A case of severe combined immunodeficiency caused by adenosine deaminase deficiency with a new mutation

Abstract

Adenosine deaminase (ADA) deficiency is a rare autosomal recessive disorder of purine metabolism that leads to severe combined immunodeficiency (SCID) by primarily affecting lymphocyte development and function. ADA deficiency is a medical emergency. Early diagnosis and treatment could provide low morbidity and mortality. Patients present in the first months of life with failure to thrive, diarrhea, oral candidiasis and opportunistic infections. Herein we report a case of a 3 month old patient with ADA deficient SCID having a novel splicing mutation.

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Accepted Manuscript
A case of severe combined immunodeficiency caused by adenosine deaminase
deficiency with a new mutation
Deniz Aygun, Ozden Turel, Murat Kardas, Emel Torun, Micheal Hershfield, Yıldız
Camcıoglu
PII: S1875-9572(17)30412-6
DOI: 10.1016/j.pedneo.2016.10.008
Reference: PEDN 685
To appear in: Pediatrics & Neonatology
Received Date: 24 May 2016
Revised Date: 10 September 2016
Accepted Date: 14 October 2016
Please cite this article as: Aygun D, Turel O, Kardas M, Torun E, Hershfield M, Camcıoglu Y, A case of
severe combined immunodeficiency caused by adenosine deaminase deficiency with a new mutation,
Pediatrics and Neonatology (2017), doi: 10.1016/j.pedneo.2016.10.008.
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Title: A case of severe combined immunodeficiency caused by adenosine deaminase deficiency
with a new mutation
Deniz Aygun
1
E mail: fdenizaygun@gmail.com
Ozden Turel
2
E mail: barisbulent98@yahoo.com
Murat Kardas
2
E mail: mdkardas@gmail.com
Emel Torun
2
E mail: dr.emeltorun@gmail.com
Micheal Hershfield
3
E mail: michael.hershfield@duke.edu
Yıldız Camcıoglu
1
E mail:camciy@yahoo.com
1 Department of Pediatric Infectious Diseases, Clinical Immunology and Allergy, Istanbul
University, Cerrahpasa Medical Faculty, Istanbul, Turkey
2 Department of Pediatrics, Bezmialem Vakif University Medical Faculty, Istanbul
3 Division of Rheumatology, Department of Medicine, Duke University Medical Center, Durham, USA
Address for Correspondence: Department of Pediatric Infectious Diseases, Clinical Immunology and
Allergy, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey
PEDN
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Phone Number: +90 (532)7868682
Fax Number: +90 (212) 6328633
E-mail: fdenizaygun@gmail.com

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A Case of Severe Combined Immunodeficiency Caused by Adenosine Deaminase
Deficiency with a New Mutation
Introduction
Adenosine deaminase (ADA) deficiency is among the most common causes of severe
combined immunodeficiency, characterized by dysfunction of the T, B, and natural killer
(NK) cells (T-B-NK-SCID) and severe lymphopenia.
1
ADA is a key enzyme in the purine
salvage pathway, the absence of which causes lymph-toxic deoxyadenosine triphospate
(dATP) accumulation, inhibiting ribonucleotide reductase, a critical enzyme for DNA
replication and repair. This effect impairs the lymphocyte development and function resulting
in severe combined immune deficiency (SCID).
1,2
ADA deficiency is autosomal recessively inherited through mutations in the ADA gene, which
is located on chromosome 20q13.12. Herein, we will describe the identification of a novel
splicing mutation in the ADA gene in a patient with SCID.
Case presentation
A 3-month-old girl was referred for recurrent fever, pneumonia, diarrhea, chronic dermatitis,
failure to thrive, and motor retardation. The patient was the daughter of consanguineous
parents and had a female sibling who had died due to recurrent infections. On a physical
examination, her weight, height, and head circumference were all less than the third
percentile. She suffered from oral thrush and a diffuse brownish colored macular rash on the
trunk. Chest auscultation revealed bilateral crackles at the lower zones. Chest X-ray, indicated
the absence of thymus shadow; a para-cardiac infiltration and an inferolateral squaring
scapulae were demonstrated (Figure 1).
Laboratory tests revealed mild anemia with profound lymphocytopenia, and
hypogammaglobulinemia (Table 1). A lymphocyte subgroup analysis revealed a severe
combined immunodeficiency. Purine nucleoside phosphorylase (PNP) and adenosine

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deaminase (ADA) enzyme activities were measured in the extracts of dried blood spots on
filter paper by a laboratory in the Duke University Medical Center in Durham, NC, USA.
ADA activity was absent, whereas PNP activity was in the normal range. The total
deoxyadenosine nucleotides (dAXP) in the erythrocytes were markedly elevated, confirming
the diagnosis of ADA deficiency.
To define the mutation, genomic DNA was amplified, and the entire coding region, along
with the exon-intron boundaries of the ADA gene, was sequenced. The patient was found to be
homozygous for a point mutation c.478+3G>C, which causes an IVS5 splicing mutation
(IVS5+3G>C) (Figure 1). Her mother, father, and sister were carriers of this mutation, and her
brother was was wild -type (no mutation). To our knowledge, this is a novel mutation.
As she had no matched family donor, hematopoietic stem cell transplantation (HCT) was
unavailable. Enzyme replacement therapy with polyethylene glycol-modified bovine ADA
(PEG-ADA) was initiated. During the follow-up, the level of ADA activity significantly
increased, and dAXP were almost normal.
Discussion
The prevalence of SCID is estimated to be approximately 1:50,000 live births in western
countries,
1
whereas it is reported as 4:40,000 in Turkey.
3
The relatively higher prevalence of
immunodeficiencies may be explained by the high rate of consanguineous marriages. T-B-
NK+ is the most common type of SCID in our country, but the rate of ADA deficiency is only
4%.
3
The disease is characterized by severe lymphopenia with low numbers of T, B, and
NK cells. Although eosinophilia is a typical feature of Omenn syndrome, eosinophilia
accompanied by absolute lymphopenia has also been reported, as in the present case.
4

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ADA-SCID patients suffer from recurrent infections, a failure to thrive, and neurologic
manifestations. Extensive dermatitis, and persistent diarrhea can also develop.
In individual
patients it is often unclear whether an involvement of these organs is caused by the metabolic
effects of ADA deficiency itself or if it is secondary to the immunodeficiency.
Patients may also have prominent metaphyseal changes that are suggested to be
reversible by enzyme replacement therapy.
5
Our patient had a flaring of costochondral
junctions. The skin rash of the patient was interpreted as a maternal engraftment syndrome
that develops by a mechanism similar to a graft a versus host disease as a response to maternal
lymphocytes.
6
However, maternal engraftment in patients with SCID due to ADA deficiency
has not been directly documented.
More than 70 mutations of the ADA gene including missense, splicing, deletion and nonsense
type have been described for ADA deficiency.
7
Our patient was homozygous for a 5’ splice
site mutation in IVS5, which was detected in other family members who were carriers. The
consanguinity of parents and history of a similar sibling strongly suggest that both patients
had the same immunological defect. The mutation in our patient appears to be novel.
HCST is the only curative treatment for patients with ADA deficiency. In the absence of an
HLA, an identical donor enzyme replacement with PEG-ADA could provide a temporary
solution, as in our case.
In conclusion, ADA deficiency is a medical emergency and should be suspected in every
patient with lymphopenia. The diagnosis should be confirmed by the detection of low
enzymatic activity, an elevated dAXP and a mutation analysis.

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Figure Legends:
Figure 1: A chest X ray indicating the absence of thymus and squaring scapulae, the
mutation result of the patient
Conflicts of Interest:
The authors have no conflicts of interest relevant to this article.
Abbreviations
ADA: Adenosine deaminase
dATP: deoxyadenosine triphospate
HCT: Hematopoietic stem cell transplantation
Ig: Immunoglobulin
NK: Natural killer
PNP: Purine nucleoside phosphorylase
SCID: Severe combined immunodeficiency
References
1.Notarangelo LD. Primary immunodeficiencies. The Journal of Allergy and Clinical
Immunology 2010;125:182–94.
2. Hershfield MS. New insights into adenosine-receptor-mediated immunosuppression and the
role of adenosine in causing the immunodeficiency associated with adenosine deaminase
deficiency. Eur J Immunol 2005;35:25–30.
3.Yorulmaz A, Artac H, Kara R, Keles S, Reisli I. Retrospective evaluation of 1054 patients
with primary immunodeficiency. Asthma Allergy Immunology 2008;6:127-34.
4. Härtel C, Strunk T, Bucsky P, Schultz C. Failure to thrive in a 14-month-old boy with
lymphopenia and eosinophilia. Klin Padiatr. 2004;216:24-5.
5. Manson D, Diamond L, Oudjhane K, Hussain FB, Roifman C, Grunebaum E.
Characteristic scapular and rib changes on chest radiographs of children with ADA-deficiency

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SCIDS in the first year of life. Pediatr Radiol 2013;43:589-92.
6.Denianke KS, Frieden IJ, Cowan MJ, Williams 99 ML, Mc Calmont TH. Cutaneous
manifestations of maternal engraftment in patient with severe combined immunodeficiency: a
clinicopathologic study. Bone Marrow Transplant 2001;28:227-33.
7. Santisteban I, Arredondo-Vega FX, Kelly S, Mary A, Fischer A, Hummell DS, et al. Novel
splicing, missense, and deletion mutations in 7 adenosine deaminase deficient patients with
late/delayed onset of combined immunodeficiency disease: contribution of genotype to
phenotype. J Clin Invest 1993;92:2291-2302.

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WBC (cell/mm
3
) 3340
Hb (g/dl) 10,5
PLT (cells/mm3) 428000
ALC (cells/mm3) 400
CD3 (cells/mm3) 240
CD4 (cells/mm3) 100
CD8 (cells/mm3) 120
CD19 (cells/mm3) 24
CD16-56 (cells/mm3) 24
IGG (mg/dl) 310
IGM (mg/dl) 128
IGA (mg/dl) 30,3
IGE (mg/dl) <17
ADA Activity (nmol/h/mg) 0.0
PNP Activity (nmol/h/mg) 1493
%dAXP 43.6
Table 1: Laboratory data
The family pedigree of the patient

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