A 10-year-old girl referred to our clinic with a six-year history of chronic watery diarrhea and unresponsiveness to a gluten free diet. She had been evaluated and treated previously for chronic diarrhea, intermittent fever, recurrent pneumonia, candida esophagitis, pancytopenia, hypoalbuminemia, hypolipidemia, vitamin B12 and folic acid deficiencies. She was diagnosed with CD, based on serologic and histopathological findings. She was placed on a strict gluten free diet for a year, but diarrhea did not improve. She has two healthy brothers. Her parents were consanguineous. On physical examination, she was cachectic; with height for age below 3 % (height SDS -5.18) and weight for age below 3 % (weight SDS -5.27). Bone age and height age of the patient were 6 years, 10 months and 5 years, 3 months, respectively. She had protuberant abdomen and clubbing. Liver and spleen were palpable at 1 cm and 4 cm below the costal margins. Laboratory tests revealed mildly increased liver transaminases. Hemoglobin was 8.32 g/dl; MCV, 85 fL; RDW, 23.4 %; white blood cell, 5570/mm3; platelet, 230,000/mm3; reticulocyte count, 1 % and ferritin, 2.8 ng/ml. Coombs test was negative. Sedimentation rate was 18 mm/h, C-reactive protein, 1.78 mg/dl. Stool examinations were normal. 25-hydroxi vitamin D level was 25.7 ng/ml. Insulin like growth factor 1 (IGF-1) was 3.5 ng/mL (Normal, 108-648 ng/mL) and insulin like growth factor binding protein (IGFBP-3), 580 ng/mL (Normal, 2690-7200 ng/mL). Stimulated IGF-1 and IGFBP-3 were 2.85 ng/mL and 720 ng/mL, respectively, both markedly reduced. Basal and stimulated growth hormone levels were compatible with growth hormone insensitivity (12.9 ng/mL and 9.79 ng/mL, respectively). Anti-tissue transglutaminase IgA was positive with a titer of 200 IU/ml. Thyroid auto-antibodies, anti-saccharomyces cerevicea antibody and pANCA were negative. Bone mineral density showed severe osteoporosis (Z score, -5). Chest X-ray showed reticular density in the parenchyma of the lung. High-resolution chest tomography showed bilateral tubular bronchiectasis. Smear staining for acid resistant bacteria and tuberculosis PCR, and culture were negative. Upper gastrointestinal endoscopic examination revealed scalloping in the duodenal mucosa. Colonoscopy showed nonspecific nodularity in the colon mucosa. Histopathological examination of duodenum revealed total villous atrophy, crypt hyperplasia and intraepithelial lymphocytosis. Biopsies of the other parts of the gastrointestinal tract demonstrated mild reflux esophagitis, chronic active gastritis and focal cryptitis in the colon. She suffered from sepsis, disseminated intravascular coagulation, severe dehydration, metabolic acidosis, severe electrolyte imbalance and renal tubulopathy. Her clinical findings were improved by antibiotherapy and intravenous fluid therapy. Oral prednisone was started with the diagnosis of refractory CD, but she was not responsive.
Immunologic investigation was undertaken for primary immunodeficiency disease because of her chronic diarrhea, celiac antibody positivity, celiac-like mucosal findings, recurrent pulmonary infections with bronchiectasis, severe sepsis and severe growth retardation.
Immunological evaluation revealed normal IgG, elevated IgA and slightly decreased IgM levels with normal isohemagglutinin titer, normal T, B, NK cell counts and normal activation response to PHA and anti-CD3 (Tables 1 and 2 in supplementary data). She has slightly decreased switched memory B cells.
In light of the clinical and biochemical findings, initial genetic studies focused on sequencing the gene for STAT5B, which proved to be wild type. A novel homozygous frameshift mutation in the LRBA-gene c.5505delT (p.Ile1836*) was highlighted as the causal variant in whole exome sequencing analysis (Fig. 1). Sanger sequencing confirmed this variant to be homozygous in the patient and absent in the unaffected brother (Family Studies and Gene Analysis in Supplementary data).
As she has HLA fully matched healthy sibling donor and multiple organ dysfunction (bronchiectasis, tubulopathy and severe colitis), a novel non-myeloablative conditioning regimen consisting of BU/Flu/ATG, was applied. She received 8 x 106 peripheral blood CD34+cells/kg from her brother. CsA (-1) and methotrexate (+1,+3, +6) was used for GvHD prophylaxis. The early post-transplantation period was uncomplicated and she was discharged at +37. She has herpes zoster at +5 mo. treated with acyclovir. She is now 1 year post-transplant, with 97 % donor chimerism. Her health improved markedly, with an increased growth velocity (15 kg/ year and 10 cm/year) following the HSCT.