Clinical Guideline

CHROMOSOME 22Q 11 MICRODELETION (DI

GEORGE) SYNDROME – IMMUNOLOGICAL
INVESTIGATIONS AND MANAGEMENT
PRINCIPLES

SETTING Women and Children/Paediatric Division - Bristol Royal Children Hospital

FOR STAFF All clinical staff

PATIENTS All children with confirmed 22Q 11 microdeletion (Di George) syndrome

_____________________________________________________________________________
GUIDANCE
For a complete overview of the syndrome, please refer to the UK MaxAppeal Consensus
Document on 22Q 11 Deletion Syndrome, 2011
(http://www.maxappeal.org.uk/downloads/Consensus_Document_on_22q11_Deletion_Sy
ndrome.pdf)

Background

 Deletion of the long arm of Chromosome 22 (22q 11) is associated with DiGeorge
Syndrome (22q11DS), velocardiofacial (VCP) syndromes and conotruncal anomaly face
syndrome. The deletion is a de novo mutation in about 90-95% of patients. A small
number of children do not have this mutation and the syndrome may be caused by other
genetic defects.

 The classical di George Syndrome manifestations are included in the acronym of

“CATCH 22” – Cardiac, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia,
but other organs can be involved. Developmental delay and behaviour abnormalities are
more common in the children with CHARGE syndrome.

 This guideline will focus on the immunological abnormalities of these syndromes only.

 The immunological defects observed in 22q11 deletion are not completely understood
but they are believed to derive mostly from the abnormal maturation of the thymus.
During early embryonal life, patients with DiGeorge Syndrome (DGS) have abnormal
development of the 3rd and 4th pharyngeal pouches, which give origin to the thymus,
parathyroid glands and the great vessels.

 The clinical manifestations of the syndrome are variable and affect the heart, palate,
thymus and parathyroid but other organs may also be affected.

 The incidence of Di George Syndrome is about 1 in 4000.

Version 6.1 14/04/2020 - Author(s) S. Vergnano, J. Bernatoniene, M. Roderick, A. Finn, J Metz – Paediatric Immunology and Page 1 of 6
Review 1/2023 Infectious Diseases
Immunology
Immunodeficiency is common in patients with DGS and can range from recurrent
sinopulmonary infections (partial DGS) to severe combined immunodeficiency (SCID) (complete
DGS)

The severity of the immunodeficiency is related to the degree of thymic hypoplasia.

Complete form (rare ~0.5-1.5% of all 22q11 deletions)

 A type of severe combined immunodeficiency (SCID) and is life threatening if not
corrected with immune reconstitution
 Associated with absent or reduced numbers of naïve CD3+ T cells (<50/mm3). The
thymus is absent or aplastic.
 The response to mitogen is absent or diminished.
 Children with CHARGE syndrome can also manifest a SCID like phenotype.

Incomplete form
 Approximately 75% of patients with 22qDS have abnormalities of their immune system;
about 30% of children have mild to moderate lymphopenia with or without low serum
immunoglobulins and 3% require immunoglobulin replacement.

 Most patients with DGS have impaired T-cell production although CD3+ T-cell counts
gradually improve in most patients.

 The improvement in CD3+ T-cell counts reflects decreased age-related decline in T-cell
counts and increased accumulation of memory T cells secondary to lymphocytic
homeostatic proliferation.

 T-cell function may also be abnormal, although the deficiency is not usually severe.

 Humoral immunodeficiencies can be associated with partial DGS, including poor B cell
maturation, an increased prevalence of immunoglobulin A (IgA) and Immunoglobulim M
(IgM) deficiency, and functional antibody defects (ie, polysaccharide antibody deficiency).

 Again, these defects generally improve with age, but in some cases reduced IgA and IgM
may continue to persist. Approx 6% develop a progressive hypogamma requiring Ig
replacement (ESID, 2018)

 There is an increased incidence of autoimmune phenomena in patients with DGS and

22qDS, estimated at 10%.

Clinical signs and symptoms

The classic triad of features of DGS on presentation is cono-truncal cardiac anomalies,

hypoplastic thymus, and hypocalcemia

The degree of immunodeficiency and clinical phenotype is quite variable and can include:
 the children with relatively normal immunity
 the children with frequent URTI and LRTI, particularly in infancy (also due to local
anatomic abnormalities associated with the syndrome e.g cleft palate, GORD)

Version 6.1 14/04/2020 - Author(s) S. Vergnano, J. Bernatoniene, M. Roderick, A. Finn, J Metz – Paediatric Immunology and Page 2 of 6
Review 1/2023 Infectious Diseases
  a small number of children with complete di George will present in early infancy with
severe infections with opportunistic pathogens and a clinical picture similar to
children with severe combined immunodeficiency syndrome
 a small number of children with low immunoglobulins may develop lung damage,
including bronchiectasis if not appropriately treated.

Diagnosis:

 Diagnosis by Fluorescence In Situ Hybridization (FISH) identifies 95% of cases. Array

comparative genome hybridisation (aCGH), genome wide microarrays and multiplex
ligation-dependent probe amplification (MPLA) identify all mutations.

 Children with Di George’s syndrome may present at a very early age with severe
infections or more frequently are referred for assessment of their immune system from
other specialties.

Initial Immunology Investigations:

 Lymphocyte subsets including naïve and memory T cells by fluorescence-activated cell

sorting (FACS)
 Serum immunoglobulin A/G/M levels
 Response to vaccines (tetanus and HiB or pneumococcus) from 1 year of age. Broader
response to vaccines such as MMR, diphtheria, meningitis, tetanus are considered later
in life to establish the need for further vaccinations.
 T cell response to mitogens (phytohaemagglutinin (PHA), PMA/ionomycin, and anti-CD3
antibody) for children with CD3 count <0.4) (ref Max Appeal) or if clinically indicated.
 Analysis of TRECs is indicated for infants suspected of having complete DGS
 Flow cytometry can be used to determine T-cell repertoire (T-cell receptor [TCR] V-beta
chain diversity), and additional analysis for recent thymic emigrants should be considered
(ie, CD31 expression).

Management

Complete form:

 Early Referral to Great Ormond Street immunology team for consideration of Thymic
or Bone marrow transplantation – (non T cell depleted) – if matched sibling donor available

Special considerations prior to the transplantation:

 The children must be isolated in a positive pressure cubicle when in hospital

 If blood products are needed they should be irradiated, CMV negative and
leucocyte-depleted
 If breast fed milk should be CMV negative
 Start on PCP prophylaxis: Cotrimoxazole (30mg/kg once daily).
 Start HSV prophylaxis: Acyclovir (see BNF for dose)
 Start Antifungal prophylaxis: Fluconazole (see BNF dose by age)
 Immunoglobulin replacement
 Avoid live vaccines

Version 6.1 14/04/2020 - Author(s) S. Vergnano, J. Bernatoniene, M. Roderick, A. Finn, J Metz – Paediatric Immunology and Page 3 of 6
Review 1/2023 Infectious Diseases
Incomplete form

Treatment varies according to their degree of immunodeficiency. Treatment is supportive and all
of the following can be considered in children with reduced T cells and or serum
immunoglobulins, and recurrent infections:
 antimicrobial prophylaxis:
o Cotrimoxazole either 450mg/m2 (max 960 mg) twice a day for 3 days a week,
or daily once a day (if CD4+ T cells <500/mm3)
o in case of a lesser degree of immunocompromised (T cells >=500/ mm3) and
repeated infections consider azithromycin 10mg/kg for 3 days every 2 weeks
 immunoglobulin replacement if infections are still frequent despite antimicrobial
prophylaxis (Lukas M; Lee M;Lortan J; Lopez-Granados E; Misbah S)

Vaccination:

 All children can receive routine non-live vaccines (DPT, Hib, Men B and ACWY, Prevenar
13 and inactivated polio vaccine)
 The administration of live vaccines to patients with T cell abnormalities is contraindicated,
however the risk of natural infection continues to exist thus, the decision to administer
live vaccines to patients with DGS is made on a case-by-case basis, following a
discussion of the risks and benefits with the patient or caregivers.
 MMR, intranasal influenza (LAIV), BCG, rotavirus, and oral polio virus vaccines can be
given to children with incomplete Di George that fulfil the following criteria:
o Normal response to killed vaccine antigens
o Normal or near normal T cell response to mitogens
o CD4+ T cells >400/ mm3
o CD8+ T cells >300/ mm3

Follow up
In some DGS patients, immunologic changes are observed over time, including a diminished T cell repertoire,
diminution of the naive T cell pool, and static thymic output and it suggest that these patients may be at risk for
increasing frequency of infections with age. Therefore longer term follow up & monitoring may be required.

Complete form: same as per SCID guidelines

Incomplete form:

 6 monthly reviews if :
o Clinically indicated (eg, history of frequent infections)
o Significant lymphopenia and or low serum immunoglobulins
o Requires longer term antimicrobial prophylaxis or immunoglobulin replacement
o Evidence of autoimmune complications
 Yearly for 2 years for the patients with initially normal lymphocyte subset and
immunoglobulins
 Then see once at 2 years and discharge if no infectious complications warn the
GP/family of the risk of autoimmune complications in adolescence early adulthood and
low threshold for FBC/TFT if very tired/ pale.

Version 6.1 14/04/2020 - Author(s) S. Vergnano, J. Bernatoniene, M. Roderick, A. Finn, J Metz – Paediatric Immunology and Page 4 of 6
Review 1/2023 Infectious Diseases
Follow up investigations:

Blood:
 Lymphocyte subsets including memory T cells – yearly for the first 2 years and then as
clinically indicated
 Serum immunoglobulins – yearly for the first 2 years, unless abnormal/clinically
symptomatic or on immunoglobulin replacement therapy in which case please follow the
replacement therapy guidelines. If all normal px can be discharged with advise, if
persistent T cytopenia and frequesnt/unusual infections, continue follow up
 Conjugate vaccine response (Hib, diphtheria, tetanus, pneumococcus and Men C) at 12-
18 months.
 Polysaccharide vaccine responses are not recommended by paediatric infectious
disease experts, considering the risk of hyporesponsiveness to conjugate vaccines
following polysaccharide vaccinations
 Regular serum calcium monitoring for hypocalcemia may be needed in the first year of
life;
 GP to arrange: Full blood count (if clinically stable) & Thyroid function test Anti- thyroid
antibodies and DAT (direct antiglobulin test) if clinically indicated in older children as they
are at increased risk of autoimmune processed in adolescence

Radiology and Lung function are not routinely necessary but to be considered in children with
recurrent chest infections and requiring immunoglobulin replacement therapy. Referral to a
respiratory physician may is rarely required.

Annual Di George Multidisciplinary Team Meeting (MDT) Clinic. Optimal long-term

management of patients with DGS or 22qDS requires a multidisciplinary team, as well as
monitoring for the many disorders associated with this syndrome. Ideally, this would include
cardiologists, community paediatricians, endocrinologists, speech and language therapists,
physiotherapists, ENT specialists., etc. although the need for these subspecialists depends
upon the patient’s phenotype. The involvement of immunologists is restricted to children whith
significant immunodeficiency. Parents of affected children should be offered genetic testing.

Support groups and leaflets:

Source Contact details

Max Appeal www.maxappeal.org

22q11 Support Group http://www.cix.co.uk/~melcom/22q11/22qgrp.htm

Version 6.1 14/04/2020 - Author(s) S. Vergnano, J. Bernatoniene, M. Roderick, A. Finn, J Metz – Paediatric Immunology and Page 5 of 6
Review 1/2023 Infectious Diseases
REFERENCES Consensus Document on 22q11DS11 Deletion Syndrome (22q11DS) 2011, Max
appeal

Habel A; Herriot R; Kumararatne D; Allgrove J; Baker K; H Baxendale; Bu’Lock F;

Firth H; Gennery A; Holland A; Illingworth C; Mercer N; Pannebakker M; Parry A;
Roberts A; Tsai-Goodman B
Towards a safety net for management of 22q11.2 deletion syndrome: guidelines for
our times; Eur J Pediatr (2014) 173:757–765

Davies EG; Immunodeficiency in DiGeorge syndrome and options for treating cases
with complete athymia Frontiers in Immunology; 2013; 4 (322 ):1-9

Markert ML, Boeck A, Hale LP, Kloster AL et al. Transplantation of thymic tissue in
complete Di George syndrome. N Engl J Med 1999 Oct 14; 341 (16): 1180-9

Lukas M; Lee M;Lortan J; Lopez-Granados E; Misbah S; Chapel H Infection

outcomes in patients with common variable immunodeficiency disorders:
Relationship to immunoglobulin therapy over 22 years; 2010; J Allergy Clin
Immunol;125:1354-60.

RELATED None
DOCUMENTS
AND PAGES
AUTHORISING Paediatric Immunology Governance
BODY

SAFETY None
QUERIES AND Dr Stefania Vergnano, Consultant Paediatrician, Infectious Disease &
CONTACT Immunology
Dr Jolanta Bernatoniene, Consultant Paediatrician, Infectious Disease &
Immunology
Professor Adam Finn, Consultant Paediatrician, Infectious Disease &
Immunology
Dr. Marion Roderick, Consultant Paediatrician, Infectious Disease &
Immunology

(Monday-Friday 9am-5pm): contact ID registrar bleep 3997 or ID Consultant

on service via switchboard

Version 6.1 14/04/2020 - Author(s) S. Vergnano, J. Bernatoniene, M. Roderick, A. Finn, J Metz – Paediatric Immunology and Page 6 of 6
Review 1/2023 Infectious Diseases