Giant cell pneumonia with DiGeorge syndrome
Clinical History
A 7 month-old male was admitted for severe pneumonia with respiratory compromise. Laboratory studies demonstrated leukocytosis and profound hypocalcemia. An inherited immunodeficiency syndrome was suspected. A CT scan of the chest revealed bilateral lobar pneumonia, and no thymus was seen. Dual-probe fluoresence in-situ hybridization for deletions of 10p13p14 and 22q11.2 was performed on the peripheral blood, revealing hemizygosity for 22q11.2 deletion. Flow cytometry on the peripheral blood revealed markedly decreased number of circulating CD45RA- and CD62L-positive naïve T-cells. Sputum was obtained via nasopharyngeal aspiration. Bacterial and fungal cultures were negative, but immunofluoresence for respiratory syncitial virus (RSV) was positive. The patient required mechanical ventilation shortly after admission. Despite aggressive antibacterial, antifungal and antiviral treatment, his respiratory function rapidly declined, and he died a few days after presentation.
Pathological Findings
At autopsy, no thymus tissue was present in the mediastinum. The great vessels were abnormal, with a vascular ring (right aortic arch with left ligamentum arteriosum ) encircling the trachea and esophagus. The lungs were extremely boggy and heavy with severe diffuse bilateral consolidation. There were no facial abnormalities.
Diagnoses
DiGeorge syndrome
Giant cell pneumonia
Discussion
DiGeorge syndrome is a congenital disorder characterized by abnormal development of the third and fourth pharyngeal pouches, which most notably give rise to the thymus and parathyroid glands. In most cases, DiGeorge syndrome, as well as the associated velocardiofacial syndrome, are associated with a hemizygous deletion of 22q11. Deletion of the TBX1 gene within this region is believed to be the principal defect leading to the disease phenotype.1 A broad spectrum of abnormalities is seen in DiGeorge syndrome, but the triad of immune deficiency, cardiovascular abnormalities, and hypoparathyroidism constitute the classic syndrome. “Complete” DiGeorge syndrome refers to patients with athymia, defined as a profound decrease in the number of “thymic emigrants” (naive T-cells) in the blood. A subset of patients with so-called “atypical complete” DiGeorge Syndrome develops autoimmune phenomena (primarily rashes and lymphadenopathy) associated with oligoclonal T-cell proliferation, and presumably due to a lack of thymic T-cell education.2 This patient’s profound immunosupression resulted in an overwhelming respiratory RSV infection.
In this clinical scenario, the differential diagnosis for the patient’s giant cell pneumonia is limited to viral infection. While the term “giant cell pneumonia” is usually reserved for cases due to measles, varicella-zoster, parainfluenza, and RSV infection may also result in the formation of multinucleated giant cells. The characteristic morphological feature of measles infection is eosinophilc intranuclear and intracytoplasmic inclusions. Varicella-zoster typically lacks intracytoplasmic inclusions, while RSV and parainfluenza lack intranuclear inclusions.3 In this case, immunohistochemical stains for RSV were strongly positive, and other viral stains were negative.
The typical histological findings in RSV infection are a combination of necrotizing bronchiolitis and interstitial pneumonia. Sloughed bronchial epithelium often fills bronchial lumina, and occasionally, diffuse alveolar damage and alveolar wall necrosis is seen. Giant cell pneumonia, as seen in this case, is a rare manifestation.3
1. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007 Oct 20;370(9596):1443-52.
2. Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007 May 15;109(10):4539-47. Epub 2007 Feb 6.
3. Katzenstein A, Askin F. Surgical Pathology of Non-neoplastic Lung Disease, 4th ed. (Major Problems in Pathology v. 13) Philadelphia: Elsevier 2006.
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