Nijmegen Breakage Syndrome and MRN and NHEJ Pathway Deficiencies

Nijmegen breakage syndrome (NBN), Nijmegen breakage syndrome-like disorder (RAD50), ataxia-telangiectasia-like disorder (MRE11), LIG4 syndrome, Cernunnos-XLF deficiency (NHEJ1) and XRCC4 deficiency: radiosensitivity, chromosomal instability, immunodeficiency and cancer predisposition

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

The table brings together the entities in the class of defects in the recognition and repair of DNA double-strand breaks (DSB) that share microcephaly, growth failure and cellular sensitivity to ionising radiation. Ataxia-telangiectasia, Fanconi anaemia, Bloom syndrome and severe combined immunodeficiency due to Artemis or DNA-PKcs deficiency are included only in the differential diagnosis.

1. Introduction

1.1. Original description

In 1979 a Dutch boy was described with microcephaly, growth and developmental delay, immunoglobulin A (IgA) deficiency and chromosomal rearrangements similar to those of ataxia-telangiectasia (A-T), involving chromosomes 7 and 14 with breakpoints at 7p13, 7q35, 14q11 and 14q32 [1]. The finding that a deceased brother had had a similar picture led investigators at the University of Nijmegen, in the Netherlands, to publish in 1981 the formal description of a new chromosomal instability disorder, which they named after the city: Nijmegen breakage syndrome (NBS) [1, 28]. In 1985, Seemanová and colleagues described families in what was then Czechoslovakia with microcephaly, normal intelligence, immunodeficiency and an unparalleled predisposition to lymphoreticular malignancies, which they designated a new autosomal recessive disorder; these families were later recognised as having the same syndrome [9, 29].

1.2. From ataxia-telangiectasia variant to gene cloning

Patients' cells share with those of A-T sensitivity to ionising radiation and radioresistant DNA synthesis, so NBS was for years regarded as a variant of A-T, although it has neither ataxia nor telangiectasias [1]. Complementation studies divided patients into two groups, ataxia-telangiectasia variant 1 (AT-V1, or NBS) and variant 2 (AT-V2, or Berlin breakage syndrome) [1, 2]. In 1998 the gene was cloned and named NBS1, now NBN; its product, nibrin, proved to be a novel double-strand break repair protein, mutated in both complementation groups, and most patients were homozygous for a five-base-pair deletion [1, 30]. In the same issue of the journal, Carney and colleagues showed that nibrin forms a complex with the proteins hMre11 and hRad50, linking double-strand break repair to the cellular DNA damage response [31].

1.3. Expansion of the class

Identification of the MRE11-RAD50-NBN (MRN) complex and of the non-homologous end joining (NHEJ) pathway made it possible to recognise other disorders with clinical overlap. In 1999, MRE11 variants were identified in patients with a neurological picture similar to that of A-T, ataxia-telangiectasia-like disorder (ATLD) [4, 32]. In 2001, O'Driscoll and colleagues described LIG4 variants in patients with developmental delay, immunodeficiency and a phenotype close to NBS, LIG4 syndrome [10, 33]. In 2006 Cernunnos-XLF deficiency (NHEJ1) was described, a radiosensitive severe combined immunodeficiency (SCID) with microcephaly [6, 22]. In 2009, Waltes and colleagues identified biallelic RAD50 variants in a patient followed from birth for chromosomal instability, establishing NBS-like disorder (NBSLD) [3, 34]. From 2015 onwards, patients with XRCC4 variants were described, with microcephalic primordial dwarfism and endocrine dysfunction without clinical immunodeficiency [7].

1.4. Nomenclature and classification

The name NBS is retained; the gene symbol changed from NBS1 to NBN, and the term “non-syndromic microcephaly” that appears among the alternative OMIM titles is considered misleading by the authors of the main clinical review [1, 2]. The 2024 classification of inborn errors of immunity of the International Union of Immunological Societies (IUIS) places NBS among the combined immunodeficiencies with syndromic features, in the subgroup of DNA repair defects, alongside A-T, Bloom syndrome, immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome and RIDDLE syndrome; LIG4 and Cernunnos-XLF deficiencies are in T−B−NK+ SCID alongside RAG, Artemis and DNA-PKcs deficiencies; NBSLD appears among the bone marrow failure syndromes [19]. ATLD and XRCC4 deficiency are not included in this classification, consistent with the absence of clinical immunodeficiency [19]. ATLD is genetically heterogeneous: ATLD2 (OMIM 615919) results from variants in PCNA [4].

1.5. Definition of the entities

NBS is an autosomal recessive chromosomal instability disorder caused by biallelic hypomorphic NBN variants, which presents at birth with microcephaly and is accompanied by combined cellular and humoral immunodeficiency, radiosensitivity, premature ovarian insufficiency in females and a risk of malignancy, mainly lymphoid, that exceeds 60% by age 25 years [1, 9]. NBSLD is the disorder due to biallelic RAD50 variants, with microcephaly and severe growth restriction, without immunodeficiency in most published patients [3]. ATLD1 is a slowly progressive autosomal recessive cerebellar ataxia due to hypomorphic MRE11 variants, with cellular sensitivity to radiation but without telangiectasias or immunodeficiency [4]. LIG4 syndrome, Cernunnos-XLF deficiency and XRCC4 deficiency are defects of the ligation step of NHEJ; the first two cause combined immunodeficiency of variable severity with microcephaly and bone marrow failure, and the third causes microcephalic primordial dwarfism with endocrine dysfunction, without clinical immunodeficiency [5–7].

2. Molecular Genetics and Pathophysiology

2.1. Two pathways for repairing double-strand breaks

Double-strand breaks are repaired by two pathways. Homologous recombination uses the sister chromatid as a template and is available only in the S and G2 phases of the cell cycle; NHEJ joins the ends directly, is active throughout the cycle and predominates in G0 and G1 [5, 35]. It is estimated that each mammalian cell sustains 10 to 50 double-strand breaks per day, mainly from reactive oxygen species [5]. The same machinery repairs the programmed breaks that the RAG1 and RAG2 recombinases introduce into the variable (V), diversity (D) and joining (J) segments of the T-cell receptor and immunoglobulin genes during V(D)J recombination, and takes part in immunoglobulin class-switch recombination; this dual function explains the association between radiosensitivity, immunodeficiency and lymphomas in the class [5, 35, 36]. The Oxford Desk Reference separates defects in damage recognition and signalling (A-T, ATLD, NBS, NBSLD and RIDDLE syndrome) from NHEJ defects (ligase IV, Artemis, DNA-PKcs and Cernunnos deficiencies), all radiosensitive, and considers the group probably underdiagnosed [35].

2.2. The MRN complex and nibrin

Nibrin (p95), encoded by NBN at 8q21.3 [37, 38], is ubiquitously expressed and has no homology with other known proteins; it contains in its amino-terminal region a forkhead-associated (FHA) domain and two BRCA1 carboxy-terminal (BRCT) domains, and in its carboxy-terminal region the MRE11-binding and ATM kinase-interacting domains [1, 9]. Together with MRE11 (a nuclease with exo- and endonuclease activity) and RAD50 (an ATPase with coiled-coil and zinc-hook domains that keep the ends close together), it forms the MRN complex, one of the first sensors of double-strand breaks [39, 40]. After ionising radiation, the complex forms nuclear foci at break sites; nibrin is required for this translocation, interacts with MDC1 through the FHA domain, and is required for ATM monomerisation and autophosphorylation and also for signalling by the ATR kinase [1, 9]. MRN detects, processes and signals the break, initiates end resection that opens the way to homologous recombination, and takes part in the degradation of stalled replication forks and in telomere maintenance [39, 41]. Absence of nibrin prevents recruitment of ATM and of the resection factor CtIP to breaks, compromising NHEJ and homologous recombination [36].

Cellular and murine models explain part of the phenotype. Conditional Nbn-null fibroblasts completely lose the G2/M checkpoint after bleomycin, and null B lymphocytes have G2/M and intra-S defects comparable to those of ATM-deficient cells, without phosphorylation of SMC1, CHK2 and BRCA1 [1]. Radiation-induced apoptosis is reduced when nibrin is absent, which reduces the elimination of severely damaged cells; checkpoint and proliferation defects, p53-dependent apoptosis in developing neurons and deficient ATR signalling are proposed mechanisms for the growth failure and microcephaly [1]. There is no gross defect of V(D)J recombination, but there is subtle disturbance in the resolution of RAG-induced breaks at the immunoglobulin heavy-chain (IGH) locus and a class-switching defect (fewer than 50% of null B lymphocytes switch from IgM to IgG1 or IgG3 in vitro) [1]. Telomere-telomere fusions and accelerated telomere shortening occur in A-T and NBS [1].

2.3. The founder variant and the p70 product

The Slavic founder variant, NM_002485.5:c.657_661del, p.(Lys219AsnfsTer16), historically designated 657del5, c.657_661delACAAA or p.K219fsX19, lies in exon 6 and is hypomorphic [1, 9, 12]. It gives rise to two fragments: an amino-terminal 26 kDa fragment (p26) and a carboxy-terminal 70 kDa fragment (p70), produced by alternative translation initiation at an upstream cryptic codon [1, 42]. Nbn nullity is lethal in the mouse embryo, but p70 expression rescues null cells and animals; in patients, above-average p70 levels are associated with a lower occurrence of cancer, a dosage effect reflecting differences in proteolytic degradation [1]. All NBS-associated variants known to GeneReviews lie in exons 6 to 10, probably because the disease requires production of a carboxy-terminal fragment by translation reinitiation in the same reading frame, which limits the variants capable of causing the syndrome [9]. Early truncating variants described in cancer patients (p.L19* and p.N71fs) produce a 45 kDa fragment by alternative initiation that retains MRE11 binding [43]. The disease mechanism is partial loss of function [9].

2.4. Spectrum of NBN variants

Table 2.1 lists the clinically significant variants described in the sources, normalised in VariantValidator with the MANE Select transcript, and their ClinVar classification at the time of consultation.

No deletions or duplications of one or more NBN exons causing NBS have been described [9].

2.5. Genotype-phenotype correlation, penetrance and allelic disorders

The founder variant and most loss-of-function variants produce the typical picture, with complete penetrance in the homozygous or compound heterozygous state [9, 35]. There are documented exceptions. A 53-year-old woman homozygous for c.741_742dup had microcephaly, chromosomal instability, immunodeficiency and primary amenorrhoea, but a milder overall phenotype, because her cells produced abundant amounts of an alternative transcript lacking exons 6 and 7, encoding a 73 kDa nibrin with an internal deletion; her sister, with a similar picture, had died at age 20 years of lymphoma [9, 46]. Two adult siblings with biallelic truncating variants (NM_002485.5:c.330T>G p.(Tyr110Ter) and NM_002485.5:c.1125G>A p.(Trp375Ter)) had normal stature, head circumference and facies and were referred only for premature ovarian insufficiency and oligo-terato-asthenozoospermia, but their cells showed chromosomal instability, hypersensitivity to radiation and altered checkpoints [44]. In 2025 the oldest patient with a biallelic pathogenic variant was described, a man with prostate cancer homozygous for c.2140C>T, without syndromic features; the authors count seven published patients with mild NBS and propose an attenuated form due to hypomorphic variants [49]. In 2026, 21-year-old Spanish monozygotic twin sisters, compound heterozygous for two novel variants, were diagnosed in adulthood with a presentation of antibody deficiency, ovarian dysfunction and, in one of them, peripheral T-cell lymphoma [50]. Monozygotic twins compound heterozygous for c.657_661del and c.643C>T had profound congenital microcephaly, poor cerebral gyration and severe epilepsy, but no chromosomal instability or cellular sensitivity to radiation [1, 45].

Outside classic NBS, GeneReviews recognises no other germline NBN phenotypes [9], but OMIM associates the c.511A>G variant with aplastic anaemia and susceptibility to acute lymphoblastic leukaemia (ALL): a Japanese girl with aplastic anaemia, without features of NBS, was homozygous for this variant and had a marked increase in spontaneous chromosomal aberrations [38, 48]. The age and mosaic status of this case differ between the secondary sources (11 years and homozygosity in OMIM; 9 years and mosaicism with a predominance of homozygous cells in the 2012 review) [1, 48]. The cancer risk of heterozygotes for NBN variants is covered in section 8.

2.6. NBSLD: RAD50

RAD50 (5q31.1) [51] encodes the ATPase of the MRN complex, which binds and holds broken ends close together, regulates the nuclease activity of MRE11 and is required for resection, efficient ATM activation, homologous and meiotic recombination and telomere maintenance [40]. Patients' cells lack radiation-induced MRN foci, ATM activation is markedly reduced, the G1/S checkpoint fails and DNA synthesis is radioresistant; the phenotype is corrected by the wild-type protein [34, 40, 52, 53]. The first patient was compound heterozygous for a maternally inherited nonsense variant and a paternal variant that extends the protein by 66 amino acids; the second was homozygous for a variant causing exon 15 skipping with a minor p.(Val842Ala) transcript [3]. In 2026 two more Chinese children were described, one compound heterozygous for NM_005732.4:c.2165_2166insT, p.(Lys722AsnfsTer6), and for an intronic splicing variant with partial intron retention confirmed by minigene assay, and another with p.His1269ArgfsTer2 and p.Ser844Asn [12, 21, 54]. Orphanet also includes MRE11 among the NBSLD genes, on the basis of loss of function [14].

2.7. ATLD: MRE11

MRE11 (11q21) [55] encodes the nuclease of the MRN complex. ATLD1 results from biallelic hypomorphic variants; patients' lymphoblastoid cell lines show a marked and consistent reduction in MRE11 protein [4, 24]. Activation of the canonical ATM targets (KAP1, CHK2) may be preserved, and the reproducible defect is failure of S-phase checkpoint activation after camptothecin, proposed as a functional assay for assessing variant pathogenicity [24, 56]. A Japanese patient with a homozygous missense variant (NM_005591.4:c.140C>T p.(Ala47Val)) had only slightly reduced levels of MRE11, RAD50 and nibrin and a mild myoclonic ataxia phenotype [4]. Stewart and colleagues estimated, from the length of the coding sequences, that about 6% of cases clinically classified as A-T might have MRE11 variants [4].

2.8. Ligation defects in NHEJ: LIG4, NHEJ1 and XRCC4

In classical NHEJ, the Ku70/80 heterodimer binds to the break and recruits the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs); this phosphorylates Artemis, a nuclease that opens the hairpins of the coding ends in V(D)J recombination; the complex formed by DNA ligase IV, XRCC4 and Cernunnos-XLF performs the final ligation, with polymerase μ filling gaps and terminal deoxynucleotidyl transferase (TdT) adding nucleotides at the junctions [5]. When the classical pathway fails, an alternative PARP1-dependent pathway uses microhomologies and generates deletions, which explains why V(D)J recombination is not completely lost [5].

DNA ligase IV, encoded by LIG4 (13q33.3) [57], is the ATP-dependent ligase that seals breaks [11]. Complete knockout is lethal in the mouse and all human variants are hypomorphic: missense variants near the catalytic site preserve 5% to 10% of adenylation and joining activity, and others alter the β-sheet and ATP pocket of the amino-terminal domain [5, 39]. Severity correlates with residual activity: missense variants are associated with combined immunodeficiency, and early truncating variants, which produce the shortest proteins, with SCID phenotypes [5, 58]. The variant NM_206937.2:c.833G>A, p.(Arg278His), described as mild, is classified as pathogenic in ClinVar; two linked polymorphisms (p.Ala3Val and p.Thr9Ile) halve ligase activity and, combined with p.Arg278His, lower it to the level of patients with immunodeficiency [10, 12]. Mice homozygous for this variant have growth retardation, reduced longevity and fertility, radiosensitivity, incomplete block of B and T development, autoantibodies and thymomas, a phenotype similar to human leaky SCID [10]. Patients' cells have deficient break repair with normal checkpoints, unlike NBS cells [10, 11].

Cernunnos-XLF, encoded by NHEJ1 (2q35) [59], is a 299-amino-acid protein that interacts with XRCC4 and stabilises and activates the ligase IV complex, favouring ligation of non-complementary ends [22]. Variants lie in the globular head, which interacts with XRCC4, and in the coiled-coil domain; nonsense variants predominate, followed by missense, splicing, frameshift and large deletions (10.2% deletions, insertions and duplications), with no clear correlation between type or location and severity [22, 39]. The variant NM_024782.3:c.532C>T, p.(Arg178Ter), which removes about the carboxy-terminal third, is pathogenic in ClinVar and has been described in 18 patients, mostly Turkish [12, 22]. Two unrelated patients homozygous for the same nonsense variant had opposite presentations and immunological profiles, so the genotype does not predict severity [60]. The cells have shortened telomeres, undetectable telomerase and premature senescence of haematopoietic stem cells, which contributes to bone marrow aplasia [6]. OMIM also associates with NHEJ1 an autosomal recessive microphthalmia/coloboma (MCOPCB13), but the mechanism is different: the homozygous variant, found in two consanguineous Iranian Jewish families, lies in an intron of NHEJ1, in an enhancer of the IHH gene, and patients have microphthalmia, anophthalmia or optic nerve coloboma without other features of the class [61].

XRCC4, encoded by XRCC4 at 5q14 [62], stabilises ligase IV in the final ligation. Patients with biallelic variants have no clinical immunodeficiency and V(D)J recombination appears normal, although functional studies show a compromised T-cell receptor repertoire [5, 36]. Variants in NHEJ1, LIG4 and XRCC4 skew the T-cell receptor repertoire even without profound lymphopenia, suggesting that receptor diversity, more than lymphocyte count, determines immune protection [36]. NHEJ also takes part in formation of the cerebral cortex, which explains the microcephaly of DNA-PKcs, ligase IV and XLF deficiencies, usually absent in Artemis deficiency [22].

2.9. Heterozygosity and haploinsufficiency

Mice heterozygous for a null Nbn variant have a significantly higher incidence of tumours without loss of the wild-type allele, which led to NBN being considered a haploinsufficient tumour suppressor [1]. Monoallelic missense LIG4 variants with haploinsufficiency have been associated with immune dysregulation (pneumonitis, autoimmune cytopenias, granulomatous parotitis and lymphoproliferation, with reduced and activated regulatory T cells) [39], and a heterozygous frameshift LIG4 variant co-segregated with non-syndromic premature ovarian insufficiency in a three-generation Chinese family, with cellular studies supporting haploinsufficiency [63]. These observations come from isolated families and functional studies and do not yet define a second disorder with dominant inheritance.

3. Clinical Spectrum and Manifestations by System

3.1. NBS: frequency of features

Table 3.1 summarises the frequency of the main manifestations of NBS according to GeneReviews.

Source: GeneReviews [9].

3.2. Growth and skull

Microcephaly, defined as head circumference below −2 standard deviations (SD), is present at birth and should alert the neonatologist; it progresses with age and may reach −9 SD in older children [1]. The anterior fontanelle is barely palpable and closes in the first weeks; microcephaly may be masked by hydrocephalus, until a ventriculoperitoneal shunt is placed, or by large subarachnoid cysts, and macrocephaly with schizencephaly and large cerebrospinal fluid spaces has been described [1, 9]. Follow-up of more than 70 Polish patients showed weight, length, head circumference and chest circumference at birth lower than those of the population; growth deficiency persists until 2–3 years, after which there is some gain in height and weight but not in head circumference, the pubertal growth spurt is weak in boys and absent in girls, and the mean adult height of more than half of patients is at the lower limit of normal [1]. Thyroid and adrenal function and insulin-like growth factor 1 (IGF-1) were normal and malnutrition was excluded [1]. There is no catch-up growth, so the disproportion between head and body becomes more pronounced [9].

3.3. Face, skin and skeleton

The facies is similar among patients and becomes more marked with age: sloping forehead and receding mandible, which accentuate the midface, upslanting palpebral fissures, prominent nose (long and beaked or upturned) and relatively large ears; cleft lip and palate and choanal atresia have occurred in isolated cases [1, 9]. Café-au-lait spots and/or vitiligo are present in about 50% to 70% of patients; three Polish patients had progressive generalised depigmentation; multiple pigmented naevi are common; the hair is fine and sparse in childhood and may turn grey in the second or third decade [1]. Sarcoidosis-like cutaneous granulomas, refractory to treatment, preceded the diagnosis of diffuse large B-cell lymphoma by 1 to 6 years in three patients [1]. Fifth-finger clinodactyly and partial syndactyly of the second and third toes occur in about half of patients; polydactyly, mainly preaxial, hypoplastic or absent thumb, hip dysplasia and agenesis of a rib or of the sacrum have been described [1, 9].

3.4. Central nervous system and neurodevelopment

The brain is small, with underdevelopment of the frontal lobes and a weight equal to or less than half of that expected; communicating hydrocephalus, agenesis or hypoplasia of the corpus callosum with colpocephaly, neuronal heterotopias (schizencephaly, pachygyria, partial lissencephaly) and arachnoid cysts have been described [1]. Despite severe microcephaly, most children reach motor milestones at the usual time and have good comprehension; speech delay is common and requires articulation therapy [1]. Follow-up of 48 Polish patients showed cognition close to average or borderline in early childhood, with hyperactivity, and gradual deterioration at school age, to mild to moderate intellectual disability; personality is described as cheerful and shy, with good interpersonal skills [1, 9]. Ataxia is not part of the picture [1]. Monozygotic twins with profound microcephaly, poor gyration and severe epilepsy and one patient with schizencephaly are exceptions [1].

3.5. Immunity and infections

The immunodeficiency is combined, variable between patients and within the same patient over time, with a tendency to progress [1]. In the European Society for Immunodeficiencies (ESID) registry series analysed by Wolska-Kuśnierz and colleagues, IgG deficiency was present in 62% of patients and IgA deficiency in 57%; subclass deficiencies (IgG4, IgG2 and IgG3, in decreasing order) are common even with normal total IgG; B lymphocytes (CD19+/CD20+), CD3+ T cells and CD4+ T cells were reduced in 80% to 89%; and in vitro proliferation to antigens and mitogens was moderately or severely reduced in most [9, 64]. In the Polish studies, CD4+ T lymphocytes are reduced in about 90%, naïve CD4+CD45RA+ cells almost absent and the CD4/CD8 ratio below 1.0 in more than 70%, with normal or increased NK cells; B lymphocytes are reduced in 72% to 75% and normal in 12% to 18%, sometimes increased with immunoglobulin deficiency, indicating an intrinsic class-switching defect [1]. Severe hypogammaglobulinaemia (IgG <2.0 g/L, low IgM and very low or undetectable IgA) is present in 20% to 24%; total immunoglobulins are normal in about 20%; only 25% have natural antibodies against three pneumococcal polysaccharides, and most do not produce protective anti-HBs after hepatitis B vaccination [1, 65]. In 46 patients, recent thymic emigrants and naïve cells were markedly reduced and senescent and exhausted populations (CD57, KLRG1, PD-1) increased [66].

The most common infections are respiratory (sinusitis, pneumonia, bronchitis), progressing to bronchiectasis, respiratory failure and death in some patients; these are followed by otitis media, mastoiditis and urinary and gastrointestinal infections, and secondary amyloidosis caused fatal renal failure in patients with persistent infections [1, 9]. Opportunistic infections are rare (about 5% in the ESID series), but prolonged antibiotic therapy favours colonisation by Pseudomonas aeruginosa and oral candidiasis affects about a third of patients; tuberculosis has been described in three [1, 9]. Lymphotropic and hepatotropic viruses (Epstein-Barr virus, EBV; cytomegalovirus, CMV; hepatitis B and C viruses) may have a severe chronic course, with lymphadenopathy, hepatosplenomegaly and pancytopenia mimicking lymphoma; in the Polish cohort, 68% had genetic material of lymphotropic viruses (EBV in 63%), usually with monoclonal gammopathy [1]. About 38% of Polish patients have persistent IgM and/or IgG monoclonal gammopathy, and about 73% without lymphoma have persistent clonal rearrangements of the B- and T-cell receptor genes, which progress with viral load and preceded lymphoma by up to 3 years [1]. Some patients with laboratory immunodeficiency do not have frequent infections or need immunoglobulin until adulthood [1]. In a prospective Russian cohort of 35 patients, 80% had laboratory signs of immunodeficiency but only 51% had significant infections [67].

3.6. Autoimmunity and granulomas

Autoimmune complications, including lymphocytic interstitial lung disease and cutaneous granulomas, affected 34% of the Russian cohort [67]. After rubella vaccination, patients with NBS developed cutaneous and visceral granulomas containing rubella virus, a complication shared with other immunodeficiencies [9, 68]. Pulmonary granulomas without an infectious agent, cutaneous necrobiotic granulomas, autoimmune haemolytic anaemia and factor V deficiency associated with T-cell prolymphocytic leukaemia have been described [1, 9].

3.7. Haematology

Aplastic anaemia, typical of Fanconi anaemia, has been described in at least three Slavic patients with NBS, one of them with EBV-associated B-cell lymphoma [1].

3.8. Puberty, gonads and reproduction

In girls with NBS, homozygous for the founder variant, the Polish longitudinal study documented absence of the pubertal growth spurt and poor development of secondary sexual characteristics, low oestradiol and elevated gonadotrophins, with a biphasic pattern: follicle-stimulating hormone (FSH) was normal only between 4 and 9 years, and in the other age groups met criteria for premature ovarian insufficiency; ultrasound showed small or streak ovaries and a hypoplastic uterus [1, 9]. In boys, puberty starts spontaneously and progresses as in peers, although male fertility has not been studied in detail; cryptorchidism and other genitourinary anomalies have been described [1, 9]. There are no reports of patients with NBS having offspring [1, 9]. A bilateral ovarian germ cell tumour has been described in a 46,XX woman with NBS and hypergonadotrophic hypogonadism [9].

3.9. Kidney, urinary tract and other malformations

Renal hypoplasia or aplasia, horseshoe or duplex kidney, renal ectopia, pelvi-ureteric duplication and hydronephrosis are relatively common and favour urinary infections; hypospadias, urethro-anal fistula and anal atresia or hypoplasia (at least six patients) have also been described [1]. Other isolated malformations include tracheal hypoplasia and congenital hip dysplasia [9].

3.10. Malignancies

NBS has one of the highest cancer incidences among the chromosomal instability syndromes, and malignancy is the main cause of death [1]. The main series are shown in Table 3.2.

NHL predominates: in the Polish registry, about 45% are of B-cell and 55% of T-cell origin, mainly diffuse large B-cell lymphoma (DLBCL) and T-lymphoblastic lymphoma, with a high frequency of consecutive lymphomas; Burkitt and Burkitt-like lymphoma, Hodgkin lymphoma, prolymphocytic leukaemia, B- and T-cell ALL and acute myeloid leukaemia (AML) also occur [1, 9, 70, 71]. In the Eastern Slavic cohort, DLBCL accounted for 38.1% of NHL and T-lymphoblastic lymphomas for 31.0%, followed by peripheral T-cell lymphomas (11.9%), rare in children without a syndrome; 75% of DLBCL had pulmonary involvement and almost all NHL were at an advanced stage; of the 12 cases of ALL, only one was B-cell [20, 39]. Hodgkin lymphoma is rare (3.3% in the Slavic cohort), with extranodal gastric location described [20, 39]. Malignancy was more frequent in boys (55.2% vs 34.2%; p=0.017), but girls with cancer had poorer event-free survival (16.6% vs 46.8%; p=0.036), especially after age 14 years [20]. In 27 of the 136 Slavic patients, NBS was diagnosed only after the malignancy, at a mean age of 8 years [20].

Solid tumours are a minority: medulloblastoma, glioma, rhabdomyosarcoma with a strong association with perianal location, neuroblastoma, papillary thyroid carcinoma, gonadoblastoma, meningioma, Ewing sarcoma and gastric carcinoma [1, 39, 72]. In 2025 two Serbian children with NBS and high-risk neuroblastoma were described [73]. Radiotherapy of central nervous system tumours caused severe complications and death in three patients with NBS not yet diagnosed [9, 74, 75]. Second malignancies, mainly de novo lymphomas confirmed by clonality, affect up to 33% of patients treated for B-cell lymphoma [1, 39]. Contributing to lymphomagenesis are deficient resolution of RAG-induced breaks at the IGH locus (with complex translocations in the lymphomas), telomere dysfunction, EBV infection and elevated IgM in B-cell NHL, and oxidative stress [39]. Homozygous probands from the Czech Republic and Slovakia born up to 1989 developed cancer earlier than those from Poland, a difference attributed by the authors to natural and medical radiation exposure, albeit within permitted limits [76].

3.11. Survival and quality of life

In the ESID series, 61% of the 149 patients were alive (median age 14.3 years), and the probabilities of survival at 5, 10, 20 and 30 years were 95%, 85%, 50% and 35%, lower in patients with malignancy [64]. In the international cohort of 241 patients, overall survival at 20 years was 44.6% ± 4.5%, 29.6% in patients with cancer and 86.2% in the others (p <10⁻⁵) [69]. In the Eastern Slavic cohort, only 12 patients (8.9%) survived beyond 18 years, and survival at 20 years was 23.9% with cancer and 30.4% without cancer, values lower than the Polish ones, which the authors attribute to a younger cohort and deficient care in adulthood [20]. The 11 adults surveyed (median 24.6 years) had completed basic education with their peers, six were employed, one woman had a university education and her own family, and the SF-36 questionnaire showed markedly reduced quality of life in the physical and mental domains [20]. These series reflect patients treated in different periods and health systems and are not directly comparable.

3.12. NBSLD

Published patients have severe prenatal and postnatal growth restriction, congenital microcephaly, borderline to mild intellectual disability and normal sexual development, without immunodeficiency, myelodysplasia or early neurodegeneration [3]. The index patient, followed from birth, had at 23 years mild to moderate psychomotor delay, mild non-progressive spasticity and ataxia, “bird-like” face, weight, height and head circumference below the 3rd centile, normal puberty, hyper- and hypopigmentation, severe hypermetropia, no infections, normal immunoglobulin subclasses and no malignancy, and lived in an apartment in assisted living; alpha-fetoprotein (AFP) had been elevated at 5 months and normalised by 2 years [3, 34]. A Turkish girl also had bilateral sensorineural deafness, a narrow foramen magnum with mild herniation of the cerebellar tonsils, a Wolff-Parkinson-White pattern and café-au-lait spots [3, 52]. A third child extended the picture to bone marrow failure and B-cell immunodeficiency, so the absence of immunodeficiency is not the rule [40, 53]. The 2026 Chinese cases included bilateral cryptorchidism, brachydactyly, café-au-lait spots, borderline lymphopenia without immunodeficiency and a final height of 151.5 cm at age 15 years after growth hormone [21, 54].

3.13. ATLD

ATLD1 begins in early childhood with slowly progressive cerebellar ataxia, cerebellar atrophy on magnetic resonance imaging (MRI), oculomotor apraxia, dysarthria and often dystonia or facial dyskinesia, with normal or mildly affected cognition [24]. The course is slower than that of A-T: two cousins from a consanguineous family were still walking at 25 and 20 years, two Italian siblings had no telangiectasias or malignancies in the fourth decade, and ten Saudi patients homozygous for the same variant, the oldest aged 37 years, had no tumours, telangiectasias, elevated AFP or low immunoglobulins [4]. The phenotype is broader than the classic description: a Japanese patient presented at age 9 years with progressive subcortical myoclonus and only at 40 with mild ataxia, without oculomotor apraxia or cerebellar atrophy, and another patient with predominant cervical and facial dystonia was diagnosed by exome in the fifth decade; hypergonadotrophic hypogonadism and hypersegmented neutrophils have been pointed out as clues [4, 24]. Chromosomal instability on karyotype is present only in a minority [24].

3.14. LIG4 syndrome

Of the 28 patients published up to 2016, 26 had non-progressive congenital microcephaly, often with severe growth restriction of intrauterine onset; four had “bird-like” or Seckel-type facies (beaked nose, prominent midface, sloping forehead and micrognathia) and 13 bilateral epicanthic folds and nasal anomalies; eight had skeletal anomalies (hypoplasia, syndactyly, polydactyly, hip dysplasia), three hypogonadism and ten skin changes (photosensitivity, psoriasis, eczema, erythroderma, bruising, hypopigmentation, extensive plantar warts) [5]. Neurodevelopment ranges from normal to profound impairment [5]. Twelve patients were identified through combined immunodeficiency with profound T- and B-cell lymphopenia and variable hypogammaglobulinaemia, often with elevated IgM; four had SCID and one SCID with features of Omenn syndrome [5]. Infections with P. aeruginosa, Acinetobacter baumannii, Pneumocystis jirovecii and viruses, with early bronchiectasis, and progressive bone marrow failure with thrombocytopenia, neutropenia and pancytopenia have been described, and most patients do not meet the IUIS criteria for SCID [39]. In a series of 11 patients identified among 138 with microcephalic primordial dwarfism, mean head circumference was −10.1 SD and height −5.1 SD; nine developed cytopenia requiring transfusion, none had combined immunodeficiency diagnosed before screening, six had retrospective signs of immunodeficiency, four needed HCT and none had a malignancy [5, 11, 58]. In one family, two of three siblings affected at the cellular level were asymptomatic [5, 77]. Six patients published up to 2016 had malignancies, mainly lymphomas (two EBV-associated), as well as leukaemias and one squamous cell carcinoma [5, 39]. The first patient, clinically normal, developed ALL and died of radiation encephalopathy eight months after prophylactic cranial irradiation [5]. In 2026 an 18-year-old man was described with extensive viral warts due to α and β HPV, bronchiectasis, chronic diarrhoea, absent B lymphocytes and almost undetectable naïve cells, compound heterozygous for NM_206937.2:c.833G>T, p.(Arg278Leu), and c.833G>A, p.(Arg278His) [12, 78].

3.15. Cernunnos-XLF deficiency

XLF deficiency presents in the first months or years with recurrent bacterial, viral and parasitic infections, T- and B-cell lymphopenia, hypogammaglobulinaemia with increased IgM, normal NK cells, growth retardation and microcephaly, “bird-like” facies and malformations [6, 22]. Progression to bone marrow aplasia and pancytopenia is common and is associated with short telomeres and stem cell senescence; autoimmune cytopenias occur in about 23%, mainly in leaky forms [6, 22]. In the 17 published patients with the p.(Arg178Ter) variant, growth retardation was present in all, microcephaly in 88.2%, infections in 70.6%, cytopenias in 35.3%, facial dysmorphism in 29.4%, developmental delay in 17.6% and malignancy in 5.9% [22]. BCG vaccine complications have been described in six patients, and a cerebral DLBCL in one child [22, 39]. Survival without HCT is rare: one patient died at 16 years of severe varicella and CMV reactivation, two patients died of septic shock at 4 and 18 years, and missense or splicing variants, which allow partially functional protein, predominate among survivors beyond 8 years, including a man who lived 30 years without transplantation [6, 22]. A 26-year-old Pakistani man without HCT had refractory cytopenia with monosomy 7 that disappeared, replaced by a clone with a 20q deletion [6].

3.16. XRCC4 deficiency

In six patients from five families, identified among 208 with microcephalic primordial dwarfism, median head circumference was −3.59 SD at birth and −8.15 SD later, and height −4.94 SD at birth and −4.6 SD later, without clinical immunodeficiency or bone marrow failure in most [7]. In adults, hypergonadotrophic hypogonadism, multinodular goitre and diabetes mellitus or early metabolic syndrome appear; progressive ataxia with onset between the second and fifth decades has been described, one patient was initially diagnosed with Cockayne syndrome, monozygotic twins had dilated cardiomyopathy and some patients had tumours [7].

4. Clinical Recognition and Red Flags

4.1. When to suspect NBS

The reference clinical review proposes as main symptoms microcephaly, usually present at birth, recurrent respiratory infections and malignancies, mainly haematological (NHL, ALL), but also solid tumours; as additional criteria, the characteristic facies, which becomes more evident with age, mild growth retardation, premature ovarian insufficiency, absence of neurological signs with good psychomotor development and better cognition in early childhood with gradual decline [1]. The family history supports the suspicion when there are siblings with microcephaly or hydrocephalus, early deaths of siblings from severe infections or malignancy, or relatives with malignancies [1]. GeneReviews adds the sloping forehead, upslanting palpebral fissures, prominent nose, large ears and retrognathia, and growth deficiency that is most marked from birth to 2 years [9].

Although microcephaly was present at birth or shortly afterwards in 80% of Russian patients, the mean diagnostic delay was 6.5 years [67]; in the Eastern Slavic cohort, the median age at diagnosis was 3.5 to 5 years, later in small towns and rural areas, and in 27 of 136 patients the diagnosis was made only after the malignancy [20]. Early diagnosis prevents severe infections, unnecessary exposure to diagnostic radiation and adverse reactions to radiotherapy [1].

4.2. Alert settings

4.3. Red flags in patients already diagnosed

Symptoms of lymphoma in an immunodeficient patient may be mistaken for infection: fever, lymphadenopathy, anorexia and wasting, weight loss, weakness, dyspnoea, cough and hepatosplenomegaly require investigation for malignancy [1, 9]. Delay in the diagnosis of lymphoma due to non-specific symptoms explains the frequency of advanced stages with multiorgan involvement [39]. Chronic viral infections with EBV or CMV with lymphadenopathy and pancytopenia may mimic lymphoma [1]. Monoclonal gammopathy and persistent clonal B- and T-cell receptor rearrangements, with rising EBV load, preceded lymphoma by up to three years in the Polish cohort, but the predictive value of these markers has not been established [1].

4.4. Newborn screening

T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) were low in most Russian patients with NBS, regardless of age, which makes newborn SCID screening potentially useful for detecting them; low KREC was associated with autoimmune and oncological complications [67]. The IUIS notes that NBS may show low TREC and T lymphocytes on newborn screening [19], and the EBMT/ESID guideline states that LIG4 and Cernunnos-XLF deficiencies and NBS may be detected by newborn SCID screening [23]. In XLF deficiency, lymphopenia is present from the neonatal period [22]. The sources consulted do not describe the sensitivity of TREC screening specifically for NBS.

4.5. ATLD, NBSLD, LIG4, XLF and XRCC4

ATLD should be considered in a child with slowly progressive cerebellar ataxia, oculomotor apraxia and dystonia, without telangiectasias, with normal AFP and immunoglobulins [24]. NBSLD and XRCC4 deficiency enter the work-up of microcephalic primordial dwarfism with radiosensitivity, and XRCC4 deficiency also that of adult endocrine dysfunction with extreme short stature [3, 7]. LIG4 syndrome should be sought in the presence of prenatal microcephaly with growth restriction, bone marrow hypoplasia, recurrent infections with lymphopenia and hypogammaglobulinaemia with elevated IgM [5]. XLF deficiency should be considered in infants with T−B−NK+ SCID, microcephaly and complications of live vaccines, such as BCG [22].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria for NBS

The diagnosis is established in a proband with suggestive findings and biallelic pathogenic or likely pathogenic variants in NBN, and/or with absence of nibrin on immunoblotting (western blot) [9]. The 2012 review lists the elements of the diagnosis: characteristic clinical manifestations, spontaneous and induced chromosomal instability, increased cellular sensitivity to ionising radiation in vitro, combined cellular and humoral immunodeficiency, variants in both NBN alleles and complete absence of full-length nibrin [1]. Immunoblotting is the only non-molecular test with confirmatory value; chromosomal instability and radiosensitivity are suggestive [41].

5.2. Molecular tests and strategy

Source: GeneReviews [9].

Almost all patients from Poland, the Czech Republic and Ukraine are homozygous for the founder variant; in a study of eight unrelated Russian patients, 15 of the 16 alleles were c.657_661del; in the USA, about 70% of patients are homozygous, 15% compound heterozygous with a second variant and 15% homozygous for another variant, and almost all American carriers of the founder variant have Eastern European ancestry [9]. In the Eastern Slavic cohort of 136 patients, all were homozygous for the founder variant except one Russian patient with c.657_661del/c.681del [20]. In Slavic populations, sequencing of exon 6 (or testing for the founder variant on a Guthrie card or EDTA blood) is the first step; in other populations, or without access to molecular testing, the karyotype may be the first investigation, and comparative genomic hybridisation is not suitable for this purpose [1]. Outside founder populations, a multigene panel including NBN and the genes of the differential diagnosis is an alternative, with the caveat that the genes included and sensitivity vary between laboratories and that broad panels increase variants of uncertain significance (VUS) [9]. Genomic analysis (array, panel, exome or genome) is useful given the heterogeneity of the repair disorders [35].

5.3. Cytogenetics

The constitutional karyotype is normal, but 10% to 60% of phytohaemagglutinin (PHA)-stimulated lymphocytes show abnormalities (chromatid and chromosome breaks, aneuploidies, markers, partial endoreduplication and rearrangements) [1]. Inversions and translocations between chromosomes 7 and 14, with breakpoints at 7p13, 7q35, 14q11 and 14q32 (T-cell receptor and immunoglobulin heavy-chain loci), occur in the great majority of patients; GeneReviews gives 10% to 50% of metaphases and the 2012 review 10% to 35% [1, 9]. The most frequent aberration is inv(7)(p13q35), followed by t(7;14)(p13;q11), t(7;14)(q35;q11), t(7;7)(p13;q35) and t(14;14)(q11;q32) [1]. The frequency of these rearrangements partly distinguishes the entities: 10% to 35% of metaphases in NBS, 5% to 10% in A-T, 1% to 8% in ATLD and 1.5% to 4% in NBSLD [1]. Poor lymphocyte response to PHA may prevent the study; sister chromatid exchanges are not increased, which distinguishes NBS from Bloom syndrome; lymphoblastoid cell lines and fibroblasts show different aberrations [1]. Monozygotic twins with NBS without chromosomal instability have been described [1, 45].

5.4. Radiosensitivity and functional assays

The colony-forming ability of lymphoblastoid cell lines after ionising radiation or radiomimetics is comparable to that in A-T and two to four times lower than in controls, and radioresistant DNA synthesis, which reflects the S checkpoint defect, is present in the great majority [1]. These assays require a lymphoblastoid cell line and are performed mainly in research laboratories, with limited clinical availability; the Oxford Desk Reference specifies 5 mL of blood in lithium heparin for the radiosensitivity assay and 6 weeks for nibrin immunoblotting [9, 35]. A simpler assay in peripheral blood mononuclear cells (increasing irradiation, CD3/CD28 activation and 6-day proliferation with interleukin 2) separates controls, which retain about 70% relative viability after 2 Gy, from patients with ATM, LIG4, Artemis or Cernunnos deficiency, who fall to 10% or less; obligate ATM carriers do not have increased radiosensitivity, and a normal result with strong clinical suspicion justifies repeating the test in fibroblasts [82]. The PROMIDIS-α (PROximal-MIddle-DIStal) biomarker, which uses next-generation sequencing to analyse usage of the proximal and distal segments of the T-cell receptor α, detects signatures of repair deficiency [36, 82]. Radiosensitivity results take weeks and should be requested in parallel with molecular testing when transplantation is planned [36].

The response to alkylating agents is equivocal in NBS (insensitivity or moderate hypersensitivity), and a positive DEB test contributed to a misdiagnosis of Fanconi anaemia followed by transplantation [1, 47]. Once NBN variants have been excluded, hypersensitivity to radiation confirmed by colony survival or radioresistant DNA synthesis points to LIG4 syndrome, NHEJ1 deficiency, NBSLD or ATLD [1]. The presence of full-length nibrin with a normal sequence excludes NBS [1].

5.5. Immunological assessment

The initial profile includes absolute counts of T lymphocytes (CD3+, CD4+, CD8+), naïve and memory T-cell subsets (CD45RA, CD45RO), B lymphocytes (CD19+, CD20+) and NK cells (CD16+CD56+), proliferation to mitogens or antigens (PHA, anti-CD3, anti-TCR), IgG, IgA, IgM and IgG subclasses, complement fractions C3 and C4, monoclonal proteins, EBV DNA load, HBs antigen (or hepatitis B virus DNA) and hepatitis C virus RNA, and B- and T-cell receptor rearrangements in peripheral blood; serology is not suitable for diagnosing viral infections in these patients [1, 9].

5.6. Diagnosis of the other entities

In NBSLD there is no biochemical marker; the assays of instability, radiosensitivity, radioresistant DNA synthesis, RAD50 immunoblotting and MRN foci are research tools, shared with NBS and ATLD, and the diagnosis requires biallelic RAD50 variants [40]. In ATLD, MRE11 immunoblotting in lymphoblastoid cell lines and the S checkpoint defect after camptothecin support the diagnosis; normal AFP and immunoglobulins distinguish it from A-T, but a normal result does not exclude it, nor does normal activation of KAP1 and CHK2 [24, 56]. In LIG4 syndrome, immunophenotyping, a blood count showing pancytopenia and radiosensitivity guide the diagnosis; increased use of microhomologies at junctions and restricted CDR3 length are research findings; increased 7;14 translocations are present in many patients; and no patient with LIG4 variants has been described without sensitivity to radiation [5]. In XLF deficiency, TREC, immunophenotyping, receptor repertoire and direct radiosensitivity testing confirm a repair defect, but not the gene, which is distinguished from DCLRE1C, PRKDC, LIG4 and NBN by molecular testing [82, 83].

5.7. Algorithm

The original flowchart of the 2012 review is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC3314554/figure/F5/ [1].

5.8. Test limitations and reporting

Targeted testing for the founder variant does not detect the other variants; sequencing detects point variants and small insertions/deletions but not exonic deletions, which have not been described in NBS [9]. Deep intronic or splicing variants require RNA studies, as shown by the intronic RAD50 splicing variant confirmed by minigene assay and the NBN c.1064_1124+9del deletion in the Spanish twin sisters [50, 54]. The proportion of variants detected by a method is not equivalent to the clinical sensitivity of the diagnosis. If only one parent is a carrier, the explanation may be a de novo variant, parental mosaicism or uniparental isodisomy — one patient homozygous for the founder variant had maternal isodisomy of chromosome 8 [1, 9]. The report should state the gene, the MANE transcript with version (NM_002485.5 for NBN), the variant in HGVS nomenclature with the historical designation where it exists (c.657_661del, 657del5), zygosity, the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), for which pathogenic and likely pathogenic are equivalent for clinical decision-making, and the technical limitations [9, 12]. The c.643C>T and c.511A>G variants have conflicting classifications in ClinVar and require cautious interpretation [12]. A negative panel result does not exclude the diagnosis if the clinical picture and functional assays are suggestive.

5.9. Prenatal and preimplantation diagnosis

Once both pathogenic variants in the family have been identified, prenatal diagnosis by chorionic villus sampling (usually at 11 weeks) or amniocentesis and preimplantation genetic diagnosis are possible; planning should be done with a specialised laboratory [1, 9, 35].

6. Differential Diagnosis

Microcephaly, growth retardation, immunodeficiency and bone marrow failure are common to several disorders of the detection, processing and repair of double-strand breaks; the early growth deficiency of NBS may suggest thyroid hormone or growth hormone deficiency or skeletal dysplasias [9]. The conditions most often confused with NBS are Fanconi anaemia and LIG4 syndrome [1]. In terms of the combination of chromosomal instability and immunodeficiency, the closest disorder is A-T, which differs in its neurological manifestations [1]. Table 6.1 summarises the entities to consider; GeneReviews also includes Rubinstein-Taybi syndrome (CREBBP, EP300), with recurrent infections and microcephaly but without cellular sensitivity or chromosomal instability [9].

6.1. NBS and A-T

NBS and A-T share immunodeficiency, radiosensitivity, radioresistant DNA synthesis, 7;14 translocations and lymphoma risk, because nibrin is required to activate ATM [1]. They are distinguished clinically: NBS has microcephaly from birth and no ataxia or telangiectasias, whereas A-T has progressive ataxia, telangiectasias and elevated AFP, with microcephaly only exceptionally; the combination of AFP, immunoglobulins, head circumference and telangiectasias is usually sufficient, but confirmation is molecular [1, 35]. The November 2023 revision of GeneReviews removed ATM from the differential diagnosis table for NBS, without changing this clinical comparison [9].

6.2. NBS and Fanconi anaemia

The overlap is real: some patients with NBS have moderate sensitivity to alkylating agents, aplastic anaemia and thumb anomalies, and a family homozygous for p.(Tyr363Ter) was diagnosed and transplanted as Fanconi anaemia before the diagnosis was revised [1, 47]. In Fanconi anaemia, progressive bone marrow failure and radial anomalies predominate, and DEB- and mitomycin C-induced breaks are the diagnostic marker; the Oxford Desk Reference reports, in a reference laboratory, DEB-induced breaks of 0.00–0.23 per cell in controls and 0.48–18.40 in patients with Fanconi anaemia [35]. The 2016 review of LIG4 syndrome states that microcephaly is not a feature of Fanconi anaemia, whereas GeneReviews and the Oxford Desk Reference record it in about a third of patients [5, 9, 35].

6.3. NBS and NHEJ defects

LIG4 syndrome reproduces the facies, microcephaly and growth retardation of NBS, but has more frequent bone marrow failure, more intense radiosensitivity and normal checkpoints in cells [5, 10]. The clinical phenotype of Dubowitz syndrome (prenatal and postnatal growth restriction, eczema, telecanthus, epicanthic folds, blepharophimosis, ptosis and a nose with a broad bridge and tip) is a complex of genetically distinct disorders that includes dyskeratosis congenita and LIG4 deficiency, so these diagnoses should be sought in a child with that picture [84]. XLF deficiency usually presents as SCID in infancy, with elevated chromosome breaks but without 7;14 rearrangements [9]. XRCC4 deficiency has more extreme microcephaly and dwarfism and endocrine dysfunction, without clinical immunodeficiency [7]. Seckel syndrome due to ATR shares the microcephaly and “bird-like” facies, but has neither radiosensitivity nor immunodeficiency [5].

6.4. NBSLD and ATLD

NBSLD is distinguished from NBS by usually normal immunity, normal puberty and mild neurological signs (spasticity, non-progressive ataxia); ATLD is distinguished from A-T by the absence of telangiectasias, a slower course and normal AFP and immunoglobulins [1, 4]. The cancer risks of heterozygotes do not transfer from one MRN complex gene to another (section 8) [85].

7. Treatments and Risk Management Strategies

7.1. Evidence base

No clinical practice guidelines for NBS have been published; management recommendations come from GeneReviews and the 2012 expert review, and transplantation recommendations from the joint 2021 guideline of the European Society for Blood and Marrow Transplantation (EBMT) and ESID, based on retrospective observational studies [1, 9, 23]. There are no randomised trials for any element of the management of these disorders, nor any medicine authorised in the USA or the European Union (EU) with an indication directed at the repair defect [41]. Patients should have an attending physician (paediatrician or family doctor) familiar with the disease, systematic supervision by an immunologist and an oncologist, an endocrinologist and gynaecologist from puberty onwards in girls, and psychological, social and educational support [1].

7.2. Assessment after the diagnosis of NBS

Main source: GeneReviews, Table 4 [9].

7.3. Immunodeficiency

Infections are treated with antimicrobials directed at the agent; the infection spectrum of NBS is not opportunistic, and long-term antibiotic, antiviral or antifungal prophylaxis is not routinely recommended [9]. Immunoglobulin replacement, intravenous (IVIg) or subcutaneous (SCIg), is considered in severe hypogammaglobulinaemia with frequent infections; most patients with IgG deficiency eventually need it, and the consensus cited in the 2012 review is a dose that keeps serum IgG above 5.0 g/L (at least 4–6 g/L), with home SCIg as an effective and well-tolerated alternative [1, 9]. Bronchiectasis is treated as usual [9]. Inactivated or acellular vaccines are recommended and live vaccines (BCG, measles, mumps, rubella, varicella) are not given [1, 9]. The vaccine response may be poor, as shown by the low frequency of protective anti-HBs after hepatitis B vaccination [9, 65]. In LIG4 syndrome and XLF deficiency, which are closer to SCID, the review of LIG4 syndrome and the 2025 case describe long-term antibiotic (co-trimoxazole), antifungal (fluconazole) and sometimes antiviral prophylaxis, immunoglobulin replacement, granulocyte colony-stimulating factor (filgrastim) for neutropenia, irradiated blood products and protective isolation until transplantation [5, 22, 39, 83]. In oncology, the I-BFM review recommends immunoglobulin, antifungal and antibacterial prophylaxis in patients with NBS and severe immunodeficiency during chemotherapy (section 7.4) [86].

Table 7.1 presents the dosing of normal human immunoglobulin, with the specific consensus as the reference and the European labels for comparison.

The target of the specific consensus (>5 g/L) is lower than the minimum of 6 g/L in the European labels; the consensus is the reference, and adjustment is based on infection frequency and not only on the trough level. The labels note that, after immunoglobulin, live attenuated vaccines lose efficacy for 3 months (for measles, up to 1 year) [87]. Both products have centralised authorisation in the EU, valid in Portugal, where the common name is normal human immunoglobulin.

7.4. Malignancies

Symptoms of lymphoma in an immunodeficient patient can be misleading, the diagnosis requires an experienced pathologist and, in doubtful cases, molecular cytogenetics, and patients should be treated according to general protocols, because there are no dedicated protocols [1, 9]. Treatment-related toxicity is greater: deaths are mainly due to sepsis, and early anthracycline cardiomyopathy has been described; in the Eastern Slavic cohort, 9 of 49 treated patients (18.4%) died before remission or relapse, 7 of them during induction, and 5 died in remission of infection, haemorrhage or multiorgan failure [1, 20].

The intensity of chemotherapy is the main point of divergence between sources. GeneReviews states that reduced doses did not decrease adverse effects and contributed to more relapses and poorer survival [9]; the 2012 review records the practice of limiting cyclophosphamide and ifosfamide and avoiding epipodophyllotoxins, but considers that reduction probably impairs outcomes and that doses above 80% of those prescribed are feasible, NHL relapse being the main cause of failure [1]. The review by the international Berlin-Frankfurt-Münster (I-BFM) group, with the Polish database, summarises in its abstract that it is reasonable to reduce chemotherapy by up to 50% in patients with clinically proven severe immunodeficiency, mainly anthracyclines, methotrexate, alkylating agents and epipodophyllotoxins, and to omit bleomycin and radiotherapy [86]. In the text, the numbered recommendations are more precise: test for the founder variant before any oncological treatment if there is a feature suggestive of NBS; give standard doses to patients with no history of severe infections or immunoglobulin supplementation; in severely immunodeficient patients, short oral fluoroquinolone prophylaxis at least during induction and reinduction of ALL or T-lymphoblastic lymphoma and in all cycles of B-cell NHL, and antifungal prophylaxis with posaconazole throughout treatment except maintenance, stopping the azole before vincristine; MRI or ultrasound instead of CT; and HCT or targeted therapy when important drugs or radiotherapy have been omitted and in second malignancies [86]. The same authors note that acute cardiotoxicity has been described with a total anthracycline dose of 190 mg/m², much lower than the usual threshold of 400–450 mg/m², that topoisomerase inhibitors should be limited, that renal and urinary anomalies should be factored into dose adjustments, that rituximab is the only antibody tested specifically in NBS and that blinatumomab and CAR-T cells may be less effective because of the intrinsic immunodeficiency [86]. In a German series of 38 children with A-T or NBS treated with BFM or CoALL protocols, 22 at reduced intensity, overall survival at 10 years was 58%, with no apparent disadvantage from the reduction, but with second malignancies in 10 patients (10-year incidence of 25%) [89]. The 2022 review of DNA damage response defects describes as options a reduced starting dose with escalation, full dose with longer intervals and substitution of cytotoxic agents, and points to immunotherapy (anti-CD30, anti-PD-1, anti-PD-L1, anti-CD38) as an alternative [82]. In the Slavic cohort, complete remission was achieved in 71.4% of the 49 treated patients (12 of 13 T-lymphoblastic lymphomas, 10 of 12 ALL, 10 of 15 DLBCL and none of the 4 peripheral T-cell lymphomas); 24.5% relapsed or progressed, at a median of 8 months, and none of these achieved a second remission [20].

Solid tumours are treated according to type, with protocols adapted to tolerance, avoiding radiotherapy and radiomimetic chemotherapeutic agents; brain tumours should be treated with chemotherapy only, because irradiation of the central nervous system caused three deaths [1, 9]. In 2025, successful treatment of relapsed ALL in a Polish child with NBS with combined anti-CD19 immunotherapy was described, and the case of gastric Hodgkin lymphoma in section 10 was treated with pembrolizumab after relapse [90, 91]. In LIG4 syndrome, prophylactic cranial irradiation for ALL was fatal in the first patient described [5].

7.5. Haematopoietic cell transplantation

Indications. GeneReviews recommends considering HCT after the first remission of a haematological malignancy [9]. The EBMT/ESID guideline considers the data insufficient to recommend HCT as routine treatment in the radiosensitive disorders (LIG4 and XLF deficiencies and NBS) and that the indication should be decided case by case, weighing risks and benefits and, where possible, in consultation with experienced centres [23]. According to the Slavic cohort, the guidelines of the EBMT inborn errors working party recommend HCT in all patients with NBS in first complete remission of lymphoma or leukaemia, and there are insufficient data to recommend it for all patients with a cellular defect without symptoms [20]. In LIG4 syndrome and XLF deficiency with a SCID or bone marrow failure phenotype, HCT is the only curative treatment for the immunodeficiency and bone marrow failure; it does not improve the microcephaly or neurodevelopment [5, 22, 92]. In A-T, the guideline sees no place for routine HCT [23].

Outcomes. The main series are shown in Table 7.2.

These series are retrospective, with heterogeneous indications, periods, donors and regimens, selection bias (patients who reach transplantation alive) and short follow-up for second malignancies; the superiority of reduced-intensity conditioning rests on non-randomised comparisons, and relative rates should be read alongside absolute rates.

Conditioning. Radiotherapy should be avoided because of catastrophic toxicity, and conventional doses of alkylating agents are poorly tolerated, with multiorgan failure and early mortality [23]. The guideline recommends protocol F, a modified version of the regimen used in Fanconi anaemia, in patients with DNA repair disorders and radiosensitivity, except Artemis deficiency [23]. Table 7.3 lists the published doses.

The low-dose busulfan regimen was associated with graft failure and low myeloid chimerism in NBS, and the largest Russian group reported that RIC caused graft failure and mixed chimerism [20, 93]. In the series of 87 patients, patients with RIC had less severe mucositis, veno-occlusive disease or post-transplant lymphoproliferative disease (7/59 vs 8/22; p=0.0215); the most frequent cause of death was multiorgan failure (45%), followed by infection (38%), and adenovirus, CMV or EBV viraemias affected 30% [92]. Radiosensitivity should be assessed before conditioning when a molecular diagnosis is not available [36, 82]. The reasoning for Artemis deficiency does not carry over: in that deficiency, high-dose cyclophosphamide alone does not reliably restore B-cell immunity, and management follows that of SCID [94]. The use of these drugs in conditioning follows transplantation guidelines and not the doses in their respective labels.

Post-transplant follow-up. Growth and developmental delay persist after HCT; susceptibility to infections and cytopenias resolve; thyroid autoimmunity and autoimmune cytopenias have been described; and surveillance for second malignancies should be prolonged [23, 92].

7.6. Hypogonadism, puberty and growth

Hormone replacement therapy is recommended in girls with hypergonadotrophic hypogonadism, at the appropriate age, to induce secondary sexual characteristics and prevent osteoporosis and metabolic, cardiovascular and psychosocial sequelae, with monitoring of sexual characteristics and uterine development [1, 9]. Neither GeneReviews nor the 2012 review gives doses; the dosing below is extrapolated from analogous conditions treated with the same drugs, premature ovarian insufficiency (guideline of the European Society of Human Reproduction and Embryology, ESHRE, with ASRM, CREWHIRL and IMS, 2024) and Turner syndrome (international guideline of 2024).

During hormone therapy, GeneReviews recommends monthly breast self-examination [9]; the premature ovarian insufficiency guideline states that hormone therapy does not increase the risk of breast cancer compared with women of the same age without ovarian insufficiency [95]. Boys start puberty spontaneously and need only periodic monitoring [1]. Growth hormone is not part of the recommended management: in a boy with NBSLD, treated with recombinant growth hormone without prior genetic testing, height went from −3.35 to −1.28 SD, and the authors warn of the theoretical risk of tumours in chromosomal instability disorders [21].

7.7. Neurodevelopment, ATLD and supportive care

Speech therapy corrects articulation problems, and psychological assessment before schooling and every few years guides educational support [1]. In ATLD there is no disease-modifying treatment; support includes physiotherapy, occupational and speech therapy, mobility aids and symptomatic treatment of dystonia, and there is no published policy on radiation exposure, although the cells are radiosensitive [24]. In LIG4 syndrome and XLF deficiency, haematological support (transfusions of irradiated blood products) and filgrastim for neutropenia form part of the bridge to transplantation [5, 22].

7.8. Agents and circumstances to avoid

NBS cells are as radiosensitive in vitro as those of A-T, and conventional doses of radiotherapy can be lethal; the family should be aware of this risk so as to be able to discuss options if a malignancy occurs [9]. Unnecessary exposure to ionising radiation should be avoided, preferring MRI and ultrasound to radiography and computed tomography (CT); hand radiography for bone age should be avoided [1, 9]. Live vaccines (BCG, measles, mumps, rubella, varicella) are not given [9]; rubella vaccine caused granulomas containing vaccine virus in patients with NBS and BCG caused BCG-itis in XLF deficiency [22, 68]. In countries where BCG is universal, the authors of the 2025 case suggest a blood count before live vaccines to detect lymphopenia [22]. In conditioning and chemotherapy, conventional-dose alkylating agents and radiotherapy should be avoided or reduced, as described in 7.4 and 7.5 [23, 86]. The same precautions regarding radiation apply to the other entities in the class, although ATLD has no formal recommendation [5, 24].

7.9. Regulatory status

For heterozygotes with metastatic castration-resistant prostate cancer, the FDA label for talazoparib includes NBN among the repair genes that define the indication, which is not the case in the EU.

7.10. Registered clinical trials

No results have been published from these trials, all single-arm and from the same sponsor. The search of ClinicalTrials.gov found no therapeutic trials directed at LIG4 syndrome, XLF deficiency or ATLD, which does not prove their absence from other registries.

7.11. Developments in the last 12 months

No regulatory application, opinion or authorisation relating to these disorders was identified in the sources consulted.

7.12. Pregnancy, perioperative care and transition

There are no reports of pregnancy in women with NBS, who have ovarian insufficiency in almost all cases [1, 9]. In the perioperative period, the principles are to avoid imaging with ionising radiation when an alternative exists, to transfuse irradiated blood products in patients with combined immunodeficiency and to maintain immunoglobulin replacement [9, 22]. Transition to adult care is critical: in the Slavic cohort, survival lower than in the Polish cohort was partly attributed to deficient care of adults with severe complications, and adult survivors had physical and cognitive limitations and reduced quality of life [20].

7.13. Divergences between recommendations

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All the entities in this article are autosomal recessive [9, 35]. The parents of a patient are presumed to be heterozygous, and molecular testing of both is recommended to confirm this and calculate the recurrence risk [9]. If the variant is found in only one parent, with confirmed paternity and maternity, the possibilities are a de novo variant in the proband, post-zygotic mosaicism in a parent or uniparental isodisomy; a patient homozygous for the founder variant through maternal isodisomy of chromosome 8 has been described [1, 9]. In each pregnancy of a carrier couple, the risk of an affected child is 25%, of a heterozygous child 50% and of a non-carrier 25% [9]. No offspring of patients with NBS are known [1, 9]. The parents' siblings have a 50% probability of being carriers [9]. In Slavic populations, the carrier frequency of about 1:155 to 1:177 increases the risk that an unrelated partner is a carrier, and ancestry-specific frequencies should replace the worldwide average in counselling [1, 9, 41].

8.2. Cascade testing

Testing for the familial variants should be offered to asymptomatic adult relatives, to identify heterozygotes who may benefit from cancer surveillance; the evidence of cancer risk in young carriers is insufficient to justify testing or screening in childhood, so testing of minor siblings is deferred [1, 9]. Carrier testing presupposes prior identification of the familial variants, and counselling on reproductive options should be offered to young adults who are carriers or at risk, ideally before pregnancy [9].

8.3. NBN heterozygotes: cancer risk

This is the point on which the sources diverge most. GeneReviews, revised in 2023, recommends surveillance of heterozygous parents and adult siblings for malignancies, especially breast cancer in women and prostate cancer in men, while acknowledging that there are no consensus protocols [9]. The founder variant was found at increased frequency in patients with breast cancer, prostate cancer, medulloblastoma and melanoma in Polish studies, one of which proposed NBS1 as a prostate cancer susceptibility gene [9, 103]. ClinGen, on the other hand, classified the relationship between NBN and hereditary breast carcinoma as refuted (14/03/2023), while maintaining the recessive relationship with NBS as definitive [18]. In the American population-based CARRIERS study (32,247 women with breast cancer and 32,544 controls), the founder variant was not associated with increased breast cancer risk [104]; in the BCAC consortium (60,466 cases and 53,461 controls), NBN was not among the genes with truncating variants associated with overall risk [105].

Table 8.1 summarises the meta-analysis of 53 studies on the MRN complex genes [85].

In a pan-cancer series of 34,046 patients with paired tumour and germline sequencing, 0.25% were carriers of pathogenic NBN variants (40% with the founder variant), tumours more often lost the wild-type allele (OR 2.7) and the variants were enriched relative to European controls (OR 1.9; replication OR 1.8) [43]. In 4325 children with B-cell ALL, damaging NBN variants were over-represented (OR 1.8; p=0.004), mainly missense variants in the amino-terminal domains, without poorer survival in carriers, who can receive standard treatment [106]. The earlier manifestation of cancer in Czech and Slovak homozygotes than in Polish ones was interpreted as reflecting radiation exposure and as a possible explanation for the higher risk reported in Czech heterozygotes [76]. In summary, current evidence does not support managing female heterozygotes as carriers of a moderate-risk breast cancer gene, as the Oxford Desk Reference did in 2017 [18, 104, 107], but suggests increased risks of melanoma, pancreatic cancer and prostate cancer; surveillance of heterozygotes follows general programmes and the tumour-specific recommendations for moderate-penetrance genes, without a specific consensus protocol [9, 85].

8.4. RAD50 and MRE11 heterozygotes

ClinGen classified RAD50 as refuted for hereditary breast carcinoma (14/03/2023) and for familial ovarian cancer (23/02/2024), and GeneGuidance records the same classification for MRE11 (breast on 14/03/2023 and ovary on 15/12/2023) [18, 24]. Isolated RAD50 or MRE11 heterozygosity should not lead to high-risk breast MRI, risk-reducing mastectomy or salpingo-oophorectomy, and the risks of NBN or ATM do not transfer to these genes [24, 40, 85]. In a study in a founder population, MRE11 variants annotated as pathogenic in ClinVar often lacked evidence for that classification [24, 108]. The frequency of RAD50 variants in ClinVar reflects the volume of cancer panel testing and not the burden of NBSLD [40].

8.5. LIG4 and NHEJ1

Parents and siblings heterozygous for NHEJ1 variants have normal immunity, and an HLA-identical carrier sister was used as a donor, with limited long-term safety data [22]. Monoallelic LIG4 variants associated with immune dysregulation and premature ovarian insufficiency are recent observations in isolated families [39, 63].

8.6. Prenatal and preimplantation diagnosis

With both variants identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic diagnosis are possible; the decision is personal and benefits from discussion before pregnancy [1, 9]. The authors of the Slavic cohort note that family planning in regions with the founder variant is not yet widespread [20].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Worldwide prevalence and the Slavic founder effect

There are no reliable estimates of the worldwide prevalence of NBS; GeneReviews gives about 1:100,000 live births, a value that Orphanet records as a not-yet-validated worldwide birth prevalence [9, 13]. The distribution is very uneven: the founder variant c.657_661del has a carrier frequency of about 1:155 in Poland, the Czech Republic and Ukraine (1:177 newborns in another estimate), 1:176 in newborns from north-eastern Bavaria and about 1:34 among the Sorbs, an isolated Slavic group in south-eastern Germany [1, 9, 109, 110]. These frequencies measure carriers and not patients.

The concentration in western Belarus and western Ukraine, close to the Polish border, defines an Eastern Slavic focus parallel to that of the RAG1 founder variant originating in the Vistula basin [20]. The disease has also been described in other European countries, in North and South America, in Morocco, in New Zealand and in patients from the Middle East [1, 20]. Prevalences per population depend on ascertainment and registration and are not equivalent to birth incidence.

9.2. Other entities

NBSLD has a prevalence below 1/1,000,000 and fewer than ten published patients [14, 21]; ATLD has an unknown prevalence, with family series in Saudi Arabia (ten patients from three families with the same variant), Italy, Japan and Pakistan [4, 15]; LIG4 syndrome numbered 28 cases in 2016 [5, 16]; XLF deficiency about 55 cases in 2025, with the p.(Arg178Ter) variant mainly in Turkish patients [22]; and XRCC4 deficiency is known from small series of various origins (Saudi Arabia, Italy, Chile) [7]. These disorders are more frequent in populations with consanguinity [83].

9.3. Portugal and Brazil

The sources consulted do not include prevalence data for NBS or the other entities in Portugal or Brazil; the Brazilian handbook of genetic syndromes mentions NBN only as a moderate-penetrance gene for breast and ovarian cancer, according to the 2020 NCCN, a classification since revised [18, 111]. The absence of data in the sources does not demonstrate an absence of patients.

9.4. Reference networks and patient associations

ERN RITA (European Reference Network on Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases) is the reference network for immunodeficiencies [25]; paediatric malignancies fall under ERN PaedCan [26], and tumour predisposition syndromes under ERN GENTURIS [27]. The ESID registry is the largest European registry of patients with NBS [1, 112]. International associations of patients with primary immunodeficiencies include IPOPI and the Immune Deficiency Foundation [113, 114]; GeneReviews also lists MedlinePlus [9].

10. Illustrative Clinical Case

Batiuk and colleagues described in 2023 a 14-year-old boy of Eastern European ancestry, followed in the USA, with NBS diagnosed at 6 months after his older sister had genetic testing that revealed the “NBS1 657del5” deletion, corresponding to NBN NM_002485.5:c.657_661del, p.(Lys219AsnfsTer16); two siblings and a cousin also had NBS [12, 91]. He had combined immunodeficiency with low B lymphocytes and deficient T-cell function, microcephaly, short stature (Z-score below −2), bronchiectasis and lymphopenia with IgG deficiency on regular IVIg [91]. At 8 years, during an admission for pneumonia with pleural effusion, a uric acid of 7.2 mg/dL and lactate dehydrogenase of 2711 U/L led to the discovery of a right thoracic mass and lesions in the kidneys, spleen, pelvis and tibiae, with partial bone marrow involvement: a DLBCL, treated with the ANHL1131 protocol at reduced dose because of the chromosomal instability, with remission maintained for 6 years [91].

At 14 years, he was referred for eight months of daily postprandial periumbilical pain, attributed to reflux and partly relieved by omeprazole, and for a 9% weight loss over six months, with weight below the 3rd centile (Z-score below −6); physical examination, blood count, biochemistry, C-reactive protein and coeliac disease antibodies were normal, but faecal calprotectin was 318.2 µg/g [91]. Endoscopy showed nummular white gastric lesions (https://pmc.ncbi.nlm.nih.gov/articles/PMC10120165/figure/Fig1/), chronic gastritis without Helicobacter pylori and focal ileitis; histology showed Reed-Sternberg cells strongly positive for CD30 and CD15, without EBV or CMV, and MRI revealed lymphadenopathy in the lesser sac and at the cardia (https://pmc.ncbi.nlm.nih.gov/articles/PMC10120165/figure/Fig6/); the diagnosis was stage IIB gastric classical Hodgkin lymphoma [91]. He received two cycles of OEPA (vincristine, etoposide, prednisone and doxorubicin) at 30% and 40% of the full dose, without the COPDAC cycles (cyclophosphamide, vincristine, prednisone and dacarbazine) to avoid alkylating agents, and achieved complete remission; nine months later he was admitted with intestinal perforation with relapse, received a further cycle of OEPA at 30% and was switched to pembrolizumab while transplantation was being considered [91].

The case brings together the elements of the natural history described in the preceding sections: early family diagnosis, immunodeficiency on immunoglobulin replacement, a first aggressive B-cell lymphoma at 8 years and a second lymphoid malignancy, at a rare location, whose non-specific digestive symptoms delayed the diagnosis [39, 91]. The dose reductions applied were individual decisions and do not correspond to a validated protocol; GeneReviews and the 2012 review warn that reduction may increase the risk of relapse, and the EBMT/ESID guideline and GeneReviews place HCT in first remission as the option to consider [1, 9, 23]. The characteristic facies of NBS in a child aged 3.5 years can be seen in the 2012 review (https://pmc.ncbi.nlm.nih.gov/articles/PMC3314554/figure/F1/), and the facies and BCG-itis of an infant with XLF deficiency in the 2025 case (https://pmc.ncbi.nlm.nih.gov/articles/PMC12613498/figure/Fig2/) [1, 22].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In NBS, malignancy is the main determinant of survival: in the ESID series, survival at 5, 10, 20 and 30 years was 95%, 85%, 50% and 35% [64]; in the international cohort of 241 patients, overall survival at 20 years was 44.6%, 29.6% in patients with cancer and 86.2% in the others [69]; and in the Eastern Slavic cohort only 8.9% of patients survived beyond 18 years [20]. Survival after a cancer ranges from 18% to 40% across series, and second malignancies and relapses, which in the Slavic cohort did not achieve a second remission, worsen the prognosis [20]. In the Polish series of 17 patients with NHL, survival was better in B-cell than in T-cell lymphomas [1]. Respiratory infections with bronchiectasis can cause respiratory failure and death, and humoral deficiencies worsen the long-term prognosis [9, 64]. HCT in first remission and pre-emptive HCT were associated with better survival and a lower incidence of cancer in observational studies [67, 69], and low KREC is a marker of greater severity [67]. ATLD has a slow course, with patients walking in the third decade and free of tumours until the fourth [4]. In LIG4 and XLF deficiencies with SCID, survival depends on HCT; without transplantation, prolonged survival is rare and associated with hypomorphic variants [5, 22]. After HCT with RIC, survival in LIG4, XLF and NBS deficiencies was 79% [92].

11.2. Surveillance in NBS

11.3. Follow-up of the other entities and after transplantation

After HCT, surveillance should include long-term second malignancies, autoimmunity (thyroid and cytopenias), growth and development, which do not improve with transplantation [23, 92]. In NBSLD and XRCC4 deficiency, surveillance of growth, development and endocrine function (gonads, thyroid, blood glucose in XRCC4 deficiency) and attention to possible malignancies are based on case reports [3, 7, 54]. In ATLD, follow-up is neurological and rehabilitative [24]. In non-transplanted LIG4 and XLF syndromes, blood count and immunity should be monitored because of progression to bone marrow failure and autoimmune cytopenias [5, 6]. The sources consulted do not propose formal intervals for these entities.

12. Summary and Final Considerations

Nijmegen breakage syndrome is an autosomal recessive disorder due to hypomorphic variants in NBN, the adaptor subunit of the MRN complex that detects double-strand breaks and activates ATM. In most patients, who are of Slavic ancestry, the cause is homozygosity for the founder variant NM_002485.5:c.657_661del, which produces a partially functional p70 fragment. The picture combines microcephaly from birth, facies with a prominent midface, growth retardation, progressive combined immunodeficiency, premature ovarian insufficiency, gradual cognitive decline and radiosensitivity, with a risk of malignancy, mainly NHL, of about 40% at 10 years and close to 70%–80% at 20 years, which is the main cause of death. The diagnosis is confirmed by testing for the founder variant or NBN sequencing, supported by 7;14 translocations and nibrin immunoblotting. Management is based on immunoglobulin replacement, avoidance of live vaccines and ionising radiation, adapted treatment of malignancies, hormone therapy in girls and HCT with reduced-intensity conditioning, especially in first remission. In the same class, NBSLD (RAD50) and XRCC4 deficiency cause microcephalic dwarfism with little or no immunodeficiency, ATLD (MRE11) a slowly progressive ataxia without telangiectasias or immunodeficiency, and LIG4 syndrome and Cernunnos-XLF deficiency (NHEJ1) radiosensitive combined immunodeficiencies with microcephaly and bone marrow failure, immunologically curable by HCT. In heterozygotes, current evidence refutes the breast cancer risk associated with NBN, RAD50 and MRE11 as moderate-risk genes and points to increased risks of melanoma, pancreatic cancer and prostate cancer in NBN carriers, without a consensus surveillance protocol.

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