Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

ICD-10 Coding

Disorder Category

Abnormal Finding

Tested By

Citrin deficiency arises from a deficiency of citrin protein, whose role in mitochondrial transport is critical to the citric acid/Krebs and urea cycles. This condition is not to be confused with Citrullinemia Type 1 (primary defect of arginosuccinate synthetase).

There are 3 subtypes of citrin deficiency largely defined by the timing of their symptom onset:

1. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), also known as neonatal-onset type II citrullinemia, typically presenting before 1 year of age
2. Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) with symptom onset from 1 year of age to adolescence
3. Citrullinemia type II (CTLN2), also known as adult-onset type II citrullinemia, presenting in adulthood

In all 3 subtypes, patients will have a naturally developed preference for protein and lipid-rich foods and relative avoidance of carbohydrates, regardless of treatment. Clinical manifestations are highly variable and range from neonatal cholestasis and liver dysfunction in NICCD to failure to thrive and dyslipidemia in FTTDCD, and hyperammonemia with neuropsychiatric symptoms in CTLN2. It is unclear why some patients develop a more severe form of the condition.

The therapeutic approaches vary based on the form of citrin deficiency but typically consist of some nutritional guidance with a diet high in protein and lipids and low in carbohydrates. Supplementation with various vitamins and minerals may be necessary, and in some cases of CTLN2, liver transplantation may be indicated.

Clinical Characteristics

• Fat-soluble vitamin supplementation (ADEK)
• Medium-chain triglyceride enriched formulas

Incidence

Inheritance

Next Steps After a Positive Screen

• Contact the family and evaluate the infant for poor feeding, vomiting, jaundice, lethargy, and tachypnea.
• Consult a metabolic geneticist in Medical Genetics (see NM providers [2]) to provide emergency treatment/referral for symptoms of vomiting, hypotonia, tachypnea, seizures, or signs of liver disease. See the ACT Sheet for Elevated Citrulline (ACMG) for additional information.
• Contact Newborn Screening Services (see NM providers [3]) to determine what testing is required.

Confirming the Diagnosis

• To confirm the diagnosis, work with Newborn Screening Services (see NM providers [3]).
• Biochemical testing following an abnormal newborn screen may include plasma ammonia, plasma amino acids, lactate, and liver function tests. Additional testing and potentially hospitalization may be necessary for symptomatic patients in consultation with a metabolic geneticist.
• Confirmation can be made with genetic testing for variants in the SLC25A13 gene.
• In addition to genetic testing, findings suggestive of citrin deficiency may include hyperammonemia, citrullinemia, increased plasma tyrosine, argininemia, galactosemia, increased plasma threonine-to-serine ratio, and increased pancreatic secretory trypsin inhibitor (PSTI) levels.

If the Diagnosis is Confirmed

• For evaluation and ongoing collaborative management, consult Medical Genetics (see NM providers [2]).
• Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill. See Citrullinemia - Information for Parents (STAR-G).
• Assist in the maintenance of a high-protein and lipid diet and supplementation of necessary vitamins and minerals.
• Regular monitoring of growth parameters. For those identified after irreversible consequences, assist in management, particularly with developmental and educational resources. See Early Intervention for Children with Disabilities/Delays (see NM providers [34]).
• A dietician may work with the family to devise an optimal approach to dietary management. See Dieticians and Nutritionists (see NM providers [1]).
• Genetic Testing and Counseling (see NM providers [5]) to assist the family in understanding the diagnosis and risks for future pregnancies and relatives.