19.3 Genetics, Inborn Errors of Metabolism & Pediatric Pharmacogenomics
Key Takeaways
Evaluate sepsis and metabolic disease in parallel. Obtain glucose, acid–base data and a promptly processed ammonia level while beginning stabilization.
Use ammonia level, trajectory and neurologic findings to decide how urgently to clear ammonia. Tailor calories and substrate management to the suspected disorder.
Use the analyte-specific newborn screening pathway. For 22q11.2 deletion, use the recommended diagnostic test and assess calcium and immune function before vaccine and transfusion decisions.
Apply pharmacogenomic results to the specific drug, indication and age. Check U.S. labeling for separate contraindications and screening requirements.
A newborn with poor feeding, tachypnea, lethargy or seizures can have sepsis, a metabolic disorder, or both. Evaluate and stabilize in parallel. Ask about age at onset, recent feeding or fasting, illness, a known emergency plan, unexplained sibling deaths and newborn screening. Some affected newborns look well initially. Symptoms can begin before a screening result returns.
Suspected metabolic crisis
Check bedside glucose, blood gas, electrolytes, lactate, plasma ammonia, liver tests, coagulation and urine ketones. Calculate the anion gap by subtracting the sum of chloride and bicarbonate from sodium. For sodium 138, chloride 104 and bicarbonate 12 mEq/L, the gap is 22 mEq/L. Use the laboratory reference range and interpret the result alongside lactate and ketones. In a neonate, marked ketonuria with an increased gap points toward an organic acidemia. A single urine ketone result cannot establish the diagnosis.
Draw a free-flowing venous or arterial sample for ammonia. Avoid prolonged tourniquet use and hemolysis. Send it for immediate processing under the local laboratory protocol. The pediatric kidney replacement consensus specifies transport on ice. Repeat a questionable result promptly, and start treatment in parallel when encephalopathy or a markedly elevated result makes the risk high. Collect plasma amino acids and acylcarnitines and urine organic acids and orotic acid early when feasible. Treat hypoglycemia or shock without waiting for samples. Pediatric hyperammonemia consensus · Ammonia specimen stability study
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Stabilize and call metabolic specialists early. Support the airway and circulation and treat hypoglycemia. Evaluate for infection and treat suspected sepsis in parallel.
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Reverse catabolism. For acute neonatal hyperammonemia, an initial glucose infusion rate (GIR) of 8–10 mg/kg/min is one consensus approach. Monitor glucose, electrolytes and fluid balance. Tailor the glucose concentration and delivery to the child's age, condition and access. D10 contains 100 mg/mL. In a 3 kg neonate receiving D10 at 14.4 mL/hr, the GIR is 8 mg/kg/min.
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Tailor substrate management. Temporarily withhold protein in a suspected hyperammonemic urea-cycle crisis. Plan early reintroduction with the metabolic team as ammonia falls, typically within 24–48 hours. Avoid fasting in fatty-acid oxidation disorders. Use glucose as initial energy support and discuss IV lipids with the metabolic team when a fatty-acid oxidation defect remains possible. An initial pattern suggestive of a urea-cycle disorder does not establish that fat oxidation is intact.
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Treat hyperammonemia and prepare for rapid clearance. Use serial ammonia and neurologic findings with urgent metabolic and nephrology input. For suspected urea-cycle decompensation, the team may use IV sodium phenylacetate and sodium benzoate with arginine when appropriate for the suspected enzyme defect. Avoid arginine in arginase deficiency. Marked elevation above 500 µmol/L, such as the 620 µmol/L neonatal case below, warrants immediate preparation and initiation of extracorporeal clearance alongside medical treatment. Rapid neurologic deterioration, seizures or encephalopathy, a rapid rise, or poor response may justify clearance at a lower concentration. High-dose continuous venovenous hemodialysis is preferred by the pediatric consensus when feasible. Intermittent hemodialysis may provide rapid clearance, with modality and rebound monitoring guided by the treating team. Urea-cycle guideline · Pediatric kidney replacement consensus · U.S. AMMONUL label
| Disorder | Clues | Initial disease-specific action |
|---|---|---|
| Urea-cycle disorders such as ornithine transcarbamylase deficiency | High ammonia with early respiratory alkalosis and no major anion gap elevation may be the first pattern. Glucose can be normal. | Temporarily interrupt protein, provide calories, and use the urgent ammonia-lowering approach above. Plasma amino acids and urine orotic acid help narrow the enzyme defect. |
| Organic acidemias such as methylmalonic and propionic acidemia | Increased anion gap, ketosis, and sometimes secondary hyperammonemia or cytopenias. An elevated C3 screen can occur in either disorder. | Interrupt excess precursor intake and reverse catabolism with specialist guidance. Consider levocarnitine, carglumic acid for selected hyperammonemic presentations and hydroxocobalamin evaluation in suspected methylmalonic acidemia. Biotin treats biotinidase deficiency. Evidence does not support routine biotin treatment for isolated propionic acidemia. MMA/PA guideline · U.S. CARBAGLU label |
| Fatty-acid oxidation disorders such as MCAD and VLCAD deficiency | Hypoglycemia with inappropriately low ketones during fasting or illness is a clue. Long-chain disorders can also cause cardiomyopathy or rhabdomyolysis. | Avoid fasting. Give IV dextrose when intake is inadequate or the child is hypoglycemic or decompensating. The acylcarnitine pattern, history and confirmatory testing guide disorder-specific nutrition. Pediatric MCAD acute illness guidance · Long-chain FAOD guideline |
| Classic galactosemia | Poor feeding, jaundice, liver dysfunction or coagulopathy after milk exposure. Consider associated E. coli sepsis. | Replace breast milk or lactose-containing formula with a suitable galactose-restricted formula in suspected classic disease. Treat suspected neonatal sepsis promptly. Donor red cells can mask low erythrocyte GALT activity, so tell the testing laboratory about transfusion and coordinate confirmation. GalNet guideline · ACMG testing standard |
Newborn screen and acute genetic findings
Follow the state program and the analyte-specific ACMG ACT sheet. Contact the family, assess clinical status and consult the appropriate specialist promptly for a time-critical result. For example, elevated C8 suggests MCAD, elevated C3 can reflect a propionate disorder, and elevated leucine requires follow-up for maple syrup urine disease. Confirmatory plasma amino acids including alloisoleucine help identify maple syrup urine disease, in which leucine accumulation can cause cerebral edema. A sick infant requires urgent evaluation even if the newborn screen is pending or was reported normal. ACMG ACT sheets · ACMG leucine ACT sheet
Elevated 17-hydroxyprogesterone (17-OHP): Assess immediately for poor feeding, vomiting, dehydration, atypical genitalia or shock. Consult pediatric endocrinology the same day. Prematurity and stress can raise screening 17-OHP. Check serum electrolytes, glucose and confirmatory 17-OHP with the endocrine team. Salt-wasting 21-hydroxylase deficiency can present in the first weeks even with typical external genitalia. Give parenteral hydrocortisone and resuscitate promptly for suspected adrenal crisis. ACMG 2024 CAH ACT sheet · Endocrine Society CAH guideline
- Down syndrome: Use cervical positioning precautions during airway management and investigate new neck pain, gait change or myelopathic signs. Routine cervical screening films in asymptomatic children are not recommended. Obstructive sleep apnea, airway anomalies and atrioventricular septal defect can affect respiratory support. Check neonatal CBC with differential by day three for transient abnormal myelopoiesis and other hematologic findings. AAP Down syndrome report
- 22q11.2 deletion: Consider with interrupted aortic arch type B, truncus arteriosus, tetralogy of Fallot, palatal findings or hypocalcemia. Chromosomal microarray is preferred for initial diagnostic testing. A targeted FISH probe can miss deletions outside its coverage and is useful for selected family testing when the familial deletion is known to be covered. Check calcium and obtain CBC with differential and absolute lymphocyte count at diagnosis. Consult immunology about lymphocyte subsets, T-cell function and vaccine decisions. For confirmed deletion pending immune assessment, AAP recommends CMV-negative, irradiated components when transfusion is needed and deferral of live-virus vaccines. Coordinate with transfusion medicine. AAP 22q11.2 report · 22q11.2 immunology guidance
- Marfan and Loeys–Dietz syndromes: Both increase risk of aortic aneurysm and dissection. Risk in Loeys–Dietz depends on genotype and phenotype and can occur at smaller diameters. With concerning sudden chest, back or abdominal pain, mobilize the aortic team and arrange urgent imaging, usually CT angiography when feasible. For suspected acute aortic syndrome with adequate perfusion, the ACC/AHA guideline uses IV beta blockade first when tolerated, adding a vasodilator if pressure remains high. Shock requires urgent cause-directed support. In patients with a known aneurysm or increased aortic risk, U.S. ciprofloxacin labeling reserves use for situations without alternative antibacterials. ACC/AHA aortic disease guideline · U.S. CIPRO label
- Williams syndrome: Supravalvar aortic and pulmonary arterial stenoses, coronary involvement, hypertension and infantile hypercalcemia can affect acute care. Sedation and anesthesia can carry substantial cardiovascular risk. Involve an experienced pediatric cardiac anesthesia team and plan to maintain coronary perfusion and hemodynamic stability. AAP Williams syndrome report · Cardiovascular consensus
Pharmacogenomics in acute care
Interpret a result using the specific drug, age, indication and phenotype. CPIC explains how to act on a result. U.S. prescribing information may separately define who needs testing or who should avoid a drug.
| Result | Implication and decision |
|---|---|
| CYP2D6 and codeine or tramadol | Ultrarapid metabolizers generate more active opioid metabolite and risk respiratory depression. Poor metabolizers can have reduced analgesia. CPIC advises avoiding these agents in both phenotypes. U.S. analgesic labeling contraindicates both below age 12 and after tonsillectomy or adenoidectomy below age 18. Avoid in adolescents with respiratory risk factors such as obesity, obstructive sleep apnea or severe lung disease per pediatric guidance. CPIC opioids · AAP pediatric acute pain |
| CYP2D6 and ondansetron or atomoxetine | For ondansetron in an ultrarapid metabolizer, CPIC suggests an alternative such as granisetron when appropriate. Poor metabolizers can have higher atomoxetine exposure. Use the pediatric CPIC titration table, clinical response and adverse effects. CPIC ondansetron update · CPIC atomoxetine |
| CYP2C19 and voriconazole, clopidogrel or a proton pump inhibitor | For pediatric voriconazole, use an alternative in ultrarapid or poor metabolizers when possible. Rapid metabolizers can start standard therapy with therapeutic drug monitoring. Reduced clopidogrel activation in intermediate or poor metabolizers matters in specific indications. The supporting outcome data are mainly adult. Use specialist guidance for children; adding clopidogrel did not improve clinical outcomes in the infant systemic-to-pulmonary shunt trial. For selected PPIs such as omeprazole or pantoprazole, CYP2C19 affects exposure; use drug-, indication- and duration-specific CPIC guidance. CPIC voriconazole · CPIC clopidogrel · Infant shunt trial · CPIC PPIs |
| TPMT and NUDT15 and thiopurines | Reduced function increases myelosuppression risk with mercaptopurine, thioguanine and azathioprine. Use the CPIC 2025 update tables, published in 2026, for the specific drug, indication and combined phenotype. Large starting-dose reductions may be needed in malignancy and an alternative is often appropriate in nonmalignant disease for poor metabolizers. Monitor blood counts and adjust with the treating service. CPIC thiopurines |
| HLA-B*15:02 and HLA-A*31:01 | HLA-B*15:02 raises SJS/TEN risk with carbamazepine and oxcarbazepine. Check ancestry and drug labeling for testing and use an alternative in a positive, drug-naïve patient per CPIC. HLA-A*31:01 increases risk of several cutaneous reactions to carbamazepine, including DRESS; choose an alternative if available in a carbamazepine-naïve patient. CPIC HLA and anticonvulsants |
| G6PD deficiency and rasburicase or methylene blue | U.S. labels contraindicate both drugs in known G6PD deficiency. Screen higher-risk patients before rasburicase. If hemolysis or methemoglobinemia occurs on rasburicase, stop it immediately and permanently and provide emergency support. Confirm suspected methemoglobinemia with blood co-oximetry. A normal enzyme assay during acute hemolysis or after red-cell transfusion can miss deficiency. CPIC G6PD · ELITEK label · PROVAYBLUE label |
| UGT1A1 and conventional irinotecan | Poor metabolizers such as *28/*28, *6/*6 or *6/*28 have increased SN-38 exposure and risk of severe neutropenia. U.S. CAMPTOSAR labeling advises considering at least one starting dose-level reduction. The exact reduction depends on the regimen; use the pediatric oncology protocol and monitor toxicity. CAMPTOSAR label |
A 4-day-old term neonate has progressive lethargy, poor feeding, tachypnea and hypotonia. Glucose is 74 mg/dL. The blood gas shows pH 7.49, PCO₂ 25 mmHg and bicarbonate 19 mEq/L. The anion gap is 10 mEq/L, urine ketones are absent, and a promptly processed plasma ammonia is 620 µmol/L. What is the best immediate metabolic plan alongside stabilization and evaluation for infection?
Give empiric antibiotics and repeat the ammonia in 12 hours before treating the elevation.
Start soy-based formula and give IV bicarbonate for presumed metabolic acidosis.
Use a low-rate glucose infusion and await newborn screening before starting ammonia-lowering therapy.
Temporarily stop protein, provide IV glucose, and start specialist-guided IV ammonia scavengers and arginine while arranging immediate extracorporeal clearance.
A 10-month-old with a repaired interrupted aortic arch and confirmed 22q11.2 deletion needs a red-cell transfusion. The immune evaluation is pending. Which preparation follows AAP guidance and reduces the risk of transfusion-associated graft-versus-host disease?
Irradiated, CMV-negative red blood cells
Unirradiated whole blood to preserve donor T-lymphocyte immune support
Routine crossmatched blood without irradiation, paired with an immediate live MMR vaccine
Use fresh frozen plasma in place of red cells.
A 9-year-old with Burkitt lymphoma receives rasburicase for tumor lysis. Hours later he develops dark urine, falling hemoglobin and altered mental status despite high-flow oxygen. Blood co-oximetry shows methemoglobin 32%. The team retrieves a prior result documenting G6PD deficiency. Which response is most appropriate?
Repeat rasburicase and give IV methylene blue.
Continue rasburicase and give red cells without addressing the methemoglobinemia.
Stop rasburicase permanently, support oxygen delivery, and obtain urgent critical care, toxicology and transfusion input for red-cell support and possible exchange. Avoid methylene blue.
Give ascorbate alone and wait for the methemoglobin level to fall before escalating.
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