22q11-grand rounds-9-23المهم-10ep - copy
TRANSCRIPT
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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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Safety of Live Viral Vaccines in 22q11.2 Deletion Syndrome
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
Perez, et al. PEDIATRICS Vol. 112 No. 4 October 2003
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Safety of Live Viral Vaccines in 22q11.2 Deletion Syndrome
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.
Perez, et al. PEDIATRICS Vol. 112 No. 4 October 2003
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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!