Didier George: BCHM 550 Small Group Case – 22q11.

2 DS (Deletion Syndrome)

Written by Godwill James, M.D., and Andrew K. Sobering, Ph.D

Presenting complaint: Didier George is a 2 and a half year-old male who was referred for genetic testing following
frequent hospitalizations for suspected immunodeficiency (based on recurrent infections), abnormal facies, and cardiac
defects.

Past medical history: At birth, Didier presented with a cleft palate which was repaired in his second year of life. At the
age of two months, Didier was admitted through the emergency department due to restlessness and irritability. During
his first year of life, physical examination revealed facial and cardiovascular abnormalities. The patient was diagnosed
with pneumonia several times which was treated (with hospitalization). Between the ages of 2 months to 2 years of
age, he had 4 hospital admissions, the last being due to irritability, bluish discolorations of the lips, fever and cough.
Examination showed lethargy, cyanosis and bilateral crepitations. During this time, comparison of chest X-rays revealed
grade II cardiomegaly, consistent with Tetralogy of Fallot (TOF) diagnosis with pneumonia. The TOF was surgically
repaired soon after his second birthday. He was readmitted a week ago following marked irritability and restlessness.
During this hospital admission, MRI showed that the cardiomegaly was stabilized. The MRI also revealed that the
thymus was absent.

Genetic and immunological testing revealed the following:

1) Serum calcium: hypocalcemia (patient is 7.1mg/dl;
normal range is 8.5-10.2mg/dl)
2) Hypogammaglobulinemia
3) Deficiency of CD4 and CD8 cells with inversed
relation
4) TREC assay reveals reduced T-cell numbers
5) G-banding karyotype result was equivocal
(ambiguous) for DiGeorge syndrome;
subsequently, the genetics laboratory
recommended array CGH test be done to confirm
this diagnosis.

Figure 1: Karyotype of the patient. One geneticist diagnosed this as a deletion on chromosome 22, another
cytogeneticist wasn’t sure. (from http://www.pathology.washington.edu website)

Figure 2: Result from

the array CGH assay.

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 Didier George: BCHM 550 Small Group Case – 22q11.2 DS (Deletion Syndrome)

Based on the array CGH test, a diagnosis of 22q11.2 DS (also known as DiGeorge syndrome) was made. The patient was
treated symptomatically and multidisciplinary management instituted, including referral to cardiologists, immunologists,
and counselors for the parents. His condition has improved remarkably following these interventions.

Students are urged to read page 120 in the Korf and Irons 4th edition text for clinical snapshot 6.3. References include:
Gene Reviews, OMIM, and Uptodate.com.

QUESTIONS about 22q11.2 DS

General aspects of 22q11.2 DS

1. What is the underlying developmental abnormality associated with the sequela of features found in patients
with 22q11.2 DS? (Briefly describe)
2. 22q11.2 DS is one of the most common microdeletion syndromes, with an incidence of approximately 1 in 2,000
births. What are some of the common names associated with 22q11.2 deletion syndrome?
3. What are the common manifestations of DiGeorge syndrome?
4. Which organs are commonly affected in this syndrome?

Discuss genetic aspects of DiGeorge syndrome

5. What is the inheritance pattern of DiGeorge syndrome?
6. What could explain the appearance of a child with a confirmed case of DiGeorge syndrome from parents whose
genome does not contain the mutation?
7. What could explain the appearance of more than one affected child from parents who do not have the
mutation?
8. The 22q11.2 region is considered a hotspot for a deletion to occur during meiosis or mitosis. What is a possible
explanation for this?
9. What does the term “contiguous gene deletion” mean?
10. What does the term “micro-deletion” mean with respect to DiGeorge syndrome?
11. G-banding karyotype was done in this case and the result was equivocal (ambiguous) for DiGeorge syndrome,
leading the genetics lab to suggest another test to confirm the diagnosis.
a. How could fluorescence in-situ hybridization be used to diagnose this condition? In other words, how
could FISH be confirmatory in this case where G-banding failed to offer a clear diagnosis?
b. What is a disadvantage of using FISH compared to G-banding karyotype?
c. How could comparative genome hybridization microarray be used to diagnose the condition in this
patient? Why could array CGH be confirmatory in this case where G-banding failed?
d. What is a potential disadvantage of using array CGH in this case
12. What is the underlying concept behind microarray technology?
13. Comment on the use of professional language when describing a patient who has a dysmorphology – include
how to document the medical records, and how to discuss with the patient (or the parents of the patient.

After the immunology portion of this course, you will be able to discuss other aspects of this syndrome such as:
14. Discuss the immunologic basis for the recurrent infections in this patient.
15. What explains why T-cells in patients with DiGeorge syndrome fail to properly develop?
16. What best explains why B-cells are also affected in DiGeorge syndrome?
17. Explain the possible reason for the hypocalcemia observed in this patient’s results.
18. Patients with DiGeorge syndrome have increased predisposition to autoimmune disorders.