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Congenital atresia and stenosis of the intestine
Published in Mark Davenport, James D. Geiger, Nigel J. Hall, Steven S. Rothenberg, Operative Pediatric Surgery, 2020
Sharon G. Cox, Alastair J.W. Millar, Alp Numanoglu
The etiology of some familial multiple atresia syndromes may be due to genetic mutations (TTC7A) and are associated with immune deficiency syndromes (MIA-SCID). These are typically multiple Type I atresias within the small intestine with the most proximal being a pyloric atresia. It is usually a fatal condition without small intestinal and bone marrow transplantation.
Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR)
Published in Immunological Investigations, 2021
Farzaneh Rahmani, Elham Rayzan, Mohammad Reza Rahmani, Sepideh Shahkarami, Samaneh Zoghi, Arezoo Rezaei, Zahra Aryan, Mehri Najafi, Meino Rohlfs, Tim Jeske, Majid Aflatoonian, Zahra Chavoshzadeh, Fatemeh Farahmand, Farzaneh Motamed, Pejman Rohani, Hossein Alimadadi, Alireza Mahdaviani, Mahboubeh Mansouri, Marzieh Tavakol, Mirjam Vanderberg, Daniel Kotlarz, Christoph Klein, Nima Rezaei
P6-P10 had single gene mutations associated with maintenance of gut epithelial barrier and infantile syndromic diarrhea. P6 and P7 were sisters with identical homozygous mutations in the TTC7A gene (Avitzur et al. 2014), who presented with severe diarrhea early after birth along with evidence of severe apoptotic colitis, but no apparent immunodeficiency or intestinal atresia similar to what has been reported in patients with TTC7A deficiency before (Broome et al. 2019; Lien et al. 2017). The A832 T mutation results in amino acid substitution in a highly conserved site for mutation in TTC7A, the tetratricopeptide repeat domain. This has proved to be deleterious to protein plasma membrane expression and intracellular singling (Avitzur et al. 2014). Despite reports showing that homozygous variants of TTC7A often prove fatal in early childhood (Broome et al. 2019), P7 is alive at 8 years old and doing well on hypoallergenic, and dairy and nuts restricted diet, and parenteral nutrition. Patient P8 similarly presented with a typical syndromic diarrhea phenotype and had a mutation in the TTC37 gene which has been associated with the THES syndrome type 1 in the literature (Hartley et al. 2010; Rider et al. 2015). THES is characterized by a classic pentad of intractable diarrhea, facial dysmorphism, trichorrhexis nodosa, immune abnormalities, and growth retardation (A. Fabre et al. 1993), although several patients have been described with atypical forms including predominance of IBD-like features, or combined immunodeficiency associated with late-onset diarrhea (Busoni et al. 2017; Hosking et al. 2018; Vely et al. 2018). The classic pentad of THES was absent in our patient, who instead presented with refractory metabolic acidosis, severe vomiting and diarrhea and pre and postnatal growth delay. He was born at 35 weeks of gestation with a birth weight of 1500 g and is currently a 7-year-old boy with developmental delay and weight and height both below 10th percentile. P9 had a novel mutation in NOX1 gene, which was associated with VEO-IBD in two other patients (Hayes et al. 2015; Lipinski et al. 2019; Schwerd et al. 2018). NADPH oxidase is crucial to maintain gut epithelial barrier towards microbiota through generation of superoxide species and modulation of colonic epithelial proliferation and postmitotic differentiation (Coant et al. 2010; Kawahara et al. 2004). The importance of the reactive oxygen species generated by the NADPH oxidase system in gut barrier function is further exemplified by a higher prevalence of IBD-like symptoms in CGD, which is caused by inactivating mutations in components of the phagocyte NADPH oxidase complex (Uhlig 2013). Between 40% and 74% of patients with CGD develop IBD, often with CD-like phenotype and with symptom onset above 2 years old (Khangura et al. 2016; Marks et al. 2009).