What is the diagnosis for a neonate with congenital bone marrow failure and cholestasis with normal gamma-glutamyltransferase (GGT) levels?

From the Guidelines

Congenital marrow failure associated with cholestasis and normal gamma-glutamyl transferase (GGT) in a neonate is highly suggestive of a genetic disorder, such as Familial Intrahepatic Cholestasis 1 (FIC1) disease, which requires prompt evaluation and management by a multidisciplinary team of specialists. The normal GGT level in this scenario is a key distinguishing feature that points towards disorders of bile acid synthesis or transport, rather than other causes of neonatal cholestasis 1.

Initial Management

Initial management should include:

• Supportive care with fat-soluble vitamin supplementation (vitamins A, D, E, K) to address potential deficiencies
• Medium-chain triglyceride (MCT)-enriched formula to promote nutrition
• Ursodeoxycholic acid (10-15 mg/kg/day divided twice daily) to promote bile flow, which may improve cholestasis in about 30% of cases, as seen in FIC1 disease 1
• For the bone marrow failure component, granulocyte colony-stimulating factor (G-CSF) at 5-10 mcg/kg/day may be needed for neutropenia, and transfusion support with irradiated blood products for severe anemia or thrombocytopenia

Genetic Testing and Diagnosis

Genetic testing is essential and should include targeted gene panels for cholestasis and bone marrow failure syndromes or whole exome sequencing to identify the underlying genetic disorder. The diagnosis of FIC1 disease, for example, is based on clinical manifestations, liver histology, and genetic testing, as well as specific tests excluding other causes of childhood cholestasis 1.

Prognosis and Long-term Implications

Prognosis varies by specific diagnosis, but many of these conditions have serious long-term implications, so early diagnosis is crucial for appropriate genetic counseling and consideration of potential transplantation options (liver and/or bone marrow) in eligible cases. In FIC1 disease, partial external biliary diversion (PEBD) or ileal exclusion (IE) can significantly slow disease progression, and liver transplantation may be an option for patients with advanced liver disease 1.

Key Considerations

• The normal GGT level is a critical clue that distinguishes this condition from other causes of neonatal cholestasis
• Early diagnosis and management are crucial to improve outcomes and prevent long-term complications
• A multidisciplinary approach, including neonatology, hematology, and hepatology specialists, is essential for optimal care.

From the Research

Congenital Marrow Failure in Cholestasis with Normal GGT in Neonate

• Congenital bone marrow failure syndromes (CBMFS) are extremely uncommon diseases that can present in the neonate 2
• CBMFS should be considered when a single or multiple blood cell lineages are low secondary to failure of production 2
• Diagnosis in the neonatal period requires a high index of suspicion, particularly when the neonate has a family history of CBMFS, is small for gestational age, or has other physical abnormalities 2
• Inherited bone marrow failure syndromes (IBMFS) are a rare yet clinically important cause of neonatal hematological and non-hematological manifestations, and may present with cytopenias in the neonatal period or with congenital physical abnormalities and progress to pancytopenia later in life 3
• A thorough family history and detailed physical examination are integral to the work-up of any neonate in whom there is a high index of suspicion for an IBMFS 3
• Correct detection and diagnosis of these disorders is important for appropriate long-term medical surveillance and counseling not only for the patient but also for appropriate genetic counselling of their families regarding recurrence risks in future children and generations 3

Treatment and Management

• The treatment approach for bone marrow failure is very dependent on the underlying cause, which makes it all the more critical to have an accurate diagnosis 4
• First line management essentially consists of either hematopoietic stem cell transplant or immunosuppressive therapy 4
• Hematopoietic stem cell transplantation is a viable option for bone marrow failure syndromes in children, including those with congenital etiologies 5
• Advances in the genetic interrogation of patient samples have led to identification of inherited germline diseases and appreciation that patients with inherited bone marrow failure disorders may be normal in appearance with few expected clinical clues 6