Ataxia telangiectasia (AT) is a rare systemic autosomal recessive disorder (OMIM*208900) caused by mutations in ATM [51], manifest by progressive cerebellar ataxia, oculocutaneous telangiectasia, gonadal sterility, postnatal growth retardation, a high incidence of predominantly lymphoid tumors and variable, often progressive immunodeficiency.

Mutations in Ataxia-Telangiectasia Mutated (ATM, OMIM*07585), located on 11q22-23 and encompasses 66 exons is associated with AT. The estimated incidence of ataxia telangiectasia is 1 in 20,000 to 100,000 live births [252].

The majority of children are healthy in infancy and begin walking normally, but are slow to develop further, with difficulty standing still without wobbling (Table 9.1). Patients usually present to neurologists with cerebellar ataxia before telangiectasia appear. As the disease progresses, patients develop dysarthria, with complex movement disorders, and become wheelchair reliant. Abnormal eye movements develop, particularly oculomotor apraxia. Most never attain normal speech due to problems with articulation, and speech is slow with misplaced emphasis placed on single words or syllables. Swallowing difficulties develop over time. Telangiectasias appear mainly on bulbar conjunctivae between 3 and 5 years of age (Fig. 9.1), and exposed areas of the skin, particularly the external ear, nose, face, and neck. Other skin manifestations include café-au-lait macules and hypopigmented patches.

Immunodeficiency occurs in approximately 70 % of patients. Recurrent sinopulmonary infection may be a presenting feature, sometimes concomitant with raised IgM and low or absent IgG [185]. Sinopulmonary infection may be associated with recurrent aspiration, common over the age of 10 years, which can lead to chronic lung disease [150] The incidence of infection is variable and more common when null mutations are present on both ATM alleles [79, 239]. Antibody responses to bacterial antigens are generally reduced, particularly those directed against carbohydrate polysaccharide antigens [226]. However, opportunistic infection is extremely unusual. Lymphocytic interstitial pneumonitis has rarely been described [257].

From 10 years of age, the incidence of malignancy is 1 % per year, and around 10–20 % of patients with ataxia telangiectasia will develop malignancy [195], (85 % of which are lymphomas and acute leukemias).

Diagnosis is based on clinical features as described above, and laboratory features. Serum alpha-fetoprotein is invariably raised, although the level does not correlate with disease severity. Laboratory immunological abnormalities include immunoglobulin deficiency, particularly absence or marked reduction of IgA and IgG2; raised IgM has been described. Humoral immune deficiency becomes more severe with increasing age in some individuals, but recurrent sinopulmonary infection is exacerbated by recurrent aspiration with increasing neuromuscular incordination. Poor polysaccharide antibody responses are common, such as those derived against pneumococcal antigen. Lymphocytopenia also occurs, but is generally not progressive [49, 145].

Cytogenetic analysis reveals spontaneous abnormalities, including chromosomal breakage, translocations, and rearrangements particularly involving the immunoglobulin and T lymphocyte receptor gene loci on chromosomes 7 and 14 (chromosome 7/14 translocation).

Newborn screening for severe combined immunodeficiency by quantitative analysis of T-lymphocyte receptor excision circle DNA episomes in the neonatal blood spot has detected some patients with ataxia telangiectasia in the newborn period [160].

Treatment is supportive. Median survival is currently 25 years. Prophylactic antibiotics may be used for those with recurrent bacterial infection – rarely immunoglobulin substitution may be required. Treatment of those patients that develop malignancy is extremely challenging, as tumors are often aggressive, and all ataxia telangiectasia cells are extremely vulnerable to damage by chemotherapeutic agents that cause DNA-DSB. Death may caused by extreme sensitivity to chemotherapy for malignancy [25]. The incidence of late complications following radiotherapy may be higher in some affected patients. Reduced intensity regimens have been used [195] in treating malignancy in some cases [124, 158, 227]. Hematopoietic stem cell transplantation (HSCT) has been offered to some patients, although adverse effects from the chemotherapy can be fatal [100]. A successful outcome may cure the malignancy [266], but neurological deterioration is unlikely to be halted. Novel approaches to treatment currently in development are the use of antisense oligonucleotides to correct splicing, frameshift and missense mutations to convert absent or unstable protein to partially or fully functional protein, or the use of ribosomal read-through agents to surmount premature termination codons, and permit normal protein expression [80]. Female ATM heterozygotes harbor an increased risk of breast cancer [195]. Heterozygosity for ATM may also confer increased risk of other malignancies [217], and sensitivity to chemotherapeutic agents or radiation [198, 294].

Ataxia telangiectasia-like disorder or ATLD (OMIM*604391) is an extremely rare form of DNA repair defect [93, 256].

Ataxia telangiectasia-like disorder, caused by mutations in MRE11A (OMIM*600814) on chromosome 11q21, is extremely rare, with few patients reported [66, 90, 140, 165, 189, 202, 241, 265].

Whilst the clinical features are similar to those found in patients with ataxia telangiectasia, progressive cerebellar ataxia is later in onset and also of slower progression than in patients with ataxia telangiectasia (Table 9.1). Additionally, telangiectasia is absent. Lymphoid tumors have not been reported, although poorly differentiated lung adenocarcinoma has been described. A few patients are microcephalic [165].

Immunoglobulin levels are normal, although antigen-specific antibodies have been reported as deficient, particularly those derived against pneumococcal polysaccharide antigen. Defective immunoglobulin isotype switching has been reported.

Treatment is supportive.

Nijmegen breakage syndrome (OMIM*251260) is a rare autosomal recessive disorder of DNA-DSB repair, was first described in 1981 in a Dutch patient [286]. It is due to mutations in NBN (OMIM*602667) on chromosome 8q21 [286].

Whilst the exact incidence is unknown, many Nijmegen breakage syndrome patients are ethnically from Eastern Europe, particularly Poland and Czech and Slovak republics where the prevalence of the founder mutation (657del5) ranges from 1/154 to 1/190 and the incidence is estimated to be 1/95,000 live births [270].

Nijmegen breakage syndrome is characterized by progressive severe microcephaly and a “bird-like” face (Fig. 9.2), intrauterine growth retardation and short stature (Table 9.1). Most patients have severe microcephaly, with occipito-frontal circumference significantly below the third percentile [286]. Microcephaly is pre-natal in 75 % of cases, develops during early infancy in the remaining patients and is progressive, associated with a decline in cognitive skills giving rise to mild to moderate mental retardation by 7–10 years of age. Associated with this are abnormal facies with a sloping forehead, receding mandible, prominent mid-face, long nose, and upward slant of the palpebral fissures. The characteristic facial features become more prominent as the microcephaly progresses. Other malformations occuring in 50 % of patients include clinodactyly and syndactyly, gastrointestinal tract atresia or stenosis, choanal atresia, cleft lip and palate, hydronephrosis, and hip dysplasia. Hypergonadotropic hypogonadism is common in males and ovarian dysgenesis and premature ovarian failure occurs in females [50]. Café-au-lait spots and depigmented skin lesions are common, and cutaneous non-caseating granulomas have been rarely described [272, 298].

Immunodeficiency is common. Many affected individuals experience recurrent upper and lower respiratory tract infections including pneumonia, bronchitis, sinusitis, otitis media, and mastoiditis [183]. Bronchiectasis is the second leading cause of death in patients with Nijmegen breakage syndrome. Opportunistic infections have not been reported but there is generalized immune dysfunction such as autoimmune thrombocytopenia and hemolytic anemia more frequently than expected [183, 206].

Patients have a predisposition to malignancy, particularly of the reticulo-endothelial system [207]. Malignancy is the leading cause of death for these patients – 40 % develop malignancy before 20 years of age [183]. Most are lymphomas, but there are rare instances of glioma, rhabdomyosarcoma, and medulloblastoma [52, 67, 103]. There is an increased risk of malignancy in heterozygous carriers [188, 230, 302].

Diagnosis is determined on clinical and laboratory features, but a definitive diagnosis requires genetic confirmation, as other radiosensitive disorders can mimic Nijmegen breakage syndrome. Severe microcephaly is the prominent feature associated with mild retardation and characteristic facial features. Laboratory features include absent or low levels of one or more immunoglobulin classes or IgG subclasses in up to 80 % of patients [107]. Most patients demonstrate T and B lymphocytopenia, with a reduction in class-switched memory B lymphocytes [75, 168, 210]. Most patients have reduced in vitro proliferative responses to mitogens.

As in ataxia telangiectasia, the characteristic laboratory abnormality in Nijmegen breakage syndrome is chromosome instability and radiosensitivity. Chromosomal breakage, translocations, and rearrangements, especially chromosome 7/14 translocations are common (Fig. 9.3). Sensitivity to ionizing radiation can be demonstrated using a clonogenic survival or γ-H2AX assay, with sensitivity comparable to that observed in patients with ataxia-telangiectasia. Similar karyotypic abnormalities can be seen following exposure to DNA-crosslinking agents, such as mitomycin C, as found in Fanconi anemia [97]. Immunoblotting and molecular genetic testing are required to confirm the diagnosis. The 657 del 5 mutation of NBS1 is present in 85 % of cases in the United States. In patients with an appropriate ethnic background, targeted sequencing simplifies the task of genetic confirmation in many cases.

There is no specific treatment for Nijmegen breakage syndrome. Subjects should be evaluated for immunodeficiency and treated with antibiotic prophylaxis and immunoglobulin replacement where appropriate. Increasing numbers of patients with severe immunodeficiency or resistant or secondary malignancy, have successfully undergone HSCT with reduced-intensity conditioning regimens, although may remain at increased risk of developing secondary malignancies [5].

Patients have a high risk of developing malignancy, predominantly lymphomas [207]. The increased sensitivity to ionising radiation and chemotherapy complicates treatment of malignancies [17, 76], but reduced intensity regimens have led to successful treatment with reduced toxicity [25]. Life expectancy is reduced because of the risk of developing malignancies or severe infections.

One patient has been reported with Nijmegen Breakage Syndrome-like features, which was due to mutation in another gene rather than NBN [18].

In that patient with Nijmegen Breakage Syndrome-Like Disorder (OMIM*613078), compound heterozygous mutations in RAD50 (OMIM*604040) was detected, which is one of the components of the MRN complex, were found [18].

The clinical features comprised pre-natal growth failure with microcephaly, poor post-natal growth and ‘bird-like’ facies. Speech delay was also noted; moderate psychomotor retardation, with mild spasticity and a non- progressive ataxic gait have persisted. Cutaneous features included multiple cutaneous pigmented naevi and hypo-pigmented areas. There was no significant infectious history. At latest follow-up, aged 23 years, there was no evidence of myelodysplasia or lymphoid malignancy.

Lymphocyte numbers, proliferations to mitogens and immunoglobulin levels were normal. Chromosomal instability with 7:14 translocations was noted and there was lymphocyte sensitivity to ionizing radiation. In this individual, one mutation created a premature stop codon, the other led to an abnormally large polypeptide [281].

In this one patient, the phenotype of RAD50 deficiency more closely resembles that of Nijmegen Breakage Syndrome than ataxia telangiectasia, unlike MRE11 deficiency. Although immunodeficiency was not reported in this patient, given the function of RAD50 in the MRN complex in TCR and BCR formation and CSR, it is possible that immunodeficiency will be a feature in other patients. Our current knowledge would suggest that treatment should be symptomatic.

Radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties (RIDDLE) syndrome (OMIM*611943). To date, only two patients have been reported in the literature with Radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties (RIDDLE) syndrome (OMIM*611943) [71, 243].

RIDDLE syndrome is due to mutations in RNF168 (OMIM*612688) on chromosome 3q29, coding for a ubiquitin ligase.

The first patient presented with mild facial dysmorphism, short stature, learning difficulties and mild motor abnormalities. No oculocutaneous telangiectasia were reported. The second patient presented with short stature and microcephaly. There was no history of learning difficulties and schooling was normal. Conjunctival telangiectasia were present and the patient exhibited a mild wide-based gait. Recurrent sino-pulmonary infections were documented. In early adulthood he developed progressive interstitial lung disease from which he subsequently died.

An isolated low serum IgG level was noted in early childhood, with normal IgM and IgA and normal T- and B-lymphocyte numbers documented in the first patient. In the second, serum IgA was low, but IgG and IgM were normal. Alphafetoprotein was raised in the second patient. B-lymphocytes from the patient demonstrated increased use of microhomology across the Sm-Sa and Sa-Sg3 switch regions, with a reduced frequency of mutations and insertions; findings that are similar, although less severe, to those found in LIG4 deficiency, and suggestive of abnormal class switch recombination [213]. Somatic hypermutation was normal.

Cells from both patients exhibited radiosensitivity to ionizing radiation, with reduced survival of fibroblasts in the colony survival assay and in the second patient, persistence of radiation-induced γ-H2AX foci was demonstrated. Biallelic nonsense mutations in RNF168, coding for a ubiquitin ligase – important in the formation of chromatin ubiquitinylation – were subsequently reported in the first patient [242], and a homozygous nonsense mutation was reported in the second.

There is some clinical and biochemical overlap with this syndrome and ataxia-telangiectasia. RNF168 has a role in organising chromatin to facilitate long-range NHEJ, which appears essential for CSR, but not VDJ recombination.

The first patient was treated with replacement immunoglobulin from early childhood and was well at time of publication of the report.

Bloom syndrome (OMIM*210900) is an autosomal recessive disorder, which is rare, most commonly found in the Ashkenazi Jewish population.

Bloom syndrome is due to defects in BLM (OMIM*604610) on chromosome 15q26.1, which encodes RecQL3 DNA helicase, critical in suppressing crossover formation between sister chromatids and resolving Holliday junctions during DNA replication [285].

Bloom syndrome is characterized by proportionate pre- and post-natal growth deficiency, photosensitive, telangiectatic, hypo- and hyper-pigmented skin (Fig. 9.4), predisposition to malignancy and chromosomal instability (Table 9.1). There is an increased incidence of diabetes mellitus. Immunodeficiency, although common, is variable and generally not severe [74, 133, 269]. Life-threatening infection may rarely occur [99].

Low concentrations of one or more immunoglobulin isotypes are the most frequently found immunological abnormality [133, 143, 269]. However, impaired T-lymphocyte proliferation, diminished CD4+ T- lymphocyte numbers and impaired function are also described [259].

Cytogenetic analysis reveals a characteristic increase in sister-chromatid exchange (Fig. 9.5). The Bloom syndrome protein has no role in VDJ recombination [14, 131], and only a minor role in CSR, although microhomology-mediated end joining was observed at Sm-Sg3 switch regions, possibly implicating BLM in the resolution phase of CSR [15].

T- and B-cell-receptor recombination occurs in the thymus and bone marrow, respectively. Early lymphocyte progenitors undergo successive stages of lineage commitment, generating a functional lymphocyte receptor repertoire. Between critical developmental stages of VDJ rearrangement of the T-cell b- and a-chain, and B-cell IgH and IgL chain, the lymphocyte precursors undergo intense proliferation. During this phase, cells experience the normal replicative stress of proliferating cells, and in doing so, accumulate abnormal replication intermediates, normally resolved by Bloom syndrome protein.

Treatment is symptomatic – prophylactic antimicrobial agents may be administered if the symptoms warrant treatment, and surveillance for development of malignancy should be performed.

Dyskeratosis congenita (DKC) is a rare genodermatosis with multisystem complications, caused by inherited defects in the telomerase complex [24]. It is characterized by cutaneous poikiloderma, nail dystrophy, and premalignant oral leukoplakia. Patients have a significant risk for developing aplastic anemia, myelodysplasia and malignancies.

Dyskeratosis congenita is a rare systemic disorder due to defects in one of nine proteins that are key to chromosome telomere maintenance.

DKC is a genetically heterozygous disorder. X-linked recessive (OMIM*305000), and an autosomal dominant (OMIM*127550) subtypes, which are due to defects in the enzyme telomerase [174, 275], are among well-known forms of DKC. However, several autosomal recessive subtypes and some more autosomal dominant subtypes have already been described. Details of known subtypes of DKC are presented in the Table 9.2.

Eukaryotic chromosomes end with tandem repeats of simple sequences. These GC rich repeats allow telomere replication and stabilize chromosome ends [108]. Each round of DNA replication in the senescent cells would result in the shortening of one of the two daughter DNA molecules [109]. Telomerase is an enzyme that protects against progressive shortening of the chromosomes at each successive cell division [109, 118]. It is a ribonucleoprotein which consists of a nucleolar protein named dyskeratin [123], a reverse transcriptase (TERT) and an RNA template that dictates the synthesis of the G-rich strand of telomere terminal repeats. In addition, three other proteins: GAR1, NHP2 and NPO10 are associated with dyskeratin in the core nucleoprotein formation.

The defect in telomerase function or activity results in accelerated telomerase shortening in DC cells and is associated with increased loss of cells by replicative cell senescence particularly from tissues that need constant renewal such as the dermatologic and hematopoietic systems [174].

The genetic defect for the X-linked form is located on Xq28 and associated with the DKC1 gene (OMIM*300126), that is translated into a 514 amino acid protein, dyskeratin. It is a core protein in the structure of active telomerase since it is associated with the H/ACA class of small nucleolar RNAs and is associated with telomerase RNA (hTR), which contains an H/ACA consensus sequence. Furthermore, it has a pseudouridylation activity (guiding the conversion of uracil to pseudouracil in ribosomal RNA) that is an essential step in ribosomal biogenesis, in some mammals like mice [223]. The latter is not established in humans however.

The autosomal dominant DKC is due to mutations in the telomerase RNA component (TERC, OMIM*602322) gene [275]. TERC is a 451 nucleotide RNA and consists of four structural domains: the pseudoknot domain, CR4-CR5 domain, the H/ACA domain and the CR7 domain. The pseudoknot and CR4-CR5 domains together with reverse transcriptase enzyme are required for its catalytic function while the H/ACA and CR7 domains are for TERC RNA accumulation. Several mutations in TERC have been found in several of the TERC domains. All of these mutations result in reduced telomerase activity either due to RNA stability/accumulation or catalytic defect. Furthermore it is seen that patients with autosomal dominant DKC have a greater risk of malignancies and the greater severity in disease activity in successive generations [276]. A number of patients with aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplasia (MDS) have mutations in TERC too [274, 296].

The other protein component of the telomerase is reverse transcriptase (TERT), a class of DNA polymerase that uses RNA templates for replication. Heterozygous mutations of TERT have been revealed in some autosomal dominant forms of DKC [12]. Mutations in TERC have also been found in the autosomal-dominant form of the inherited bone marrow failure syndrome and in a subset of patients with aplastic anemia and myelodysplasia [277].

Høyeraal-Hreidarsson syndrome [129, 130] is an X-linked multisystem disorder [1] characterized by severe growth retardation, bone marrow failure, neurological abnormalities and immunodeficiency [23]. Knight et al. revealed that HH is a severe variant of DKC with mutations in dyskeratin gene [142] and other studies confirm that this syndrome is a genetic telomerase defect [254, 295].

Female patients with HH have been reported with a severe phenotypic variant of the autosomal recessive form of DKC due to a novel homozygous TERT mutation. In two unrelated consanguineous families has also been detected [58, 163].

The classical clinical presentation is characterized by a triad of oral leukoplakia, reticular pigmentation, particularly of the upper torso, and nail dysplasia. There is an increased risk of bone marrow failure, myelodysplasia and acute myeloid leukemia, as well as squamous cell carcinomata of the head and neck or of anogenital malignancy. Neurodevelopment is generally normal. The age at onset, and the severity of symptoms is variable, ranging from mild phenotypic features with normal bone marrow function to early onset barrow failure associated with the classical triad of symptoms.

Hoyeraal Hreidarsson syndrome (OMIM*300240) is a severe form of DKC, associated with cerebellar hypoplasia and presenting in early childhood. Severe developmental delay, growth failure and early bone marrow failure are all features of this phenotype [129, 163].

Revesz syndrome also presents in early childhood [215]; patients have bilateral exudative retinopathy as well as the typical features of DKC with significant developmental delay. Intracranial calcification and sparse, fine hair have also been described.

Diagnostic investigations include measurement of telomere length, which in patients with DKC are abnormally short compared to age-matched controls. Mutation analysis of the nine genes implicated in patients with DKC will confirm the diagnosis.

Treatment is symptomatic, and patient-specific. HSCT is curative for marrow failure, myelodysplasia or acute leukemia. For patients with no suitable donor, androgen treatment may help bone marrow failure. Other malignancies should be treated as indicated. Careful follow-up is required to monitor the development of significant clinical features requiring intervention.

Rothmund-Thomson syndrome (OMIM*268400) is another rare autosomal disorder, associated with DNA repair defects.

Rothmund-Thomson syndrome is characterized by poikiloderma, sparse hair and eyelashes, small stature, skeletal and dental abnormalities, cataracts, and an increased cancer risk particularly osteosarcoma and hematological malignancy. Whilst the skin is typically normal at birth, the rash, which manifests as erythema, swelling, and blistering on the face which spreads to the buttocks and extremities, characteristically develops between 3 and 6 months of age and evolves over years to chronic reticulated hypo- and hyperpigmentation, punctate atrophy, and telangiectases. Immunodeficiency is rarely reported [65].

Recently, rapid bone marrow failure involving the myeloid, lymphoid, and erythroid lineages has been reported in murine models with multipotent progenitor cells lacking RECQL4, associated with increased replicative DNA damage and failed cell-cycle progression [233].

The diagnosis is clinical, and confirmed by genetic analysis. Patients with Rothmund-Thomson syndrome usually have alopecia of the head and eyebrows, while their skin lesions are usually seen in sun-exposed areas. Skeletal manifestations, cataracts, and predisposition to malignancy in Rothmund-Thomson syndrome are also distinguish it from other immunodeficiency diseases with skin involvement such as poikiloderma with neutropenia (OMIM*604173). (See Sect. 4.​15 for more details)

Management is supportive and includes use of barrier sunscreens to prevent skin cancer. One patient has been treated successfully with HSCT [33].

In addition to above-mentioned diseases, there are some other DNA repair defects associated with immunodeficiencies. Some of them have already been explained in other chapters. DNA ligase IV deficiency (OMIM*606593) and Cernunnos-XLF deficiency (OMIM*606593) are rare radiosensitivity disorders with very few patients reported, which share many clinical features. (See Sect. 2.​3 for more details)

One patient with primordial dwarfism was reported (OMIM*616541) to have a homozygous missense mutation in XRCC4 gene (OMIM*194363), which encodes for a protein that is part of the LIG4-Cernunnos/XLF-XRCC4 complex. Whilst the cells demonstrated sensitivity to ionizing radiation, no information was available on an immunophenotype [231]. More patients have subsequently been described, and although clinical immunodeficiency has not been described [21, 61, 179, 221, 231], biochemical immunological abnormalities have been reported in one patient [113].

One patient has been reported with compound missense mutations in LIG1 (OMIM*126391) [20, 284].

Fanconi anemia (OMIM*603467) is a clinically heterogenous autosomal recessive or X-linked disorder, due to abnormalities in one of fifteen proteins important in DNA inter-strand cross-linking repair.

PMS2 deficiency (OMIM*276300) due to mutations in the PMS2 gene (OMIM*600259), encoding the PMS2 component of the mismatch repair machinery, was also described as B cell-intrinsic CSR deficiency [209].

MCM4 deficiency (OMIM*609981) or natural killer cell and glucocorticoid deficiency with DNA repair defect (NKGCD) is due to mutations in the MCM4 gene (OMIM*602638) [101]. (See Sect. 6.​15 for more details)

DNA ligase IV deficiency and Cernunnos-XLF deficiency are due to mutations in LIG4 and NHEJ1, respectively.

Fanconi anemia is estimated to affect 1:360,000 births [251], but particular genotypes are more common in specific populations, notably Ashkenazi Jews, Spanish Gypsies, and black South Africans [43, 147, 177].

DNA ligase IV deficiency or LIG4 deficiency was initially described in a clinically and developmentally normal patient who developed T cell acute lymphoblastic leukemia, exhibited disproportionately severe cytopenia following treatment, and died following an extreme reaction to radiotherapy, including marked and prolonged cytopenia, severe desquamation and radiation-induced encephalopathy [216]. Several LIG4-deficient patients have subsequently been described [232]. Microcephaly with ‘bird-like’ dysmorphism, developmental delay, growth failure, lymphocytopaenia, hypogammaglobulinaemia and marrow hypoplasia are predominant features [178, 194]. Radiosensitive-SCID with microcephaly and growth delay is a recognized presentation, as well as the Omenn syndrome variant [36, 112]. Large B cell lymphomas have been reported, not always associated with Epstein-Barr virus, as well as T cell acute lymphoblastic leukemia [16, 85, 263].

Patients with cernunnos-XRCC4-like Factor (C-XLF) deficiency, due to mutations in NHEJ1 were described after LIG4 deficiency [3, 35]; the clinical and immunological phenotype is similar, with T and B lymphocytopenia, with a normal number of NK cells [59]. Microcephaly with ‘birdlike’ dysmorphism and developmental delay is characteristic, and patients classically experience recurrent viral, bacterial and opportunistic infection – autoimmune cytopenia has also been described [41]. To date, lympho-reticular malignancy has not been described.

The patient with PRKDC deficiency first presented at 5 months of age with classical symptoms of recurrent oral candidiasis and lower respiratory tract infections, and a T-B-NK+ SCID phenotype. Microcephaly was not present and there was no developmental delay [268]. The second patient had a markedly different phenotype. Although there were features of T-B-NK+ SCID, as in the first patient, there were significant other morphological anomalies including pre-natal growth failure, microcephaly, facial dysmorphism with prominent forehead, wide nasal bridge, long philtrum with thin upper lip, small chin, low-set ears with overfolded helices, overlapping fingers, and postaxial polysyndactyly of the right foot. Additionally he had micropenis. The patient suffered severe developmental delay and intractable seizures [292].

Clinical features of DNA ligase I deficiency, overlapping with those of Bloom syndrome and ataxia telangiectasia, include pre- and post-natal growth retardation, developmental delay with normal cognitive development, facial dysmorphism with elf-like features, and photosensitivity. Immunodeficiency manifested as recurrent sinopulmonary infections from early childhood, with evolving IgA deficiency, relative hypogammaglobulinemia of IgG and normal IgM. An evolving neutropenia and lymphocytopenia with poor proliferative response to mitogens was described. In adolescence, the respiratory status deteriorated. There was no development of secondary sexual characteristics. Centripetal patchy cutaneous venous dilatation appeared, and there were some bulbar conjunctival telangiectasia. Hepatosplenomegaly developed associated with lymphocyte infiltration of the portal tract, suggesting lymphoma. The patient developed a severe cutaneous herpes zoster infection and died from pneumonia in early adulthood. Two further siblings, unrelated to the index case, have subsequently been identified, presenting with features consistent with severe combined immunodeficiency (personal communication with A. Worth). Additional features included multicystic dysplastic kidneys and severe anemia. One patient successfully underwent HSCT. LIG1 forms a complex with nibrin, and both molecules co-localise at replication factories to repair DSBs by homologous recombination at stalled replication forks [267]. Thus, defects in LIG1 may be associated with failure to repair DNA damage during lymphocyte proliferation, rather than failure to complete NHEJ during TCR and BCR formation.

Fanconi anemia is characterized by bone marrow failure, and other anomalies including skeletal, renal, cardiac and gastrointestinal defects, skin hypo-pigmentation and predisposal to malignancy, particularly leukemia or head and neck squamous carcinomas [9, 220]. Whilst most immunological manifestations relate to bone marrow failure, some patients present in infancy or early childhood with significant or prolonged infections, more consistent with immunodeficiency [180]. Features that suggest a diagnosis of Fanconi Anemia include a history of parental consanguinity or family history of anemia, physical abnormalities or cancer.

Diagnostic laboratory features for DNA ligase IV deficiency and Cernunnos-XLF deficiency include the immune-phenotype described above, in association with the characteristic clinical findings. In addition to T and B lymphocytopaenia, many patients with either syndrome have normal or raised IgM, and low IgA and IgG, often with impaired specific antibody responses. Both LIG4 and cernunnos-XLF have a role in class switch recombination, as well as VDJ recombination. Moderate impairment of VDJ recombination is observed in LIG4– and NHEJ1-deficient fibroblast VDJ recombination assays with an almost normal frequency of coding and signal joint formation but marked infidelity of coding and signal joint formation. Patients with LIG4 and NHEJ1 mutations also have altered resolution of CSR junctions, with greater use of microhomology at Sμ-Sα junctions [203]. Radiosensitivity can be demonstrated by exposing fibroblasts to ionizing radiation, and measuring survival, or by measuring γH2AX foci, which accumulate at the site of DNA-dsb, and disappear as the breaks are resolved. In cell lines deficient in LIG4 or NHEJ1, γH2AX foci persist when they have resolved in normal cells.

The first patient with PRKDC deficiency had a homozygous three-nucleotide deletion and homozygous missense mutation in PRKDC. Fibroblasts were sensitive to ionising radiation, with a DSB-repair defect comparable to that seen in artemis-deficient cells. The coding joints showed long stretches of palindromic nucleotides, and an end-joining assay demonstrated an increase in the use of microhomology, which was similar to that seen in artemis-deficient cells. A profound DSB-repair defect in the second patient was demonstrated using the γH2AX assay, which was distinctively different from that seen in artemis or LIG4 deficiency. A compound missense mutation and an exon deletion were uncovered in PRKDC.

An assessment should include a complete blood and differential count, and a bone marrow aspiration, biopsy, and cytogenetic evaluation, renal and urological assessment, including an ultrasound to rule out renal dysplasia, hydronephrosis, and/or genitourinary or reproductive tract malformations. An otological examination to assess for hearing loss or structural ear abnormalities should also be performed. Laboratory assessments include a diepoxybutane or mitomycin C chromosome fragility test of blood lymphocytes. Fibroblasts can be used to identify the Fanconi anemia complementation group and mutation analysis determines and/or confirms the initial complementation group result and identifies the specific causative gene. Fifteen genes associated with Fanconi anemia have been identified to date, of which 14 are inherited in an autosomal recessive fashion, and 1 (FANCB) is X-linked. Although cells from patients generally show hypersensitivity to agents that cause DNA inter-strand crosslinks, a few also demonstrate sensitivity to ionising radiation [175]. Whilst most of the Fanconi Anemia proteins form a core ubiquitin ligase complex, the FAND2-FANCI heterodimer is ubquitinated by this complex, and subsequently co-localises to chromatin with other DNA repair proteins, including the MRN complex [180]. Fanconi anemia proteins do not have direct a role in lymphocyte receptor development or modification. The effects on immunity more likely result from the effects of inter-strand DNA crosslinks occurring during cellular development, which lead to bone marrow failure.

Treatment is supportive, and includes anti-viral and anti-bacterial prophylaxis. Many patients will require immunoglobulin replacement. Autoimmunity should be treated as appropriately, and for autoimmune cytopenias, steroids, rituximab and high-dose immunoglobulin (2 g/kg) may be required. Lympho-reticular malignancies are particularly difficult to treat, as they are often aggressive, and yet patients are intolerant of the chemotherapy. HSCT has been tried, particularly for patients with marrow hypoplasia or severe recurrent infection. Reduced intensity regimens seem best tolerated. Patients will need to be carefully followed in the future to monitor for late sequalae, and, in particular, the development of secondary malignancies.

Treatment of DNA ligase I deficiency should be symptomatic with prophylactic antimicrobials. The role of HSCT has yet to be determined.

Management of patients with Fanconi Anemia requires multi-disciplinary input. Whilst most patients develop bone marrow failure, the age at onset is extremely variable, even within families. Patients are at high risk of developing myelodysplasia or acute myeloid leukemia. Close monitoring is required to assess possible onset of myelodysplasia or leukemia and identify cytogenetic abnormalities that require immediate intervention. HSCT is currently recommended to cure marrow aplasia, and prevent or cure progression to myelodysplasia or leukemia. Patients with Fanconi Anemia have an extremely high risk of developing squamous cell carcinoma of the head and neck. From the age of 10 years, it is recommended to obtain a thorough examination from an ear, nose and throat specialist, oral surgeon or other doctor experienced in head and neck cancer detection, bi-annually. Human Papilloma virus vaccination should be given to both boys and girls, to possibly prevent squamous cell carcinoma associated with the Human Papilloma virus. Unfotunately, successful treatment with HSCT does not prevent the occurrence of head and neck squamous cell carcinoma, and may increase the risk of such tumors developing. Carriers of autosomal recessive Fanconi Anemia are asymptomatic, except those who carry mutations in FANCD1 (BRCA2), who have an increased risk of hereditary breast and ovarian cancer [128, 280].

Immunodeficiency, Centromeric Instability, Facial Dysmorphism (ICF) Syndrome is a rare autosomal recessive disease. Few individuals with ICF1 (OMIM*242860), ICF2 (OMIM*614069), ICF3, and ICF4 have been reported.

ICF syndrome is due to mutations in DNMT3B (ICF1) (OMIM*602900) [117], ZBTB24 (ICF2) (OMIM*614064) [62], CDCA7 (ICF3) (OMIM*609937), and HELLS (ICF4) (OMIM*603946) [261].

The dysmorphic facial features are variable and often mild (Table 9.1). Typically, patients exhibit a broad flat nasal bridge, hypertelorism, and epicanthic folds. Other features less often described include micrognathia, macroglossia and low-set ears. Delayed psychomotor development is apparent in some patients.

The immunodeficiency is variable, but commonly leads to severe recurrent infections, most commonly presenting in early childhood [240, 287]. Although severe respiratory infections are common, many infections are suggestive of impaired T lymphocyte function. Many patients present with agammaglobulinemia, despite the presence of B lymphocytes [116].

ICF syndrome is characterized by agammaglobulinemia or hypoglobulinemia in the presence of B lymphocytes and pathognomic DNA rearrangements of the centromere-adjacent heterochromatic region of chromosomes 1 and/or 16 (and occasionally chromosome 9) in mitogen-stimulated lymphocytes, detected during routine cytogenetic examination of metaphase chromosomes [264]. Immunological investigations include enumeration of the lymphocyte phenotypes and assessment of immunoglobulin levels. The diagnostic test for ICF syndrome is standard metaphase chromosome analysis of peripheral blood which exhibit the characteristic changes (Fig. 9.6), namely:

It is unclear how the chromosomal changes lead to the immunodeficiency. The heterochromatic region DNA rearrangements exhibit DNA hypomethylation. At least four genes are responsible for the disease – DNMT3B, ZBTB24 CDCA7 and HELLS.

Initial management is symptomatic. Prophylactic immunoglobulin replacement should be administered. In view of the co-existent T lymphocyte immunodeficiency, ant-pneumocystis and anti-fungal prophylaxis may be administered. Death is commonly from opportunistic or pulmonary infections and the prognosis is particularly poor in children with intractable diarrhea and failure to thrive. Allogeneic HSCT has been successfully performed for ICF syndrome [98].

‘So went Satan forth from the presence of the Lord, and smote Job with sore boils from the sole of his foot unto his crown.’ With this citation from the book of Job 2:7, Davis, Schaller, and Wedgwood coined the term Job’s syndrome in 1966 [60]. They reported two red-haired, fair-skinned girls who had frequent sinopulmonary infections, severe dermatitis, and recurrent staphylococcal skin infections that were remarkable for their lack of the features of classical inflammation, including warmth, hence the term ‘cold’ abscesses. The syndrome was further defined and clarified by Buckley et al., who noted similar infectious problems in two boys with severe dermatitis, characteristic facies, and elevated IgE levels, leading to the term Buckley’s syndrome [39]. Following this report, elevated levels of IgE and a defect in neutrophil chemotaxis were identified in the two girls from the initial report, showing that Job’s syndrome and Buckley’s syndrome represented the same condition [125]. This syndrome is now often referred to as Hyper-IgE syndrome (OMIM*147060).

To date the Hyper IgE Syndrome has been recognized as multi-organ dysfunction characterized by both immunologic and non-immunologic manifestations and classically presenting with the clinical triad of (i) recurrent (cold) skin abscesses, (ii) recurrent (typically cyst forming) pneumonia, and (iii) elevated IgE (>10-times the upper limit of the norm) [110].

In 2007, heterozygous mutations in the gene encoding the Signal Transducer and Activator of Transcription 3 (STAT3) (OMIM*102582) were found to underlie most cases of the autosomal dominant form of HIES (AD-HIES) [126, 173].

Minegishi et al., have shown that the observed mutations have a dominant-negative effect on the healthy allele and hence impair STAT3 signaling [173].

STAT3 plays a central role in signal transduction induced by multiple cytokines, including IL-6, IL-10, IL-11, IL-17, IL-21 and IL-22. As a consequence cell types requiring a stronger STAT3 signal, including but not limited to e.g. the Th17 cells, are defective, explaining the multisystem involvement of this primary immune deficiency.

Cytokines are important mediators of cell activation, differentiation, and migration, acting through binding to their cytokine receptors, which are expressed on the respective immune cells. Most cytokine receptors are composed of several transmembrane proteins, some of which change their conformation upon ligand binding allowing the phosphorylation of tyrosine kinases such as the Jaks and Tyk2, which are associated with the cytosolic part of the cytokine receptor. The phosphorylated Jaks then in turn phosphorylate the Signal Transducers and Activator of Transcription (STATs). Two phosphorylated STATs form one homo- or heterodimer, which translocates into the nucleus and binds to genomic DNA to initiate cytokine-specific downstream gene expression.

HIES is a multisystem disease with variable clinical manifestations (Table 9.3). Affected individuals may have some, but not all the features of HIES, depending on the age at which they present. AD-HIES typically first manifests with a neonatal rash and affects the immune system, connective tissue, skeleton, and dental development, with variations in severity. The rash typically starts on the face and scalp in the first few weeks of life, and is usually pustular and eczematoid [44, 83]. Biopsies show eosinophilic infiltrates and bacterial cultures typically grow Staphylococcus aureus. The rash often persists throughout childhood, but can be controlled with antistaphylococcal therapies, consisting of antibiotics, topical antiseptics such as diluted bleach, or both [208]. Abscesses are often caused by Staphylococcus aureus, and have been described as being “cold”, indicating the lack of tenderness and warmth, typically seen with boils of that size. It is a typical observation in these patients that due to the lack of STAT3 (first named “APRF”, acute phase response factor) signaling, the severity of infections or inflammation is not appreciated by the patient, e.g. due to abrogated IL-6 signaling.

Pneumonia, often caused by Staphylococcus aureus or Haemophilus influenza, typically leave lung cavities (pneumatoceles) which are one of the life-limiting factors oft this disease. Pneumatoceles may be manifold or become huge as shown in Fig. 9.7. Similar to the variability seen with boils, the extent of pneumonia may be out of proportion to the systemic signs of illness (e.g. fever, malaise), leading to delayed diagnosis. Bronchoscopy may be needed to establish the specific bacterial diagnosis and also assists in clearance of copious but viscous pus. Pneumatocele formation and bronchiectasis typically follow these pyogenic pneumonias. Structural parenchymal defects tend not to subside, but serve as sites for future infections [93, 110]. One of the most feared complications in this form of the hyper IgE syndrome is the colonization of these pneumatoceles with Aspergillus fumigatus: eradication is almost impossible, surgery is complicated, lung transplant often disapproved, and dissemination into the brain is a real threat.

Mucocutaneous candidiasis is common in HIES, typically manifesting as thrush, vaginal candidiasis and onychomycosis [110]. Much less frequently, disseminated histoplasmosis and cryptococcosis occur, typically in isolated nonpulmonary locations such as in the intestine or tongue [135].

STAT3-HIES has a characteristic facial appearance that develops during childhood and adolescence, characterized by asymmetry, broad nose, and deep-set eyes with a prominent forehead (Fig. 9.8) [37, 110].

Musculoskeletal abnormalities in HIES include scoliosis, minimal trauma fractures, osteopenia, hyperextensibility and degenerative joint disease [110]. Minimal trauma fractures occur in about half of individuals with HIES, and frequently involve the ribs and long bones. Osteopenia and osteoporosis also occur, but appear to be independent of the minimal trauma fractures. Osteoclast-mediated bone resorption is abnormal in HIES and likely relates to osteopenia and fractures [55, 152].

Most individuals with HIES fail to exfoliate their primary teeth normally, often requiring surgical extraction of some or all primary teeth to allow the secondary teeth to emerge normally [193]. Characteristic variations of the oral mucosa, tongue, roof of mouth and cheeks include central depressions of the tongue that may relate to Candida infections and central band-like protrusions of the palate [78].

HIES is associated with an increased rate of non-Hodgkin’s lymphoma (NHL), the majority of which is B-cell origin and aggressive histology [151]. Several individuals responded to treatment and were apparently cured, but there was an increased mortality, which may in part be due to delayed diagnosis. Other reported malignancies have included Hodgkin’s lymphoma, leukemia, and cancers of the vulva, liver and lung [200].

The diagnosis of STAT3 deficiency can be made based on a combination of clinical and laboratory findings. For this purpose a clinical HIES scoring system based on 19 clinical and laboratory findings has been developed to help with the diagnosis. In this scoring system more specific and objective findings are assigned more points. Scores of at least 40 points suggest HIES, whereas a score below 20 made the diagnosis unlikely. For intermediate values, no firm conclusion can be reached [111].

Further to this, an alternative scoring system to predict the presence of a mutation in STAT3 has been suggested [290].

This scoring system divided patients into three categories: (1) possibly mutant STAT3, with an IgE >1,000 IU/mL plus a weighted score of >30 of recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic facies and high palate; (2) probably mutant, with these features and a lack of Th17 cells or a definite family history of HIES; and (3) definitely mutant, with these features and a dominant-negative heterozygous mutation in STAT3.

Characteristically IgE in serum is elevated, often > 10-times the normal value of age matched control values, typical are IgE values between 20.000 and 100.000 IU. Newborns are supposed to have no IgE in serum, hence levels of a few hundred may already be diagnostic in these young patients, especially when there is a family history of autosomal-dominant hyper IgE syndrome and other causes for the IgE elevation such as helminth infections have been excluded.

The elevated IgE levels do not require specific therapy, they are polyclonal and not believed to be associated with pathology in patients with STAT3 deficiency.

STAT3 is a lineage defining transcription factor for the Th17 cell lineage, as RORγt is under its control. RORγt in turn controls the expression of IL17 and IL22, the two key interleukins of Th17 cells. In patients with defective STAT3 signaling, the development of this specific T cell subset was shown to be impaired [48, 157, 258], rendering the testing for the presence or absence of this T cell population ex vivo a diagnostic test for this type of the hyper-IgE syndrome.

In addition to the lack of the Th17 cell compartment, patients with STAT3 deficiency also have been described to have a Th2 cell deviation [244] and suffer from a specific antibody deficiency. Other than that, laboratory values such as the white blood cell count and other lymphocyte subsets, as well as functional tests such as lymphocyte proliferation or cytotoxicity or neutrophil degranulation and chemotaxis are not uniformly aberrant in this condition, which complicates the diagnosis.

The therapeutic approach involves prevention and management of infections with long-term administration of systemic antibiotics and antifungals. Lung abscesses may require surgery but possible complications require close attention.

Bone marrow transplantation has been published in only four patients [105, 181]. One of these has died following transplant-related complications, but the other three are well and alive more than 12 years following transplant. The author hence encourages performing this procedure early enough in patients developing live-threatening complications such as lung cysts or lymphoma.

Recurrent lung and skin infections and chronic dermatitis are characteristic of Hyper-IgE syndrome. Therefore organ-specific treatment of complications is also needed.

With regard to the treatment of pneumonia, the choice of the antibiotic regimen is either guided by sensitivity testing (if available), or by empiric decision based on the knowledge of the frequent pathogens observed in patients with the hyper-IgE syndrome (see above). The management of pneumatoceles is difficult and requires specialist knowledge in tertiary referral centers used to manage patients with this condition. It always entails the collaborations with chest physicians and surgeons, as well as the pediatrician/internist. Recurrent lung infections with Staphylococcus (often leading to abscess formation) or Aspergillus are common. Prophylactic antibiotic therapy, TMP/SMX 160/400 mg or cephalexin 500 mg twice a day/dicloxacillin to prevent Staphylococcal infection is essential. Antifungal prophylaxis (fluconazole 100 mg weekly) has also been considered useful as cutaneous fungal infections are common. Pulmonary rehabilitation is recommended. The use of immunoglobulins may be considered if antibody deficiency is documented.

The possibility of fracture should be considered even with relatively minor trauma. Calcium and vitamin D and biphosphonates may be prescribed. Children should be monitored carefully for scoliosis, and as necessary, retained primary teeth extracted if needed.

Mortality in Hyper-IgE syndrome has been due to pulmonary hemorrhage as a result of Pseudomonas pneumonia, invasive pulmonary aspergillosis and other complicated lung abcesses [77]. Embolectomy may be required. Coronary artery aneurysms have been reported [34]. Congenital patent ductus arteriosis also seen in association with Hyper-IgE syndrome should be treated using standard measures. There are rare reports of improvement of clinical indicators with administration of IFN-γ, however, evidence is not sufficient to consider this to be standard therapy.

Dedicator of Cytokinesis number 8 (DOCK8) deficiency (OMIM*243700) is an autosomal recessive immunodeficiency syndrome, which is characterized by a combined defect in humoral and cellular immunity [86, 299]. Many DOCK8-deficient individuals were initially diagnosed with an autosomal recessive form of the hyper-IgE syndrome (HIES). This syndrome overlaps phenotypically to some extent with the autosomal dominant form of HIES caused by STAT3 mutations. Shared symptoms of DOCK8 and STAT3 deficiency include high serum levels of IgE, eczema, recurrent staphylococcal skin abscesses, frequent upper and lower respiratory tract infections, candidiasis, and hypereosinophilia. Individuals with STAT3 mutations may develop pneumatoceles, which are rarely seen in DOCK8-deficient patients. Mutations in STAT3 also often lead to non-immune symptoms involving dentition, bone and connective tissue. In contrast, DOCK8-deficient patients present frequently with allergies, severe and refractory cutaneous viral infections and sometimes with neurological symptoms. However, not all DOCK-patients demonstrate the full spectrum of this syndrome, especially in early childhood; therefore it can sometimes be difficult to distinguish between DOCK8 and STAT3 deficiency based on clinical presentation or laboratory results alone.

DOCK8 is a member of the DOCK family of guanine nucleotide exchange factors (GEFs), which function as activators of small G proteins. Possibly DOCK8 is located at the cell membrane just downstream of the T cell receptor, mediating cellular activation to the cytoskeleton via CDC42, RAC1, and WASP [224]. DOCK8 is highly expressed within the immune system, especially in lymphocytes, suggesting crucial functions in these cell types and DOCK8 deficiency appears to impair the CD4+ and CD8+ T cell proliferative responses [148].

The mutations in DOCK8 encompass large deletions, point mutations that alter splicing to cause nonsense mutations, inframe nonsense mutations, and small insertions and deletions that cause out-of-frame nonsense mutations [86].

Allergies were seen in three quarters of the patients with food allergies in two thirds of the patients, and additional environmental allergies in the remainder; in addition, asthma was diagnosed in one third of the patients.

Upper respiratory tract infections are very prevalent (96 %) in DOCK8-deficient individuals, leading to pneumonia in almost all patients, followed by bronchiectasis formation in more than a third of cases. Pneumatoceles, however, were only documented in a singleton of 43 documented cases.

Susceptibility to viral infections is very characteristic for this primary immune deficiency: More than half of the patients (up to 60 %) suffer from severe and recurrent outbreaks of Herpes viruses including HSV, VZV, CMV and EBV. More than one third of the patients suffer from severe and recurrent outbreaks of Molluscum contagiosum. About 30 % of patients suffer from human Papilloma virus infections, and a few patients from fatal polyoma virus infection (JC virus infection causing PML). Candidasis was present in 70% of patients.

An ill-defined CNS involvement is further complicating the disease and leads to severe neurological impairment, often followed by death.

Although developed for the autosomal-dominant phenotype of the Hyper-IgE syndromes (which later turned out to be STAT3 deficiency), the NIH scoring sheet [111] can also be used to diagnose other forms of this condition. A diagnostic cut-off of 40 points has been proposed for the autosomal-dominant variant, whereas almost all of the DOCK8 patients had more than 20 points. Hence, by lowering the diagnostic cut-off, the use of this scoring sheet can also be advised for the autosomal-recessive Hyper-IgE patients.

Additionally, CD4 T cells and CD8 T cells may be low during the first 10 years of life, this is not a universal finding in patients with DOCK8 deficiency. Moreover, the role of the Th17 cell compartment in this condition is still being debated. B cell numbers are mostly normal and NK cells are either lowish or may be slightly decreased. As expected in patients with a form of the Hyper-IgE syndrome, eosinophil counts are consistently elevated.

With regards to the immunoglobulin serum levels, IgE is always above 1000 IU, and other isotypes are also rather elevated with the exception of IgM which is often below 700 mg/dL.

The treatment of choice in this condition is the HSCT [13, 19, 166, 248]. Four of the first five patients published are still alive and well, however, the author knows of additional patients who are performing exceptionally well after receiving a new bone marrow. While waiting for the perfect match, the management of Molluscum contagiosum is a therapeutical challenge. Following curettage, local injections of both IFNα and IFNγ have been tried with variable success.

After the report of the first six families with PGM3 deficiency (OMIM*615816) [229], there seems to be a strong genotype-phenotype correlation with more severe mutations in PGM3 (OMIM*172100) leading to a more severe impairment of the enzymatic function of the protein, leading to a more severe clinical phenotype. This phenotype is, however greatly variable in between families, leading from 35 y/o patients who suffer from immunologic, neurologic, and skeletal impairment to patients who succumbed in childhood due to their disease.

As two of the initial six families have, however, been published as Hyper-IgE families prior to the discovery of their genetic cause, the listing of this condition in the chapter of the hyper IgE syndromes seems plausible.

PGM3 deficiency is a glycosylation disorder. PGM3 is a phosphoglucomutase involved in the production of UDP-GlucNAc, which UDP-GlucNAc is a central precursor of protein glycosylation. PGM3 mutations in patients with the Hyper-IgE syndrome are hypomorphic mutations leaving some protein present, albeit with reduced enzymatic activity [229]. As many proteins of the immune system are highly glycosylated, with the neutrophils being the most glycosylated white blood cells, an ineffective glycosylation is likely to impair immunity. Other glycosylation disorders also have various degrees of immune dysfunction as part of their clinical phenotype [229].

The phenotype of PGM3 deficiency is still under observation following the first 17 patients only published in 2014 [229]. However, it becomes clear that there are aspects of the Hyper-IgE immunodeficiency syndrome (e.g., staphylococcal skin and chest infections, elevated IgE, and skin eczema), in addition to the congenital glycosylation phenotype. The latter specifically includes a neurologic and musculoskeletal impairment with mentally challenged children, myoclonus and hypotonia [301]. Moreover, although not seen in all patients, the renal impairment also seems to be part of the phenotype [297].

As it is true for other glycosylation defects, laboratory findings vary in between patients. With the limited experience from the first 17 patients from six families we observed the following:

In addition, T cell proliferation was normal following strong stimuli such as PHA, but reduced following stimulation with antigen-specific stimuli such as tetanus or PPD, but results depended on the glucose level provided in the culture medium.

Applying the NIH-HIES score PGM3-deficient patients scored 40 points and higher with the exception of one patient (27 points).

As this condition has only recently been described, specific treatment is only currently being developed. The replenishing of the UDP-GlucNAc pool seems a plausible option and is currently being evaluated at the National Institutes of Health, Bethesda, Maryland. Whether a bone marrow transplantation will alleviate the immune-mediated features of the disease is unknown; the search for a suitable matched sibling donor may however, be complicated by the fact that PGM3 is located on chromosome 6 and a crossover between the HLA locus and PGM3 may not be present in siblings.

Comèl-Netherton syndrome or Netherton syndrome (NETH, OMIM*256500) is a rare autosomal recessive disorder of the skin, hair and immune system. In 1964, Wilkinson [289], delineated the triad of congenital ichthyosis or Ichthyosis linearis circumflexa, Trichorrhexis invaginata and Atopy, as Netherton syndrome. Ichthyosis linearis circumflexa (ILC) was first described by Comel et al. in 1949 [56]. Trichorrhexis invaginata (TI) also known as bamboo hair had been described in 1958 by Dr. Netherton [182]. Trichorrhexis invaginata is considered to be pathognomonic, but may be difficult to detect. Patients also exhibit atopic manifestations including eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia [234].

Chavanas et al. [46, 47] established their report in 2000, which clarified that mutations in SPINK5 (OMIM*605010) and subsequent elimination/inactivation of the serine protease inhibitor LEKTI are the molecular cause of NETH. Other studies confirmed it later [26, 153, 237]. This gene, 61 kb in size, consists of 33 exons and encodes a Kazal-type serine protease inhibitor [27, 68, 119]. This protein is highly expressed in thymus and mucous epithelia, and thereby termed LEKTI for Lympho-Epithelial Kazal-Type related Inhibitor. LEKTI may play a role in anti-inflammatory and/or antimicrobial protection of mucous epithelia. Furthermore, it has a critical role in the process of normal desquamation. Several proteases such as the stratum corneum trypsin-like serine protease [84] and stratum corneum chymotryptic enzyme [127], are thought to play a key role during this process. It could potentially be controlled by LEKTI, through the proteolysis of intercellular adhesion molecules and organization of lamellar body-derived lipid structures in the stratum corneum [134]. Lack of regulation of target serine proteases could lead to impaired proteolysis of membrane-bound receptors, premature secretion of lamellar body contents and disturbance in the formation of the intercellular lipid layers [89], that cause defective epidermal barrier. As SPINK5 is highly expressed in the thymus [159], defective LEKTI expression might have an effect on T-cell differentiation, thus explaining the unbalanced Th2 immune response with markedly elevated IgE levels and the increased susceptibility to infections characteristic for NETH.

NETH may first appear as severe congenital generalized exfoliative erythroderma. Later, serpiginous scaling and migratory polycyclic erythematous patches surrounded by a doubled-edged scale (Ichthyosis linearis circumflexa) may become visible (Fig. 9.9). These are usually found in flexural areas of untreated patients and leave no atrophy, scarring or pigmentation [56, 136].

All patients had abnormal hair [136, 234]. Hair growth on the scalp, eyebrows and body may be sparse. Individual hairs are dry, straight, lusterless and brittle. Scalp hair grew to 1–3 cm before breaking; especially on the occipital area due to friction. This hair shaft abnormality usually develops during the infancy or early childhood and may improve with age. The eyebrows are particularly more preferential to examine microscopically showing the characteristic ball-and-socket appearance or Bamboo hair (Fig. 9.10).

The invagination is caused by the softness of the cortex in keratinized zone, probably because of the reduced number of disulfide bands. Scalp scaling (39 %), lichenified or eczematous changes (30 %), palm or sole involvement (16 %), pruritus (11 %), excess vellous hair (9 %), heat intolerance (7 %), and abnormal teeth or nails (5–7 %) are other ectodermal manifestations. Some percentages of the patients may have mental retardation, neonatal hypernatremia, decreased growth, and serum aminoaciduria [234].

Trichorrhexis invaginata associated with congenital icthyosiform erythderma or ILC make the clinical diagnosis possible. Recurrent infections occur in 28–30 % of cases with NETH, of which chronic upper respiratory tract and staphylococcal skin infections are the most common [106, 234]. IgG abnormalities (both hypo and hyper IgG) are presented in 12 % [234]. Elevated levels of serum IgE (mean of 4,751 IU/mL in one series), positive skin test or RAST results, selective antibody deficiency to protein/polysaccharide antigens, associated with IgA-IgG₂ deficiency, and decreased delayed type hypersensitivity responses has been reported in isolated cases or series [108, 247]. An increased incidence of deep tissue infections has not been reported.

Treatment is usually symptomatic and should be adjusted to the patient’s needs. Topical emollients, keratolytics and corticosteroids may help. Low dose acitretin [120, 121] has been effective, but should be avoided in erythrodermic neonates, and its long-term use is limited due to its potential side effects. Topical calcineurine inhibitors [225, 249], tacrolimus and pimecrolimus creams, and topical calcipotriol [104] have been effective in some patients. These treatments should be given with caution because of their systemic absorption [8] via the dysfunctional skin barrier.

Ex vivo gene therapy studies suggest that SPINK5 gene transfer may mediate localized correction of skin architecture inside and outside of the grafted area [73].

Several other defined single gene mutations have been described to result in syndromes with features of HIES as well as other abnormalities.

A homozygous deleterious mutation in TYK2 (OMIM*176941) was the first genetic defect published in a patient diagnosed with a Hyper-IgE syndrome due to his susceptibility to cutaneous staphylococcal infections and high serum concentrations of IgE [172]. However, this patient also had BCGitis and Salmonella infections. He also suffered from recurrent cutaneous herpes simplex virus reactivations. The report of this patient paved the way for the subsequent identification of STAT3 deficiency, which is the signaling molecule directly downstream of the Janus kinase Tyk2. Since this initial report of a Tyk2-deficient patient who had a Hyper-IgE phenotype but additionally experienced BCGitis, which is not characteristic for the Hyper-IgE syndromes, there are also some other patients described with mutations in TYK2, who interestingly did not have a hyper-IgE phenotype, but an immunodeficiency characterized by the susceptibility to mycobacterial infections [146]. (See Sect. 6.​7 for more details)