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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.

any cardiac defects? cleft palate?

the DDX is velocardiofacial syndrome -deletion 22q11-of which you can have a digeorge syndrome picutre -but these patients tend to have conotruncal cardiac abnormalities

wide spectrum of presentations –but supposed frequency is 1 in 4000 births– sometimes the FISH for the deletion gets ordered prior to consultation by geneticist

The only cardiovascular defect I identified was the vascular ring (right aortic arch with left ligamentum arteriosum), and there were no facial or palate abnormalities.

My only encounter with DiGeorge syndrome was during my blood bank rotation. It is important to remember that 22q11 deletion syndrome is an indication for the use of irradiated blood products to prevent transfusion associated graft versus host disease. Transfusion associated graft versus host disease occurs when a donor stem cell implants and proliferates within the recipients bone marrow. This form of graft versus host disease is universally fatal. In immunocompetent individuals, destruction of donor stem cells is mediated by CD8+ T cells. In 22q11 syndrome, this population may be depleted or dysfunctional. HIV/AIDS patients, on the other hand, do not typically need irradiated blood products. While the CD4+ T cells may be decreased, the CD8+ population is usually unaffected. HIV/AIDS, therefore, does not increase the risk of transfusion associated graft versus host disease.

Interestingly, DiGeorge syndrome is actually not uncommon at all: incidence of about 1:4000 to 1:6000 live births (reference below). It is a very common etiology of cardiac defects in new borns (can’t remember the number right now…). Also about 8% of babies with cleft palate have DiGeorge.

Check out http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=12837874&dopt=AbstractPlus“>this link.

I am an adult age 47 with DiGeorge Syndrome. I have had 3 attacks of Pneumonia in the past 18 months. I have Hypoparathyroidism along with severe Hypocalcemia and I sometimes have leukocytosis.

I receive calcium infusions 3 times per week because my calcium levels crash immediately. I am then subject to Carpopedal spasm and Grand Mal Seizures for which I have had many. Each Grand Mal Seizure gets progressively worse with each attack.

I now have Chronic Kidney Disease Stage 3 due to Nephrocalcinosis of the Kidneys. I have a small right kidney. It is 3 times smaller than the left Kidney.

I also have Osteoporosis (Verified by Bone Biopsy) along with Vitamin D Deficiency and Osteoarthiris and Gout with elevated Uric Acid levels in the high range.

Does anyone have a clue as to why I would have recurring attacks of Pneumonia with Leukocytosis and Hypocalcemia? Are all of these issues linked to DiGeorge Syndrome?

There may be problems with the immune system - in particular, T-lymphocytes may not function properly, leading to frequent infections.

and the hypocalcemia is secondary to parathyroid aplasia.

If thw pt. needs trombocyte transfusion I assume they must be irradiated too?

Yes, since DiGeorge syndrome results in a severe deficit in cell-mediated immunity, irradiation of transfused platelets is needed to prevent a graft-verus-host process.