A Term Neonate with Multiorgan Dysfunction, Severe Metabolic Acidosis, and Hyperkalemia.

A full-term female infant is delivered at 39 weeks’ gestation by a 21-year-old gravida 4, para 3 woman with limited prenatal care. She is born via precipitous vaginal delivery at a local urgent care center with rupture of membranes less than 1 hour before delivery. Maternal group B Streptococcus status is unknown, and a drug screen is positive for tetrahydrocannabinol. The neonate's birthweight is 3,238 g, appropriate for gestational age, and Apgar scores are 8 and 8 at 1 and 5 minutes, respectively. She is transferred to a nearby level II nursery for further evaluation and care. She is initially well-appearing but uncoordinated with breastfeeding. At 11 hours after birth, she develops nonbloody, nonbilious emesis and respiratory distress.On examination, she is ill-appearing with intermittent grunting, lethargy, subcostal and intercostal retractions, and hypothermia. A sepsis evaluation is conducted and the complete blood cell count is normal. A urinalysis is performed due to hematuria and reveals a large amount of blood and protein. Urine glucose is normal (12 mg/dL [0.67 mmol/L]) and negative for ketone bodies. Feeding attempts are discontinued and she is started on nasal cannula, intravenous fluids, and empiric antibiotics. Blood and urine cultures remain sterile. At 18 hours after birth, she becomes acutely bradycardic and hypoxemic requiring cardiopulmonary resuscitation, including intubation, chest compressions, and epinephrine. A comprehensive metabolic panel reveals severe hyperkalemia (8.5 mEq/L [8.5 mmol/L]) and hypoglycemia (34 mg/dL [1.9 mmol/L]). Blood gas measurement shows severe metabolic acidosis, with a pH of 7.12, Pco2 37 mm Hg (4.9 kPa), bicarbonate 15.4 mEq/L (15.4 mmol/L), and base deficit −12. Electrocardiography reveals wide complex ventricular tachycardia (Fig 1). She receives multiple boluses of calcium gluconate, furosemide, albuterol, and sodium bicarbonate for severe hyperkalemia with electrocardiographic changes. She is transferred to a level IV NICU for further evaluation and management.She requires a high glucose infusion rate with intravenous fluids for refractory hypoglycemia for 3 days. Urine ketone bodies during this time continue to be negative. Her potassium continues to remain elevated (maximum of 9.5 mEq/L [9.5 mmol/L]), requiring multiple intravenous sodium bicarbonate and calcium gluconate boluses and eventually dialysis. Electrocardiographic changes seen with hyperkalemia, including third-degree heart block with wide complex ventricular tachycardia, continue to present until the hyperkalemia is corrected with dialysis. Echocardiography shows right ventricular hypertrophy with diminished biventricular function and severe pulmonary hypertension. She is started on inotropic support (epinephrine, vasopressin, and hydrocortisone) for resistant refractory hypotension and metabolic acidosis. Inhaled nitric oxide is started for pulmonary hypertension with progressive improvement in oxygenation. Despite this improvement, she develops hepatomegaly and hepatic dysfunction with elevated liver function tests (alanine aminotransferase 1,103 U/L [18.4 μkat/L] and aspartate aminotransferase 3,409 U/L [57 μkat/L]) and coagulopathy requiring multiple blood product transfusions. She develops seizures requiring phenobarbital and levetiracetam. Head ultrasonography shows ventricular dilation, vermian hypoplasia with periventricular echogenicity, and findings consistent with Dandy-Walker malformation (Fig 2). Renal ultrasonography reveals bilateral renal dysplasia with multiple small cysts and absent cortical medullary differentiation.A full-term neonate presented at less than 24 hours with respiratory failure and lethargy. She went on to have an event requiring cardiopulmonary resuscitation. She was noted to have hypoglycemia, hyperkalemia, third-degree heart block, and metabolic acidosis. She subsequently was found to have cardiac arrhythmias (including ventricular tachycardia), biventricular dysfunction, pulmonary hypertension, systemic refractory hypotension, hepatic failure, dysplastic kidneys, Dandy-Walker malformation, and seizures.SepsisRenal failure secondary to dysplastic kidneysMetabolic disorders^ Organic acidemia^ Fatty acid oxidation defects^ Urea cycle defects^ Chromosomal disorders^ CiliopathiesRefractory nonketotic hypoglycemia in the setting of metabolic acidosis and multiorgan dysfunction is suggestive of a metabolic disorder. Given the broad differential, an extensive evaluation was conducted. Microarray and chromosomal analysis were normal. A ciliopathy panel revealed 6 variants of unknown significance. The newborn screen reported high levels of C16 (28 mmol/L, reference value <8.5 mmol/L), C16-OH (0.265 mmol/L, reference value <0.09 mmol/L), and 17-hydroxyprogesterone (45.7 ng/mL, reference value <35 ng/mL). This combination placed the infant at increased risk for carnitine/acylcarnitine translocase deficiency, carnitine palmitoyltransferase II deficiency (CPT II), glutaric acidemia type II, congenital adrenal hyperplasia, and long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency. Serum/plasma carnitine profile showed marked elevated C16 and C18:1 in association with low acetyl signal. Also, the free carnitine was low and C2 was high. The medium-chain acylcarnitine profile was normal. These findings support the diagnosis of a fatty acid oxidation disorder, likely CPT II deficiency or carnitine/acylcarnitine translocase deficiency. CPT II full mutation analysis identified 2 disease-causing allelic mutations (c.680C>T [p.Pro227Leu] and c.1507C>T [p.Arg503 Cys]) in the CPT2 gene. Together, they are predicted to be associated with CPT II deficiency. In this case, the diagnosis is the neonatal form of CPT II deficiency.Fatty acid oxidation disorders are a group of autosomal recessive conditions with an incidence of 1 in 5,000 to 10,000 births and are an important cause of neonatal mortality. (1)(2) The carnitine palmitoyltransferase system is an essential part of the mitochondrial fatty oxidation pathway responsible for importing the long-chain fatty acyl-CoAs into the mitochondrial matrix from the cytosol. (1)(3) An error in this system results in CPT II deficiency. CPT II deficiency may result in 1 of 3 distinct presentations, a differentiation based on the individual's age at presentation and the organ systems affected (Table). (1)(2)(4) As seen in this case, the lethal neonatal form of CPT II deficiency becomes apparent in the first few days after birth. Infants with this form of the disorder present with respiratory distress, hepatic dysfunction, arrhythmias, and cardiac failure. In many cases, infants also have dysmorphic features such as brain malformations, cystic renal dysplasia, hepatomegaly, and cardiomyopathy. (1) Infants with the neonatal form of CPT II usually live for a few days to a few months, and curative treatment is unavailable.The severe infantile (hepatocardiomuscular) form typically presents within the first year of age with hypoketotic hypoglycemia, seizures, or hepatic failure usually triggered by fasting, fever, or viral illness. Infants with this form of CPT II deficiency are at risk for acute liver failure, cardiomyopathy, encephalopathy, and sudden death. (1)(2)(3)(5) The adult (myopathic) form is the least severe type of CPT II deficiency. It is characterized by episodes of hematuria, myalgias, and rhabdomyolysis, which may be triggered by exposure to fasting, high temperatures, or infections. Individuals with this form usually have no signs or symptoms of the disorder between episodes. (1)The implications of a diagnosis are pertinent for the entire family. CPT II deficiency is inherited in an autosomal recessive pattern. Important clinical features and multiple prediction programs determine if allelic variations are a variance of unknown significance or pathogenic. As biological parents of the affected individual are likely to be carriers of these mutations, genetic confirmation of their carrier status is recommended to aid in counseling about recurrence risk. Recurrence risk in future pregnancies if both parents carry a mutation is 25%. In these situations, preimplantation genetic testing or prenatal diagnosis via either chorionic villus sampling or amniocentesis can be considered for future pregnancies. Siblings of the index cases are at risk of either being carriers of the mutation or having a form of CPT II deficiency themselves. Presymptomatic testing can be considered through targeted gene mutation analysis.The infant required hemodialysis and continuous renal replacement therapy during her hospitalization. Her respiratory status improved and she ultimately underwent extubation but could never effectively feed by mouth. Once the diagnosis of neonatal CPT II deficiency was confirmed, discussions were held with the family about the poor prognosis and their goals of care. She was eventually discharged from the hospital on nasal cannula, nasogastric feeds, and phenobarbital with home hospice support. Five days after discharge, she developed abdominal distention and lethargy. She was brought to the hospital to determine if the cause of her clinical change was reversible. The distention was caused by worsening hepatomegaly. As this resulted from her underlying diagnosis, the family elected to take her home without further medical testing or interventions. She was given a “do not resuscitate” status and died peacefully at home with the support of hospice.Fatty acid oxidation defects should be considered in cases of refractory nonketotic hypoglycemia with metabolic acidosis. (2)Abnormal newborn screening for CPT II deficiency warrants further confirmatory testing with acylcarnitine profile and CPT II full mutation analysis. (6)CPT II deficiency is an autosomal recessive disorder of the mitochondrial ß-oxidation of long-chain fatty acids. (1)The neonatal form of CPT II deficiency is lethal and can present in the first days after birth, usually with multiorgan dysfunction and refractory metabolic acidosis. (1)(4)(6)