some cases of common variable immunodeficiency may be due to a mutation in the sbds gene of...

Some cases of common variable immunodeficiency may be due to amutation in the SBDS gene of Shwachman–Diamond syndrome

S. Khan,* J. Hinks,† J. Shorto,†

M. J. Schwarz† and W. A. C. Sewell*‡

*Path Links Immunology, Scunthorpe General

Hospital, Scunthorpe, N. Lincs, †National

Genetics Reference Laboratory, St Mary’s

Hospital, Manchester, and ‡Department of

Biomedical Sciences, University of Lincoln,

Lincoln, UK

Summary

Known genetic defects currently account for only a small proportion ofpatients meeting criteria for ‘probable’ or ‘possible’ common variable immu-nodeficiency (CVID). A 59-year-old male with a 12-year history of CVIDon intravenous immunoglobulin (IVIG) is presented who developed bron-chiectasis, cytopenias and malabsorption that are recognized complicationsof CVID. Work-up for his malabsorption suggested the possibility ofShwachman–Diamond syndrome, confirmed by mutation testing. With theidentification of the molecular defect in Shwachman–Diamond syndrome(SDS), it is becoming clear that not all SDS patients have the prominentfeatures of neutropenia or pancreatic malabsorption. A meta-analysis of pub-lished immunological defects in SDS suggests that four of 14 hypogamma-globulinaemic SDS patients meet criteria for ‘possible’ CVID. Mutations in theSBDS gene may therefore be the fifth identified molecular defect in CVID.

Keywords: common variable immunodeficiency, immunodeficiency,

Shwachman–Bodian–Diamond syndrome gene, Shwachman–Diamondsyndrome

Accepted for publication 16 October 2007

Correspondence: W. A. C. Sewell, Path Links

Immunology, Scunthorpe General Hospital,

Cliff Gardens, Scunthorpe, North Lincolnshire

DN15 7BH, UK.

E-mail: [email protected]

Introduction

Common variable immunodeficiency (CVID) is a primaryimmunodeficiency disorder of unknown cause, and cur-rently identified genetic mutations (ICOS, CD19, TACI,BAFFR) account for less than a fifth of cases [1]. The fact thatsome CVID patients have variable degrees of cytopenia,develop lymphoid nodular hyperplasia and subsequentlymphoma points to a failure of bone marrow B celldifferentiation. Various immunological abnormalities,including low immunoglobulins and absent vaccineresponses that would fit criteria for ‘probable’ or ‘possible’CVID, have been recognized in some patients suffering fromShwachman–Diamond syndrome (SDS). This syndrome canpresent with a very broad array of signs, and recent advancesin the genetics of SDS have demonstrated that many patientswith SDS do not necessarily display the ‘classical’ features.Characteristic features include cytopenias (usually but notinvariably neutropenia), skeletal defects and pancreaticinsufficiency. Recent identification of the Shwachman–Bodian–Diamond syndrome (SBDS) gene at Chr7q11 hasled to identification of cases without neutropenia or tran-sient pancreatic insufficiency [2].

We report a case of CVID on intravenous immunoglo-bulin for 12 years with complications of lymphopenia,

lymphoid nodular hyperplasia and transient pancreaticinsufficiency and found to be heterozygous for a mutation inSBDS gene.

Case presentation

A 49-year-old man with no children presented initially in1995 to the haematology department with repeated earinfections over 6 years, requiring myringotomy andgrommet insertion. Over the next 3 years, he had recurrentHaemophilus influenzae pneumonia and was then found tohave panhypogammaglobulinaemia (IgG 3·7 g/l which fell to1·3 g/l, IgM < 0·2 g/l, IgA < 0·2 g/l) and lymphopenia [totallymphocyte count 0·8 ¥ 109/l; total T cells 0·622 ¥ 109/l(normal 0·7–2·1), CD4 T cells 0·337 ¥ 109/l (0·3–1·4), CD8 Tcells 0·233 ¥ 109/l (0·2–0·9), CD19 B cells 0·110 ¥ 109/l(0·1–0·5), natural killer cells 0·143 ¥ 106/l (0·09–0·6), a/b Tcell receptor (TCR) 82% and g/d TCR 4% of T cells]. Assess-ment of vaccine responses was not undertaken given thedegree of his hypogammaglobulinaemia; a diagnosis ofCVID was made and treatment with intravenous immuno-globulin (IVIG) was commenced. At the time of diagnosishe was noted to have short stature (150 cm), but did nothave neutropenia or steatorrhoea or other features ofmalabsorption. Over the next 12 years, the following

Clinical and Experimental Immunology ORIGINAL ARTICLE doi:10.1111/j.1365-2249.2007.03556.x

448 © 2008 British Society for Immunology, Clinical and Experimental Immunology, 151: 448–454

mailto:[email protected]

abnormalities developed: inflammatory nasal polyps, arthri-tis (knee, wrist), anaemia (haemoglobin 8·9 g/dl), eosino-philia (1·6 ¥ 109/l) and abnormal liver function tests (alanineaminotransferase 233 m/l and alkaline phosphatase 490 m/l)and was shown to have bronchiectasis and fused ectopickidneys in his right iliac fossa (Fig. 1a–d).

Severe malabsorption developed resulting in hypocalcae-mic tetany, hypoalbuminaemia and difficulty maintainingtrough IgG levels. A duodenal biopsy revealed lymphoidnodular hyperplasia (Fig. 1d) that responded poorly tosteroid therapy. Faecal immunoelastase levels were abnormal(108 mg/g; normal > 200 mg/g), suggesting exocrine pancre-atic insufficiency. Hydrogen breath test, sweat chloride andshort synacthen tests were normal. Genetic testing for SDSwere undertaken.

Materials and methods

DNA was extracted from peripheral blood [5 ml in ethylene-diamine tatraacetic acid (EDTA)] using the Autopure LSTM

system (Qiagen, Crawley, UK) according to the manufactur-er’s instructions. Analysis of the SBDS gene was then per-formed in two stages. The first stage of analysis involvedamplification of exon 2 of the SBDS gene by polymerasechain reaction (PCR), according to the method of Boococket al. [3]. In brief, two separate PCR reactions were set up:one using primers specific for the SBDS gene and one using‘dual-specific’ primers that amplified exon 2 of both theSBDS gene and its pseudogene. The oligonucleotidesequences 5′-3′ of the primers for analysis of exon 2 usedwere as follows: forward specific, AAATGGTAAGGCAAATACGG; reverse specific, ACCAAGTTCTTTATTATTAGAAG; forward dual specificity, GGGATTTGTTGTGTCTTG;and reverse dual specificity, CTTTCCTCCAGAAAAACAGC.

Each reaction contained CM129 buffer (ABgene, Epsom,UK), primers (each 10 mM) and 50–100 ng DNA. Cyclingconditions were: 95°C for 15 min, followed by 30 cycles of(95°C 1 min, 55°C 1 min, 72°C 1 min), a final extension stepat 72°C for 10 min, and cooled to 4°C indefinitely. Both PCRproducts were subjected to separate restriction endonucleasedigestions with Bsu36I and Cac8I, the former detecting themutation ca. 183_184TA > CT and the latter detecting ca.258 + 2T > C. PCR products were subjected to electrophore-sis in an agarose gel stained with ethidium bromide. Theresulting products were photographed under ultravioletlight (Fig. 2).

The second stage of analysis was to sequence the entirecoding region of the gene. Exons 1–5 were amplified in 20 mlreactions using the primers outlined in Table 1. Each reac-tion contained CM102 buffer (ABgene), primers (10 mM)and 50 ng DNA. Cycling conditions were: 95°C for 3 min,followed by 30 cycles of (95°C for 1 min, 55°C for 1 min,72°C for 1 min), a final extension step at 72°C for 5 min, andcooled to 4°C indefinitely. The resulting PCR product wascleaned up using AMPureTM (Agencourt, Beckman CoulterUK, High Wycombe, UK) magnetic bead technology on aBeckman NX liquid handling robot. These products werethen sequenced using the Big DyeTM (Applied Biosystems,Warrington, UK) Terminator version 1·1 and N13 primers.The sequencing products were cleaned up using CleanSEQTM

magnetic bead technology (Beckman Coulter UK) on aBeckman NX liquid handling robot. All the samples were runon the ABI PrismTM 3730 capillary electrophoresis sequencer(Applied Biosystems).

Sequence traces were analysed with Staden sequenceanalysis software (http://staden.sourceforge.net).

A meta-analysis of immunological abnormalities inSDS was performed. Case series and reports of SDS were

(a) Left lower lobe bronchiectatic

changes

(b) Fused right iliac fossa ectopic

kidneys and mild hydronephrosis

(not reported in either of the

syndromes)

(c) Marked OA changes

medial aspect knee joint

(d) Duodenal biopsy showing

nodular lymphoid hyperplasia

with prominent germinal centre:

feature of CVID rather than SDS

Fig. 1. X-rays and computerized tomography/magnetic resonance imaging abnormalities and duodenal biopsy (histology) in our patient. (a) Left

lower lobe bronchiectatic changes. (b) Fused right iliac fossa ectopic kidneys and mild hydronephrosis (not reported in either of the syndromes).

(c) Marked osteoarthritis changes medial aspect knee joint. (d) Duodenal biopsy showing nodular lymphoid hyperplasia with prominent germinal

centre - feature of common variable immunodeficiency rather than Shwachman–Diamond syndrome.

SBDS mutation in CVID

449© 2008 British Society for Immunology, Clinical and Experimental Immunology, 151: 448–454

http://staden.sourceforge.net

identified from medline, embase and Dialog DataStar usingthe following search terms: immunoglobulin, Shwachman–Diamond syndrome, Shwachman–Bodian syndrome, con-genital lipomatosis of pancreas, hypogammaglobulinaemia,immunodeficiency or pancreatic insufficiency.

Results

SBDS genetic analysis

PCR products generated by SBDS-specific primers digestedwith Cac8I revealed the presence of ca. 258 + 2T > C muta-tion, while digestion of PCR products with Bsu36I did notreveal the second common ca. 183–184TA > CT mutation(Fig. 2). These gene conversion mutations on exon 2 derivedfrom the pseudogene sequence account for 74% of SDSmutations. Owing to the autosomal recessive nature of the

syndrome, entire gene sequencing of the coding region(exons 1–5) was carried out, which failed to reveal anyfurther mutations. Our patient is thus heterozygous for theca. 258 + 2T > C mutation of SDS.

Meta-analysis of hypogammaglobulinaemia in SDS

The results of the meta-analysis of published immunologicalabnormalities are tabulated on a case-by-case basis, and theresulting cohort subdivided into those meeting currentEuropean Society of Immunodeficiency (ESID) criteria forCVID, hypogammaglobulinaemia and other immunologicalabnormalities (Table 2). Of seven published cases and seriesof SDS, three patients met criteria for ‘possible’ CVID, 10 forhypogammaglobulinaemia and three had other immuno-logical abnormalities.

1 2 3 4 5 6 7 8

(a)

(b)

Fig. 2. (a) Polymerase chain reaction (PCR) products generated by Shwachman–Bodian–Diamond syndrome (SBDS)-specific primers, digested

with Bsu36I. The upper band represents the undigested amplimer; the lower bands are the digested products created by the presence of a Bsu36I

site, arising from the ca. 183_184TA > CT mutation. Lane 1 is a 100 base pairs (bp) ladder. Lanes 2, 3, 4, 5 and 8 are negative. Lanes 6 and 7 are

heterozygous for ca. 183_184TA > CT. (b) PCR products generated by SBDS-specific primers, digested with Cac8I. The upper band represents the

undigested amplimer; the lower bands are the digested products created by the presence of a Cac8I site, arising from the ca. 258 + 2T > C mutation.

Lane 1 is a 100 bp ladder. Lanes 2, 3, 4, 6 and 7 are heterozygous for ca. 258 + 2T > C. Lane 5 is homozygous for ca. 258 + 2T > C. Lane 8 is negative.

Table 1. Primers used in sequence analysis of exons 1–5 of the Shwachman–Bodian–Diamond syndrome (SBDS) gene. Primers are all 5′-tagged with

N13 tails (small capitals).

Primer Oligonucleotide sequence 5′-3′ Amplicon size

Exon 1 forward GTAGCGCGACGGCCAGTTAAGCCTGCCAGACACAC 543

Exon 1 reverse CAGGGCGCAGCGATGACCCGAACCAACCAAATAAAGA

Exon 2 forward GTAGCGCGACGGCCAGTGGGATTTGTTGTGTCTTG 369

Exon 2 reverse CAGGGCGCAGCGATGACCTTTCCTCCAGAAAAACAGC

Exon 3 forward GTAGCGCGACGGCCAGTGCTCAAACCATTACTTACATATTGA 462

Exon 3 reverse CAGGGCGCAGCGATGACCCAGACCCATTATTTTAATG

Exon 4 forward GTAGCGCGACGGCCAGTGCCTTCACTTTCTTCATAGT 514

Exon 4 reverse CAGGGCGCAGCGATGACGAAAATATCTGACGTTTACAACA

Exon 5 forward GTAGCGCGACGGCCAGTGCTTGCCTCAAAGGAAGTT 492

Exon 5 reverse CAGGGCGCAGCGATGACCACTCTGGACTTTGCATCTT

S. Khan et al.


Tabl

e2.

Met

a-an

alys

isof

stu

dies

inSh

wac

hm

an–D

iam

ond

syn

drom

e(S

DS)

pati

ents

wh

ofu

lfilc

rite

ria

for

com

mon

vari

able

imm

un

odefi

cien

cy(C

VID

)an

dot

her

imm

un

olog

ical

abn

orm

alit

ies.

Dis

ease

cate

gory

Age

/sex

Rec

urr

ent

infe

ctio

ns

IgG

leve

ls(g

/l)

IgM

leve

ls

(g/l

)

IgA

leve

ls

(g/l

)

Vac

cin

e

resp

onse

s

CD

19

cells

(%)

CD

4/

CD

8

rati

o

CD

16/

CD

56

cells

(%)

Neu

trop

hil

chem

otax

isR

efer

ence

‘Pos

sibl

e’C

VID

7/M

Bac

teri

al+

vira

l7·

0*0·

30·

8A

bsen

t/††

242·

2‡1·

0§A

bnor

mal

[4]

18/M

Bac

teri

al+

vira

l4·

8§0·

30·

7N

orm

al/††

1·2§

0·5§

1·8§

–[4

]

41/F

Bac

teri

al5·

8§ (6·3

–12·

9g/

l)–

–A

bsen

t

(pn

eum

ococ

cal)

–N

orm

al–

–[5

]

59/M

Bac

teri

al1·

3§<

0·2§

<0·

2§–

1·10

§1·

4§1·

43§

–In

dex

case

Hyp

ogam

ma-

glob

ulin

aem

ia

ofot

her

typ

es

4m

onth

/F

1·5/

M

Bac

teri

al

Bac

teri

al

3·8§

(6·0

–15·

75g/

l)

6·8

0·40

§(0

·7–2

·3g/

l)

<0·1

§

0·07

§(0

·2–1

·4g/

l)

0·3

Abs

ent

–

CD

20–6

(10–

30%

)

–

2·0

–

3 –

Abn

orm

al

–

[6]

[7]

2/M

Bac

teri

al+

vira

l6·

1§,¶

0·3

0·2§

––

––

–[4

]

–B

acte

rial

–Lo

w–

–N

orm

alN

orm

al–

Abn

orm

al[8

]

–B

acte

rial

––

Low

–N

orm

alLo

w–

Abn

orm

al[8

]

–B

acte

rial

––

Low

–N

orm

alN

orm

al–

Abn

orm

al[8

]

–B

acte

rial

–Lo

w–

–N

orm

alN

orm

al–

Abn

orm

al[8

]

16/M

Bac

teri

al0·

36§

0·03

§0·

12§

––

––

–[9

]

3/M

Nil

4·8§

0·07

§A

bsen

t§–

––

––

[10]

6·5/

FN

il3·

8§0·

780·

18§

––

––

–[1

0]

Oth

er

imm

un

olog

ical

abn

orm

alit

ies

8/M

Bac

teri

al+

vira

l9·

80·

30·

7–/

††9·

32·

31·

5§A

bnor

mal

[4]

17/M

Bac

teri

al8·

20·

411

·1–

––‡

–A

bnor

mal

[4]

14/F

Bac

teri

al16

·51·

32·

7N

orm

al/††

151·

0§3·

5§–

[4]

*Low

IgG

1le

vels

;† Low

anti

-Bis

ohae

mag

glu

tin

inle

vels

;‡ low

lym

phoc

yte

prol

ifer

atio

nto

con

can

aval

inA

/pok

ewee

dm

itog

en;§ lo

wfo

rag

e;¶ lo

wIg

G1

and

IgG

3le

vels

;–,n

otst

udi

ed/a

vaila

ble.



Discussion

This case describes a man with CVID on IVIG for 12 yearswho was found to have a heterozygous mutation in the SBDSgene of SDS (OMIM no. 260400). Current ESID criteria forCVID include ‘probable’ CVID in those aged > 2 years withlow IgG and another low isotype level (IgA or IgM) withabsent vaccine responses, and ‘possible’ CVID in thosewith low immunoglobulin of any isotype with absentvaccine responses [11]. The cytopenias seen in CVIDpatients are considered to be ‘autoimmune’, although anti-bodies against cellular components are not usually identi-fied, suggesting a degree of bone-marrow suppression. SDSis a bone marrow failure disorder, and while neutropenia isthe most consistent feature, additional cytopenias includingaplastic anaemia can develop [12]. Bone marrow CD34+ cellsin SDS are unable to form haemopoietic colonies and havehigh rates of apoptosis via the Fas signalling pathway [13].Various other immunological abnormalities, such as lowimmunoglobulins, low T cells and natural killer (NK)cells, have been described. Features common to both CVID

and SDS include the predominance of bacterial infections(Staphylococcus aureus, H. influenzae and Pseudomonasspecies) over fungal infections [14] and chronic diarrhoea/malabsorption, but pancreatic investigations are usually notundertaken in patients with CVID. The features of CVIDand SDS are compared and contrasted in Table 3.

SDS is an autosomal recessive disorder which usually pre-sents early in life with recurrent infections, neutropenia andpancreatic insufficiency. Complications of aplastic anaemia,myelodysplastic syndromes or leukaemia occur in those whoreach adult age [12]. It has an extremely heterogeneous clini-cal presentation, as does CVID, but 90% of patients meetingclinical criteria have mutations in the Shwachman–Bodian–Diamond syndrome gene (SBDS) (see Table 4 for summaryof genetic mutations identified in CVID and SDS). TheSBDS gene located on chromosome 7q11 is highly conservedin archaea, plants and eukaryotes [3,16]. The protein is pre-dicted to have 250 amino acids and gene conversion duringmeiosis with its neighbouring pseudogene, SBDSP (theduplicon of SBDS gene located 5·8Mb distally with nucle-otide sequence homology of 97%), which results in the

Table 3. Clinical features of Shwachman–Diamond syndrome (SDS) and common variable immunodeficiency (CVID).

SDS CVID

Common features to both diseases

Recurrent infections Recurrent infections

Malabsorption due to exocrine pancreatic dysfunction (may be transient)

hyperplasia, coeliac-like disease, chronic Giardia lamblia infection)

Malabsorption (inflammatory bowel disease, lymphoid nodular

Haematological abnormalities Haematological abnormalities (?autoimmune)

• Neutropenia (intermittent/persistent) • Cytopenias (neutropenia, lymphopenia, thrombocytopenia)

• Thrombocytopenia • Anaemia (red cell aplasia)

• Anaemia

Low immunoglobulins � absent vaccine responses in some cases

(Table 2)

Low immunoglobulins and absent vaccine responses (ESID

diagnostic criteria)

Abnormal liver function tests (fatty liver) Abnormal liver function tests (granulomatous CVID, rest unknown)

Autoimmunity (hypothyroidism) Autoimmunity (haematological abnormalities, thyroid disease,

neuropathy)

Malignancy Malignancy

• MDS (10–44%) • Gastric carcinoma

• Leukaemia (5–24%) • Lymphoma

Other features

Growth and skeletal abnormalities

• Metaphyseal chondrodysplasia

Multi-systemic granulomatous disease (eye, lymph nodes, skin, liver,

spleen, GI tract)

• Osteoporosis/osteomalacia Large granular lymphocytosis

• Short stature

• Thoracic cage defects

Neurological problems

• Global apraxia

• Generalized weakness/hypotonia

Cardiovascular problems

• Myocardial fibrosis

Oral/dental

• Mucositis/periodontal infections

• Dental dysplasia

Psychological problems

• Cognitive and attention deficits

S. Khan et al.


majority of mutations seen in SDS patients. Although thefunction of the protein remains unknown, SBDS proteinshuttles in and out of the nucleolus [17] and studies in yeasthomologues suggest a role in ribosomal RNA processing[18,19]. Homozygous early truncating mutations result incomplete loss in SDS function and are lethal at the embryostage [18,20], explaining the absence of patients with suchmutations. Among the various mutations described, muta-tions ca. 258 + 2T > C and ca. 183_184TA > CT account for74% of SDS mutations but the ca. 258 + 2T > C mutationalone may also result in the clinical phenotype [21]. It hasbeen suggested that the absence of mutations in currentlyknown genes does not necessarily preclude diagnosis if thepatient fits clinical criteria [22] and equally neutropenia orpancreatic insufficiency may not be present in some patients.Phenotypic–genotypic correlations have not been found

[23], and it is possible that other genes controlling RNAmetabolism affect SDS function [24]. SDS shares its nucle-olar and RNA involvement with other syndromes such ascartilage–hair hypoplasia (short stature and skeletal abnor-malities), dyskeratosis congenita (mutations in small nucle-olar and telomerase RNA) and Diamond–Blackfan anaemia(mutations in the RPS19 gene encoding ribosomal proteinS19) [25].

Our patient now has normal pancreatic function, hasnever had neutropenia and has only the ca. 258 + 2T > Cmutation. Hepatomegaly, elevated liver enzymes and malab-sorption due to pancreatic insufficiency seen in SDS mayimprove over time in about half the patients [2,26]. Randomfaecal elastase determination can provide sufficient informa-tion of pancreatic exocrine function [27] but, as adultpatients with SDS may be pancreatic sufficient, the clinical

Table 4. Prevalence of identified genetic mutations in common variable immunodeficiency (CVID) and Shwachman–Diamond syndrome (SDS).

Disease Gene

Location on

chromosome Protein function Mutations identified Prevalence (%) References

CVID ICOS 2q33 T cell stimulation, isotype

switching, germinal

centre formation

Complete deletion of

exon 2 and intron 2,

or partial deletion

of intron 1 and intron

3 result in partial

deletion of ICOS mRNA

and absent protein

2

Deletional event

during meiotic

recombination

[1]

CVID CD19 16p11.2 Crucial role in signalling

on antigen stimulation

as part of B cell

receptor complex

Two families with

homozygous null

mutations (insertion

of adenine in exon 6 and

deletion of guanine and

adenine in exon 11) in the

CD19 gene

< 1 [1]

CVID TNFRSF13C

(BAFFR)

22q13.1–31 BAFF/BAFFR interaction:

B cell survival factor,

marginal zone

differentiation, T cell

co-stimulation

Homozygous deletion

in the transmembrane

region of BAFFR in one

autosomal recessive

CVID family

< 1 [1]

CVID &

IGAD

TNFRSF13B

(TACI)

17p11.2 TACI mediates isotype

switching in B cells

Missense mutation and single

nucleotide insertion in one

allele of TNFRSF13B

5–10 [1,15]

SDS SBDS 7q11 SBDS protein:

exact function

unknown; has a role in

ribosome biogenesis

with nucleolar and

non-nucleolar functions

Two common heterozygous

loss-of-function mutations

apart from others [12]:

ca. 258 + 2T > C: Disrupts

donor splicing site and use of

upstream donor site leads to

frameshift mutation and

premature truncation at 84th

AA (84CfsX3) ca. 183_184

TA > CT: Introduction

of in-frame stop codon at

62nd AA lysine (K62X);

homozygous K62X null

mutation is embryonically

lethal

SDS: 90%

CVID: unknown

Recurring mutations

arise from gene

conversion

between SBDS and

SBDSP during

meiotic

recombination

[3,16]



criterion of exocrine pancreatic insufficiency does notappear to be essential for the diagnosis of SDS. Pancreaticinsufficiency may be ameliorated by enzyme supple-mentation. Accordingly, genetic testing to screen for SBDSmutations could be considered in selected CVID patientswith unexplained weight loss, chronic severe diarrhoea andrecurrent anaemia. Abnormal neutrophil chemotaxis couldalso be used to support the diagnosis of SDS, as it should benormal in CVID, but this assay is not readily available inmost centres and there are no external quality assuranceschemes for this test. Our patient appeared to be a typicalCVID patient - suggesting that other patients with thesecommon features of CVID could also have SBDS mutations.Defects in ribosomal processing can affect cell function atvarious stages that explain the heterogeneity of other dis-eases with ribosomal defects. Given that the four establishedgenetic defects (ICOS, CD19, TACI, BAFFR) account for< 20% of cases of CVID, screening studies of CVID patientswith suggestive clinical and laboratory features for SBDSmutations may be useful in establishing whether or notSBDS is the ‘fifth’ CVID gene.

Acknowledgements

We are grateful to Dr Carol Hunt and Dr Loraine Sheehanfor providing the histopathology pictures, Dr Simon Maslinfor comments on the radiographic images and to DrGeorgina Hall for useful communications regarding genesequencing in SDS.

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some cases of common variable immunodeficiency may be due to a mutation in the sbds gene of...

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