47, 67, 68]. Immunoglobulin corrects only the humoral component: three Japanese patients died of viral infections on regular treatment, and pneumonia progressed despite immunoglobulin and anti-infectives in an ICF2 girl with a ZBTB24 deletion [50, 68]. The target of 5 g/L cited for ICF in 2006 is lower than the >800 mg/dL target of the 2025 North American parameter and than the minimum trough of 6 g/L of the European summaries of product characteristics; the current reference is the guideline [20, 23, 92].

No label names ICF syndrome; the indication rests on classification as a primary immunodeficiency with impaired antibody production (European labels) or as a primary humoral immunodeficiency, a definition that in the North American label includes, but is not limited to, congenital agammaglobulinaemia, CVID, X-linked agammaglobulinaemia, Wiskott-Aldrich syndrome and the severe combined immunodeficiencies [7, 92, 93]. The table compares the doses of the guideline and of the labels.

The guideline dose lies within the label ranges; the main difference is the target, higher in the North American guideline (IgG >800 mg/dL) than the European minimum (≥6 g/L) [23, 92]. In the event of measles exposure, the labels indicate 0.4 g/kg (400 mg/kg) as early as possible (within 6 days, according to the North American label) and a maintenance dose of at least 0.53 g/kg (530 mg/kg) every 3–4 weeks if the risk of exposure persists [92, 93].

Adverse effects occur in 5–15% of intravenous infusions (fever, chills, headache, nausea, myalgia, blood pressure changes) and are generally mild and rate-dependent; severe ones are rare and include thrombosis, renal failure, aseptic meningitis, haemolysis (more in blood groups A and AB), arrhythmia and transfusion-related acute lung injury [23]. The North American label has a boxed warning about thrombosis, renal dysfunction and acute renal failure and contraindicates the product in previous anaphylaxis to human immunoglobulin, in hyperprolinaemia (the stabiliser is L-proline) and in IgA deficiency with anti-IgA antibodies and a history of hypersensitivity [93]. In the event of a reaction, the infusion is slowed or stopped for 15–30 minutes and premedication with paracetamol or ibuprofen, an antihistamine and/or hydrocortisone one hour beforehand may be used; the products are not interchangeable, changes of product should be decided by the physician, and central venous catheters are not recommended solely to administer immunoglobulin, the subcutaneous route being preferred when venous access is difficult [23].

In Portugal the normal human intravenous immunoglobulins Privigen®, Kiovig®, Octagam®, Flebogamma DIF®, Gamunex 10%® and Ig Vena® and the subcutaneous Hizentra®, Cutaquig® and HyQvia® (the latter with recombinant hyaluronidase) are, among others, authorised and marketed [95]. In Brazil, the active registrations with the Agência Nacional de Vigilância Sanitária (ANVISA) include, among others, Octagam®, Flebogamma®, Gamunex®, IgVena®, Intratect®, Panzyga®, Sandoglobulina®, Hizentra®, Cuvitru® and the human immunoglobulin from Hemobrás [96].

7.3. Prophylaxis and treatment of infections

The 2025 practice parameter recommends targeted antimicrobial prophylaxis in inborn errors of immunity with increased susceptibility (strong recommendation, high certainty) [23]. For antibody deficiencies with respiratory infections it proposes azithromycin, with amoxicillin or co-trimoxazole as alternatives (conditional, low); for combined immunodeficiencies with a severe T defect it proposes co-trimoxazole against Pneumocystis at a dose of 5 mg/kg of the trimethoprim component, maximum 160 mg, twice daily (conditional, low), and in SCID 5 mg/kg (maximum 160 mg) two to three times a week (strong, high), with pentamidine, atovaquone or dapsone as alternatives [23]. The indication for co-trimoxazole against Pneumocystis in ICF rests on the occurrence of PJP with normal T subsets [14, 20, 52]. In the EBMT/ESID cohort, 12 of 18 patients were on antibacterial prophylaxis (mainly co-trimoxazole; also azithromycin and ciprofloxacin), 6 of 18 on antifungal prophylaxis (itraconazole, fluconazole) and 5 of 18 on aciclovir; two received valganciclovir for persistent cytomegalovirus infection [17]. In three Japanese patients, infections decreased after co-trimoxazole and/or an antifungal was added to immunoglobulin [68]. Use in ICF is an extrapolation from the combined immunodeficiencies; the reference dose is that of the guideline, and the North American label of Bactrim® serves as comparison.

Azithromycin is preferred when there is chronic lung disease, because of its antimicrobial and anti-inflammatory properties: in a randomised placebo-controlled trial in adults with primary antibody deficiency and chronic lung disease on immunoglobulin, it reduced exacerbations, admissions and antibiotic courses [23]. The practice parameter also recommends rapid microbiological diagnosis in acute infections and longer antimicrobial courses than in immunocompetent people (suggestion) and education about environmental exposures [23]. In the combined immunodeficiencies only irradiated, cytomegalovirus-negative and leucodepleted blood products should be used (strong, moderate) [23]. Bronchiectasis requires chest physiotherapy and antibiotic therapy, as in the patient diagnosed at 42 years [19], and the Oxford handbook recalls that it arises mainly when diagnosis is late, replacement is inadequate or infections are not treated aggressively [43].

7.4. Vaccination

In severe inborn errors of immunity, including the combined immunodeficiencies and antibody deficiencies, all live viral vaccines (including the live measles, mumps and rubella vaccine, the rotavirus vaccine, the live attenuated influenza vaccine and the dengue vaccine) and live bacterial vaccines (BCG and oral typhoid) are contraindicated (strong, low) [23]. Rubella vaccine virus has been found in cutaneous granulomas of patients with inborn errors of immunity, and wild rubella was fatal in a girl with ICF [23, 72]. On immunoglobulin replacement and with adequate T function, inactivated, recombinant or mRNA vaccines, such as those for seasonal influenza and COVID-19, may be given (conditional) [23]. Household contacts should follow the schedule, including live vaccines, except for the oral polio vaccine and the ACAM2000 vaccine; if a sibling receives the oral rotavirus vaccine, hand washing is recommended for one month after nappy changes [23]. After transplantation, responses to revaccination against tetanus and pneumococcus were adequate in 8 of 8 patients assessed [17].

7.5. Nutritional and gastrointestinal support

Enteropathy and failure to thrive require nutritional assessment, treatment of gastrointestinal infections and, when necessary, tube or parenteral nutrition (3 of 18 patients in the transplant cohort) [7, 17]. Non-infectious enteropathy is immunological in nature and responded to transplantation in all evaluable patients [17].

7.6. Immune dysregulation, cytopenias and neoplasms

When present, autoimmune manifestations affect the prognosis and require immunosuppression [67]. In the transplant cohort, three of the six patients with immune dysregulation were treated with corticosteroids, azathioprine, tacrolimus or mesalazine, and immune dysregulation was the major indication for transplantation in four patients [17]. The practice parameter recommends prompt treatment of cytopenias and neoplasms (strong) and surveillance with a full blood count in patients with antibody deficiency and immune dysregulation, because of the incidence of autoimmune cytopenias and haematological neoplasms [23]. EBV-associated lymphomas and haemophagocytic lymphohistiocytosis were treated with chemotherapy or immunochemotherapy (including rituximab, corticosteroids, etoposide and ciclosporin) to obtain remission before transplantation [17, 65].

7.7. Haematopoietic stem cell transplantation

Allogeneic HSCT is the only curative treatment of the immunodeficiency in ICF syndrome [7, 17]. The 2008 review recommended considering it in severe infections or failure to thrive, and up to 2021 fewer than ten transplants had been published in ICF1 [38, 98]. The 2024 international EBMT/ESID cohort gathered 18 patients from 12 centres, transplanted between 2003 and 2021 (6 ICF1, 4 ICF2, 4 ICF3, 2 ICF4 and 2 ICFX), with a median age at transplantation of 4.3 years (0.5–19) [17]. The genetic diagnosis was at times delayed by up to 14 years after the onset of symptoms [17]. The indications were infections or combined immunodeficiency (83%), enteropathy or failure to thrive (56%), immune dysregulation (22%), myelodysplasia or neoplasm (17%) and pre-emptive transplantation after early diagnosis (11%) [17]. The donors were HLA-identical siblings or relatives in 39%, matched unrelated donors in 50% and mismatched donors (one haploidentical relative and one 9/10 unrelated) in 12%; the source was bone marrow in 56% and peripheral blood in 44% (with ex vivo depletion of TCRαβ and CD19 lymphocytes in three); conditioning was myeloablative in half and of reduced intensity in the other half, with a preference for reduced intensity when there was organ damage; 89% received serotherapy (antithymocyte globulin or alemtuzumab), and GvHD prophylaxis combined ciclosporin or tacrolimus with methotrexate or mycophenolate mofetil in 78% [17].

The results were favourable: all evaluable patients engrafted (median 17 days), overall survival was 83% (all deaths in the first five months, with a mean follow-up of 51 months), event-free survival was 72%, infectious complications after transplantation occurred in 71% (viral in 65%: adenovirus, cytomegalovirus, EBV and respiratory and gastrointestinal viruses; bacterial in 3 patients; fungal, due to Aspergillus, in 1), acute graft-versus-host disease (GvHD) occurred in 35% (grade III in 12%, intestinal, in two patients with previous infectious diarrhoea) and there was no chronic GvHD [17]. Donor chimerism was complete (>90%) in 15 of 17 survivors; cellular recovery was 77% at one year and 93% at the last follow-up; all survivors normalised their T and B lymphocyte counts and all but two stopped immunoglobulin (one previously treated with high-dose rituximab and another with only nine months of follow-up) [17]. Chronic infections, enteropathy, failure to thrive and immune dysregulation resolved in all survivors, and no patient with previous myelodysplasia, neoplasm or lymphohistiocytosis relapsed [17]. The three deaths occurred in a 17-year-old ICF1 patient transplanted for myelodysplasia (respiratory syncytial virus on day +41), in a 15-year-old ICF2 patient previously treated for lymphoma (multiorgan failure with persistent adenovirus on day +145, despite two donor lymphocyte infusions) and in a 5-year-old ICFX patient with parenteral nutrition-dependent colitis (conditioning toxicity and sepsis on the day before infusion) [17]. The three patients diagnosed through family history and transplanted by 3 years of age survived, and naïve CD4 T lymphocytes normalised only in the younger transplanted patients (median 2.2 versus 8.5 years), which suggests cumulative thymic damage with age [17]. The mean age at transplantation was 12.4 years in patients with bronchiectasis, 13.5 years in those transplanted for immune dysregulation and 13.1 years in those transplanted for neoplasm or lymphohistiocytosis, against 2.0 years for the other indications [17]. Two patients with stable mixed chimerism (44–85% donor cells) had a good course, which supports the use of reduced-intensity conditioning in the most vulnerable patients [17, 98]. Humoral recovery occurred in 87% (13/15), CD3 lymphocytes were normal in 92% at one year and in all at the last follow-up, and antimicrobial prophylaxis was continued for more than a year in four patients, all with previous bronchiectasis [17]. One of the patients in this cohort, a Caucasian boy with ICF1, the son of non-consanguineous parents, presented at 6 months with fever, severe neutropenia (absolute neutrophil count of 0), pneumonia, adenovirus, coronavirus OC43 and astrovirus infections and adenoviraemia, with motor delay, subtle hypertelorism, flat nasal bridge, epicanthus and syndactyly of the 2nd and 3rd toes, and with normal PHA proliferation, T function and naïve T lymphocytes; he was transplanted at 22 months with bone marrow from an HLA 10/10 sibling after reduced-intensity conditioning with alemtuzumab, fludarabine, melphalan and thiotepa, maintained mixed chimerism despite a CD34+ cell boost and, at 2.5 years, was off immunoglobulin and free of severe infections [98]. In the French cohort, an ICF1 patient transplanted for severe autoimmunity and pancytopenia died of an unknown cause six years later [67]. The authors concluded in favour of timely transplantation, including pre-emptive transplantation [17].

The updated guidelines of the EBMT/ESID inborn errors working party (2026) classify transplantation in the combined immunodeficiencies as standard treatment when a matched donor is available, although they allow the category of «clinical option» when the decision depends on the natural history, the genotype-phenotype correlation, quality of life, comorbidities, age, donor, risks (including fertility) and the wishes of the patient and family [84]. Pre-transplant comorbidities, especially active infections, bronchiectasis and lung or liver damage, are major predictors of outcome; it is recommended that active infections be treated before transplantation and that treosulfan-based regimens be preferred when there is severe liver or lung damage [84]. The HLA-identical sibling remains the first choice (with survival similar to that of a matched unrelated donor), excluding affected family donors; the recommended doses are 2–4 × 10⁸ nucleated cells/kg for bone marrow and 5–8 × 10⁶ CD34+ cells/kg for peripheral blood [84]. The reduced-intensity protocols (C, D and E) are intended for patients with organ damage or older patients, accepting more mixed chimerism, and protocol F, with low-dose alkylating agents, is reserved for DNA repair defects with radiosensitivity; in adolescents and adults, poorer results are associated with high comorbidity, active dysregulation or permanent damage, which favours a more pre-emptive approach [84]. ICF syndrome is not named in these guidelines or treated as a radiosensitive disease, and no source consulted recommends protocol F for it; the regimens published in ICF include busulfan with cyclophosphamide, fludarabine with melphalan and thiotepa, fludarabine with treosulfan (with or without thiotepa) and haploidentical regimens with post-transplant cyclophosphamide [17, 52, 98]. The North American practice parameter recommends considering transplantation in combined immunodeficiencies with a severe cellular defect or severe or refractory complications (strong, moderate) and lifelong follow-up thereafter [23]. Transplantation does not correct the centromeric instability, the dysmorphism, the intellectual disability or the extra-haematopoietic manifestations, and its effect on the risk of non-haematological neoplasm is unknown [16, 52, 98]. The late complications described include autoimmune thyroiditis (in one case derived from a donor with subclinical hypothyroidism), vitiligo, severe deafness and precocious puberty after pneumococcal meningitis, short stature treated with growth hormone and primary ovarian insufficiency after conditioning with busulfan and cyclophosphamide [17].

7.8. Regulatory status

No medicine has an indication approved specifically for ICF syndrome in the United States or the European Union, and there is no approved targeted therapy [7, 16].

7.9. Trials and outcome series

There are no randomised trials or controlled comparisons between immunoglobulin alone, immunoglobulin with prophylaxis and transplantation; the series are retrospective, with selection bias (the transplant cohort includes only transplanted patients, and deaths before transplantation do not enter the denominator), long periods and heterogeneous treatments, so survival rates cannot be compared directly between series [7, 14, 17]. The overall survival of 60–84% described in older cohorts, mostly untransplanted, is not comparable with the 83% of the transplant cohort [17].

7.10. Developments of the last 12 months and research

Between November 2025 and October 2026 no registered therapeutic clinical trial for ICF syndrome was identified on ClinicalTrials.gov, no regulatory application and no targeted therapy in a clinical phase [99]. The developments are diagnostic, genetic or related to organisation of care: ClinGen classified the relationship of CDCA7 with ICF3 as moderate (April 2026) [13]; missense variants of the BTB domain of ZBTB24 that act as loss of function were published [48], as were new variants in CDCA7, HELLS and ZBTB24 in a Chinese series [62], a multi-exon deletion of ZBTB24 [50], a diagnosis of ICF2 at 28 years with septic shock [18], Palestinian cases treated with immunoglobulin [53, 100], the immune profile by mass cytometry of an ICF2 patient with intracellular pathogen infections [69], a fatal vasculitis associated with chronic active EBV [78], reviews on maintenance of methylation in heterochromatin [16, 101, 102] and the updated EBMT/ESID transplant guidelines (May 2026) [84]. Pharmacological approaches that increase the residual activity of DNMT3B or compensate for HELLS and CDCA7, and gene therapy in haematopoietic stem cells, are theoretical proposals without clinical studies [16]. The absence of results in the search does not prove the non-existence of ongoing studies.

7.11. Agents and situations to avoid

Live vaccines are contraindicated in the patient [23]. Non-irradiated or cytomegalovirus-positive blood products should be avoided [23]. ICF shares with other chromosomal instability diseases cellular hypersensitivity to some DNA-damaging agents [20], but the sources consulted do not describe specific recommendations on ionising radiation or alkylating agents in ICF, unlike in ataxia-telangiectasia and Nijmegen syndrome [84, 87]. In renal disease or with thrombotic risk factors, intravenous immunoglobulin requires monitoring of renal function and hydration [23, 93].

7.12. Pregnancy, perioperative care and transition

The sources consulted do not describe pregnancies in women with ICF syndrome, apart from the woman with ICF2 diagnosed at 28 years who had a daughter born by caesarean section three years earlier [18]. In pregnancy on immunoglobulin, the practice parameter recommends monthly monitoring of IgG, because requirements increase [23], and co-trimoxazole has an embryofetal risk described in the label [97]. In the perioperative period, the general precautions of the combined immunodeficiencies apply (irradiated, cytomegalovirus-negative blood products, continuation of immunoglobulin and prophylaxis) [23]. Survival into adulthood, increasingly frequent with antimicrobial treatment, exposes patients to late complications such as bronchiectasis, cirrhosis, progressive multifocal leukoencephalopathy and neoplasms, and makes a structured transition to adult immunology necessary [19, 20, 73, 84].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk

The four types of ICF syndrome are transmitted in an autosomal recessive manner: the parents of a patient are, as a rule, asymptomatic heterozygotes, and each pregnancy carries a 25% risk of an affected child, 50% of a carrier and 25% of a non-carrier [1, 3, 4, 6, 87]. Consanguinity is frequent in the published series, but most cases are not familial and there are patients born to non-consanguineous parents [14, 19, 20, 98]. De novo variants have been described: in an ICF1 patient one of the two variants was not present in the parents, and in an ICF4 family the mother had only one of the variants, which may correspond to paternal origin or to a de novo variant [1, 40]. For this reason, study of both parents is necessary to confirm the phase and calculate the recurrence risk. The risk for the healthy siblings of a patient of being carriers is two thirds. Carriers do not have immunodeficiency; some heterozygotes for DNMT3B variants show partial hypomethylation of D4Z4 and NBL2 and, if they have a permissive chromosome 4, may be at risk of digenic facioscapulohumeral dystrophy, which should be mentioned in the counselling of ICF1 families [24, 25].

8.2. Cascade testing, siblings and donors

The siblings of a patient should be studied early, because neonatal diagnosis through family history allows immunoglobulin to be started before infections and transplantation to be planned in good conditions: the three patients of the EBMT/ESID cohort diagnosed through family history and transplanted by 3 years of age survived, one of them after pre-emptive transplantation at 1 year [17, 20]. Methylation biomarkers in whole blood allowed the diagnosis of a newborn in a family with an affected child [83]. When choosing a sibling as donor, the sibling should be studied to exclude being affected, especially in diseases of variable expression [84]. The Oxford handbook recommends, in severe immunodeficiencies that may require transplantation, considering collection and storage of cord blood from unaffected siblings and, when there has been no prenatal diagnosis, sending the cord blood for targeted study, arranging this in advance with obstetrics and the laboratory [43].

8.3. Prenatal and preimplantation diagnosis

Prenatal diagnosis by molecular study on chorionic villus biopsy, from 11–12 weeks, is possible when the two family variants have been identified [43, 85, 87]. Karyotyping of villi or amniotic fluid is not reliable, because normal cultures may show decondensation and rearrangements of 1qh and 16qh [20]. Preimplantation genetic diagnosis is based on the same variants. Before the genes were identified, linkage analysis and fetal blood sampling were used [20, 86].

8.4. Counselling of minors and of the extended family

Carrier testing in healthy minor siblings has no immediate clinical benefit and may be deferred until reproductive age, unlike the diagnosis of possibly affected siblings, which is urgent [17, 43]. In consanguineous families and in populations with frequent marriages between relatives, the probability of other cases in the extended family is greater, and the syndrome should be actively sought in children with dysmorphism and recurrent infections [56]; carrier testing of relatives of reproductive age may be discussed in counselling when the family variants are known. Counselling should address the variability of the disease, even between siblings with the same variant [55].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

Orphanet classifies ICF syndrome, across the four types, in the prevalence class below 1 per 1,000,000; this is a class and not a measured rate, and there are no population studies of prevalence or incidence [2, 7]. The figures available are case counts: about 14–15 patients described in 1994–1995, about 50 in 2006, 66 in the European registry in 2013, 118 in the 2021 systematic review and fewer than 120 according to a 2025 report [14, 15, 20, 30, 31, 53]. The increase in diagnoses in Europe and Japan and the scarcity of cases described in the United States already suggested underdiagnosis in 2006 [20]. ICF1 accounted for 52% of the patients in the European registry and 60% of the cases in the systematic review; ICF2 for 30% in both; ICF3 for 4% and ICF4 for 6% in the systematic review [14, 15]. These proportions describe published and genotyped patients, not the population frequency of the genotypes.

9.2. Geographical distribution and populations with consanguinity

The patients come from very diverse populations: the European registry included patients of Dutch, German, English, Scottish, Italian, Austrian, French, American, Turkish, Moroccan, Lebanese, Jordanian, Saudi, Japanese and Pakistani origin [14]. Consanguinity was frequent in the Turkish, Moroccan and Lebanese patients [14]. The 2006 review already included African American patients [20]; the four initial ICF4 families (five patients) were of English, Japanese, French and Italian origin, only one consanguineous [6]; and a Cape Verdean patient with ICF2 was compound heterozygous for two truncating ZBTB24 variants, NM_014797.3:c.787A>T p.(Lys263*) and p.(Cys327Trpfs*54) (the latter in the published designation, on protein NP_055612.2) [49, 103]. There are series or cases from Saudi Arabia (where three ICF types were identified by exome in hypogammaglobulinaemic patients), Iran, Lebanon, Palestine and China [53, 54, 56, 57, 59, 61, 62, 70, 100, 104]. In the Japanese cohort, six patients were labelled as CVID [68]. No founder variants with a known population frequency have been identified; some variants recur in families of the same origin, such as DNMT3B c.2421-11G>A in Turkish patients, c.2450A>G in Moroccan patients and ZBTB24 c.958C>T in Turkish and Japanese patients [14, 49]. In ICF2 there is male predominance (79% of published cases) [22]. In the sources consulted there are no epidemiological data from Portugal or Brazil; the absence of cases published in these sources does not demonstrate the absence of patients.

9.3. Special populations

Adults form a growing group: a 42-year-old man diagnosed late, a woman diagnosed at 28 years and a 40-year-old patient with progressive multifocal leukoencephalopathy show that the disease may reach adulthood undiagnosed or with a previous diagnosis, and that survival adds late complications [18–20, 73]. In adolescents and adults with comorbidities, transplantation remains possible, but the results depend on the burden of organ damage and active dysregulation [17, 84].

9.4. European reference network and patient organisations

The competent European reference network is ERN RITA (rare immunodeficiencies, autoinflammatory and autoimmune diseases; https://ern-rita.org/). The European Society for Immunodeficiencies (ESID; https://esid.org/) maintains the European registry and the clinical criteria [74]. Patient organisations include the International Patient Organisation for Primary Immunodeficiencies (IPOPI; https://ipopi.org/), the Associação Portuguesa de Doentes com Imunodeficiências Primárias (APDIP; https://www.apdip.pt/), the Immune Deficiency Foundation in the United States (https://primaryimmune.org/) and Immunodeficiency UK (https://www.immunodeficiencyuk.org/), formerly PID UK, cited by the Oxford handbook [43].

10. Illustrative Clinical Case

Gössling and colleagues described, in 2017, a boy who was the fifth child of consanguineous Moroccan parents; the couple's first daughter had died at 5 months, in Morocco, of respiratory failure of unclear cause, and three siblings were healthy [52]. He was born weighing 3200 g (38th centile) and measuring 51 cm (72nd centile); at 2.5 months he weighed 5300 g (12th centile) [52]. At 4 months he was admitted for the first time for recurrent and prolonged upper and lower respiratory infections with hypoxaemia: bilateral bronchopneumonia with parainfluenza virus 1 and 3 and Pneumocystis jirovecii, purulent conjunctivitis and perforated otitis media due to Haemophilus influenzae [52]. The immunological assessment showed IgG of 52 mg/dL and IgA and IgM below 5 mg/dL, CD20+ B lymphocytes of 1329/µL, all naïve, without memory B cells (CD20+IgD−CD27+ 0/µL), CD4 of 1840/µL, CD8 of 450/µL, NK of 208/µL and normal T proliferation to PHA [52]. The PJP was treated with intravenous co-trimoxazole, corticosteroids and oxygen, and regular intravenous immunoglobulin with prophylactic co-trimoxazole prevented further severe pulmonary infections [52]. The patient had hypertelorism, telecanthus, flat nasal bridge, epicanthus and low-set, posteriorly rotated ears (figure 1 of the article, with the patient's photograph and the pedigree, https://pmc.ncbi.nlm.nih.gov/articles/PMC5491950/figure/F1/), and the karyotype showed whole-arm deletions, translocations and multibranched chromosomes involving chromosomes 1, 9 and 16 (figure 2 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC5491950/figure/F2/: the karyogram shows, in place of one chromosome 1, a multiradial figure with several arms joined near the pericentromeric region, the terminal deletion of part of the long arm of a chromosome 7 and a single chromosome 16); sequencing identified the homozygous variant DNMT3B NM_006892.4:c.1807G>A, p.(Ala603Thr), already described in 1999 [8, 34, 52].

At 5 months he weighed 6600 g (8th centile), with a diagnosis of failure to thrive [52]. At 6 months he underwent HSCT with bone marrow from his 5-year-old sister, HLA 10/10 identical, with reduced-toxicity myeloablative conditioning (thiotepa, treosulfan and fludarabine) and antithymocyte globulin, 24.7 × 10⁶ CD34+ cells/kg and GvHD prophylaxis with ciclosporin and methotrexate [52]. He had grade 4 mucositis, grade 1 skin toxicity, grade 2 nausea and vomiting and grade 2 renal impairment (World Health Organization scale), with complete recovery; leucocyte engraftment occurred on day +21 and neutrophil engraftment on day +22, he was discharged on day +47 and ciclosporin was stopped on day +120 without GvHD [52]. In the following months he had infections with respiratory syncytial virus (treated with ribavirin), influenza, coronavirus, rotavirus and adenovirus, all resolved [52]. Six months after transplantation he had IgG of 571, IgA of 57 and IgM of 51 mg/dL, memory B cells present (7/µL), a normal full blood count and stable chimerism with 2.9% autologous cells in blood and 1–5% in marrow [52]. At 1 year of age, neurological development corresponded to that of a 7-month-old child, he weighed 8590 g (9th centile) and measured 75 cm (18th centile) [52]. This patient was included in the EBMT/ESID cohort as a pre-emptive transplant, alive at 2.3 years of follow-up with more than 95% donor cells [17]. The case illustrates the typical presentation in an infant with an opportunistic infection despite normal T lymphocytes, the value of a targeted karyotype, the benefit of early diagnosis and transplantation and the limit of transplantation, which does not correct the centromeric instability, the dysmorphism or the developmental delay [52]. Transplantation at 6 months with a matched sibling accords with the trend of the series towards timely transplantation, but the decision on pre-emptive transplantation remains individual and does not constitute routine defined by a specific guideline [17, 84].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Without treatment, the immunodeficiency is severe and most patients described died in the first or second decade, mainly of infections [14, 33]. In the European registry, 11 of 23 ICF1 patients died (between 0.75 and 19 years), 3 of 13 ICF2 (between 4 and 13 years) and 1 of 8 ICFX (at 40 years); the causes were sepsis, respiratory failure, respiratory infections, encephalopathy or encephalitis, infection after transplantation for myelodysplasia, angiosarcoma and Hodgkin lymphoma [14]. The mortality described for ICF2 is 20% [55]. The overall survival of older cohorts, mostly untransplanted, ranged between 60% and 84% [17]. The prognosis is worse in patients with severe infections in the first year of life, chronic or intractable diarrhoea and failure to thrive, and more favourable in the absence of combined immunodeficiency [20, 38]. The immunodeficiency is progressive, with accumulation of bronchiectasis, immune-mediated organ damage (colitis, hepatitis, nephritis) and haematological neoplasms with age, which worsens the outcome of late transplantation [14, 17]. The prognosis has improved with immunoglobulin and antibiotic prophylaxis, and more and more patients reach adulthood [20, 67]. After transplantation, overall survival was 83% in the EBMT/ESID cohort, with independence from immunoglobulin and resolution of the immunological manifestations in the survivors [17]. Neurological development and the risk of non-haematological neoplasms do not depend on transplantation [16, 98].

11.2. Follow-up

Patients should be followed by a clinical immunologist in a centre experienced in inborn errors of immunity and in transplantation [43, 84]. The sources consulted do not establish surveillance intervals specific to ICF for most tests; the intervals defined come from the North American practice parameter for immunoglobulin replacement, and the remaining items follow from the complications documented in the series.

12. Summary and Final Considerations

ICF syndrome is an autosomal recessive combined immunodeficiency caused by defects in heterochromatin methylation: DNMT3B variants (ICF1) impair the establishment of methylation during development, and ZBTB24 (ICF2), CDCA7 (ICF3) and HELLS (ICF4) variants impair its maintenance, in a pathway in which ZBTB24 activates CDCA7 transcription and the CDCA7–HELLS complex remodels pericentromeric chromatin. Hypomethylation of satellites 2 and 3 of chromosomes 1, 9 and 16 produces the characteristic multiradial figures in stimulated lymphocytes, and the same factors participate in DNA repair by non-homologous end joining and in immunoglobulin class switching. The clinical picture combines hypo- or agammaglobulinaemia with naïve B lymphocytes present and without memory B cells, respiratory and gastrointestinal infections from the first year of life, opportunistic infections even with normal T counts, enteropathy, failure to thrive, mild facial dysmorphism and developmental delay, with intellectual disability in all ICF2 patients of the European series and in about half of the ICF1 patients. The immunodeficiency progresses with age, with decline in T lymphocytes, immune dysregulation, cytopenias, myelodysplasia in ICF1 and EBV-associated lymphomas in ICF2, and newborn screening by TREC does not identify most patients. Diagnosis rests on immunophenotyping, the karyotype of stimulated lymphocytes with explicit mention of the suspicion and sequencing of the four genes, with copy number analysis and study of the parents; cytogenetics confirms the syndrome but not the type, and a normal routine karyotype does not exclude it. The mainstay of treatment is continuous immunoglobulin replacement, according to the doses and targets of the inborn errors of immunity guidelines, combined with antimicrobial prophylaxis, including against Pneumocystis, avoidance of live vaccines and nutritional support; haematopoietic stem cell transplantation is the only curative treatment of the immunodeficiency, with overall survival of 83% in the largest cohort and better results when performed early, before organ damage. There are no targeted therapies or ongoing clinical trials, and the evidence remains limited to retrospective series, which makes follow-up in reference centres and patient registration necessary.

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