J ALLERGY CLIN IMMUNOL

VOLUME 122, NUMBER 6

LETTERS TO THE EDITOR 1217

Simultaneous presentation of 2 rare hereditaryimmunodeficiencies: IL-12 receptor b1 defi-ciency and ataxia-telangiectasia

To the Editor:About 150 primary immunodeficiencies (PIDs) have been

described, with more than 100 genetic etiologies identified, asreviewed by Casanova and Abel.1 Most known PIDs are rare andfirst manifest symptoms in infancy or early childhood. They con-fer predisposition to various clinical phenotypes, including infec-tion and cancer. Most PIDs predispose affected children toinfectious diseases, the nature and range of which depend onthe condition. Autosomal recessive IL-12 receptor b1 (IL-12Rb1) deficiency is the most common cause of hereditarypredisposition to mycobacterial diseases and salmonellosis inotherwise healthy patients, as reviewed by Filipe-Santos et al.2

Many PIDs also confer predisposition to cancer, whether becauseof impaired control of oncogenic viruses, impaired DNA repair, orboth. The best known example is ataxia-telangiectasia (A-T),which is associated with a high rate of lymphoma and leukemia,as reviewed by Lavin et al.3 Known PIDs are typically rare, with aprevalence between 1/100,000 and 1/1,000,000 cases per livebirths. We report the first patient with 2 hereditary PIDs: IL-12Rb1 deficiency and A-T.

A 7-year-old Arab girl had presented in the Allergy-Immunol-ogy Clinic of Hamad Medical Corporation in Doha, Qatar, sinceearly childhood because a sister died at age 10 years with A-T (Fig1). She was full-term, from an uneventful pregnancy, born tohealthy, first-degree cousins. At age 4 days, laboratory workupshowed a low lymphocyte count but normal IgG, IgA, and IgMlevels. Lymphocyte subsets revealed low proportions of CD3,CD4, and CD8. She was thus considered as a probable case ofA-T. She had her immunization series except live vaccines andwas given inactivated poliomyelitis vaccine.

At 14 months, she was admitted to the hospital with a 10-dayfever without other symptoms. Blood cultures were positive forSalmonella serotype group D. She was treated with Ceftriaxoneintravenously for 10 days. Blood cultures became negative after4 days of Ceftriaxone, and the patient was discharged from thehospital. Two weeks later, the patient was readmitted with a his-tory of a 2-day fever; she was otherwise asymptomatic. Blood cul-ture again was positive for Salmonella serotype group D. Shereceived 14 days of Ceftriaxone intravenously and was dis-charged with negative blood cultures. Two weeks later, she wasreadmitted again with a 3-day fever (40.68C). Blood cultureswere again positive for Salmonella serotype group D. She re-ceived a 10-day course of intravenous Ceftriaxone and Amikacinand was discharged from the hospital.

At age 22.5 months, she was admitted to the hospital with fever,limping, and a painful, swollen left knee for 4 days with limitedrange of motion. There was extensive oral candidiasis. Notelangiectasia were noted over eyes, ears, or nose. She hadbilateral, submandibular, mobile, nontender lymph nodes of 2 3 2cm. Blood and urine cultures were negative. MRI with contrast forthe left lower limb showed multiple discrete lesions in themetaphysis and diaphysis of the proximal tibia and fibulaenhancing on contrast medium. She was diagnosed as havingacute osteomyelitis. She received a 14-day antibiotic course ofintravenous Ceftriaxone and Cloxacillin, with oral antifungaltreatment for candidiasis, and was discharged from the hospital.

At age 45 months, she was admitted to the hospital with another4-day fever. Physical examination revealed an underweight, feb-rile child without ocular or cutaneous telangiectasia. There wasenlargement of bilateral submandibular, nontender, mobile lymphnodes (1.5 3 2 cm). Ultrasound of the neck revealed multiple, en-larged, right-sided lymph nodes of submandibular (1.2 3 0.9 cm),intraparotid (1.5 3 1 cm), and jugulodigastric (2.1 3 0.7 cm)location. On the left side, jugulodigastric nodes measured 2.6 3

0.9 cm. Blood culture was again positive for Salmonellaserotype group D. A 14-day course of intravenous Ceftriaxonewas initiated.

The recurrent Salmonella infections prompted further testingfor a genetic predisposition. She was proven to have IL-12Rb1deficiency on the basis of impaired expression of IL-12Rb1 byEBV-transformed B cells by using flow cytometry with 2 anti-bodies that recognize different epitopes (Fig 2). She was alsohomozygous for the C186S (556T>A) mutation in IL12RB1.This mutation had been previously shown to confer IL-12Rb1 de-ficiency in other related kindreds of Arabic descent (families 12and 13 in Fieschi et al4). She was started on IFN-g (50 mg/m2 sub-cutaneously 3 times a week) and prophylactic daily oral ciproflox-acin. She has since been doing well, with no recurrence ofsalmonellosis over a period of more than 1 year.

At age 5.5 years, she started showing an ataxic gait similar tothat of her older sister. This was accompanied by bilateralconjunctival telangiectasia and an abnormal finger-to-nose test.Serum alpha-fetoprotein was now 132 IU/mL. The diagnosis ofA-T was confirmed on the basis of increased radiosensitivity ofan EBV-transformed B-cell line, as described by Sun et al,5

lack of A-T mutated (ATM) protein by Western blotting, asdescribed by Chun et al,6 and absence of ATM kinase activity,as described by Nahas et al7 (Fig 2). In addition, DNA sequencingrevealed homozygosity for the 8395del10 mutation in the ATMgene. Because of the radiosensitivity noted in the patient’sB-EBV cell line, 3 unrelated patients with IL-12Rb1 deficiencywere also tested; all had normal colony survival responses to1 Gy of irradiation and expressed normal levels of ATM protein.Conversely, cell lines from other, unrelated patients with A-T ex-pressed normal levels of IL-12Rb1, as detected by flow cytometry(Fig 2).

When the patient was asymptomatic, erythrocyte sedimenta-tion rate, C-reactive protein, C3, and C4 were normal. As forserum immunoglobulins, IgG was elevated at 2170 mg/dL, IgMwas elevated at 615 mg/dL, and IgA was undetectable at <7mg/dL. The proportions of lymphocyte subpopulations showedpersistently low CD3 and elevated CD4 counts, with normalCD8 and CD19 and elevated CD3-CD161CD561.

FIG 1. Family pedigree of proband (II.6). A sister (II.1) died at age 10 years

with severe bronchiectasis secondary to A-T. Another sister (II.2) died at 2

months with sepsis. Parents are first-degree cousins.

J ALLERGY CLIN IMMUNOL

DECEMBER 2008

1218 LETTERS TO THE EDITOR

Patients with 2 seemingly unrelated genetic disorders areextraordinarily rare experiments of nature and can be difficultto diagnose. We report the simultaneous presentation of 2 rare he-reditary immunodeficiencies, A-T and IL-12Rb1 deficiency, in achild from Qatar. These diagnoses are based on both functionaland genetic assays. Her EBV-B cells did not express IL-12Rb1and were radiosensitive, thereby displaying typical cellular phe-notypes for both diseases. The patient was homozygous for dis-ease-causing mutations in ATM (8395del10) and IL12RB1(C186S). The 2 genes are located on distinct chromosomes(IL12RB1: 19p13.1; ATM: 11q23.1) and the fortuitous associationof the 2 autosomal recessive syndromes was favored by parentalconsanguinity.

The prevalences of A-T and IL-12Rb1 deficiency in the Gulfregion are unknown, but the prevalence world-wide is low forboth: for A-T, about 1 in 40,000 live births, and for IL-12Rb1deficiency, about 1 in 100,000 to 1,000,000 births. Therefore, thelikelihood of the same disease affecting a random child can beestimated at approximately 1 in 4 3 109 to 1 in 4 3 1010 births.However, this estimate would be higher in ethnic groups with ahigher coefficient of consanguinity or inbreeding, such as theGulf region, as noted by Bener et al.8 To our knowledge, this isthe first association of 2 PIDs and is almost certainly a spurious co-incidence. On the other hand, our study suggests that other patientswith 2 recessive diseases are likely to be diagnosed in regions ofthe world where consanguineous marriages are common, thus em-phasizing the importance of a complete family history.

A second underlying syndrome should be considered inpatients with clinical features that are not commonly associatedwith the primary diagnosis. For example, recurrent extraintesti-nal, nontyphoidal salmonellosis has never been reported in

FIG 2. Expression of IL-12Rb1 protein and ATM kinase activity in response

to irradiation in EBV-B cell lines derived from the patient and unrelated

controls.

patients with A-T, as noted by Nowak-Wegrzyn et al.9 The IL-12Rb1 deficiency could have also caused recurrent mycobacterialdisease. Likewise, ataxia and telangiectasia are not seen with IL-12Rb1 deficiency. A further compounding factor might arise ifthe 2 disorders were to ameliorate or aggravate one another.

The fact that the clinical features of IL-12Rb1 deficiency andA-T in our patient were so characteristic of each disorder stronglysuggests that the pathogenesis of each does not intersect with theother. The course of salmonellosis was typical of IL-12Rb1deficiency, as reviewed by Filipe-Santos et al.2 Likewise, the ratesof neurologic progress and the telangiectasia were characteristicof A-T. The unchanging cellular phenotypes corresponding toeach of the disorders further support the conclusion of indepen-dent pathophysiologies for IL-12Rb1 deficiency and A-T. Thisis not surprising given that IL-12Rb1 deficiency creates a cell sur-face defect, whereas ATM deficiency affects primarily intranu-clear signaling.

This said, it will be important to follow the patient, because IL-12 has been shown to exert antitumoral actions in the mousemodel, whether directly or via the induction of IFN-g, as noted byElzaouk et al.10 The compounded effects of the 2 genetic defi-ciencies on the immune system may lead to the development ofeven more severe malignancy than seen in patients with A-T.Moreover, the progressive lymphopenia commonly seen in A-Tmay worsen the susceptibility to infections caused by mycobacte-ria and Salmonella as the patient matures. Finally, diagnostic pro-cedures involving ionizing radiation and the use of radiomimeticdrugs should be avoided in patients with A-T, and this principleapplies here as well. This may conflict with other clinical deci-sions, further complicating the patient’s long-term treatment.

Mohammad Ehlayel, MDa

Ludovic de Beaucoudrey, MScb,c

Francesca Fike, BScd

Shareef A. Nahas, PhDd

Jacqueline Feinberg, PhDb,c

Jean-Laurent Casanova, MD, PhDb,c,e

Richard A. Gatti, MDd

From athe Section of Allergy-Immunology, Department of Pediatrics, Hamad Medical

Corporation, Doha, Qatar; bthe Laboratory of Human Genetics of Infectious Diseases,

Institut National de la Sante et de la Recherche Medicale, U550, Paris, France; cParis

Descartes University, Necker Medical School, Paris, France; dthe Departments of

Pathology and Laboratory Medicine and Human Genetics, University of California,

Los Angeles School of Medicine, Los Angeles, Calif; and ethe Pediatric Hematol-

ogy-Immunology Unit, Necker Hospital, Assistance Publique-Hopitaux de Paris,

Paris, France. E-mail: jean-laurent.casanova@inserm.fr.

S.A.N and R.A.G. were supported by grants from the Ataxia-Telangiectasia Medical

Research Foundation and National Institutes of Health grants (NS052528 and

AI067769). The Laboratory of Human Genetics of Infectious Diseases is supported

in part by grants from the Schlumberger and BNP Paribas Foundations. L.d.B. is sup-

ported by grant from the Fondation pour la Recherche Medicale as part of the PhD pro-

gram of Pierre et Marie Curie University (Paris, France). J.-L.C. is an International

Scholar of the Howard Hughes Medical Institute.

Disclosure of potential conflict of interest: The authors have declared that they have no

conflict of interest.

REFERENCES

1. Casanova JL, Abel L. Primary immunodeficiencies: a field in its infancy. Science

2007;317:617-9.

2. Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J,

et al. Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular,

cellular, and clinical features. Semin Immunol 2006;18:347-61.

3. Lavin MF, Gueven N, Bottle S, Gatti RA. Current and potential therapeutic

strategies for the treatment of ataxia-telangiectasia. Br Med Bull 2007;81-2:

129-47.

4. Fieschi C, Dupuis S, Catherinot E, Feinberg J, Bustamante J, Breiman A, et al.

Low penetrance, broad resistance, and favorable outcome of interleukin 12

TABLE I. Immunity before and 3 years after BMT

Before transplant After transplant Normal range

IgG (g/L) 6.6* 7.8 0.8-6.5

IgM (g/L) <0.07 0.4 0.19-0.96

IgA (g/L) <0.07 0.5 0.04-0.4

CD3 (cells/mL) 1275 4081 2000-6900

CD4 (cells/mL) 859 2589 1400-5100

CD8 (cells/mL) 438 1392 600-2200

CD19 (cells/mL) 3 1069 700-2500

CD56 (cells/mL) 188 367 100-1000

Phytohemagglutinin

(stimulation index)

patient/control

2/578 1010/878 >50

T-cell receptor

excision circles

(copies/0.5 mg DNA)

5.3 3574 >300

*On intravenous immunoglobulin replacement therapy.

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VOLUME 122, NUMBER 6

LETTERS TO THE EDITOR 1219

receptor beta1 deficiency: medical and immunological implications. J Exp Med

2003;197:527-35.

5. Sun X, Becker-Catania SG, Chun HH, Hwang MJ, Huo Y, Wang Z, et al. Early

diagnosis of ataxia-telangiectasia using radiosensitivity testing. J Pediatr 2002;

140:724-31.

6. Chun HH, Sun X, Nahas SA, Teraoka S, Lai CH, Concannon P, et al. Improved

diagnostic testing for ataxia-telangiectasia by immunoblotting of nuclear lysates

for ATM protein expression. Mol Genet Metab 2003;80:437-43.

7. Nahas SA, Butch AW, Du LT, Gatti RA. Rapid-flow cytometry-based SMC1 phos-

phorylation assay for identification of ataxia-telangiectasia homozygotes and het-

erozygotes. Clin Chem 2008. In press.

8. Bener A, Hussain R, Teebi AS. Consanguineous marriages and their effects on

common adult diseases: studies from an endogamous population. Med Princ Pract

2007;16:262-7.

9. Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM.

Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr 2004;144:

505-11.

10. Elzaouk L, Moelling K, Pavlovic J. Anti-tumor activity of mesenchymal stem cells

producing IL-12 in a mouse melanoma model. Exp Dermatol 2006;15:865-74.

Available online August 21, 2008.

doi:10.1016/j.jaci.2008.07.005

Omenn syndrome is associated with mutationsin DNA ligase IV

To the Editor:Omenn syndrome (OS) is a fatal variant of severe combined

immunodeficiency (SCID), unless treated with allogeneic bonemarrow transplant (BMT). Initially OS was associated withmutations in the recombination activating gene (RAG) 1 and 2.1

Subsequently, we and others identified mutations in genes suchas RNA component of ribonuclease mitochondrial RNA, adeno-sine deaminase, IL-2 receptor g, and IL-7 receptor a in patientswith OS.2 We report here, for the first time, the occurrence ofOS in a patient with a novel mutation in the DNA ligase IVgene, which was corrected after allogeneic bone marrowtransplant.

The girl, born to nonconsanguineous parents after an unevent-ful pregnancy, weighed 2.5 kg (3rd percentile), and her headcircumference was 30 cm (<3rd percentile). At 3 weeks of age,she developed protracted universal scaly erythroderma, hepato-splenomegaly, generalized lymphadenopathy, and diarrhea. Therash and diarrhea improved after treatment with cyclosporine Abut worsened on discontinuation of treatment.

Eosinophils were markedly increased (2120 cells/mL; normal,5-700 cells/mL). Evaluation of the immune system, performed aspreviously described,3 revealed a low but relatively preservednumber of circulating CD31 T cells coexpressing either CD41

or CD81 (Table I ). T-cell response to mitogen stimulation andT-cell receptor excision circles were markedly reduced. Analysisof T-cell receptor Vb families demonstrated skewed T-cell reper-toire, with excessive expansion of 3 T-cell receptor families—Vb

5.1, Vb 12, and Vb 13.6—while most other families were under-represented (Fig 1). B cells were practically absent, and serumIgA and IgM levels were reduced. There was no evidence for ma-ternal engraftment. Sequences of the genes for RAG1 and RAG2,Artemis, RNA component of RNase mitochondrial RNA, adeno-sine deaminase, Ku70, Ku80, and IL-7 receptor a were normal(not shown). Sequencing of DNA ligase IV gene from the patientand the parents revealed 3 heterozygous mutations (Fig 2). Oneallele carried a C26T polymorphism and A845T transition result-ing in H282L substitution near the ATP binding site, which werepreviously described.4 The other allele had a novel 5-nucleotide

deletion (AAAGA) after the A nucleotide in position 1746, caus-ing a frameshift at R581 and a downstream putative prematurestop.

At 6 months of age, after myeloablative conditioning with 16mg/kg busulphan and 200 mg/kg cyclophosphamide (each over aperiod of 4 days), the patient received unmodified HLA-matchedunrelated donor BMT. She experienced graft-versus-host diseaseof the skin and gastrointestinal system, which resolved after pro-longed treatment with cyclosporine, methylprednisolone, andmycophenolate mofetil. After transplant, she also had respiratoryfailure, cardiac chamber hypertrophy, EBV infection, hyperten-sion, and renal abnormalities, which all resolved. Currently, 3.5years posttransplant, she continues to have microcephaly with in-creased intracranial pressure, short stature, and developmentaldelay. Repeated analysis prior to and more than 3 years postBMT, demonstrated complete donor chimerism. Chimerism wasdetermined by studying polymorphism in a variable number oftandem repeats or a cytosine-adenine dinucleotide repeat (CA)nrepeat in varying regions in the genome as previously described.3

Immune evaluations as long as 3 years after transplant showednormal T-cell and B-cell numbers, T-cell responses to mitogens,T-cell receptor excision circles, and immunoglobulin production(Table I). T-cell receptor repertoire has also normalized (Fig 1).

FIG 1. T-cell repertoire. Flow-cytometry analysis, represented as the per-

centage of cells, of various T-cell receptor Vb families in CD31 T cells ob-

tained from the patient’s peripheral blood before BMT (preBMT) and 3

years after transplant (postBMT) and normal control.