Multiple Intestinal Atresia with Combined Immunodeficiency, a New Gene Arises

Abstract

We present here a single case report of a 2-day-old female born to a 29-year-old G4P3→4 Swartzentruber Amish mother at 35 weeks gestation that presented with abdominal distension and failure to pass meconium.Family history was positive for a cousin born with multiple intestinal atresia (MIA) and combined immunodeficiency (CID) who died in his first month of life. A primary immune deficiency targeted gene panel was done, covering TTC7A, in addition to 206 other genes, with no known mutations identified.An exploratory laparotomy was performed on DOL4 with MIA observed, as well as malrotation without volvulus. Repair of pyloric atresia and multiple small bowel resections and anastomosis were performed. She was kept NPO with TPN and NG suctioning of gastric contents for bowel rest.Immunologic profiling revealed low CD3+ cells (578/µL), very low CD8+ T cells (23/µL), low CD4+ T cells (485/µL), normal NK and B cell counts, low levels of serum IgM (< 10 mg/dL) with normal levels of IgG (likely maternal) and IgA. Mitogen stimulation testing was normal. Sanger sequencing showed a homozygous c.4867 T>G (p.Tyr1623Asp) mutation in PIK4A confirming the diagnosis of Gastrointestinal Defects and Immunodeficiency Syndrome 2 (GIDID2). Despite surgery, the patient continued to have large volume NG output without return of bowel function. Other treatment options, including long term TPN, potential small bowel and liver transplants, and HSCT were discussed, but the family elected for hospice given the poor prognosis. She passed away on DOL 28. PI4KIIIα, encoded by PI4KA, catalyzes the conversion of phosphatidyl inositol to phosphatidyl inositol-4-phosphate while using TTC7A as a scaffolding protein. This process is critical for development of enterocyte polarity and actomyosin contractility in multiple cell types. PI4KA mutations have only recently been implicated in causing MIA with CID and can be missed in many genetic screens. GIDID2 is a devastating disease in which intestinal surgery provides only an immediate mechanical fix, without improving mortality. Further research on the molecular mechanisms that govern GIDID2 is critically needed to identify new treatment modalities. Furthermore, awareness of PI4KA mutations in newborns with MIA with CID is critical, particularly in Amish populations.