Clinical features of children with 22q.11 deletion
Syndrome. Preliminary report of AIEOP
Ospedale Pediatrico Bambino Gesù
ISTITUTO DI RICOVERO E CURA
A CARATTERE SCIENTIFICO
DIPARTIMENTO DI MEDICINA PEDIATRICA
Cancrini C, Puliafito P, Di Gilio MC, Finocchi A, Soresina A, Martino S, Pignata C, Aiuti A,
Ugazio AG, Rossi P, Plebani A, for the Italian Network for Primary Imunodeficiencies.
°Children’s Hospital Bambino Gesù - University of Tor Vergata, Rome, Italy.
INTRODUCTION
AIM OF THE STUDY
In may 2005, we proposed to adopt in the context of the
Italian network for Primary Immunodeficiencies – AIEOP,
a Protocol to be applied in patients with 22q 11 deletion
syndrome. The aim was to investigate the presenting
phenotype at the diagnosis and to better define the
natural history. This could provide guidelines for the
selection of patients that must be rapidly investigate by
genetic test and for a better and earlier interdisciplinary
management of these patients.
• Define and apply uniform assistential recommendations in all the national
territory.
• Provide to all patients common diagnostic and therapeutic recommendations
• Value the natural history of each case following the eterogeneity of the clinical
aspects.
• Improve the quality of life.
Brescia
Torino Milano 7 Padova
20
27
1
Roma
33
100 PATIENTS
ENROLLMENT CRITERIA
All male and female patients of any age with deletion 22 are eligibile.
FISH for del22 is recommended for all patients that present at least two of the following clinical
aspects
Napoli
9
1.
2.
3.
4.
5.
Palermo
3
Congenital heart desease
Palatal anomalies
Neonatal hypocalcemia
Immunodeficiency and/or autoimmune disease
Facial dysmorphism
RESULTS
At September 2006 we enrolled 100 patients (55 males and 45 females). The median age
at diagnosis, was 5 months (range: 0-216 months).
In 79% patients the diagnosis was made during the first 2 years of age. In this group,
cardiac defects and neonatal hypocalcemia were the most relevant clinical features leading
to diagnosis.
In the remaining 21 patients, diagnosed after 2 years of age, speech language
impairment, development delay, recurrent infections, associated to dysmorphic features,
were the clinical manifestations raising the suspect of del22.
Recurrent infections were present in 43% of patients and autoimmune manifestations were
present in 23% of patients. One patient presents SCID with no T cells and has been
Thymus transplanted.
Immunological evaluation at diagnosis, available for 85 patients, showed a decreased
number of CD3+ T-cell in 62 patients (73%).
Molecular investigation by FISH has been performed in 49 patients’ parents; interestingly
in 3 cases mothers were healthy carriers for del22.
Two patients died for cardiovascular complications and 1 for a severe autoimmune anemia
and thromocytopenia.
4500
(CD3+, CD4+, CD8+)
4000
2500-5600
2500-5500
1900-5900
Neonatal hypocalcemia
Characteristic dysmorfic features
Ipertelorism
Prominent Nose
Hight Palat
Narrow palpebral fissures
Short Philtrum
Micrognathia
Small mouth
Small ears
ENT anomalies
Developmental Delay / Learning
difficult
26
69
26
38
18
38
10
29
46
36
37
51
45
75
29
42
20
42
11
32
51
40
41
57
Grastrointestinal anomalies
Bone anomalies
Recurrent infections
Otitis
Sinusitis
Tonsillitis
Sepsis
Pneumoniae
Bronchitis
Bronchiolitis
Candidiasis
Gastroenteritis
Urinary tract infections
Autoimmune diseases
Urogenital anomalies
21
25
51
21
5
5
8
9
23
3
1
3
5
22
5
21
25
51
21
5
5
8
9
23
3
1
3
5
22
5
Age at diagnosis (years)
Patient
IVD
IAD
PS
ATP
AAI
AA anomalies
AV bicuspidal
ADP
IVD + PA
IVD + IAD
IVD + ATP
ATP + IAD
IVD + AAI
IVD + IAD + ATP
IVD + IAD + PA
IVD + AA anomalies
IVD + double exit ventricular
AAI + IAD
PS + ATP
IVD + PA + AA anomalies
IVD + ATP + AA anomalies
IVD + IAD + AAI
IVD + ATP + PA + AAI
FT
FT + ATP + PA
GAT
Total
1200
654-3101
1400-3700
1200-2600
2000
1-2821
975-3448
961-2734
1000
647-3256
1000
378-2204
500
0
0-3 mo
3-6 mo
6-12 mo 12-24 mo
2-6 ys
1500
>6 ys
590-1600
1000
1300-3400
>2
21
1
1
0
0
0
1
0
0
1
1
1
1
0
0
0
0
1
0
0
0
0
0
0
2
0
0
10 (48%)
Total
100
8
4
2
3
1
3
1
1
9
4
6
1
8
1
1
1
1
1
1
1
1
2
2
18
1
1
83 (83%)
500-1700
620-2000
560-1700
2000
2500
<o=2
79
7
3
2
3
1
2
1
1
8
3
5
0
8
1
1
1
0
1
1
1
1
2
2
16
1
1
73 (92%)
TABLES
2500
CD4+/mm3
CD3+/mm3
Cardiac defects
1800-4000
1600-4000
1400-4300
3000
1500
%
3000
2100-6200
3500
No.
800
700-2200
446-1844
694-2503
0-2096
576-1468
650-1500
268-1829
210-840
CD8+/mm3
GRAPHICS: limphocyte subsets
Clinical Aspects
200
0
0
3-6 mo
6-12 mo 12-24 mo
2-6 ys
>6 ys
117-1093
0-797
370-1100
168-1440
245-1025
173-1231
500
0-3 mo
198-2288
600
400
490-1300
0-3 mo
3-6 mo
6-12 mo 12-24 mo
2-6 ys
>6 ys
DISCUSSION AND CONCLUSION
Our preliminary results confirm that the presenting feature is usually a congenital cardiac defect (tab) and that a high risk of delay of diagnosis exist in children presenting mild
or not cardiac involvement. Indeed, in the 17% of patients diagnosis was delayed. Pediatricians have to be awared that diagnosis is often delayed and that other clinical features
leading to the diagnosis as speech language impairment, development delay, recurrent infections could be the clinical manifestations raising the suspect of del22. Dysmorphic
features are always present but it is reported in a variable percentage depending on several clinical observators. Although a very small proportion of patients had a severe
immunodeficiency , recurrent infections were present in the 51% of patients diagnosed later; so this could be the symptom leading to the diagnosis. T cell values were decreased
as already reported but it is not predictive of infections. Interestingly, we also observed humoral defects in some patients, as several studies recently reported. Moreover
autoimmune diseases have been observed in 22 patients. Interestingly one patient had a mono-articular arthritis while chronic polyarticular arthritis has been reported more
frequently in del22. Larger and prospective studies could contribute to identify immunological parameters that influence the development of infections and autoimmune diseases.
In conclusion, we evidence a delay of diagnosis in children without cardiac defects or severe symptoms and we believe that many patients are still undiagnosed. Furthemore,
these patients are followed by different specialists that might not always understand the complexity of this condition. The application of the protocol could provide an increase
knowledge among pediatricians and specialist reducing the delay of diagnosis and favouring a correct management of these patients. Because of the wide clinical spectrum, only
an interdisciplinary team of experts in long term follow-up will warrant optimal care in these patients.
We thank all the patients and their families, the Italian association of del 22 Aidel, the Associazione Immunodeficienze Primitive (AIP).
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