Do Ribosomopathies Explain Some Cases of Common Variable Immunodeficiency?Cei 4280 96..103

Clinical and Experimental Immunology ORIGINAL ARTICLE doi:10.1111/j.1365-2249.2010.04280.x Do ribosomopathies explain some cases of common

variable immunodeﬁciency?cei_4280 96..103

S. Khan,*† J. Pereira,‡ P. J. Darbyshire,§ Summary S. Holding,¶ P. C. Doré,¶ The considerable clinical heterogeneity of patients with common variable W. A. C. Sewell† and A. Huissoon** immunodeficiency disorders (CVID) shares some similarity with bone- *Department of Immunology, Frimley Park Hospital, Frimley, Surrey, †Centre for marrow failure disorders such as Diamond–Blackfan anaemia (DBA) and Immunoglobulin Therapy, Scunthorpe General Shwachman–Diamond syndrome (SDS), now recognized as defects in ribo- Hospital, Scunthorpe, §Paediatric Oncology and some biogenesis or ribosomopathies. The recognition of a patient with DBA Haematology, Birmingham Children’s Hospital, who subsequently developed CVID lends support to our previous finding of a **Department of Immunology, Birmingham heterozygous mutation in the SBDS gene of SBDS in another CVID patient, Heartlands Hospital, Birmingham, ¶Department suggesting that ribosome biogenesis defects are responsible for a subset of of Immunology, Hull Royal Infirmary, Hull, UK, CVID. Genetic defects in the ribosomal translational machinery responsible and ‡Centro Hospitalar de Coimbra, Unidade de for various bone marrow failure syndromes are recognized readily when they Hematologia Molecular, Coimbra, Portugal manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this perspective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other con- ditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future Accepted for publication 14 September 2010 studies by testing for mutations in specific ribosomal genes. New knowledge Correspondence: S. Khan, Department of might then be translated into novel therapeutic strategies for patients in this Immunology, Frimley Park Hospital NHS group of immunodeficiency disorders. Foundation Trust, Portsmouth Road, Frimley, Camberley, Surrey GU16 7UJ, UK. Keywords: bone marrow failure, common variable immunodeficiency, E-mail: [email protected] Diamond–Blackfan anaemia, ribosome, ribosomopathy

insufficiency [4]. There is emerging evidence that loss of Introduction Shwachman–Bodian–Diamond syndrome (SBDS) protein Common variable immunodeficiency disorders (CVID) affects haematopoeisis and numbers of circulating B lym- comprise a range of hypogammaglobulinaemias, for which a phocytes [5]. Craniofacial malformation syndromes such as small number of genetic defects have been identified [1–3]. Treacher–Collins syndrome, caused by haploinsufficiency of However, these account for only a small proportion of cases the treacle protein, also affect the cells of the immune system of CVID, and the majority of patients have no identified [6], and a broader immunological defect has been described genetic cause. A number of bone marrow failure syndromes in the congenital anaemia of Diamond–Blackfan syndrome are now recognized to be due to defects in ribosome biogen- (Diamond–Blackfan anaemia: DBA) [7]. The 5q- syndrome, esis with mutations in genes coding for ribosomal proteins. a somatically acquired deletion of chromosome 5q and a Various immunological abnormalities are evident in these subtype of myelodysplastic syndrome, leads to haploinsuffi- syndromes and provide proof that failure of optimal ribo- ciency of a ribosomal protein that is also implicated in DBA. some function, ‘ribosomopathies’, can also affect cells of the The active eukaryotic ribosome, the site of protein synthe- immune system. sis, is composed of 40S and 60S subunits. Formation of the These syndromes are heterogeneous in their clinical active complex requires synthesis and assembly of core ribo- presentations: for example, patients with Shwachman– somal proteins, ribosomal RNAs, small nucleolar RNAs and Diamond syndrome (SDS) with confirmed mutations in the several other associated proteins (see Fig. 1). This process SBDS gene (Chr7q11) may not have all the characteristic begins in the nucleolus and the preribosomal units are features of neutropenia, skeletal defects and pancreatic exported into the cytoplasm for final steps in the maturation

complete deletion of one RPS19 allele) generated enormous interest in the clinical effects of disordered ribosome biosyn- thesis [8,9]. Mutations in the RPS19 gene prevent assembly of the 40S ribosomal subunit, but account for only 25% of DBA patients [9]. However, to our knowledge, there have been no reports of failure of antibody production in DBA. We present our clinical experience with the report of the first case of DBA who subsequently developed antibody deficiency, consistent with a new diagnosis of CVID, with complications of bronchiectasis and managed on immunoglobulin therapy. The previous case of CVID with mutation in the SBDS gene of SDS has been discussed briefly with additional data, as a detailed report was published in a previous issue of this Journal [10]. In the final part of this perspective paper, we review the immunological abnormali- Fig. 1. An overview of the biogenesis of the eukaryotic ribosome. ties beginning to emerge in ribosomopathy syndromes. Synthesis of ribosomal proteins and assembly of the mature eukaryotic ribosome has several step: (1) DNA transcription and RNA processing; (2) translation of ribosomal RNA (rRNA); (3) Clinical experience of ribosomopathies and modification and processing by small nucleolar RNPs (snoRNPs) and hypogammaglobulinaemia Rnase; (4) formation of immature large and small ribosomal subunits and exit from nucleolus; and (5) formation of mature eukaryotic DBA and CVID ribosome[8]. The 60S subunit has a cleft for tRNA and amino acids Clinical synopsis including investigations. A 22-year-old from the endoplasmic reticulum (ER) are translated into protein. rRNA, ribosomal RNA; mRNA, messenger RNA; tRNA, transfer RNA; female presented with bronchiectasis and hypo- AAA, amino acids. gammaglobulinemia. DBA had been diagnosed at 1 year of age and required treatment with corticosteroids and blood transfusions until the age of 6 years. There were no associ- of ribosomes [8]. The exact functions of many of these pro- ated skeletal, cardiac or congenital defects. Over the next 3 teins remain unknown. Some ribosomal proteins are now years she suffered from recurrent sinusitis, otitis media, chest known to have extraribosomal functions; for example, the infections (sputum cultures positive for Moraxella catarrha- SBDS protein has a role in stabilizing the mitotic spindle. lis and Haemophilus species) and viral warts. Immunological abnormalities in ribosomopathies may She has a sister with features of DBA – low haemoglobin at therefore provide clues as to how ribosomal proteins can 10·4 g/dl, raised mean corpuscular volume (MCV), lym- shape the immune system. phopenia, elevated fetal haemoglobin (HbF) (3%), high According to internationally accepted criteria, the diagno- erythrocyte adenosine deaminase (eADA) levels, mildly sis of CVID remains one of exclusion. The currently identi- reduced T cell numbers and slight reduction in proliferative fied four genetic mutations (ICOS, CD19, TACI, BAFFR) responses to standard mitogens. The sister’s immunoglobu- account for fewer than a fifth of cases, with no consensus on lin levels, including functional antibody levels, are normal which genetic testing should be undertaken in most cases and she has not required any specific therapy for her [1]. The current European Society of Immunodeficiency anaemia. (ESID)/Pan-American Group for Immunodeficiency Investigations in infancy showed a normocytic anaemia, (PAGID) criteria for CVID include:‘probable’ CVID in those normal serum immunoglobulins [IgG 7·3 g/l (normal range aged > 2 years with low immunoglobulin (Ig)G and another 3·0–10·5), IgA 0·28 g/l (0·1–1·2), IgM 1·07 g/l (0·3–1·5)] and low isotype level (IgA or IgM) with absent vaccine responses; good vaccine responses to conjugated Haemophilus influen- and ‘possible’ CVID in those with low immunoglobulin of zae type b and unconjugated pneumococcal polysaccharide any isotype with absent vaccine responses where other vaccines. By the age of 9, serum IgG levels had dropped to causes of hypogammaglobulinaemia have been excluded [2]. 4·94 g/l (normal range 6·0–13·0). Lymphocyte proliferation Additional similarities with ribosomopathies and CVID responses to phytohaemagglutinin, pokeweed mitogen, patients include heterogeneous presentations with T cell OKT3, tetanus, varicella and herpes antigens were reduced. defects, cytopenias and malignancies [1–3]. Intravenous immunoglobulin (IVIG) replacement therapy The initial description of DBA was of a congenital eryth- was commenced, and stopped after 8 years for reassessment roblastopenia characterized by an early arrest of pre- of immune function. Four years later, she had persistent erythroblast differentiation. The first report of loss-of- anaemia (Hb 10·0 g/dl, MCV 95·6fl) and low IgG (3·37 g/l), function mutations in a gene coding for a ribosomal protein IgA (0·96 g/l) and IgM (0·79 g/l). Bone marrow cytogenetic in this disease (non-sense, missense, frameshift, splice-site, studies were normal, excluding microdeletions in 19q13 and

Table 1. Lymphocyte proliferation results (Diamond–Blackfan syndrome and common variable immunodeficiency disorders case). Genetic analyses Patient Control Polymerase chain reaction (PCR)-based methods for mutation CD3 (OKT3) detection. Genomic DNA was extracted from the patient’s 200 ng/ml 4326 10 304 leucocytes with a commercial DNA purification kit, as per 100 ng/ml 4153 9 843 the manufacturer’s instructions. All RPS19, RPS24, RPS17, 50 ng/ml 3860 8 328 RPL5, RPL11 and RPL35a coding, promoter and 3′UTR 25 ng/ml 3129 9 025 regions (including the boundaries) were amplified by PCR PHA according to previously described methods, with minor 50 mg/ml 560 36 570 changes [11–13]. Direct sequencing of all fragments was 20 mg/ml 1150 62 300 carried out in an automatic sequencer. All sequence varia- 5 mg/ml 920 45 350 tions identified were verified on the complementary strand Lymphocyte proliferation was determined using [3H]-thymidine using an independent PCR product. uptake following the manufacturer’s recommendations. Numbers denote disintegrations per minute (dpm). PHA: phytohaemagglutinin. Multiplex ligand-dependent probe amplification (MLPA) technique for mutations in the RPS19 gene. The MLPA technique, 5q- syndrome. Specific antibody tests showed absent anti- which is used for the detection of complete or partial gene bodies against measles and reduced tetanus and pneumococ- deletions or duplications, was carried out [13,14]. This tech- cal antibody levels. She was diagnosed to have common nique is based on the simultaneous hybridization and ligation variable immunodeficiency as no other causes of low IgG of several probes matched to single exons using a single and low levels of specific antibodies were identified. High reaction tube, which is followed by PCR and analysis by resolution CT scan chest showed evidence of right middle capillary electrophoresis. Reduced peaks suggest deletions lobe bronchiectasis and bilateral lower lobe bronchiectasis (even on only one exon of a single allele) and enhanced peaks worse on the left. Intravenous immunoglobulin therapy was suggest duplication [14].Informed consent for genetic testing recommenced at this stage. was obtained from the patient and the study was approved by Lymphocyte subset analysis showed lymphopenia at the Trust’s Research and Development Department. 833 ¥ 106/ml (normal range 1500–3500), CD3+ T cells 536 (800–2700), helper CD4+ T cells 291 (400–1700), cytotoxic Results of genetic analyses. No loss-of-function mutations CD8+ T cells 191 (300–1200), CD19+ B cells 158 (100–600) were identified in RPS19, RPS24, RPS17, RPS5, RPL11 and and CD16+CD56+ natural killer cells 32 (90–600). B cell RPL35a genes that is in keeping with approximately 50% of studies showed a reduced class-switched memory B cell cases of DBA where no mutations are found in these genes subset at 2·5%. Lymphocyte proliferation responses to (RPS: ribosomal protein small subunit; RPL: ribosomal OKT3, phytohaemagglutinin and pokeweed mitogen protein large subunit). However, heterozygous polymor- remained reduced (see Table 1). Peripheral blood eADA level phisms were identified in RPS24 and RPS17 genes: RPS24 performed recently was high at 594 (normal range 40–100 u/ IVSI +26 (c > t); RPS17 IVS2 -73 (g > c), IVS2 -30 (c > t) l), consistent with the diagnosis of DBA. She has remained and nt159 T > C; and homozygous polymorphisms were well on home therapy with weekly subcutaneous immuno- identified in RPL11 gene: RPL11 -17 (c > g) and IVS5 +39 globulin infusions over the last 3 years. (a > g) (Fig. 2). The MLPA technique did not reveal any dele-

260 240 230 GGC AATTN T C Gz GGGGG CCCT GG C C A AA TTGGGG TTT

RPS24 - IVSI + 26 (C>T) RPL11 - 17 (c>g) RPL11 - IVS5 + 39 (a>g) 110 150 180 AATTN CC AA TT CCTTTTA N G CAAGGTTT N CC A

Fig. 2. Sequencing results showing the polymorphisms found in the RPS24, RPL11 and RPS17 genes. RPS17 - IVS2 -73 (G>C) RPS17 - IVS2 -30 (C>T) RPS17 - nt159 (T>C)

120 160 200 240 280 320 360 400 4000 3000 Ex4 Ex5 Ex6 ~Prom 2000 Ex3 Ex2 Ex1 1000 900 800 700 600 Fig. 3. Multiplex ligand-dependent probe 500 amplification (MLPA) results of the RPS19 400 gene. 0 tion (complete or partial) or duplication in the RPS19 gene nal lymphoid hyperplasia and malabsorption who had a het- (Fig. 3). erozygous mutation in the SBDS gene of SDS [10]. Following publication of the report, the patient was admitted with Implications. This illustrates a ribosomopathy in a patient life-threatening arrhythmias with significant electrolyte with DBA (anaemia, raised adenosine deaminase levels) imbalances secondary to malabsorption and required percu- who subsequently developed CVID. She was dependent on taneous endoscopic gastrostomy (PEG) insertion. Adjusted corticosteroids and blood transfusions but went into remis- Ca2+ levels were 1·86 mmol/l (normal range, 2·2–2·6), sion at the age of 6 years. The current definition of ‘remis- vitamin A levels were 0·55 mmol/l (normal range, 0·84–3·6) sion’ is stable, physiologically acceptable haemoglobin and 25-hydroxy vitamin D levels were 27 nmol/l (should be maintained for a minimum of 6 months without corticos- > 50 at all times with some seasonal variations). He was teroids, transfusions or other therapy [15]. T cell responses continued on pancreatic supplements (pancreozyme), to mitogens were suboptimum, as in a previous case of calcium and magnesium supplements and immunoglobulin DBA, which also showed failure of T cell proliferation to replacement therapy. human recombinant interleukin (rIL)-2 [16]. Our patient In 2005 lymphocyte subsets showed absolute B cell count therefore resembles approximately half of DBA patients at 0·110 ¥ 109/L; B cell subsets (locally derived normal per- who do not have mutations in the currently described six centages in brackets) – naive (IgD+CD27-) B cells 82% (60– ribosomal genes (RPS19, RPS17, RPS24, RPL5, RPL11 and 71%), unswitched (IgD+CD27+) memory B cells 16·4% (10– RPL35a), but the laboratory abnormalities (anaemia, raised 18%) and switched (IgD-CD27+) memory B cells 0·4% eADA levels) suggest that other genes affecting ribosomal (5–15%). By 2009, there was a significant reduction in B cell functions may be involved. A recent paper has described numbers: 0·046 ¥ 109/l. He had a further prolonged course of mutations in other genes, RPS7, RPS27A, RPL36 and admission in the intensive care with pneumonia due to drug- RPS15, evident in DBA, but we have not looked for muta- resistant Pseudomonas aeruginosa that proved fatal. tions in these genes [8]. Hypogammaglobulinaemia, One might consider this late-onset SDS rather than CVID, reduced pneumococcal antibodies, defective T cell prolif- which is rare, as most SDS patients present quite early and eration responses and reduced class-switched memory B the heterozygous mutation in this case could account for cells, all features consistent with CVID, are not assessed residual functional protein and the ‘late’ presentation. typically in DBA, so many cases may be missed. However, he had developed features of CVID long before the Persistent low IgG levels in some cases of DBA may be SDS phenotype was apparent. Malabsorption, progressive secondary to corticosteroids used for refractory anaemia, or weight loss, bi-cytopenias (anaemia, thrombocytopenia) and transient after rituximab therapy [17]. Three reports of use recurrent chest infections in spite of adequate trough IgG of IVIG in DBA were an attempt to treat the refractory levels would suggest progressive disease that strengthens the anaemia, and not for treatment of hypogammaglobuli- hypothesis that the single ca. 258 + 2T > C mutation resulted naemia [16,18,19]. The present consensus opinion is that in defective ribosomal function. IVIG therapy is ineffective for treatment of refractory Some of the interesting features of this case included anaemia in DBA [15]. However, there are rare DBA patients pelvic kidney, eosinophilia, absence of classical presentation who have recurrent infections with antibody deficiency of chronic neutropenia and identification of only one muta- (low IgG levels) requiring monthly IVIG infusions tion (ca. 258 + 2T > C frameshift mutation) in the SBDS (Adrianna Vlachos, personal communication, data not gene. This was the second report of a heterozygous mutation published). that provided evidence that a single mutation may also result in the clinical phenotype, after a Japanese report of a patient with typical SDS phenotype and with only ca. 258 + 2T > C Mutations in the SBDS gene of SDS and mutation [20]. Recently, there has been another report of a hypogammaglobulinaemia novel heterozygous mutation in the SBDS gene (exon 1, 98 We previously reported a patient with typical features of A > C) in a 4-year-old girl with virtual absence of B cells but CVID and complications of bronchiectasis, arthritis, intesti- normal immunoglobulin levels [21].

© 2010 The Authors 99 Clinical and Experimental Immunology © 2010 British Society for Immunology, Clinical and Experimental Immunology, 163: 96–103 100 Khan S. Table 2. Immunological abnormalities in ribosomopathy syndromes.

lncladEprmna muooy©21 rts oit o Immunology, for Society British 2010 © Immunology Experimental and Clinical Ribosomal gene and chromosomal location Syndrome (% patients with mutation) Clinical and laboratory features Immunological abnormalities al et

Diamond–Blackfan RPS 19 19q13·2 (25%) [10] Pallor, growth retardation, congenital anomalies of the Transient low T cells (in three patients), reduced T cell . anaemia (DBA) RPS 24 10q22-q23 (2%) [11] head, neck, upper limbs and urogenital system responses to hrIL-2; low B cell number with normal OMIM: #105650 RPS 17 15q[12] (40%), macrocytic anaemia, raised HbF, EPO and sIg+, absent ConA-induced CD8+ Tcellproduction RPL35A 3q29-qter [22] (3%) eADA levels, leukaemia [25] [7], CVID with reduced T cell mitogen responses RPL 5 and 11 (11%) [23] RPL5 and RPL11 associated with craniofacial (cleft (index case) RPS10 and 26 [24] palate) and abnormal thumbs, respectively [23] Parvovirus B19 seropositivity reaches 50% by age 15 years [26] Shwachman–Diamond SBDS 7q11·21 (90%) Recurrent infections (85%), pancreatic exocrine Neutrophil chemotaxis defect, defect in B and T cell syndrome (SDS) ?EFL1 [8,27,28] insufficiency, metaphyseal chondrodysplasia, short function and survival, low immunoglobulins, low B OMIM: #260400 SBDS mutations affect development of 60S subunit stature, malabsorption, increased risk of malignancy cells [10,21], low specific antibodies [10,21], (AML, MDS), neutropenia (95%), increased apoptosis of CD34+ marrow cells [29–31]; thrombocytopenia, aplastic anaemia CVID [10] Dyskeratosis congenita DKC1 at Chr. Xq28 encodes dyskerin Reticulated skin pigmentation, nail dystrophy, mucosal Low IgM, severe B lymphopenia (X-linked DC); • X-linked TERC (Chr. 3q26); TERT (5p15·53); TINF2 (14q12) leukoplakia, cerebellar hypoplasia T + B - NK - SCID with DKC1 mutation reported in (OMIM: #305000) NOP10 (NOLA3) Chr. 15q14–15 (Hoyeraal–Hreidarsson syndrome), serious Hoyeraal–Hreidarsson syndrome [36] • Autosomal dominant 60% lack an identifiable mutation [32–35] infections, osteoporosis, liver and lung fibrosis, • Autosomal recessive Mutations affect rRNA pseudo-uridylation aplastic anaemia, early ageing due to reduced telomere length, tumour susceptibility [25] Cartilage hair hypoplasia RNase mitochondrial RNA processing (RMRP) RNA Short stature, hypoplastic hair, metaphyseal Hypogammaglobulinaemia, low IgA and IgG subclass (CHH) gene Chr. 9p21–p12 chondrodysplasia (Ϯcone-shaped epiphysis), some [39], decreased T cell count and proliferation OMIM: #250250 70A > G (founder mutation, 92% Finnish and 48% excess risk of malignancy (lymphoma, liver, (low CD4+ with increased apoptosis) and CD8 non-Finnish) [37] duodenal, skin), anaemia (6% dependent on blood lymphopenia [40,42–44], low B cells [44], defective lncladEprmna Immunology Experimental and Clinical Certain mutations correlate with severe immunogical transfusions), neutropenia, lymphopenia, infections B cell and fibroblast proliferation [44], severe and haematological abnormalities [38] 56% (Pneumocystis, CMV) [39–41] combined immunodeficiency (Omenn syndrome) RMRP mutations affect pre5·8S (part of 60S subunit) [43,45]

Treacher–Collins Treacle gene TCOF1 5q32–q33·1 (93%) Anti-mongoloid slant of eyes, cataracts, coloboma of T cell abnormalities, impaired mitogen responses, syndrome TCOF1 mutations cause 18S rRNA methylation defect lid/uveal tract, micrognathia, ear deformities, decreased B cells with low immunoglobulins OMIM: #154500 that leads to insufficient nucleolar phosphoprotein hypoplastic zygomatic arches, macrostomia, (in some craniofacial syndromes) [6] treacle, and defects in craniofacial development [46] conductive hearing loss, cleft palate, 18S is part of 40S ribosomal subunit craniosynostosis, anaemia [47] Turner’s syndrome Human sex-linked genes RPS4X and RPS4Y encode 2 Girls with 45 XO karyotype, ring X chromosome with CVID [50,51], hypogammaglobulinaemia, T cell 00TeAuthors The 2010 © isoforms of ribosomal protein S4; RPS4 is a mental retardation and kyphoscoliosis, short stature, immunodeficiency, selective IgA deficiency, coeliac component of 40S subunit; haploinsufficiency of webbed neck, gonadal failure, cardiovascular and disease [50–56] ,

163: RPS4X hypothesized to lead to Turner’s syndrome renal malformations, hearing loss, diabetes [48,49] 96–103 AML: acute myeloid leukaemia; CMV: cytomegalovirus; ConA: concanavalin A; CVID: common variable immunodeficiency disorder; eADA: erythrocyte adenosine deaminase; EPO: erythropoietin; HbF: fetal haemoglobin; hrIL: human recombinant interleukin; Ig: immunoglobulin; MDS: myelodysplastic syndrome; NK: natural killer; rIL: recombinant interleukin; SCID: severe combined immunodeficiency. Ribosomopathies and common variable immunodeficiency

Following our finding of the SBDS mutation in one incompatible with life [8]) and certain tissues may there- patient, we subsequently checked for SBDS mutation in two fore be more susceptible to decreased production of spe- other patients. cific ribosomal proteins when they are produced at limited One patient was a 77-year-old woman with CVID, chronic rates [8,58]. anaemia due possibly to underlying myelodysplasia (proved Low IgM levels with B cell lymphopenia have been reported on bone marrow biopsy) and thrombocytopenia. The other in X-linked dyskeratosis congenita (X-linked DC), with patient was in his early 40s, with CVID and on IVIG for 8 severe combined immunodeficiency (T + B - NK - SCID) years with a 2-year history of enteropathy (chronic diar- reported in the most severe variant of dyskeratosis congenita rhoea, ongoing weight loss, coeliac-like disease with no (Hoyeraal–Hreidarsson syndrome) [36]. Premature ageing is response to gluten-free diet). No mutations in the SBDS gene also a feature of this disease [32–34] and TINF2 gene muta- were found in either of these patients. tion (a component of the telomere protection complex) [35] SDS and CVID share common features, such as recurrent leading to short telomeres has been described in X-linked DC. infections, malabsorption, cytopenias (neutropenia, throm- It is not clear whether the immune abnormalities are due to bocytopenia, anaemia), low immunoglobulins Ϯ absent the defective tRNA pseudouridylation or the short telomere vaccine responses in some cases [10], abnormal liver func- length. tion tests, autoimmunity and malignancy [myelodysplastic Turner’s syndrome (45,X0) is postulated to have a riboso- syndrome (MDS), leukaemia], and testing for mutations in mal defect due to haploinsufficiency of ribosomal protein the SBDS gene in CVID patients with most of the above RPS4X [48,49]. Variable degrees of antibody deficiency features would be worthwhile. (panhypogammaglobulinaemia [48], low IgM [50,52]) More importantly, testing for SBDS mutations would be including decreased T and B cell numbers [50,54] and important in children with persistent neutropenia, recurrent coeliac disease with IgA deficiency have been recognized in infections, growth and skeletal abnormalities where the this syndrome [53,55]. Some of these patients with Turner’s immunodeficiency disorder may have been described as syndrome have clinical syndromes of recurrent sinopulmo- CVID. A scoring system may prove useful in the future when nary infections and other features overlapping with CVID more patients are described. [50,51].

Review of immunological abnormalities in Conclusions ribosomopathy syndromes We have looked at the evidence for ribosomal defects being Ribosomopathies and bone marrow failure syndromes have associated with and possibly causative of immune abnor- variable and overlapping clinical presentations, yet most malities with features of CVID. We describe two such have subtle immune defects and a strong tendency to patients with different ribosomal defects who subsequently develop leukaemic transformation. The role of p53 in ribo- developed a presentation consistent with CVID. A review of somal dysfunction is beginning to be understood, such as the literature indicates that patients with ribosomal defects up-regulation of p53 in haploinsufficiency of certain ribo- may share abnormalities of T or B cell development with somal proteins and consequent apoptosis and cell-cycle many features of CVID, and which may not be recognized as arrest, offer interesting mechanisms of cellular effects in such by non-immunologists. Given that the four established ribosomopathies [8]. Deciphering subtle defects in the genetic defects account for fewer than a fifth of cases of immune system in these patients may help to unravel the CVID, this hypothesis could be tested in the future by more complex interaction of ribosomal proteins in the develop- detailed studies of ribosome genetics and/or function in ment of specific parts of the immune system. Table 2 lists the CVID. syndromes with known mutations in ribosomal genes and the immunological abnormalities. Disclosure Future studies will determine whether our observations This work was supported by the Centre for Immunoglobulin of polymorphisms in specific ribosomal genes associated Therapy and Department of Immunology, Hull Royal with DBA and the association of symptomatic or asymp- Infirmary. WACS is Director of Centre for Immunoglobulin tomatic hypogammaglobulinaemia. With expanding Therapy, which has received unrestricted educational grants knowledge and detection of newer ribosomal proteins, from Octapharma, Baxter, Grifols, CSL-Behring. The rest of sequencing of specific ribosomal genes and/or use of ‘func- the authors have no financial interests to disclose. tional’ assays that provide evidence of aberrant preribosomal RNA precursor accumulation would provide more tools to detect newer ribosomopathies that currently References do not have a genetic basis [8,57]. Optimal expression of 1 Park MA, Li JT, Hagan JB, Maddox DE, Abraham RS. Common ribosomal proteins appears to be critical for functioning of variable immunodeficiency: a new look at an old disease. Lancet organ systems (as complete absence of SBDS or RPS19 are 2008; 372:489–502.

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