(also known as , Duncan’s syndrome)

An immunodeficiency due (in 50% of cases) to SLAM associated protein (SAP) defect, specifically affecting the handling of EBV, affected boys are normal until they meet the virus. Following infection, they develop profound secondary immune deficiency affecting T and NK cell function and antibody responses. The following clinical patterns (not mutually exclusive) are described (and can be presenting features):

• severe infectious mononucleosis
• malignant B cell lymphoma (ie monoclonal proliferation)
• Lymphoproliferation viz hepatosplenomegaly (ie polyclonal proliferation)
• aplastic anemia
• panhypogammaglobulinemia
• haemophagocytic lymphohistiocytosis (HLH)
• vasculitis

The prognosis is very poor with 75-85% mortality. Confirmation of the diagnosis involves demonstrating EB virus genome in lymphocytes by DNA hybridization, without antibody response to EB nuclear antigen (EBNA). The mothers of affected boys also have abnormal EB virus serology, with persisting very high titers against viral capsid antigen. Treatment is with Rituximab (anti CD20), although EBV receptor is CD21. If diagnosed in a sibling before they are infected by the virus, regular IVIG as passive immunization can be attempted though its efficacy is unproven.

Autosomal forms have been described.

OMIM entry

Mixed bag of diseases, with combined T and B cell deficits. “Severe” tends to mean severe lymphopenia and panhypogammaglobulinaemia with poor prognosis. Usually a bone marrow problem, with defective maturation of precursors – so depending on where the block is there may or may not be T cells, B cells, NK cells. A problem further down the line at the signalling stage will tend to mean immunoglobulin is produced, but not functional, esp since T cell regulation is needed too. So the clinical picture may be of a combined defect even if B cells and immunoglobulin are present. On the other hand, some defects are “leaky”, ie some precursors do manage to develop past the block by having reversion mutations causing somatic mosaicism. The other possible source of T cells if present is that they may be maternal (do FACS CD3 vs TCR to discriminate). To test, find appropriate T cell markers. Such T cells usually not functional but may ameliorate severity or prevent progression.

Typical presentation

Affected babies appear well at birth and are normally grown. Problems usually start within the first few months of life. Common presentations are:

• Chronic diarrhoea and failure to thrive – often due to persistent and sometimes multiple gastrointestinal infection, +/-food intolerance.
• Candidiasis
• Severe bacterial infections esp pneumonia unresponsive to standard treatment
• Atypical infections eg Pneumocystis jiroveci/carinii, disseminated BCG infection. PCP can be acute or chronic, causes interstitial pneumonia with disproportional hypoxia for degree of illness, LDH is often raised (non-specific, implies tissue invasion).
• Reticular skin rash +/-mildly deranged LFTs – Graft-versus-host disease (GVHD) – since you can’t reject foreign tissues, you may show GVHD if maternal lymphocytes cross the placenta (usually mild) or via breast-feeding (very mild, not a contraindication). Role in gastrointestinal symptoms? More severe GVHD can follow blood transfusion – hence all lymphopenic patients should get irradiated blood to kill donor white cells. Differential is disseminated CMV, CD40 ligand deficiency, Omenns, ICF. Diagnosis is by finding 2 cell populations by chimerisms.
• Occasionally SCID can present like Langerhans cell histiocytosis with dramatic erythrodermic or scaly rash, organomegaly (Omenns).

On examination (usually), no lymph nodes; no thymic shadow on chest X-ray (development of thymus requires appropriate signals from bone marrow). Hepatomegaly (?). Investigations usually reveal lymphopenia (<2.8 in first year), and there may or may not be NK cells – the exact pattern helps you work out where the block is. Odd results may reflect presence of maternal lymphocytes! Mitogen responses (proliferation studies) are usually absent. IgG will usually be present from Mum, but gets used up quickly! IgA and IgM may be present if B cells are present, but usually limited clonal diversity so not much function and no specific antibody responses.

Subtypes

B- NK- is ADA. B+ NK+ is IL7R defect. B+ NK- is gamma chain or JAK3 (the two bind to each other). B- NK+ is RAG or Artemis. Bare lymphocytes (T but not CD4) are HLA deficient.

Complex, because the defect can relate to cytokine signalling, T-cell receptor signalling, receptor gene recombination etc.

The biggest group are T- B+ NK-: the main cause is Gamma chain deficiency, which is X-linked. About 50% of all SCID. The Gamma chain is found in numerous cytokines (IL-2, 4, 7, 9 and 15), hence why it causes severe problems. JAK3 binds to gamma chain so causes an identical syndrome.

The next main group are T- B- NK-: Adenosine deaminase (ADA) deficiency is the main cause. Accumulation of toxic deoxyadenosine triphosphate (d-ATP) in lymphocytes leads to cell death. All cell lines are reduced. Additional features are:

• Skeletal abnormalities (cupping deformities of the ends of the ribs, abnormalities of the transverse vertebral processes and the scapulae) are seen in up to 50% of cases and can be correlated with histological changes.
• Neurodevelopmental problems may also occur in some patients.

Occasional cases of ADA deficiency have been described, where inexplicably, immune function is normal. The diagnosis is confirmed by assay of red cell ADA activity (Purine lab, Guy’s). First trimester antenatal diagnosis is possible. Gene therapy is done in London and Paris.

Purine nucleoside phosphorylase (PNP) deficiency is initially less severe than ADA deficiency but progresses with age. It is autosomal recessive (gene is on chromosome 9). The toxic metabolite is deoxyguanosine triphosphate. Immunoglobulin levels and antibody responses are initially normal but in the late stages levels fall.

Reticular dysgenesis (autosomal recessive) is characterized by an absence of myeloid as well as lymphoid precursors, so no neutrophils or macrophages. Platelets and red cells are usually OK but can be low too! Even more severe than other forms of SCID, tends to present very early. Often GVHD rash. Hard to transplant…

The T- B- NK+ group are to do with VDJ recombination. The main one here is RAGs (recombination activating genes, 1 and 2) defect. If you can’t recombine these variable areas, then you can’t develop the necessary diversity in antigen receptors on T and B cells. Artemis and Ligase 4 similarly. NK don’t use them so they’re fine. Diagnose by looking at Ig gene rearrangements.

Ommen’s syndrome is a leaky B- SCID, usually a RAG defect, but characterised by:

• infiltrative skin rash resembling seborrheic dermatitis (scaling, erythroderma): histologically, proliferation of CD8/CD4 double negative cells and histiocytes.
• hepatomegaly and lymphadenopathy
• lymphocytosis but with marked eosinophilia and raised IgE levels

Diagnosis is confirmed by showing limited TCR Vbeta clonal populations (the few clones leaking past the block expand in the periphery to cause the signs). Differential is GVHD (usually milder, not lymph nodes usually), congenital ichthyosis and Nethertons syndrome (autosomal recessive ichthyosis with immunodeficiency and growth failure). Interferon gamma may produce some clinical improvement but definitive treatment is with bone marrow transplantation.

The final group, T- B+ NK+, is a mixed bag of different problems, all to do with signal transduction:

• ZAP-70 defect (CD8 deficiency, AR) – defective kinase, part of the CD3/TCR complex. Whereas CD8s are absent, CD4 and other cells are present.
• JAK-3 defect – Janus kinase 3, a tyrosine kinase, interacts with the STAT (signal transduction and activators of transcription) family (AR).
• IL7R defect

Defects in cytokine production are not really SCID:

• IL-1, IL-2 and interferon gamma deficiency described, result in a spectrum of clinical problems including failure to thrive and opportunistic infections. Humoral immunity is relatively preserved.
• Interferon gamma receptor defects predispose to disseminated atypical mycobacterial infection (see above).
• IRAK (IL1R Associated Kinase) defect – like NEMO, broad range of cytokines affected. Typical infections are Pseudomonas, pneumococci, salmonella. NOT candida, viruses, mycobacteria, fungi. 50% die within first 3 years, thereafter survival improves markedly.The following have normal cell populations but abnormal surface molecules:
  • Bare lymphocyte syndrome (AR). You have T cells, but they don’t differentiate into CD4 and CD8 cells. Usually due to defective HLA expression. T and B cell numbers are normal! CD4 count is low in Class II and the CD8 count in Class I deficiency. Confirmation of the diagnosis depends on demonstration of the absence of the HLA antigens on the cells. Other weird features:
    • lymph nodes are palpable and the thymus is normal size (not histologically normal, mind you).
    • Mitogen responses are normal but antigen specific responses and delayed hypersensitivity tests are negative.
  • CD3 deficiency – also gives normal numbers of circulating T and B cells, so thymus and lymph nodes present. CD3 actually made up of several different chains, so In delta chain defect, the T cells make it to the thymus but don’t progress into the circulation.
  • Fas (CD95) deficiency = Autoimmune Lymphoproliferative Syndrome (30% have unknown mutations). This is a cell surface molecule important in apoptosis, hence lymphoproliferation ie massive lymphadenopathy, hepatosplenomegaly (but variable). It is expressed on thymocytes and activated T cells. Most obvious manifestation of autoimmunity is cytopenias. CD4 cells are low but lymphocyte count is normal by virtue of a proliferation of CD4/CD8 double negative cells (eg 30-60% of total). LNs have characteristic histology. Rx immunosuppression, usually pred and high dose IVIG are sufficient although may need extended treatment. MMF and rituximab have been used.
  • OKT4 deficiency is a defect in an epitope on the CD4 molecule recognized by a monoclonal antibody of that name. There is a mild immunodeficiency and a tendency to autoimmune disease.
  • Idiopathic CD4 lymphocytopenia. Usually adults, but can be seen in children. Affected individuals are highly susceptible to opportunistic infections, obviously; immunoglobulin levels and antibody responses are generally normal. The CD4 cell count seems to remain stable for a prolonged period cf HIV infection. Prophylaxis against Pneumocystis carinii infection should be given.

  Management of SCID

  Flow cubicle, sterile handling, Septrin, Itraconazole, IVIG prophylaxis. If unable to get flow, discharge from general paeds ward!

  PEG-ADA available for ADA deficiency. Use d-ATP levels to guide dosing. Treat while looking for transplant match.

  BMT or PBSC if match available. Haploidentical (ie parent) BMT have poor results in Europe but currently 80% success rates in UK (cf 97% success for full HLA match). No big breakthrough in BMT science, just incremental improvements in conditioning regimens, supportive care, graft manipulation. Non SCID success rate is currently 69%; the rate is actually falling as more risky cases are now taken on. MUD for Wiskot Aldrich has 85% 10yr survival rate; a good MUD, using genomic rather than serological matching, is probably just as good as a sibling transplant. Other issues:

  • Cord transplants: new cord bank in Newcastle. Better engraftment cf regular BMT but you still need a good match to avoid GVHD. Above 15kg, 1 cord is unlikely to yield enough cells – use 2?
  • If CMV infected, then using a CMV pos donor may be a good thing!
  • Busulphan usually makes you infertile.
  • Fludarabine/melphalan and Campath looks like a good conditioning regimen but historical controls of limited meaningfulness in BMT work. With lower intensity regimens, poor engraftment can always be boosted with more stem cells…
  • 20 CGDs done in Newcastle – 1 death after conditioning, 1 chronic GVHD else all successful!
  • Note strong age effect – older kids do worse. Psychological? More established organ damage?
  • Some “unnecessary” transplants may need to be done, to avoid missing an opportunity to cure 1 case that might go on to do badly in later life.
  • GVHD is rarely a long term problem in kids. Long term complications are infertility, hypothyroidism, prior organ damage.

  Gene therapy: T cell count starts to rise from 12 weeks onwards. GVHD may present at that point, but resolves spontaneously. 8 patients done so far in UK, only 1 non-responder who was an adult (not surprising, too old for thymic reconstitution), 2 have stopped IVIG treatment. More done in Paris, but 2 cases of malignancy; risk associated with number of cells returned. New gene therapy trials for CGD and ADA-type SCID.

A neutrophil disorder.

Issue is lysosomes, so large vesicles seen in neutrophils which have reduced function. Associated with albinism, developmental delay, bleeding disorder. The connection is that all have granules, and the defect is in way that endoplasmic reticulum sorts different products into different granules.

Griscelli syndrome is similar, associated with albinism but not developmental delay or bleeding. Can predispose to haemophagocytic syndrome. Differentiate from Chediak Higashi by light microscopy of hair (unevenly distributed large melanin granules cf evenly distributed; white under polarized light cf polychromatic).

Hermansky Pudlak II has the albinism, developmental delay and bleeding, but has pigmented macrophages instead of funny neutrophils. The neutrophil numbers as well as function are reduced, whereas other subtypes do not have any immunodeficiency. Check bleeding time.

3 types, 1= beta2 integrin defect (no adhesion), 2=selectin ligand (a fucose transporter; no rolling), 3= RAP1. Classically delayed cord separation (but actually seen in any neutrophil disorder), skin ulcers esp perianal, periodontitis, raised white cell count (because they are stimulated but don’t move about normally). Developmental delay and hepatosplenomegaly is seen in type 2, bleeding disorder seen in type 3.

Chemotaxis disorders tend to produce pretty mild disease eg periodontitis only…