A number sign (#) is used with this entry because of evidence that retinal dystrophy and microvillus inclusion disease (RDMVID) is caused by homozygous mutation in the STX3 gene (600876) on chromosome 11q12.

Retinal dystrophy and microvillus inclusion disease (RDMVID) is characterized by early-onset severe retinal dystrophy in association with intractable congenital diarrhea requiring total parenteral nutrition (TPN). Intestinal biopsies show typical features of microvillus inclusion disease (MVID), including loss of microvilli, microvillus inclusions, and accumulation of subapical vesicles in epithelial cells (Janecke et al., 2021).

Because STX3 isoform B (STX3B) predominates in the retina, mutations in the STX3 gene that affect both isoform A (STX3A) and STX3B cause both retinal and gastrointestinal disease (RDMVID), whereas mutations in STX3 affecting only the STX3A transcript cause only diarrhea (DIAR12; 619445).

Wiegerinck et al. (2014) reported an 18-month-old boy (patient 2), born of first-cousin Pakistani parents, who presented with frequent watery stools and several episodes of severe metabolic acidosis in the second week of life. He had frequent pulmonary infections and experienced persistent mild acidosis, renal tubulopathy, and episodic vomiting. He developed increasing tolerance of enteral nutrition, but still required partial parenteral nutrition (PN) and daily sodium bicarbonate supplementation for adequate growth. Light and electron microscopy of duodenal and rectal biopsy specimens showed the histologic characteristics of microvillus inclusion disease (MVID), including accumulation of periodic acid-Schiff-positive subapical vesicles, intracellular microvillus inclusions, and variable loss of brush border. In contrast to classic MVID (see DIAR2, 251850), multiple microvilli were observed at the basolateral membranes. Janecke et al. (2021) restudied the Pakistani boy (P2) originally described by Wiegerinck et al. (2014) and reported that he had severe visual impairment at age 10 years, with pale optic discs. Electroretinography (ERG) at age 1 year showed A and B waves that were greatly reduced in amplitude, consistent with a dramatic reduction in light responses of photoreceptors and downstream bipolar cells, respectively; by age 10, A and B waves were almost entirely absent, suggesting progressive loss of retinal light-sensing and signaling ability. The patient was fed by gastrostomy tube, with small amounts of fluids by mouth. He showed mild global developmental delay and failure to thrive, with short stature and low weight.

Julia et al. (2019) studied an Afghan male infant who was born with abdominal distension and showed dilated bowel loops with no air in the rectum on x-rays. He developed severe metabolic acidosis on day 6 of life. He had poor oral feeding, vomiting, and low-volume mucus-like diarrhea. At age 6 weeks, duodenal biopsy revealed features suggestive of MVID; electron microscopy of samples at age 10 weeks showed subapical collections of dense granules and focal loss of surface microvilli in the duodenum, and loss of surface microvilli, apical secretory vacuoles, and atypical inclusions along the basolateral cellular borders in the sigmoid colon. The patient also exhibited an abnormal neurologic status, including poor response to sound, intermittent nystagmus, staring spells, and fluctuation between hypo- and hypertonia. Neurologic evaluation showed positive light perception but lack of tracking, and at times no downward movement of the eyes. The proband had normal bulk but increased muscle tone in the extremities and reduced truncal tone. Brain MRI and ophthalmologic and auditory examination were normal. At age 15 months, the patient was fully dependent on total parenteral nutrition (TPN) and had cortical visual impairment with optic atrophy and nystagmus as well as hearing loss and developmental delay. Janecke et al. (2021) restudied the Afghan boy (P7) originally reported by Julia et al. (2019) and reported severe visual impairment at 20 months of age, with pale optic discs; ERG showed bilateral severe rod/cone dysfunction. He was completely dependent on TPN, with a gastrostomy tube for minimal enteral nutrition.

The transmission pattern of RDMVID in the Pakistani family reported by Wiegerinck et al. (2014) was consistent with autosomal recessive inheritance.

By whole-exome sequencing in an 18-month-old Pakistani boy with intractable diarrhea due to microvillus inclusion disease, who was negative for mutation in the MYO5B gene (606540) and who later developed progressive retinal dystrophy, Wiegerinck et al. (2014) identified homozygosity for a 2-bp duplication in the STX3 gene (600876.0003). Sanger sequencing confirmed the mutation and its segregation with disease in the family. Stable expression of a truncated version of STX3 corresponding to the patient's mutant protein in Caco2 cell cultures recapitulated all histologic hallmarks of MVID.

In an Afghan male infant with MVID and visual impairment, who was negative for mutation in MYO5B and was later shown to have severe rod/cone dysfunction, Julia et al. (2019) identified homozygosity for a del/ins frameshift mutation in the STX3 gene (600876.0004) that was not found in public variant databases. The authors noted that the appearance of basolateral microvilli in intestinal cells is characteristic of STX3-associated MVID, but is not seen in patients with MYO5B-associated MVID (DIAR2; 251850).

From a database of 799 research and 1,750 clinical exomes, Maddirevula et al. (2019) identified a 6-year-old girl (case ID 17-5433) with global developmental delay, hypotonia, and nystagmus, who was homozygous for a splicing mutation in the STX3 gene (c.675+1delinsT) that was not found in the gnomAD database. No further information was reported.

Janecke et al. (2021) reported 8 patients (P2 to P9) with RDMVID who carried homozygous mutations in the STX3 gene (600876.0003-600876.0006); see GENOTYPE/PHENOTYPE CORRELATIONS.

Janecke et al. (2021) studied a cohort of 10 patients from 8 families with MVID, including 8 patients who also displayed early-onset severe retinal dystrophy. Five patients had been reported previously: P1 and P2 by Wiegerinck et al. (2014), P6 by Maddirevula et al. (2019), P7 by Julia et al. (2019), and P10 by Alsaleem et al. (2017). All 10 patients had homozygous loss-of-function STX3 variants that segregated with disease in their respective families, and all had onset of persistent diarrhea within the first week of life, with histopathology that demonstrated the characteristic features of MVID. The 8 patients (P2 to P9) with RDMVID had pathogenic variants (see, e.g., 600876.0003-600876.0006) that were located in exons shared between STX3A and STX3B transcripts, with loss of expression of both isoforms. In contrast, the 2 patients (P1 and P10) with only MVID (DIAR12; 619445) had the same nonsense mutation (R247X; 600876.0002), located in exon 9A and sparing the STX3B transcript, which predominates in the retina. Some patients with mutation in STX3 exhibited mild global developmental delay, which Janecke et al. (2021) suggested might be attributable to extensive hospitalizations, immobility caused by dependency on parenteral nutrition, and severe visual impairment.