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CORRESPONDENCE:daniel.wells@linacre.ox.ac.uk

DATE RECEIVED:September 18, 2015

KEYWORDS:Severe combinedimmunodeficiency, primaryimmunodeficiency, geneticdisorder, immune disorder,immunology

,© Wells This article isdistributed under the terms ofthe Creative CommonsAttribution 4.0 InternationalLicense, which permitsunrestricted use, distribution,and redistribution in anymedium, provided that theoriginal author and source arecredited.

CASE

A 3-month old female infant (of parents who were first cousins) presented with persistent diarrhoea,following a long course of antibiotics for “chestiness” since 1 month of age. She was considerablyunderweight. On initial full blood count, it was noticed that she had a low lymphocyte count of1.9 × 109 L − 1 and she was investigated for SCID.

COMMENTARY

Severe combined immunodeficiencies (SCIDs) are genetic diseases, first described in 1950, whichresult in impaired development and function of T lymphocytes with concomitant primary or secondaryimpairment of B (and sometimes NK) lymphocytes (Glanzmann and Riniker 1950; Buckley 2004). Theincidence is estimated at 1 in 58,000 births and it is fatal unless treated in infancy (Kwan et al. 2014).

IS THIS A TYPICAL HISTORY FOR SCID? WHAT OTHER FEATURES MIGHT BE RELEVANT? WHAT ISTHE RELEVANCE OF THE FAMILY HISTORY?

SCID patients can present differently depending on the type of SCID, their age, and the particularcombination of infections they have experienced. However, in many ways this case is a typical SCIDpatient. The mean age of presentation of SCID patients without a family history and in the absence ofnewborn screening is usually between 2 to 6 months after birth, consistent with this case (McWilliams,Railey, and Buckley 2015; Yao et al. 2013). This is the time at which the passive immunity afforded bymaternal IgG is waning and the first attempts at treatment have failed, prompting further investigations(Waaijenborg et al. 2013).

Overall more males than females are diagnosed with SCID due to the presence of an X-linked form ofSCID caused by mutations in the IL2RG gene. As females have two X chromosomes and males onlyone, X-linked diseases almost exclusively affect males. (One exception being turner syndrome, 45X0,females and the other exception being if both parents were carriers, in which case the father would beaffected.) However, there are many non X-linked forms of SCID and so the male bias is not great

MEDICINE

Case Commentary: Severe Combined ImmuneDeficiencies

DANIEL WELLS 1. University of Oxford

ABSTRACT

This case commentary concerns a 3-month old female infant (of parents who were first cousins) who presented with persistentdiarrhoea, failure to thrive, and a low lymphocyte count. The topics addressed include the typical histories for severe combinedimmune deficiencies (SCID), how SCID can be confirmed, and the relevance of immunophenotyping circulating lymphocytes in thediagnosis of different types of SCID. This commentary was created as part of the masters programme in Molecular and CellularBiochemistry at the University of Oxford.

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enough to describe this case as atypical.

Consanguinity of parents is also a common finding in SCID cases with rates of up to 70% in someregions (Aghamohammadi et al. 2014). This is due to the higher likelihood of inheriting homozygousmutations from related parents as they will share a higher proportion of their DNA than unrelatedparents (Saggar and Bittles 2008). A more detailed family history could be relevant in diagnosing SCID.For example if the child had or has any relatives, siblings especially, with any health problems or whohad died in infancy from infection (which may not have been diagnosed as SCID at the time). If any ofthese cases were true it would add to the suspicion of SCID. However, the majority of patients do nothave a family history (Chan et al. 2011). Family ancestry can also provide a clue, for example theNavajo population have a 30 fold higher risk of SCID due to a founder mutation in DCLRE1C (proteinartemis) (Kwan et al. 2015).

Persistent diarrhoea, failure to thrive (low weight for age), and respiratory infection are key clues in thiscase and are all common symptoms in SCID cases (McWilliams, Railey, and Buckley 2015; Yao et al.2013; Hague et al. 1994; Gennery and Cant 2001; European Society for Immunodeficiencies 2015;Rivers and Gaspar 2015). Severe, persistent or unusual infections are indicative of animmunodeficiency and the use of a long course of antibiotics suggests a persistent infection.Identification of the infectious organisms can reveal the presence of unusual and or opportunisticpathogens. Parainfluenza, respiratory syncytial virus, candida, Pneumocystis jiroveci, andPseudomonas aeruginosa are particularly common in SCID patients (McWilliams, Railey, and Buckley2015). If the child was vaccinated against tuberculosis at birth BCGosis may also be present(Shahmohammadi, Saffar, and Rezai 2014). The broad range of both systemic viral and bacterialseptic infection reflects the deficiencies of both the cellular and humoral arms of the immune system inSID.

If chest radiography was performed due to the “chestiness” an absent thymic shadow due to a smallunderdeveloped thymus (the location of T-cell development) can be indicative of SCID (Nickels et al.2015). The lack of visible tonsils or palpable lymph nodes can likewise be rapidly assessable cluespointing towards SCID (McWilliams, Railey, and Buckley 2015).

The low lymphocyte count is a hallmark of SCID patients, the majority of which have counts lower than3 × 109 L − 1 (McWilliams, Railey, and Buckley 2015; Gennery and Cant 2001; Hague et al. 1994;Conley, Notarangelo, and Etzioni 1999). This is due to the lack of development of T cells (andsometimes B cells) the former of which account for 70% of all lymphocytes (J. M. Puck 2012).

WHAT INVESTIGATIONS COULD BE DONE TO CONFIRM SCID AND HOW?

The lymphocyte count should be repeated possibly with the addition of a qPCR based test for T-cellreceptor excision circles (TRECs); byproducts of V(D)J recombination of TCR genes which do notreplicate with cell division and are therefore a marker of newly formed T cells (figure 1) (J. M. Puck2012). This assay is now being used in over 23 states in America as a newborn screen for SCID (Kwanet al. 2014). A TREC count of less than 25/µl occurs in almost all SCID patients (Spek et al. 2015).

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Figure 1: The deletion of the δ locus to form a TREC (J. M. Puck 2012).

Absolute counts of T cells specifically can be obtained through flow cytometry; a CD3+ T-cell count ofless than 3 × 108 L − 1 would classify as typical SCID and a count of less than 1 × 109 L − 1 as leaky SCIDor Omenn syndrome (Shearer et al. 2014).

As well as being confirmed with a low number of T lymphocytes the lack of function of these cellsshould also be tested as in some cases a low T-cell count is not due to SCID for example in intestinallymphangiectasia and cartilage hair hypoplasia. Additionally in other SCID cases T-cell count may benearly normal due to the presence of maternal T cells from trans-placental transfer (McWilliams,Railey, and Buckley 2015). T-cell function can be assayed by stimulating lymphocytes with mitogenssuch as phytohemagglutinin, concanavalin, or pokeweed mitogen and measuring proliferation by [3H]thymidine incorporation. A value of less than 10% compared to the control is indicative of SCID(McWilliams, Railey, and Buckley 2015; Conley, Notarangelo, and Etzioni 1999; Buckley 2004). HIVinfection should also be ruled out by a RT-qPCR test of HIV RNA as HIV infection can also cause a lowT-cell count and opportunistic infections. Note that as a SCID positive patient would have an impairedability to produce antibodies in response to an infection, an ELISA to test for anti-HIV antibodies wouldbe inappropriate (as it could give a false negative). Other similar diseases to rule out would include“less profound combined immunodeficiencies” such as complete DiGeorge syndrome, ZAP70deficiency, CD3γ deficiency, MHC Class II deficiency and PNP deficiency (Al-Herz et al. 2014; Conley,Notarangelo, and Etzioni 1999).

A lack of antibody production is also seen in SCID patients. This can be the result of either a lack of Bcells, for example in adenosine deaminase (ADA) deficiency where the cells undergo apoptosis, or asa consequence of lacking T-cell help. Hence, in some cases immunoglobulin testing can support thediagnosis of SCID. However, the presence of maternal IgG and naturally low levels of otherimmunoglobulins at this age can hinder the identification of a deviation from the norm (Gennery andCant 2001; Hague et al. 1994; McWilliams, Railey, and Buckley 2015).

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Mutation analysis of genes known to cause SCID, guided by flow cytometry to identify candidates, canhelp to provide a definitive diagnosis by comparison to mutations known to cause loss of function.However, the results may return variants of unknown significance and in rare cases the mutation couldbe in areas currently not associated with SCID which may require whole exome sequencing to identify(Patel et al. 2015; Kwan et al. 2014).

One form of SCID, ADA deficiency, can additionally be confirmed by low (<2% of normal) adenosinedeaminase plasma activity and high (>300 fold increase from normal) concentrations ofdeoxyadenosine metabolites which cause the apoptosis of lymphocytes in this condition (Ozdemir2006). ADA deficient patients also commonly have chondro-osseous dysplasia which would beapparent in a chest radiograph (Manson et al. 2013).

DISCUSS THE RELEVANCE OF IMMUNOPHENOTYPING CIRCULATING LYMPHOCYTES FOR THEDIAGNOSIS OF THE DIFFERENT TYPES OF SCID

Immunophenotyping is a method of determining the phenotype of cells using antibodies which bind tospecific surface proteins and are linked to a detection marker for example a fluorophore. In this contextphenotype refers to whether a lymphocyte is a T cell, B cell or NK cell. Each of these phenotypesexpress different surface molecules to which antibodies can bind and hence the type of cell can bededuced. For example T cells express CD3, with helper T cells also expressing CD4 and effector Tcells expressing CD8. B cells are CD3 negative but express CD19, and NK cells are CD3 negative butexpress CD16. The bound antibodies are often measured using a flow cytometer due to the ability torapidly measure multiple fluorophores at once (Maecker, McCoy, and Nussenblatt 2012).

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Figure 2: Lymphoid development pathways and relative position of selected SCID causingmutations (Notarangelo 2010). HSC: Hematopoietic stem cell, CLP: Common lymphoidprogenitor, DN: Double negative, DP: Double positive, NK: Natural killer.

SCIDs can be classified based on which gene contains the causal mutation. Each of these mutationsacts at a different place in the lymphocyte development pathway (figure 2) and so each class of SCIDhas a different profile of circulating lymphocytes. For example, ADA deficiency results in a build up ofS-adenosylhomocysteine and dATP due to the lack of deoxyadenosine deamination by ADA. Theselymphotoxic precursors build up and cause apoptosis in all three types of lymphocytes and so thesepatients have a T-B-NK- profile (Ozdemir 2006).

T cells and NK cells require IL-7 and IL-15 respectively for development. The IL-2 receptor commongamma chain (IL2RG) and JAK3 kinase transduce IL-2 family signals (including IL-7 and IL-15). Hencemutations in these genes can prevent development of T and NK cells so these patients have a T-B+NK- profile.

The RAG1, RAG2, and DCLRE1C genes are required for V(D)J rearrangement of the heavy chain andβ chain locus in B and T cells respectively, as part of the process of creating a diverse set of antigenreceptors. However, they are not required in NK cells and so mutations in these genes leads to a T-B-NK+ profile. Note that a positive B or NK cell phenotype denotes that this cell type is present but notnecessarily that those cells are functional.

Overall there are four different lymphocyte profiles (figure 3); all SCIDs are T cell negative but they canbe either negative or positive with respect to the presence of B or NK cells. Hence byimmunophenotyping circulating lymphocytes you can measure the levels of T, B, and NK cells andtherefore deduce which genes may be causing SCID in the patient (and therefore the types of SCIDthe patient may have). It is also possible to determine more specifically the mutation by analysing moremarkers, but as B and T-cell development occur in the bone marrow and thymus respectively this isonly possible with a biopsy and not by using circulating lymphocytes (Saint Basile et al. 2004). Henceto determine the exact type of SCID without biopsy the candidate genes must be sequenced andanalysed for mutations.

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Figure 3: Division of SCIDs based on lymphocyte profile (Al-Herz et al. 2014)

Hence immunophenotyping circulating lymphocytes is highly relevant to diagnosing the different typesof SCID as the types can be deduced by the lymphocyte profile. However, a definitive diagnosis islikely to require mutational analysis as multiple types of SCID can have the same profile due to havingmutations in different genes within the same pathway. Exceptions include ADA deficiency which can bediagnosed serologically as previously mentioned. Although this may not be necessary as AK2 deficientpatients typically die within the first few weeks of life, and so in the absence of newborn screening ADAis likely the only T-B-NK- SCID to be suspected after symptoms develop. Additionally coronin-1Adeficient patients have a detectable thymus as a mutation in this gene causes defects in the egress ofT cells from the thymus rather than their development per se (Shiow et al. 2008). However, evensequencing may return variants of unknown significance and hence only a probable diagnosis.Furthermore, as sequencing costs decrease it becomes more feasible to check all known SCID linkedgenes which reduces the utility of immunophenotyping. Although it will still be useful in the case thatmultiple mutations of unknown significance are found or in the case that the mutation is in a novelregion which could require whole exome sequencing to identify.

Currently the main treatment of SCID patients is hematopoietic stem cell transplantation (HSCT) andprognosis is generally good if the procedure is undertaken in the first few months of life and a HLAmatched donor is available. However recent advances in gene therapy approaches (for which, unlikeHSCT, the identity of the causative mutated gene must be known) could result in this being a moredesirable treatment due to faster T-cell development and the ability to avoid problems such as graftversus host disease and graft rejection due to non HLA identical donors (Touzot et al. 2015).Furthermore, as newborn screening programs expand, diagnosis can be made earlier and thereforetreatment can be started before infections develop which will also increase the percentage offavourable outcomes for these diseases.

MANUSCRIPT HISTORY

This case commentary was originally produced as part of the masters programme in Molecular and

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Cellular Biochemistry at the University of Oxford (MBiochem, Part II). The case, and the commentaryquestions were set by the course organisers. Additionally, the following limitations were imposed: Theword count must not exceed 2000 words (excluding the case, questions, citations, and figure captions),the number of references must not exceed 30, and no more than three figures or tables may be used.

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