A newborn with multiple intestinal atresias found to have variants in tetratricopeptide repeat domain 7A gene

Abstract

We report a male infant born with multiple intestinal atresias (MIA) prompting early genetic testing. Bi-allelic, compound heterozygous variants in tetratricopeptide repeat domain 7A (TTC7A) gene were identified. TTC7A is involved in transporting phosphatidylinositol 4-kinase IIIα into the plasma membrane (1). Mutations in this gene disrupt intestinal development and polarity, causing intestinal diseases such as atresia, enteropathy, and very early onset inflammatory bowel disease (VEO-IBD), as well as variable degrees of immunodeficiency (1).The identification of variants in TTC7A gene prompted an immune evaluation since as many as 75% of patients with TTC7A mutations reported in the literature have an underlying immunodeficiency (2). Flow cytometry was relatively unremarkable except for a slightly low memory T-cell count and percentage. NK-cell and B-cell numbers and percentages were appropriate for age. His phytohemagglutinin response was relatively low, but still significant, suggesting a possible component of combined immunodeficiency. To further characterize his T-cell function, we assessed his T-cell proliferation response to anti-CD3, which showed moderately decreased response of CD45+ lymphocytes and CD3+ T-cells to soluble anti-CD3 alone. However, co-stimulation with anti-CD3+anti-CD28 and anti-CD3+IL-2 normalized his T-cell proliferative response. Immunoglobulins were all low. Given his subtle T-cell defect and hypogammaglobulinemia, he was classified as having MIA with combined immunodeficiency (MIA-CID) phenotype of TTC7A.Cobalamin was tried in this patient as it has a low side effect profile and showed benefits in gut motility and intestinal tract luminal narrowing in a TTC7A zebrafish model (3). We considered investigational use of leflunomide, which showed the most promising results in the same zebrafish model (3). Bowel and hematopoietic stem-cell transplantation were considered too. Enterectomy was also offered, as this was shown to be effective in a case report of two patients with similar MIA-CID TTC7A phenotype (4). Unfortunately, the patient did not respond to steroids or cobalamin. His clinical condition worsened, and he passed away at four months of age.Mutations in the TTC7A gene result in various gastrointestinal pathologies with varying degrees of immunodeficiency in approximately 75% of patients (2). All patients with MIA or VEO-IBD should have an immune evaluation and genetic testing.