Newborn with Failure to Thrive and Diarrhea

A 33-day-old, small-for-gestational age female infant born at term to a 37-year-old gravida 2 mother with 1 previous miscarriage is admitted to the NICU. Family history showed no consanguinity. The antenatal course was complicated by fetal growth restriction which was first noticed on the antenatal scan at 12 weeks’ gestation. The mother did not have gestational hypertension, gestational diabetes, or any chronic illness. She was a nonsmoker and did not have short stature. The infant was delivered at 37 weeks’ gestation via cesarean section with a birthweight of 1,704 g (<3rd percentile). Apgar scores were 9 at 1 and 5 minutes. Her length (40 cm) and occipitofrontal circumference (30 cm) at birth were also less than the 3rd percentile as per the Fenton chart. She was discharged from the hospital on day 3 after birth. She was exclusively breastfed at home. She is now readmitted to the NICU on day 33 because of failure to thrive.On examination, she is hemodynamically stable with normal vital signs, pink extremities, active, crying, demanding feeds. She consumes 50 to 60 mL of milk at a time. Facial dysmorphism is noticed in the form of a widened nasal bridge, coarse facial features, and hypertelorism (Fig 1). She weighs 1,830 g at admission as opposed to the expected weight of 2,200 g. She shows no signs of dehydration and no hepatosplenomegaly is noted.The infant underwent investigation for failure to thrive. In the nursery, she consumed an adequate amount of milk (200–250 mL/kg per day), which ruled out faulty feeding as a cause of her poor weight gain. Feedings included both expressed breast milk and formula milk. She was started on antireflux measures (domperidone, ranitidine, and feed thickening with rice cereal) because of right perihilar opacity noted on chest radiography and failure to thrive. She developed loose stools on the 10th day of admission for which oral feeds were stopped and intravenous fluids were started. The diarrhea responded, suggesting an osmotic etiology. Sepsis screen including cultures were negative. Routine examination of the stool had normal findings and the rotavirus antigen was negative. Stool pH was 6 and reducing substances were 2+. She was started initially on soy formula, which was later changed to elemental formula because of a lack of response, considering the possibility of cow milk protein allergy (CMPA) and/or lactose intolerance. Poor weight gain and diarrhea persisted over the next 5 to 7 days. Duodenal and rectal biopsy showed a moderate increase in the number of inflammatory cells especially eosinophils (Figs 2 and 3). Based on endoscopic findings, the infant was started on intravenous methylprednisolone for a possible case of severe CMPA or food protein–induced enterocolitis syndrome. Fecal calprotectin was normal (<5 µg/g stool), which ruled out any infective and inflammatory pathology.The possibility of renal tubular acidosis was considered, but blood gases and urine pH were normal. Lack of hepatosplenomegaly ruled out storage disorders. Normal immunoreactive trypsinogen on metabolic screening ruled out cystic fibrosis. Normal titers for toxoplasmosis, other infections, rubella, cytomegalovirus (CMV) infection, and herpes simplex (TORCH) syndrome in the mother with negative CMV polymerase chain reaction in the infant ruled out intrauterine infections. Normal apolipoproteins A and B ruled out abetalipoproteinemia and hypobetalipoproteinemia.The infant’s diarrhea persisted and she did not gain weight. Though immunoreactive trypsinogen was normal, cystic fibrosis was considered a strong possibility and pancreatic enzyme replacement therapy (PERT) was started in addition to the elemental formula. The infant responded, with improved stool consistency, reduced diarrhea frequency, and better weight gain. To rule out pancreatic insufficiency, fecal elastase was sent, which was normal (492 µg/g stool). Microarray analysis was ordered at the time of admission because of the facial dysmorphism, and it was reported to be normal, following which clinical exome sequencing was sent.Clinical exome sequencing showed a homozygous single base pair deletion in exon 28 of the TTC37 gene (chr5:g.95513645delG; Depth: 73x) that results in a frameshift and premature truncation of the protein 22 amino acids downstream to codon 902 (p.Ala902LeufsTer22; ENST00000649566.1). The resultant condition is known as tricohepatoenteric syndrome (THES). This is a novel mutation and has not been reported earlier in the 1,000 genomes, ExAC. The insilico prediction of the variant is damaging by Mutation Taster 2. Because of the coexistence of immunodeficiencies in this disorder, an immunoglobulin panel was done. Serum IgA was 16 mg/dL (0.16 g/L), IgG was 107 mg/dL (1.07 g/L), and IgM was 24 mg/dL (0.24 g/L). IgG was reduced whereas IgA and IgM were within normal limits. Liver function test results were normal. The parents were given detailed genetic counseling and the infant was discharged from the hospital at 75 days of age.THES, also known as syndromic diarrhea of infancy, is a rare autosomal recessive neonatal enteropathy characterized by fetal growth restriction, infantile diarrhea, facial dysmorphism, woolly hair, and elevated liver enzymes. Poorly defined immunodeficiency, recurrent infections, skin abnormalities, and liver disease usually accompany the disorder.Diarrhea usually begins early, though it can present any time during infancy. It does not respond to any particular treatment, and usually necessitates partial parenteral nutrition. Endoscopic findings are normal in most cases. (1) To date, diarrhea has been reported to be lifelong in published cases. Hair abnormalities range from woolly to poorly pigmented to brittle with an inability to comb described in various published cases. (2) Growth failure starts early in conception as happened in our case. Most neonates weigh less than the 10th percentile at the time of birth. (3) On follow-up, growth percentiles fall further as was seen in our case. Facial dysmorphism is mild, nonspecific, and observed in almost all cases. Characteristic features including a broad head, hypertelorism, and flat nasal bridge develop as the child grows. Among cardiac defects, ventricular septal defects and arch abnormalities are common. Echocardiography findings were normal in our case. Immunodeficiency is common and these children are at risk for bacterial and viral infections. (4) They usually require intravenous immunoglobulin to prevent recurrent infections. Mild intellectual disabilities are found in 50% of cases and development assessment is required at regular intervals in these children. (5) The disease is diagnosed on clinical or whole exome sequencing in a suspected case. Of the 52 cases of THES reported so far, 69% had mutations in the TTC37 gene and 31% had mutations in the SKIV2L gene. (6) The majority of mutations are missense or nonsense type. The disease is inherited in an autosomal recessive manner. Siblings of an affected child have a 25% chance of having the disease, 50% chance of being asymptomatic carriers, and 25% chance of being normal. Once a mutation is confirmed in the child, parents can also be tested. Parents should be informed about the option of prenatal diagnosis which can be done with chorionic villous biopsy or preimplantation genetic diagnosis for future pregnancies.The infant was discharged from NICU at age 75 days, receiving elemental formula and PERT. She gained some weight on follow-up though intermittent episodes of diarrhea persisted. She died at age 5 months because of diarrhea, dehydration, and shock. She weighed 2.8 kg at the time of death.