Congenital Diarrhea From DGAT1 Mutation Leading to Electrolyte Derangements, Protein‐losing Enteropathy, and Rickets

Congenital diarrhea disorders represent a group of uncommon, clinically varying enteropathies that are often diagnostically challenging. Recent advancements in genetic and molecular testing has allowed for identification of specific genetic etiologies and elucidation of cellular mechanisms in many of these conditions (1). To date, 8 patients with congenital diarrhea due to homozygous recessive DGAT1 (diacylglycerol o-acyltransferase 1) mutations have been described, and asymptomatic family members who are heterozygous carriers (2–4). We report on a female with congenital diarrhea due to loss of function compound heterozygous mutations in DGAT1, which to our best knowledge has not yet been described. CASE The patient is a Caucasian female with chronic, severe diarrhea. She was born without complications at term (birth weight 3.572 kg, z score 0.72). She had a normal newborn metabolic screen and was gaining weight appropriately at home, although with approximately 10 formed stools per day on breastmilk and term infant formula. At one month of age, she began having emesis and poor weight gain. Over the next 2 months, her stools became watery, and she developed persistently low serum bicarbonate (15–16 mmol/L). She was trialed on numerous formulas, including cow's milk based and extensively hydrolyzed preparations. At 2 months of age, she was hospitalized for presumed milk protein intolerance, during which her albumin level was 2.3 g/dL and bicarbonate was 13 mmol/L. During a prolonged hospitalization between 3 and 4 months of age, during which she weighed 4.29 kg (z score −2.4), she developed pneumatosis intestinalis, for which she was treated with antibiotics and total parenteral nutrition. She did have positive cytomegalovirus (CMV) antibodies (immunoglobulin M [IgM] and IgG), and these were thought to contribute to her acute presentation rather than her chronic symptoms, as later intestinal tissue biopsies and cultures were negative for CMV. During that hospitalization, she underwent esophagogastroduodenoscopy and sigmoidoscopy that were visually normal. Colonic biopsies showed focal acute colitis with cryptitis, esophageal and gastric biopsies showed evidence of mild chronic inflammation, and duodenal biopsies demonstrated focal foveolar metaplasia deemed clinically insignificant by the reading pathologist. She was discharged home on a combination of home parenteral nutrition and continuous nasojejunal feeds with an amino acid–based formula, after which she did require 1 additional failure to thrive admission. She then presented to our institution at 7 months of age following several days of pronounced watery diarrhea. She was clinically dehydrated but otherwise had an unremarkable physical examination. Her weight was low (5.8 kg, z score −2.5), but her length and head circumference were preserved. Her development was age appropriate. She had severe metabolic derangements, including nonanion gap metabolic acidosis (pH 7.21, anion gap 12 mmol/L) with respiratory compensation (pCO2 16 mmHg), serum bicarbonate 6 mmol/L, serum phosphorus 2.35 mg/dL, alanine aminotransferase 237 U/L, aspartate aminotransferase 173 U/L, and alkaline phosphatase 1664 U/L. She was also found to have decreased fat-soluble vitamin levels and vitamin D deficiency rickets with secondary hyperparathyroidism, due to malabsorption. Extensive infectious, metabolic, and renal diagnostic studies were normal, as was a chromosomal microarray. She had a small bowel follow-through series notable for osteopenia and healing rib fractures, attributed to rickets. She underwent another esophagogastroduodenoscopy and colonoscopy, which were visually normal and had histologically normal biopsies throughout the esophagus, stomach, duodenum, and colon. Electron microscopy, disaccharidase panel, CD10 and periodic acid–Schiff stains, and anti-enterocyte antibodies were negative. She had a negative diagnostic immunological evaluation, including autoimmune lymphoproliferative syndrome testing. She was noted to have persistently low IgG levels and a slightly elevated stool alpha-1-antitrypsin level (0.59 mg/g), consistent with protein-losing enteropathy. Thus, she began to receive intravenous immunoglobulin (IVIG) infusions. She eventually began to tolerate a combined enteral and parenteral regimen and was discharged home. Because of the unknown etiology of her diarrhea, whole exome sequencing was performed and was significant for 2 mutations in DGAT1. Subsequently, she was transitioned to a commercial, very low-fat formula to improve protein-losing enteropathy, as detailed in previously reported patients with DGAT1 deficiency (4). She tolerated slow increases in enteral advancement and was successfully weaned off parenteral nutrition by 13 months of age. She advanced from the aforementioned formula to a low-fat diet of table foods and, at 17 months of age, weighed 11.8 kg (z score 1.3). With a low-fat diet and supplementation of calcium and vitamin D, her vitamin D, IgG (off IVIG infusions), albumin, and transaminase levels normalized. She had numerous normal serum triglycerides (range: 20–111 mg/dL) throughout her course. DISCUSSION DGAT1 deficiency is a rare, autosomal recessive condition caused by loss of function mutations in the DGAT1 gene (2–4). This gene regulates DGAT1 production, which plays a key enzymatic role in cellular diacylglycerol lipid metabolism, triglyceride synthesis, and adipose tissue formation (5). GeneDx Laboratory performed whole exome analysis by massively parallel sequencing on the Illumina system, with confirmation of pathogenic variants by capillary sequencing. This analysis identified our patient to be compound heterozygous for 2 mutations in DGAT1: a maternally inherited 3 base pair deletion at nucleotide position 1013 in exon 13, resulting in an in-frame deletion of a phenylalanine residue at codon 338 (c.1013_1015delTCT; p.Phe338del), and a paternally inherited C to G transversion at nucleotide position 1260 in exon 16, resulting in a serine to arginine substitution at codon 420 (c.1260C>G; p.Ser420Arg). These mutations have each been classified as likely pathogenic by the reporting laboratory, and clinical correlation in our patient further supports their pathogenicity. To date, there have been 3 homozygous recessive mutations described in 8 patients; this is the first described compound heterozygote (2–4). Although most cases of DGAT1 deficiency have been accompanied by hypertriglyceridemia, our patient did not have this condition, which may be due to her unique mutation. She, however, did demonstrate hypoalbuminemia, elevated stool alpha-1-antitrypsin, and improvement with a very low-fat diet, which, along with hypertriglyceridemia, are the hallmarks of the disorder (4). Although rare, with greater availability of whole exome sequencing, we anticipate a rise in the identification of these pathogenic mutations. With increased awareness of this disease and recognition of associated hallmarks, affected patients can receive a prompter diagnosis and management.