22q11.2 deletion syndrome and selective igm deficiency: An association of a common chromosomal abnormality with a rare immunodeficiency

Chromosome 22q11.2 deletion encompasses most patients previously diagnosed with velo-cardio-facial syndrome (Shprintzen’s syndrome), DiGeorge syndrome, Opitz syndrome, and conotruncal anomaly face syndrome [Thomas and Graham, 1997]. The phenotype of this syndrome is variable, including congenital heart disease, palatal abnormalities, facial dysmorphism, developmental delay, hypoplastic thymus, and hypocalcemia. The 22q11 deletion has a reported incidence ranging from 1/4,000 to 1/6,395 [Devriendt et al., 1998]. Fluorescence in situ hybridization (FISH) is used to detect the microdeletion of 22q11.2. In a cohort of 195 patients with 22q11 deletion, diminished T cell count in the peripheral blood is a common feature; however, therewasno statistically significant difference in in-vitro lymphocyte proliferation in response to either mitogens or specific antigens [Jawad et al., 2001]. In the same study, five patients were found to have selective IgA deficiency. In a separate report, 13 patients with 22q11 deletion were found to be able to generate normal antibody responses [Junker and Driscoll, 1995]. Selective IgM deficiency is a rare form of antibody deficiency that may manifest with recurrent infections, atopic dermatitis, systemic lupus erythematosus, and autoimmune hemolytic anemia [Ochs and Winkelstein, 1996]. A group of patients with selective IgM deficiency was found to have depressed antibody response to tetanus-diphtheria toxoid vaccine (Td vaccine) and to pneumococcal polysaccharide antigens despite normal IgG levels [Guill et al., 1989]. Isohemagglutinins, ordinarily thought to be IgM antibodies, were diminished in some but not all of these patients. We present the first case, to our knowledge, of 22q11.2 deletion syndrome associated with selective IgM deficiency. A 15-year-old female with 22q11.2 deletion was referred for evaluation of her immune system. The patient had a history of recurrent and chronic otitis media, chronic otorrhea, and conductive hearing loss. She had required multiple myringotomy tube placements and used a hearing aid. The patient had no history of sinusitis, pneumonia, osteomyelitis, septic arthritis, urinary tract infection, meningitis, or lymphadenitis. The patient had had no opportunistic infections, chronic diarrhea, or failure to thrive. Immunizations were received without complications, and the patient had developed uncomplicated chicken pox during early childhood. The patient was known to have velopharyngeal incompetence and developmental and speech delay, but cardiology evaluation showed no heart defect. Neither parent had a 22q11 deletion. Physical examination showed multiple anomalies including midfacial flatness, oval shape face with relatively pointed chin, upper epicanthic folds, bilateral ptosis, straight nose, and smooth philtrum with a thin vermilion border of the upper lip. The tonsils were present, the palate was high and narrow with dental malocclusion, and the ears had over-folded helices but were not low-set or posteriorly rotated. The skeletal habitus shows relatively long upper extremities. The growth parameters showed the following: head circumference within 2 SD of mean, height at 3rd centile, and weight at 25th centile for age and sex. Laboratory investigations included a complete blood count with hemoglobin 11.4 g/dl (normal: 11.5–15.3 g/ dl); platelet count 273,000/mm (normal: 140,000– 400,000); and white blood cell count 10,900/mm (normal: 4,500–13,000) with 54% neutrophil, 37% lymphocyte, 7% monocyte, and 3% eosinophil. Serum immunoglobulins showed IgM< 6 mg/dl (normal: 48– 271 mg/dl), IgG 1,170 mg/dl (normal: 694–1,618 mg/dl), and IgA 356 mg/dl (normal: 81–463 mg/dl). Repeat serum immunoglobulins showed consistent results with IgM 8mg/dl and normal IgG and IgA levels. The patient had good antibody response to Td vaccine, but she responded to only one out of six serotypes after immunization with pneumococcal vaccine (Pneumovax 23,Merck, West Point, PA). The patient had a normal level of natural isohemagglutinins, 1/16 (normal: 1/4–1/64). Free serum kappa (k) and lambda (l) light chain levels were 319 mg/dl (normal: 74–295 mg/dl) and 213 mg/dl *Correspondence to: Stephen J. McGeady, M.D., Division of Allergy & Clinical Immunology, NCC-Wilmington, Alfred I. duPont Hospital for Children, P.O. Box 269, Wilmington, DE 19899. E-mail: smcgeady@nemours.org