KIF26A is mutated in the syndrome of congenital hydrocephalus with megacolon.

Human disorders of the enteric nervous system (ENS), e.g., Hirschsprung's disease, are rarely associated with major central nervous system involvement. We describe two families each segregating a different homozygous truncating variant in KIF26A with a unique constellation of severe megacolon that resembles Hirschsprung's disease but lacks aganglionosis as well as brain malformations that range from severe to mild. The intestinal phenotype bears a striking resemblance to that observed in Kif26a-/- mice where KIF26A deficiency was found to cause abnormal GDNF-Ret signaling resulting in failure to establish normal neuronal networks despite myenteric neuronal hyperplasia. Very recently, a range of brain developmental phenotypes were described in patients and mice with KIF26A deficiency and were found to result from abnormal radial migration and increased apoptosis. Our report, therefore, reveals a recognizable autosomal-recessive human KIF26A deficiency phenotype characterized by severe ENS dysfunction and a range of brain malformations.

Tricho-hepato-enteric syndrome: Retrospective multicenter experience in Saudi Arabia.

Background: Trichohepatoenteric syndrome (THES) is a very rare disorder that is characterized by intractable congenital diarrhea, woolly hair, intrauterine growth restriction, facial dysmorphism, and short stature. Our knowledge of THES is limited due to the small number of reported cases. Methods: Thirty patients diagnosed with THES, all molecularly confirmed by whole exome sequencing (WES) to have biallelic variants in TTC37 or SKIV2L, were included in the study. Clinical, biochemical, and nutritional phenotypes and outcome data were collected from all participants. Results: The median age of THES patients was 3.7 years (0.9-23 years). Diarrhea and malnutrition were the most common clinical features (100%). Other common features included hair abnormalities (96%), skin hyperpigmentation (87%), facial dysmorphic abnormalities (73%), psychomotor retardation (57%), and hepatic abnormalities (30%). Twenty-five patients required parenteral nutrition (83%) with a mean duration of 13.34 months, and nearly half were eventually weaned off. Parenteral nutrition was associated with a poor prognosis. The vast majority of cases (89.6%) had biallelic variants in SKIV2L, with biallelic variants in TTC37 accounting for the remaining cases. A total of seven variants were identified in TTC37 (n = 3) and SKIV2L (n = 4). The underlying genotype influenced some phenotypic aspects, especially liver involvement, which was more common in TTC37-related THES. Conclusion: Our data helps define the natural history of THES and provide clinical management guidelines.

Enteroendocrine Dysfunction in Two Saudi Sisters.

Proprotein convertase (PC) deficiency is a rare autosomal recessive disorder caused by mutations in proprotein convertase subtilisin/kexin type 1 (PCSK1). It is characterized by severe malabsorptive early-onset diarrhea, obesity, and systemic endocrinopathies. Only few cases have been reported in the literature; we have add two female sisters with some difference in clinical progress. Herein, we describe two sisters with congenital osmotic diarrhea diagnosed with PC1/3 deficiency, causing malabsorptive diarrhea and enteroendocrine dysfunction, who presented with chronic enteropathy with hypernatremia but with different expressivity. PC1/3 deficiency presents with symptoms and signs that mimic glucose-galactose malabsorption. Because of the clinical paucity and heterogeneity of congenital enteropathies, whole-exome sequencing may be of great help towards early diagnosis and effective treatment.

Unusual Manifestation of Ulcerative Colitis.

The relationship of inflammatory bowel disease (IBD) and chronic recurrent multifocal osteomyelitis (CRMO) is understood as extraintestinal rheumatic manifestations. CRMO is a chronic, relapsing, inflammatory, noninfectious disorder of the skeletal system of unknown origin. The disease course is not always recurrent. The association of CRMO and ulcerative colitis (UC) is very rarely reported. We report a case of a 10-year-old Saudi female who was diagnosed with CRMO, when she developed fever in association with left foot pain, and ulcerative colitis was confirmed endoscopically and histologically based on a previous settled diarrheal illness and severe iron deficiency anemia which required blood. Both conditions responded well to IBD therapy. To the best of our knowledge, this is the first reported case of chronic, multifocal osteomyelitis associated with pediatric UC in Saudi Arabia. This report supports the use of IBD therapy in treating CRMO.

Microvillus Inclusion Disease Variant in an Infant with Intractable Diarrhea.

Microvillus inclusion disease (MVID) is a rare autosomal recessive congenital enteropathy characterized by intractable secretory diarrhea. We report a case of MVID variant with a homozygous gene mutation in syntaxin 3 (STX3). The patient is a male Saudi infant who presented shortly after birth with severe vomiting, metabolic acidosis, and mild diarrhea. Electron microscopy study for small intestinal biopsy was consistent with MVID. MYO5B gene mutation was excluded; subsequently, whole exome sequencing (WES) was performed, which revealed homozygous gene mutation in STX3. Using WES in clinical environment can be a useful tool for diagnosing difficult and rare inherited congenital enteropathies.