Diarrhea 10, Protein-Losing Enteropathy Type

A number sign (#) is used with this entry because of evidence that diarrhea-10 (DIAR10) is caused by homozygous mutation in the PLVAP gene (607647) on chromosome 19p13.

Description

Diarrhea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients (Broekaert et al., 2018; Kurolap et al., 2018).

For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700).

Clinical Features

Elkadri et al. (2015) studied a male infant with severe protein-losing enteropathy, born to consanguineous parents of Afghan descent, who presented in the first weeks of life with secretory diarrhea and hematochezia, metabolic acidosis, lethargy, poor feeding, and hyponatremic seizures. Other features included bilateral colobomata, low-set ears, micrognathia, undescended testes, and mildly dysplastic kidneys. Albumin was consistently undetectable and did not respond to repeated infusions. All immunoglobulins were low or undetectable, except for IgM. He had hypothyroidism, and lipid profile showed an elevated triglyceride level, with normal cholesterol and high-density lipoprotein levels. Electron micrographs of patient duodenum showed complete lack of diaphragms in the fenestrae and caveolae of endothelial cells of all capillaries examined, resulting in plasma protein extravasation. The authors noted that plasma levels of relatively small proteins, such as albumin, ceruloplasmin, and thyroxine-binding globulin (ranging from 65 to 140 kD), were severely reduced, whereas the level of IgM (755 kD) was normal, due to selective loss of proteins based on size. The patient had recurrent respiratory tract infections, persistent anasarca, and venous thrombosis in multiple locations; he died of sepsis at age 5 months.

Broekaert et al. (2018) reported a male infant, born to first-cousin parents of Turkish descent, who at the age of 9 days developed watery diarrhea and polyuria with hyponatremia, hypomagnesemia, hypocalcemia, and metabolic acidosis. His albumin level dropped from 28 to 4g/L by day 12 of life, and he also had markedly elevated gamma-GT (see 612346). Lipids and immunoglobulins were not measured. Clinical examination revealed moderate generalized edema, bilateral undescended testicles, and dysmorphic facial features, including hypoplastic supraorbital bulges, low-set ears, long flat prominent philtrum, anteverted nostrils, thin upper lip, downturned corners of the mouth, and high-arched palate. Abdominal ultrasound showed a massively dilated left ureter with kinking and a dilated left renal pelvis, and a mildly dilated ureter on the right side. Cranial ultrasound showed small plexus cysts and increased periventricular echogenicity, but he exhibited no neurologic abnormalities. On echocardiography, small apical atrial and ventricular septal defects were found, and ophthalmologic examination revealed multiple iris cysts. Despite total parenteral nutrition, diarrhea remained massive, indicative of secretory diarrhea. The patient developed portal vein thrombosis, and on day 15 he experienced hematochezia, likely due to disseminated intravascular coagulation, and died.

Kurolap et al. (2018) described 2 first cousins once removed from a consanguineous Arab Muslim family with protein-losing enteropathy: a man who presented at age 22 years, and a girl who presented at age 2.5 years. Both had anasarca, severe hypoalbuminemia, and hypogammaglobulinemia, and the girl also had markedly elevated triglycerides. Neither exhibited facial dysmorphism or other congenital anomalies. Low-fat diet and middle-chain triglyceride-rich formula resulted in significant clinical and laboratory improvement, whereas exposure to high fat in their diet caused rapid recurrence of disease symptoms.

Molecular Genetics

In a male infant with severe protein-losing enteropathy, born to consanguineous parents of Afghan descent, Elkadri et al. (2015) performed whole-exome sequencing (WES) and identified homozygosity for a nonsense mutation in the PLVAP gene (R358X; 607647.0001). The patient died of sepsis at age 5 months.

In a male infant with severe protein-losing enteropathy from a consanguineous family of Turkish descent, Broekaert et al. (2018) performed WES and identified homozygosity for a nonsense mutation in the PLVAP gene (Q330X; 607647.0002). The patient died at age 2 weeks.

By WES in a 22-year-old man and a 2.5-year-old girl with protein-losing enteropathy, who were first cousins once removed from a consanguineous Arab Muslim pedigree, Kurolap et al. (2018) identified homozygosity for a missense mutation in the PLVAP gene (L34P; 607647.0003). No pathogenic variants in other protein-losing enteropathy-associated genes were found in the WES data of either patient. Noting the later-onset and milder phenotype in the 2 Arab Muslim patients, the authors suggested that it might be due to the missense nature of their pathogenic variant, compatible with residual PLVAP function. Electron microscopy of patient duodenum demonstrated preserved endothelial fenestral diaphragms, and immunostaining revealed expression of PLVAP in endothelial cells of duodenal mucosal capillaries comparable to that of age- and sex-matched controls.