A Pediatric Genetic Disorder Diagnosed in Adulthood

A 41-year-old non-Hispanic white woman, accompanied by her psychiatrist, presented for immunologic consultation with an armload of medical records. The patient’s primary concerns were environmental mold exposure and a productive cough attributed to recurrent upper and lower respiratory tract infections. Although initially relating the beginning of her infections to mold exposure over the previous four years, the patient had experienced frequent respiratory tract infections since childhood, including recurrent otitis media, mastoiditis, and two episodes of pneumonia. The patient also claimed to have congenital granulocytopenia, specifically Kostmann syndrome. The patient expressed particular concern about ‘‘bowel problems,’’ which she claimed manifested as ‘‘steatorrhea,’’ inability to gain weight, and a need to eat every three to four hours to stave off emotional agitation. The patient described her stools as ‘‘rock hard’’ to ‘‘slimy.’’ Several gastroenterologists had evaluated the patient over the years, and results of endoscopies and biopsies ruled out celiac disease, chronic infections, and inflammatory bowel disease. The patient provided a list of psychotropic medications prescribed for her ‘‘atypical bipolar disorder’’ that included her specific comments regarding each (Table 1). At her initial visit, the patient was taking vitamin C supplements, acidophilus, and bovine colostrum. Family history revealed paternal alcohol abuse and kidney stones, and maternal ‘‘synthetic chemical sensitivity’’ and hypoglycemia. No family members had documented intestinal or infectious disorders. On examination, the patient was well oriented, petite, and anxious. Her height and weight were 158.4 cm and 45.9 kg, respectively. Her blood pressure was 107/64 mm Hg. There was no evidence of active upper or lower respiratory tract infection. Her cardiovascular, abdominal, and lymph node examinations were normal. There were no focal neurologic abnormalities. However, the patient displayed labile emotions and required frequent calming by her psychiatrist. Laboratory studies performed approximately two years previously revealed the following: hematocrit, 0.42; hemoglobin, 138 g/l; white blood cell count, 2.4 3 10/l; absolute neutrophil count (ANC), 0.576 3 10 /l; serum IgG, 5.8 g/l (normal 1⁄4 6.13–12.9 g/l); normal T cell subsets; normal blood chemistry profile; negative antineutrophil antibodies; and negative hepatitis B and C serologies. One year later, the patient’s ANC was 0.208 3 10/l. Antibody responses to diphtheria and tetanus toxoid vaccines were normal, but antibody responses to 12 pneumococcal serotypes, tested following immunization with unconjugated 23-valent pneumococcal vaccine, were absent. Laboratory studies at initial consultation confirmed neutropenia (ANC, 0.351 3 10/l), borderline IgG (6.10 g/l), and absent pneumococcal antibody levels. Pancreatic exocrine insufficiency was demonstrated by a low stool pancreatic elastase level (93 mcg/g; normal is greater than 200 mcg/g). Despite confounding emotional issues and exaggerated concerns regarding environmental mold exposure, the patient’s chronic neutropenia, malabsorption, and subtle immune deficiency were suggestive of a unifyin g d ia gnosis : S hwac hma nD ia mon d syndrome (SDS) [1]. Genomic analysis was performed by GeneDx, Gaithersburg, Maryland, United States. Two mutations were identified in the patient’s DNA sample and confirmed by restriction enzyme analysis of a second DNA amplification. Both mutations mimic the SBDS pseudogene and have been seen in numerous patients with SDS [2]. The mutations are designated c.183_184 TA to CT, and IVS2þ2 T to C. The former mutation causes a chain termination mutation in exon 2 at codon 62, and the latter causes aberrant splicing of the adjacent intron 2. The latter mutation is also known as c.258þ2 T to C. The most likely interpretation of this finding is SDS compound heterozygosity, with a different SBDS mutation inherited from each parent. The patient has not been seen again at this institution since the diagnosis was made.