CODE Think! Rare Mutations of STX3 Causing Microvillus Inclusion Disease

 

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Congenital diarrhea and enteropathies (CODEs) are rare diarrheal disease with infantile onset.[1] Based on the overlapping preliminary symptoms, these sick infants are often investigated for more common disorders like sepsis, hepatitis, and inborn errors of metabolism, before being considered as CODE by the clinicians. We previously reported an infant with severe malnutrition and failure to thrive.[2] The infant succumbed to the disease after weeks of intensive care having received trials of elemental amino acid formula, Ross Carbohydrate Free (+fructose) diet trials, and parenteral nutrition. Clinical exome by next-generation sequencing (NGS) revealed a pathogenic homozygous, one base pair insertion in exon 9 of the STX3 gene resulting in microvillus inclusion disease (MVID). The family sought compassionate care when diagnosis was confirmed. Further, both parents were reported to be heterozygous carriers of the pathogenic mutation through Sanger sequencing. In addition, another case report of an affected infant further supported the aforesaid statement of mutations in STX3 resulting in severe CODE.[3]

The second case was referred to us with multiorgan dysfunction syndrome (liver failure, ascites, malnutrition, dyselectrolytemia, and antenatal clues toward CODE, namely, polyhydramnios and echogenic bowel). Investigations suggested fetal–neonatal diarrhea similar to the previous case. The infant's stool osmolar gap was 130 mOsm/L (>200 would indicate a significant osmotic component and <100 would be suggestive of a pure secretory diarrhea).[4] NGS revealed a homozygous single base pair insertion in exon 9 of the STX3 gene (chr11:g.59795388dup; Depth: 135x) that resulted in a frameshift and premature truncation of the protein after 19 amino acids downstream to codon 231 (p.Asn231LysfsTer19; ENST00000337979.9) that is pathogenic for MVID. The parents of the infant preferred a surgery for intestinal transplantation, but the infant succumbed to the disease.

MVID is classically described to be caused by mutations in the gene coding of Myosin Vb, which is responsible for enterocyte polarization. The two cases discussed here are additional evidence of the fact that defects in the STX3 gene cause MVID.[5] Both infants come from a close-knit community. This would support the hypothesis as in the last case report that the Indian community is highly endogamous.[2] Hence, we seek to remind intensivists to contemplate CODE as one of the major reasons for early/severe infantile diarrhea and to appraise NGS as a potential diagnostic tool.

Publication History

Received: 27 February 2022

Accepted: 11 July 2023

Article published online:
10 August 2023

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