16p13.11 microdeletion uncovers loss-of-function of a MYH11 missense variant in a patient with megacystis-microcolon-intestinal-hypoperistalsis syndrome.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a rare condition that affects smooth muscle cells, is caused by biallelic null alleles in MYH11. We report on a girl with MMIHS in addition to growth hormone deficiency, central hypothyroidism and a tonically dilated pupil with accommodation deficit. Sanger sequencing and arrayCGH uncovered the novel heterozygous missense variant c.379C>T in MYH11 and a heterozygous 1.3 Mb deletion in 16q13.11 encompassing MYH11, respectively. Her mother carries the deletion, whereas her father is heterozygous for the c.379C>T p.(Pro127Ser) change. Proline 127 is crucial for the formation of the Adenosine triphosphate binding pocket of the MYH11 motor domain and molecular modeling indicated that p.Pro127Ser alters nucleotide binding properties. Thus, the unusual and complex clinical presentation of the patient results from compound heterozygosity for a 16p13.11 microdeletion including the entire MYH11 gene and a loss-of-function missense variant on the remaining MYH11 allele. In conclusion, we recommend genetic testing both for MYH11 sequence alterations and copy number imbalances in individuals with MMIHS and smooth muscle cell-associated abnormalities in additional organs, that is, multisystemic smooth muscle dysfunction.

Expanded ILC2s in human infant intestines promote tissue growth.

Early life is characterized by extraordinary challenges, including rapid tissue growth and immune adaptation to foreign antigens after birth. During this developmental stage, infants have an increased risk of immune-mediated diseases. Here, we demonstrate that tissue-resident, interleukin (IL)-13- and IL-4-producing group 2 innate lymphoid cells (ILC2s) are enriched in human infant intestines compared to adult intestines. Organoid systems were employed to assess the role of infant intestinal ILC2s in intestinal development and showed that IL-13 and IL-4 increased epithelial cell proliferation and skewed cell differentiation toward secretory cells. IL-13 furthermore upregulated the production of mediators of type-2 immunity by infant intestinal epithelial cells, including vascular endothelial growth factor-A and IL-26, a chemoattractant for eosinophils. In line with these in vitro findings increased numbers of eosinophils were detected in vivo in infant intestines. Taken together, ILC2s are enriched in infant intestines and can support intestinal development while inducing an epithelial secretory response associated with type 2 immune-mediated diseases.

Colectomy Followed by J-Pouch Reconstruction to Correct Total Colonic Aganglionosis.

BACKGROUND: Patients suffering from complete colonic aganglionosis (TCA) require the best surgical care possible. Only a few studies reported J-Pouch repair as the primary reconstructive surgery in TCA patients. This study adds to the current literature a thorough clinical and functional outcomes group. METHODS: Between 2011 and 2021, medical records of Hirschsprung disease (HD) patients who underwent J-Pouch reconstruction during infancy (n = 12) were reviewed. In close follow-up, bowel function and satisfaction with operation results were evaluated. The median age at the time of J-Pouch reconstruction was 16 months, and covering ileostomies were closed four months later. There were no postoperative problems. After the final repair, Pouch-related problems (PRP) occurred in 27% of the children and were treated conservatively. There was no histological evidence of pouchitis in any of the individuals. The median 24-h stooling frequency was 4-5 at the latest follow-up 51 months following enterostomy closure. CONCLUSIONS: The current study's findings support the existing literature and advocate for J-pouch repair in TCA patients. However, more research will be needed to determine the best time to undergo pouch surgery and ileostomy closure in TCA patients.