CALFAN (Low γ-Glutamyl Transpeptidase (GGT) Cholestasis, Acute Liver Failure, and Neurodegeneration) Syndrome: A Case Report with 3-Year Follow-Up after Liver Transplantation in Early Adulthood

CALFAN syndrome is an extremely rare disease consisting of recurrent pediatric acute liver failure (PALF), neurodegenerative diseases, and skeletal abnormalities associated with SCYL1 gene mutation. To date, three of 18 patients reported underwent liver transplantation in infancy and early childhood (7–23 months). Here, we report a case of CALFAN syndrome with infantile onset, recurrent jaundice/PALF requiring liver transplantation in early adulthood. At the most recent follow-up, 3 years after transplantation, the patient is doing well.

Here, we report a case of CALFAN syndrome from a 23year-old-male with recurrent bouts of PALF, hepatosplenomegaly, cerebellar atrophy, and neurocognitive difculties appeared in his infancy. Liver failure ceased at 2 years of age but hepatosplenomegaly and neurologic symptoms were persistent. Te patient was diagnosed with SCYL1 gene mutation by whole exome sequencing [3] when he was 14. Te patient's liver function was well until jaundice recurred at age 20 years. Subsequently, the patient underwent liver transplantation. Te patient has been well for 3 years after transplantation.

Case Report
Te patient, a male of white European descent with British and German ancestry, was admitted for evaluation of liver transplantation at age 20 years. Beginning at approximately 9 months of age, he presented with recurrent episodes of PALF. His mother found him icteric after febrile illness. Between these episodes, liver enzymes were normal or exhibited only mild elevations. Te patient's liver episodes ceased at 2 years of age but showed hepatosplenomegaly. Te In addition to the liver issue, his family was concerned about his developmental delay, e.g., started walking at age 2, spoke in several word phrases by age 2-3 years. At age 4, he developed a stutter, which signifcantly afected his expressive speech. Neurologic symptoms included signifcant tremors, motor disability, and peripheral neuropathy (e.g., foot drop requiring leg braces). Cavus foot was also noted. In childhood, he developed autistic behavior and attention defcits. A brain MRI at age 9 revealed mild cerebellar vermian atrophy.
At the age of 14, whole exome sequence analysis [3] revealed to harbor two variants in the SCYL1 gene, i.e., heterozygous for c.937delG (maternally inherited) and c.1509 1510delTG (paternally inherited) previously unreported [3]. His mother was heterozygote for the c.937delG variant and did not harbor c.1509 1510delTG. His father was heterozygote for the c.1509 1510delTG variant and did not harbor the c.937delG variant. Both parents are asymptomatic. He was well and started a program at age 19 years for kids with intellectual disability for the goal to live independently. His last upper endoscopy was at age 12 with no signifcant fndings. He has had regular abdominal ultrasound examinations that have been stable. His hemoglobin, albumin, and bilirubin at age 19 were within normal range.
At age 20, he developed jaundice again after fever and rhinorrhea. His LFT was notable for TB 7.7 mg/dL (DB 4.4), ALP 458 IU/L, ALT 692 IU/L, AST 304 IU/L, and INR 2.52. GGT was 20 U/L, consistent with low GGT cholestasis. Platelet count was 33,100/μL. Tere was no history of acetaminophen or salicylate use. Abdominal ultrasound showed cirrhotic morphology and splenomegaly. He did not respond to conservative management and underwent liver transplantation eventually. Te explanted liver demonstrated 1,677 gram weighed green-colored (cholestatic) parenchyma with slightly nodular surface (Figure 1). Microscopic fndings showed cirrhosis (Figure 1), cholestatic liver injury, and prominent bile ductular proliferation (Figure 2). Steatosis was minimal.
He recovered well but experienced postoperative biliary stricture requiring several occasions of endoscopic retrograde cholangiopancreatography with stent insertion. After 3 year follow-up, he has been stable with the stricture resolved. He is on tacrolimus and mycophenolate. No clinical suspicion of acute cellular rejection has been identifed, nor has posttransplant liver biopsy ever been required. Most recent LFT showed TB 2.1 mg/dL (DB 0.4), ALP 72 IU/L, ALT 18 IU/L, AST 13 IU/L, and GGT 4 U/L. However, he still wears leg braces and has limited expressive language. Follow-up brain MRI also revealed persistent cerebellar atrophy.

Discussion
SCYL1 gene encodes SCY1-like-protein 1, a member of the SCY1-like family of pseudokinase involved in intracellular transport processes and regulation of neuronal function and survival [3,9]. Mechanisms of liver injury remain unclear.
To date, 18 patients of CALFAN syndrome with SCYL1 mutation including our case have been reported. Most patients showed recurrent hepatopathy with infantile onset, triggered by febrile illness. Low or normal GGT episodes were recorded in 11 of 18 patients. "Bonafde" PALF [10] was documented in 13 of 18 patients but no fatality has been reported. Between episodes LFT and symptoms returned to baseline, however hepatosplenomegaly persisted.
Most patients' liver episodes decline or cease in early childhood. Tree of 18 patients have been reported to undergo liver transplantation at 23 months of age [1], 7 months [4], and 21 months [4] (Table 1). However, none of the cases were expected to have SCYL1 mutation at the time of transplantation. No graft failure after transplantation has been reported (follow-up for 8-11 years). Our case was transplanted at 20 years of age while the defnitive diagnosis was made at 14 years. Neurodegenerative symptoms appeared to be persistent following liver transplantation, as did our patient's.
In summary, we experienced the frst case of CALFAN syndrome requiring liver transplantation in adulthood with the defnitive diagnosis. Our patient has been doing well for 3 years following the transplantation without an episode of rejection or signifcant postoperative complication. As per literature review, graft survival is expected to be excellent.
Except our case, all of transplanted cases were found to have SCYL1 mutation after transplantation. It is also noted that the liver episodes of CALFAN syndrome appeared to decline with age. Not only is early suspicion of the syndrome with the aforementioned symptom complex important, but also the optimal timing of transplantation should be carefully considered when the diagnosis is made.

Data Availability
Te patient data used to support the fndings of this study are included within the article.

Consent
A written informed consent has been obtained from the patient.

Conflicts of Interest
Te authors declare that there are no conficts of interest related to the submission.

Authors' Contributions
All authors approved the fnal manuscript. Mariam Youssef drafted the manuscript. Katherine L Mascia was involved in data acquisition and genetic and clinical fndings. Brendan McGuire revised the manuscript, reviewed the literature. Chirag R Patel, Sameer Al Difalha, and Deepti Dhall revised the manuscript and reviewed the literature. Goo Lee was involved in study supervision.