Clinical Characteristics, In Silico Analysis, and Intervention of Neonatal-Onset Inflammatory Bowel Disease With Combined Immunodeficiency Caused by Novel TTC7A Variants

Abstract

We aimed to explore the genotypic and phenotypic characteristics of neonatal-onset inflammatory bowel disease (IBD) with combined immunodeficiency due to TTC7A mutation. We examined the clinical manifestations, imaging results, endoscopic and histological findings, interventions, and prognosis of a proband with neonatal-onset IBD and performed biochemical analyses, whole-exome sequencing (WES), and in silico analysis. Our proband developed severe early-onset diarrhea, malnutrition, electrolyte imbalance, dehydration, and recurrent infections after birth. Radiographic and ultrasonic images showed no specific manifestations. Endoscopic and histological examination revealed chronic inflammation. Immune function examination indicated immunodeficiency. WES identified compound heterozygous TTC7A mutations (c.2355+4A>G, c.643G>T) in the proband. In the expression analysis, no abnormal splicing in the TTC7A sequence was observed due to the c.2355+4A>G mutation; however, the mRNA expression was reduced. The proband’s condition did not improve after treatment with methylprednisolone or leflunomide. The proband died when treatment was stopped at the age of 5 months and 19 days. Compound heterozygous mutations (c.2355+4A>G, c.643G>T) in the TTC7A gene are described and verified for the first time. Our report expands the phenotypic spectrum of TTC7A mutations and the genotypic spectrum of very early-onset IBD with combined immunodeficiency.

Systematic review of phenotypes and genotypes of patients with gastrointestinal defects and immunodeficiency syndrome-1 (GIDID1) (related to TTC7A)

“…In the cohort of patients we observed, we confirmed several previously highlighted elements: the presence of three primary phenotypic traits -MIA, ID and E (23); a high mortality rate, with 82.3% of deaths occurring before the age of 12 months, reaffirming the severity of this disease (3)(4)(5)(6)(7)12,14,15,23,25,26), and the crucial role of parenteral nutrition (PN), as 92.1% of patients required it (3,(5)(6)(7)(11)(12)(13)(14)(15)17,18,(22)(23)(24)(25)(26)(27)(28)(29).…”

“…It appears that double NS variant is more commonly associated with intestinal atresia. This suggests that the complete absence of TTC7A has a more profound impact on the structure of the digestive tract (3)(4)(5)11,14,15,28,34), while a hypomorphic presence allows for a normally developed gastrointestinal tract but leads to a phenotype resembling very early onset-inflammatory bowel disease (VEO-IBD) (3)(4)(5)7,10,14,25). Additionally, the ELA syndrome (7,16) was exclusively linked to patients without intestinal atresia.…”

Type II Congenital Pyloric Atresia with Desquamative Enteropathy Diagnosed Postoperatively: A Case Report

“…4 In these two other described cases, despite controlling multiple infections, the diarrhea persisted and led to failure to gain weight and ultimately, treatment the patients expired. 4 The implications of the specific TTC7A mutation are important in treatment and prognosis. Patients with neonatal-onset IBD associated with TTC7A deficiency are often resistant to conventional medical treatment including immunosuppressive treatments.…”

“…The patient in this case report was treated with broad-spectrum antibiotics, IVIG, methylprednisolone, and leflunomide. 4 In these two other described cases, despite controlling multiple infections, the diarrhea persisted and led to failure to gain weight and ultimately, treatment the patients expired. 4 The implications of the specific TTC7A mutation are important in treatment and prognosis.…”

“…The average survival of patients with TTC7A nonsense mutations is less than 12 months. 4 Additional research is needed to determine optimal management strategies.…”