TBX1 copy number variant of unknown significance presenting as severe esophageal stricture and recurrent candidiasis

TBX1 Is involved in pharyngeal pouch development affecting thymus, parathyroid, craniofacial, and cardiac outflow tract development. TBX1 deletions present with phenotype of Di George syndrome. We present the case of a patient with esophageal stricture and candidiasis showing a novel TBX1 gene triplication VUS. A 27-year-old male was hospitalized for hematemesis and progressive dysphagia. The physical exam was remarkable for short stature, underweight, dental hypoplasia, alopecia and occipital vitiligo. Calcium and lymphocyte numbers were normal. Severe esophageal strictures precluded upper endoscopy. He received IV fluconazole for two weeks to continue oral antifungal indefinitely. Since infancy he has had multiple candida infections in nails and oral mucosa requiring fluconazole, and medical history of asthma and atopic dermatitis. No history of cardiac abnormalities. At 14 years old he started with progressive dysphagia. Barium swallow and endoscopies showed severe acute and chronic esophagitis and thoracic esophageal strictures with severe stenosis. Patient's sister has history of candida infections, hypocalcemia due to hypoparathyroidism, and hypothyroidism. There is consanguinity among paternal grandparents. Invitae PID panel showed VUS with TBX1 gene triplication, not previously reported. Familial genetic testing was requested for her sister to support the diagnosis of DiGeorge Syndrome. TBX1 gene deletions present a spectrum clinical phenotype including thymic hypoplasia, hypocalcemia, and congenital heart defects. TBX1 duplication and gain of function TBX1 heterozygous mutation led to protein dysfunction and a similar phenotype caused by loss-of-function mutations or deletions. TBX1 triplication could plausibly lead to dysfunctional protein expression, which requires confirmation. TBX1 is a negative regulator of thymic epithelial cell differentiation and proliferation, which could affect immune regulation and explain patient's chronic candida infections. Feeding difficulties and esophageal dysmotility have been reported in Di George syndrome. Sibling's hypocalcemia due to hypoparathyroidism could be explained by TBX1 dysfunction. APECED was considered in differential diagnosis due to chronic mucocutaneous candidiasis and sister's endocrinopathies, nevertheless, no AIRE or STAT1 mutations identified. Genetic analysis and familiar VUS have the potential to identify the cause of PIDs. TBX1 transcript and protein expression analysis will contribute to confirming the diagnostic impression.