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22q11.2deletion syndrome

(DiGeorge syndrom)

Dr. Ahmed A. Azab MBBCH,MSc,MDAss.professor of pediatrics and neonatology

Benha University ,EgyptConsultant of pediatrics and neonatology

Alnoor Specialist hospital.

April 2011


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Objectives

Summarize advances in understanding the: pathogenesis and genetics of the syndrome

health needs and immune system of patients withChromosome 22qDeletion Syndrome

Understand the spectrum of clinical presentation

Overview of the multidisciplinary approach tocaring for these patients


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Historical Perspective

Common embryologic derivation of heart, thymus

and parathyroid glands as explanation formalformations.

Combination of lack of thymus, parathyroid

glands, hypocalcemia, congenital heart disease

(TOF)

Angelo DiGeorge,

04/15/21-10/11/09

DiGeorge Syndrome, 1965

Significant overlap, Deletion of 22q11.2

1671: Nicolai Stensencleft palate and truncus arteriosus

1829: LH Harringtonhypoplastic thymus & parathyroid glands

1959: Eva Sedlackovavelopharyngeal insufficiency and DD

David Lobsdellhypoplastic thymus and parathyroid glands1978: Robert Shprintzen--Velocardial Facial Syndrome (VCFS)


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Chromosome 22q11.2 deletion syndrome

Hemizygous deletion of ch22q11.2

90% of patients with DiGeorge syndrome

80% of patients with VCFS

Also described in

CHARGE (coloboma, heart anomaly, choanal atresia, retardation and

genital and ear anomalies) Conotruncal anomaly face syndrome

Cat eye syndrome

Some pts may have deletion but not fall into a clinically

defined syndrome, or have syndrome but not deletion

DiGeorge syndrome = cardiac anomaly, hypocalcemia,poor T cell production


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Chromosome 22q11.2 deletion syndrome

1 in 3000 children Typical: conotruncal cardiac anomaly and mild

to moderate immune deficiency

Often: developmental delay, palatal dysfxn,feeding problems

Great phenotypic HETEROGENEITY!

Clinical suspicion is key to making the dx!

Compared to incidence of other diseases: Invasive MRSA 1 in 3000 (CDC, 2007)

CF 1 in 2000

Sickle cell disease: 1 in 500 African-American birthsand 1 in every 1000 to 1400 Hispanic-American births.


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Abnormality % affected Examples

Cardiac anomalies 49-83 TOF, IAA, VSD, TA

Hypocalcemia 17-60

Palatal anomalies 69-100 Cleft palate, submucous cleft,velopharyngeal insufficiency, bifid uvula

Speech Delay 79-84

Developmental delay 75% - infancy

45% - childRenal anomalies 37 Absent/dysplastic, obstruction, reflux

Ophthalmologic 7-70 Tortuous vessels, anterior segmentdysgenesis

Skeletal 17-19C-spine, vertebral, lower extremity

Behavior, psychiatric 9-50 ADHD (25%); Schizoprenia (6-30%)

Neurologic 8 Cerbral atrophy, cerebellar hypoplasia

Growth hormone def. 4

Dental 2.5 Delayed eruption, enamel hypoplasia


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Phenotype Frequency of deletion (%)

Interrupted aortic arch 50-60

Pulmonary atresia 33-45

Aberrant subclavian 25

TOF 11-17Conotruncal cardiac anomaly 7-50

Any cardiac lesion 1.1

Velopharyngeal insufficiency 64

Velopharyngeal insufficiency post

adenoidectomy

37

Neonatal hypocalcemia 74

schizophrenia 0.3-6.4

Frequency of 22q11.2 deletion

in Various Populations


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Facial appearance of patients withtypical and atypical 22q11.2 deletions.

Rauch A et al. J Med Genet 2005;42:871-876

Mild phenotype, sibling pair

3Mb and 1.5 Mb deletionsmall mouth, pointed nasal tip, mild ptosis, lowset ears

thin upper lip, mild hypertelorism and broad, high nasal bridge

F i l f i i h


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Facial appearance of patients withtypical and atypical 22q11.2 deletions.


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Diagnosis Most deletions spontaneous

(1 in 4000 to 1 in 6000)

At least 10 fold > than next most frequent human deletionsyndrome

1 in 3000 births Estimated from spontaneous mutation rate plus growing number of

familial cases

Increased survival of pts w/ cardiac anomalies

Hemizygous deletion inherited Autosomal Dominant

Affected sib w/ negative FHx relies on recognition of s/sx

Flourescence In Situ Hybridization (FISH) for 22q11.2 deletion Accurate, but time consuming and expensive


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The diagnosis is established by FISH


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FISH for 22q11.2


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When FISH is negative but classic

features present Point mutations in TBX1

Transcription factor involved in regulation ofdevelopmental processes

Expressed during embryogenesis in pharyngeal arches,

pouches and otic vesicle Candidate gene for some features seen in 22q11.2

Non-ch22 basis: Chromosome 10 terminal deletions

CHD7 (chromodomain helicase DNA-binding protein)

Prenatal exposure to teratogens isotretinoin, a vitamin A analog or acne treatment

No clear etiologic basis for some (risk of recurrence in

these, unknown)


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Deletion of Chromosome 22q11.2

This region contains >35 genes

Which genes contribute to phenotype?

Mouse studies:

TBX-1 cardiac abnormalities

All embryos w/ defects of branchial arch precursor of

Hear t and thymus!

BUT, only a subset with cardiac defect at birth could there be in utero intervention?

TBX-1: cardiac, thymus and parathyroid phenotypes

Retinoic acid is a repressor of TBX1


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TBX-1 (T-box transcription factor)

CRKL

UFD1L (Ubiquitination degradation)

HIRA (transcription factor)

Centromere

DGCR6

IDD/DGCR2TSK/DGS-GES2/DGS1

GSCL (Goosecoid-like homeobox gene)CTP (Citrate transporter)

CLTCL

TMVCF

CDCrel-1

GP1b (Platelet glycoprotein)

T10

COMT (Catechol-O-methyltransferase)

ARVCF

LZTR-1 (Transcription factor)

ZNF74

CDC45L

RANBP1

Human Ch22q11.2

Heparin cofactor

90% 8%

22 well-characterized genes


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DGCR6

IDD/DGCR2TSK/DGS-GES2/DGS1

GSCL (Goosecoid-like homeobox ge ne)CTP (Citrate transporter)

HIRA (transcription factor)

TMVCF

UFD1L (Ubiquitination de gradation)

GP1b (Platelet glycoprotein)

TBX-1 (T-box transcription factor)

T10

COMT (Catechol-O-methyltransferase)

ARVCF

ZNF74

CDC45L

RANBP1

Murine Deletions (Ch16)

VpreB2

NLVCF

Pnufl

Miceh

avecardiacdefects

Miceare

normal

Candid

ateGenes

The critical region was established by generating mice with

comparable deletions


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Tbx-1

Expressed in developing mesenchyme

Expressed in pharyngeal arches, otic vesicle, toothbuds, sclerotome

Heterozygous mutations of Tbx-1 are associated withgreat vessel defects in mice

Homozygous deficient mice have a small mandible,low set ears, a single cardiac outflow tract, deficient

thymus/parathyroid/salivary glands


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Age-specific health needs in 22q11.2 deletion

Coordinated approach (multi-specialty needs)

Phenotypes and outcomes vary tremendously

Dx mostly shortly after birth (Cardiac anomaly)

Sullivan, KE 2008


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Early Immunologic concerns:

Low T cell numbers (Mild to Moderate)75 to 80% of infants with deletion

Lack of T cells =


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Normal Thymus & T cell development

Hassalls corpuscle

Savina, PLOS Patho ens, June 2006 Volume 2 Issue 6 e62

earliest events in thymocyte

development TCR gene rearrangement

positive selection

later events negative selection

expression of CD4 or CD8
http://upload.wikimedia.org/wikipedia/commons/9/94/Thymic_corpuscle.jpg


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Role of the Thymic Microenvironment

in T cell development

Cortex

Medulla

Savina, PLOS Pathogens, June 2006 | Volume 2 | Issue 6 | e62

T cell precursors

enter here

Thymic nurse cells

TREC Assay for NBS of SCID and T cell


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TREC Assay for NBS of SCID and T cell

lymphopenia (Complete DiGeorge)

Quantitation of TRECs DNA excision circles

Byproduct of TCR gene rearragement in

developing thymocytes

Assayed in blood by quantitative PCR

(# diluted with each cell division)

DX: based on the inability to make normal #

of T cells

Results:

low or undetectable TRECs in SCID or

complete DiGeorge

High in healthy newborns

Challenges/caveats:

Maternal engraftment

poor DNA recovery/intermediate results


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Endocrine Concerns:

Hypocalcemiaexacerbated by cardiac surgery

Ca++ supplementation perioperatively Endocrine referral for:

Vit D requirements, calcium, phosphorus mngmt

Oversupplementation nephrocalcinosis

Most do well, but rare cases of late onset or recurrence

Feeding Concerns:

Poor coordination of pharyngeal muscles, tongue,

esophagus, dyspnea 2ndary to cardiac defect

D l t l


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Developmental concerns:

Speech delay: phonation, language development,comprehension

Laryngeal webs, velopharyngeal insufficiency, or VC paralysis Speech delay > receptive skills > social language skills

Speech delay + weakness pattern = typical of 22q11.2 del

Sign language vs. Speech therapy or both

Most learn to speak and communicate effectively

IQ: mean 70 with wide range normal to moderately disabled

Visuoperceptual and planning = weakest

Learning disability may be the ONLY manifestation of

22q11.2 deletion syndrome!!! School based interventions important

Neuro: 10-30% of older ptsbipolar, autistic spectrum orschizophrenia/schizoaffective d/o (significant increase over other conditions with Dev Delay)


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Immunodeficiency

Thymic hypoplasia decreased T cell #

20% no evidence of low T cells


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Mild or moderate T cell deficiency

Normal Immunoglobulins (majority)

Infrequent humoral dysfxn: IgA deficiency, impaired responses tovaccines, hypogammaglobulinemia

Normal T cell proliferative response

Most common infxn = URI Anatomy > T cell count

Opportunistic infxn infrequent

Slower age associated decline in T cell # Homeostatic proliferation of existing T cells

Normal cytokine production

Increased autoimmunity:

JIA, ITP*, celiac disease Decreased Treg, selection for self-reactive T cells

Increased allergic disease (Th2)

Live vaccines tolerated in this group T cell count >300, MMR, Varicella efficacious*

Homeostatic proliferation

*Perez E, et al. Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome. Pediatrics 2003

Th mic aplasia (Se ere)


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Thymic aplasia (Severe)

22q11.2 deletion in 50% of these cases

True thymic aplasia and absent T cells Spectrum of T cell counts from 0 normal

Difficulty in identifying pts who need transplant

Transplantation

Thymus

Fully matched peripheral blood

Peripheral T cells so that thymic education is not required(thymic aplasiaT cells have nowhere to develop)

Donor lymphocyte infusions Nave T cell compartment assessment early

CD4+CD45RA vs. CD4+CD45RO


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Thymus transplantation*

Donor thymic tissue harvested, cultured to

remove mature T cells (GVH risk) Implanted under quadriceps muscle

Partial HLA matching desirable, not required

Fxnl T cells in 3-4 months post transplant T cell repertoire initially normal but

Thymic involution prevents sustained production of T

cells sufficient #s produced to provide adequate defense

Follow up studies needed for long term outcomes

* Duke University, Dr. Louise Markert


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Oligoclonal Expansion of T cells in Thymic Aplasia

1/3 of infants with thymic aplasia caused bych22q11.2 deletion have dramatic oligoclonalexpansion of a few founding T cells

T cell count does not reflect adequacy of T cell

compartment Expanded from very small number of fxnl T cells

Clues: erythroderma (similar to Omenns syndrome)

Predominance or exclusively Memory T cells (CD45RO)

TREC negative

Oligoclonal

Referral to Immunologist!

I l i t R l


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Immunologists Role

Intervention Timing

T cell enumeration ASAP, and prior to live vaccines @ 1yr of age

T cell functional testing ASAP

TREC If suspect severe phenotype

B cell function

(Igs, titers)

ASAP then prn depending on recurrent infection

history

Calcium level ASAP and prn

FISH analysis If not known or performed

Referral for developmental

evaluation

Asap, 1yr, 18m, yearly after 2y

Antibiotic prophylaxis (TMP) CD4


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Live Vaccines in 22q11.2del Syndrome Live vaccines contraindicated in

Immunodeficiency (package insert)

T cell immunity crucial in fighting viral infectionseffectively

Better understanding of risk/benefit necessary

for 22q11.2del syndrome due to high incidenceand phenotypic heterogeneity

Less than 1% of cases severe but need to beconfident of normal T cell function and assure nosevere immunodeficiency prior to exposure

Few publications/studies examining this:


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Safety of Live Viral Vaccines in 22q11.2 Deletion Syndrome

AIM: to investigate the incidence of side effects after live viral vaccine administration in

22q11.2 deletion syndrome retrospective analysis of vaccine adverse to evaluate the frequency of live vaccine

administration and the consequences of both vaccination and withholding the vaccine.

Flow cytometric enumeration of T cells

Results:

32/59 responders vaccinated with varicella vaccine 9% of patients reported adverse events (mild)

63% of unvaccinated children developed chickenpox.

Tolerated vaccine vs. adverse events group:

no statistically significant differences in:

current ageor age at vaccination (3 vs 2.5 years) T-cell subset counts:

CD3 (1951 vs 2083 cells/uL)

CD4 (1283 vs 1463cells/uL)

CD8 (530 vs 502 cells/uL)

Perez, et al. PEDIATRICS Vol. 112 No. 4 October 2003


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Results (continued):

--52/59 responders vaccinated with measles-mumps-rubella (MMR).

Twelve (23%) of 52 reported mild side effects, including fever, rash, and constitutional

symptoms.

No severe adverse reactions were reported.

No patient reported natural disease with measles, mumps, or rubella.

No statistically significant differences between the T-cell counts in the vaccinated group

reporting side effects versus the vaccinated group without side effects

mean CD3 counts: 1928 vs 1736 cells/uL

CD4 counts: 1250 vs 1127 cells/uL

CD8 counts: 528 vs 483 cells/uL



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Conclusion: This is a cohort of patients with 22q11.2deletion syndrome who

have tolerated live viral vaccinations without evidence ofsignificant side effects.

A prospective study could address whether there are T-cellthresholds below which vaccination is unsafe

Data suggests that vaccinating children with chromosome 22q11.2deletion with live viral vaccines does not carry a significantlyhigher risk of adverse reactions compared with the generalpopulation,provided that they have no evidence of severeimmunocompromise.

withholding vaccination, can result in a high frequency of wild-type disease.



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Interdisciplinary managementCardiology

Cleft palate team

Endocrinology

Immunology

Otolaryngology/Audiology

Genetics

OrthopedicsOphthalmology

Urology

Neurology

Psychologist/PsychiatristSpeech therapy

Occupational therapy

Feeding team

Early intervention


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Considerations for the Primary Care Doctor

Incidence is 1 in 3000increase your clinical suspicion

Refer to immunologist for evaluation esp in setting ofrecurrent infection in patient with: congenital heart defect, esp any of the following:

Interrupted aortic arch (50-60%)

Pulmonary atresia (33-45%)

Aberrant subclavian (25%) TOF (11-17%)

Conotruncal cardiac anomaly (7-50%)

Neonatal hypocalcemia (74%)

Velopharyngeal insufficiency (64%)

FISH for 22q11.2 deletion Consider the heterogeneity / spectrum of the disorder and

know that outcomes are generally good but highly variablepatient to patient.

NO LIVE VACCINES UNTIL CLEARED BY IMMUNOLOGY!

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