Recurrent acute liver failure in infancy - a novel SCYL1 mutation: A case report

Abstract

BACKGROUND

Recurrent acute liver failure (ALF) in children is rare and diagnostically challenging. Despite rigorous investigations, a significant proportion of patients remain without a definitive diagnosis. Recently across the literature, biallelic pathogenic variants in the SCYL1 gene had been identified to cause a hepatocerebellar syndrome characterized by low gamma-glutamyl transferase (GGT) cholestasis, episodic ALF, and progressive neurodegeneration, collectively termed cholestasis, ALF, and neurodegeneration (CALFAN) syndrome (or spinocerebellar ataxia, autosomal recessive type 21). A high index of suspicion is paramount to recognizing this entity early, given that its presentation overlaps with more prevalent conditions, and delayed diagnosis carries significant morbidity and mortality risk.

CASE SUMMARY

We report a 19-month-old girl of Middle Eastern ethnicity, presenting with recurrent episodes of febrile illness, ALF, and low-GGT cholestasis initially misattributed to viral hepatitis. Clinical evaluation revealed subtle neurological abnormalities, including tremors and fine motor delay. The highlight of her presentation was pancytopenia, which expanded the known phenotypic spectrum. Extensive metabolic, infectious, and autoimmune investigations were inconclusive. Whole exome sequencing identified a homozygous likely pathogenic SCYL1 variant (c.1420C>T; p.Arg474*), consistent with CALFAN syndrome/spinocerebellar ataxia, autosomal recessive type 21. Liver biopsy showed degenerative and early fibrotic changes. Liver function partially improved with corticosteroids and supportive care but did not normalize; a third episode of liver failure occurred at 22 months in the setting of a febrile urinary tract infection.

CONCLUSION

SCYL1-related disease should be considered in children with unexplained recurrent ALF, particularly when low-GGT cholestasis and neurological features co-exist. Early genetic evaluation using whole exome sequencing is essential for establishing the diagnosis. Steroid therapy was transiently associated with partial biochemical improvement, although its mechanism in a genetic disorder remains uncertain. This case further demonstrates that pancytopenia may be part of the CALFAN phenotypic spectrum.

Key Words: SCYL1 mutation; Recurrent acute liver failure; Pediatric acute liver failure; Cholestasis, acute liver failure, and neurodegeneration syndrome; Spinocerebellar ataxia, autosomal recessive type 21; Hepatocerebellar syndrome; Neurodegeneration

Core Tip: Recurrent acute liver failure (RALF) in children is an uncommon but life- threatening condition that may mask underlying genetic disorders. We report a child with febrile RALF and subtle neurological findings in whom whole exome sequencing identified a homozygous SCYL1 mutation consistent with a hepatocerebellar syndrome. This case highlights the importance of early genetic evaluation in unexplained RALF, particularly when neurological features are present. Prompt recognition of SCYL1- related disease can refine diagnosis, guide management, prevent unnecessary investigations, and improve long-term clinical outcomes.

INTRODUCTION

Acute liver failure (ALF) in infants and young children represents one of the most diagnostically challenging emergencies in paediatric medicine. Despite extensive metabolic, infectious, and immunological work-up, the underlying etiology remains obscured in up to 50% of cases. Consequently, this directly interferes with timely life-saving interventions, including liver transplantation[1,2]. Recurrent ALF (RALF), defined as two or more discrete episodes of ALF, narrows the differential diagnosis considerably, pointing toward hereditary metabolic, mitochondrial, or genetic disorders. The episodic nature of RALF, characteristically triggered by intercurrent febrile illness, suggests that cellular stress pathways amplify an underlying constitutional vulnerability. Nevertheless, establishing the precise diagnosis remains difficult until advanced investigations are pursued[3].

Disorders of intracellular vesicular transport have emerged as an important and expanding cause of RALF in childhood. Mutations in NBAS, encoding a subunit of the NRZ tethering complex critical for endoplasmic reticulum (ER) to Golgi and retrograde transport, are now a well-characterised cause of RALF with multisystemic involvement[3]. Similarly, biallelic loss-of-function variants in RINT1 and SCYL1 have been identified as further members of this group[3]. SCYL1 encodes SCY1-like pseudokinase 1, a scaffolding protein essential for coat protein complex I-mediated retrograde vesicular transport from the Golgi apparatus to the ER. Impairment of SCYL1 function disrupts Golgi architecture, increases ER stress, and compromises cellular homeostasis[1,4,5]. During systemic stress such as fever, this maladaptive cellular equilibrium may collapse, triggering hepatocyte apoptosis and acute hepatic decompensation[1]. Clinically SCYL1 deficiency manifests as (cholestasis, ALF, and neurodegeneration) CALFAN syndrome or (spinocerebellar ataxia, autosomal recessive type 21) SCAR21, characterised by low-gamma-glutamyl transferase (GGT) cholestasis, RALF, and a gradual neurological phenotype encompassing cerebellar ataxia, peripheral neuropathy, and variable pyramidal signs[1,6].

We report a case of RALF in a 19-month-old girl of Arab descent caused by a homozygous SCYL1 nonsense variant (c.1420C>T; p.Arg474*), confirmed by whole exome sequencing (WES). This case is remarkable for several reasons: The presence of pancytopenia as a multisystemic feature not consistently described in prior reports; the absence of GGT elevation despite severe hepatic biochemical derangement; the early age of presentation; and the temporal association with corticosteroid therapy. We review the existing literature on SCYL1-associated disease to contextualise our findings and discuss diagnostic and management implications for clinicians encountering unexplained paediatric RALF.

CASE PRESENTATION

Chief complaints

Yellowish discoloration of the skin and eyes for two days.

History of present illness

A previously healthy 19-month-old girl presented following a five-day history of fever (up to 38.8 °C) and coryza. On day one of illness, she was assessed by a primary care physician and commenced empirically on oral amoxicillin-clavulanate. Parents were additionally advised to administer weight-appropriate paracetamol (15 mg/kg/dose every six hours as needed) for fever management. By day three of illness, fever persisted, and paracetamol use continued. On day seven of illness, parents noted progressive yellowish discoloration of the skin and sclerae, associated with poor activity and reduced appetite. There was no dark urine, pale stool, or pruritus. Bowel habits were otherwise regular. No herbal preparations or hepatotoxic medications had been administered prior to this illness. In reviewing her prior medical records at another facility, it was noted that this was the second episode of acute liver injury; the first had occurred at approximately 15 months of age following a similar febrile upper respiratory illness and had been attributed to viral hepatitis at that time, with apparent recovery to baseline over four weeks (Table 1).

Table 1 Clinical timeline: Episodes of acute liver failure.

Age	Trigger	Key laboratory findings	Treatment	Outcome
19 months	Fever + URTI; antibiotics and paracetamol given	ALT: 1840, AST: 2210, Bili: 340 μmol/L, GGT: 18 (low), INR: 2.8, pancytopenia	Corticosteroids, IV fluids, nutritional support	Partial improvement; no normalisation
21 months	Febrile illness	ALT: 980, AST: 1140, Bili: 210, GGT: 20, INR: 2.1	Supportive care; steroids repeated	Partial improvement; ongoing enzyme elevation
22 months	Febrile UTI	ALT: 2100, AST: 2450, Bili: 380 μmol/L, INR: 3.1, GGT: 24, Plt: 62	Antibiotics + supportive care	Ongoing follow-up; genetic counselling initiated

URTI: Upper respiratory tract infection; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Bili: Total bilirubin; GGT: Gamma-glutamyl transferase; INR: International normalized ratio; IV: Intravenous; UTI: Urinary tract infection; Plt: Platelets.

History of past illness

The pregnancy was spontaneous and represented the second gestation for a 28-year-old mother, with no history of prior miscarriages or stillbirths. A full-term female infant was delivered via spontaneous vaginal delivery following an uncomplicated pregnancy. Birth weight was 3000 g, with no reported perinatal complications. Developmental milestones were reportedly normal in the first year of life, though parents retrospectively recalled some fine motor clumsiness.

Personal and family history

There was no family history of liver failure, metabolic disease, or any chronic illness. The parents were non-consanguineous to the best of their knowledge. No herbal supplements were used.

Physical examination

Anthropometric measurements showed weight at the 88^th percentile and height at the 15^th percentile, suggesting relative stunting. Vital signs were within normal limits for age, with no fever at the time of examination. On general examination, there was marked icterus of the skin and mucous membranes. Abdominal examination revealed no cutaneous stigmata of chronic liver disease, no dilated abdominal veins, and no organomegaly. The patient appeared jittery. Neurological assessment was significant for brisk deep tendon reflexes, dysmetria on finger-nose testing, and truncal ataxia. Fine motor skills appeared delayed for age. No cerebellar tremor at rest was documented, though action tremor was elicited. The remainder of systemic examination was unremarkable.

Laboratory examinations

Liver function tests revealed markedly elevated transaminases with severe conjugated hyperbilirubinaemia. Critically, GGT was persistently low-normal across all three episodes (range 18-24 U/L), a finding inconsistent with biliary obstruction and highly characteristic of SCYL1-associated cholestasis. Coagulation studies were significantly deranged with an international normalized ratio of 2.8 on admission. Complete blood count revealed pancytopenia (white blood cell count: 2.1 × 10⁹/L, haemoglobin: 8.2 g/dL, platelets: 68 × 10⁹/L), a finding less consistently reported in the SCYL1 literature and suggestive of possible multisystemic involvement beyond the hepatocerebellar axis. Comprehensive laboratory values across all three episodes are presented in Table 2.

Table 2 Laboratory findings across three episodes of acute liver failure.

Parameter	Episode 1 (19 months)	Post-Rx (20 months)	Episode 2 (21 months)	Episode 3 (22 months)	Reference
ALT (U/L)	1840	320	980	2100	7-45
AST (U/L)	2210	280	1140	2450	10-40
Total bilirubin (μmol/L)	340	95	210	380	< 21
GGT (U/L)	18	22	20	24	< 50
ALP (U/L)	95	80	88	91	< 350
Albumin (g/dL)	2.9	3.4	3.1	2.8	3.5-5.0
INR	2.8	1.6	2.1	3.1	< 1.2
WBC (× 109/L)	2.1	3.8	2.4	2.0	5-15
Haemoglobin (g/dL)	8.2	9.5	8.9	8.0	11-14
Platelets (× 109/L)	68	102	75	62	150-400

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; ALP: Alkaline phosphatase; INR: International normalized ratio; WBC: White blood cell count; Post-Rx: Post-treatment at follow-up.

An extensive evaluation for causes of liver disease was undertaken and was collectively inconclusive: Viral hepatitis serology (hepatitis A, B, C, and E), herpes simplex virus, Epstein-Barr virus, and cytomegalovirus polymerase chain reaction were all negative. Autoimmune markers (antinuclear antibody, anti-smooth muscle antibody, anti-liver-kidney microsomal antibody) were negative, and immunoglobulin levels were normal. Metabolic screening, including plasma amino acids, urine organic acids, acylcarnitine profile, alpha-1 antitrypsin level and phenotype, ceruloplasmin, copper, and urine copper were all within normal limits bone marrow examination was unremarkable, with no evidence of haematological malignancy or haemophagocytic lymphohistiocytosis.

Liver biopsy demonstrated non-specific degenerative changes with early portal and perisinusoidal fibrosis, suggestive of an underlying metabolic or genetic disorder. WES identified a homozygous likely pathogenic variant in the SCYL1 gene (c.1420C>T; p.Arg474*) in the index patient, with both parents confirmed as heterozygous carriers, consistent with autosomal recessive inheritance.

Imaging examinations

Abdominal ultrasound demonstrated an echogenic liver of normal size, with mild splenomegaly and trace ascites. Magnetic resonance cholangiopancreatography demonstrated a normal hepatobiliary tree with no evidence of biliary dilation or structural abnormality. Brain magnetic resonance imaging (MRI) was unremarkable, with no evidence of cerebellar volume loss, white matter signal change, or optic nerve thinning, findings discussed further in the discussion.

FINAL DIAGNOSIS

Differential diagnosis

Given the clinical picture of recurrent, fever-triggered ALF with low-GGT cholestasis, the following differential diagnoses were systematically considered and excluded.

NBAS deficiency: The closest phenotypic mimic of SCY1 disease, also caused by vesicular transport dysfunction. NBAS deficiency characteristically presents with RALF triggered by fever and may co-occur with multisystemic features (optic atrophy, skeletal dysplasia, immunodeficiency). It was excluded by WES, which revealed no pathogenic NBAS variant.

Mitochondrial disorders: Mitochondrial hepatopathies such as POLG-related disease DGUOK deficiency, and mitochondrial DNA depletion syndromes can cause recurrent hepatic crises. However, the absence of lactic acidaemia, abnormal respiratory chain enzyme activity, or typical MRI changes (basal ganglia signal change), alongside normal mitochondrial-targeted sequencing on WES, rendered this group unlikely.

Autoimmune hepatitis: Autoimmune hepatitis type 2 was considered given the age group and potential steroid responsiveness. However, anti-liver-kidney microsomal antibody and antinuclear antibody antibodies were consistently negative, immunoglobulin levels were normal, and liver biopsy did not show the characteristic interface hepatitis pattern of autoimmune hepatitis.

Ornithine transcarbamylase deficiency and other urea cycle defects: Hyperammonaemia was not prominent, and amino acid/urine orotic acid profiles were normal.

Wilson disease: Age of presentation (19 months) is atypical; ceruloplasmin, serum and urine copper were normal, and Kayser-Fleischer rings were absent.

CALFAN syndrome

The combination of low-GGT cholestasis, recurrent fever-triggered RALF, subtle neurological findings, pancytopenia, and an unrevealing standard metabolic screen ultimately directed the diagnostic workup toward WES, which confirmed the SCYL1 diagnosis. WES yielded a diagnosis of SCAR21, caused by a homozygous SCYL1 variant (c.1420C>T; p.Arg474*). In addition, the CALFAN, can be categorized as CALFAN syndrome.

TREATMENT

During the second and most severe episode at 19 months, the patient was managed with intravenous corticosteroids (methylprednisolone 1 mg/kg/day) for five days, followed by oral prednisolone taper over six weeks, intravenous fluids and nutritional support, ursodeoxycholic acid for cholestasis, and vitamin K for coagulopathy. Over a complicated two-month hospitalization, liver function tests showed a partial biochemical response with transaminase and bilirubin values declining but not normalising. It is important to note that, as SCAR21/CALFAN is a monogenic disorder of vesicular transport, there is no established mechanism by which corticosteroids would directly modify the underlying disease process. The observed biochemical improvement is best interpreted as a temporal association, potentially reflecting the natural resolution phase of a febrile insult rather than a direct steroid effect. Spontaneous partial recovery between episodes has been reported in other published cases[1,4].

OUTCOME AND FOLLOW-UP

At 21 months, a second episode of RALF occurred in the setting of a febrile illness, managed with supportive care. At 22 months, a third episode was precipitated by a febrile urinary tract infection, treated with targeted antibiotics and supportive hepatic measures. Notably, biochemical parameters did not normalise between episodes, consistent with progressive hepatic injury and evolving fibrosis. The family underwent genetic counseling and the patient had regular follow-ups with both neurology and hepatology.

DISCUSSION

SCYL1-associated disease, encompassing both the designation CALFAN syndrome and its neurological classification as SCAR21 - is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the SCYL1 gene[1,4]. These two overlapping conditions fall under the same underlying genetic umbrella, with CALFAN emphasising the hepatic and systemic features, while SCAR21 the neurological classification; both reflect the phenotypic spectrum of SCYL-related disease. The disorder is characterised by early-onset RALF triggered by febrile illnesses, together with a gradually progressive neurological phenotype encompassing cerebellar ataxia, intention tremor, and peripheral neuropathy[1,6]. A hallmark laboratory feature is persistent low or normal GGT despite severe conjugated hyperbilirubinaemia, reflecting the intracellular rather than obstructive basis of the cholestasis[1].

From a genotypic standpoint, pathogenic variants are distributed throughout the SCYL1 gene without a clear mutational hotspot. The homozygous c.1420C>T (p.Arg474*) variant identified in our patient is a nonsense mutation in exon 11. This variant has been previously reported in at least one other patient with a phenotypically similar presentation (Incecik et al[6]), and is therefore not novel in the absolute sense. However, it has not been documented in large variant databases (ClinVar, gnomAD) as a population-frequency variant, and its pathogenicity in our patient is supported by homozygosity in an individual with a characteristic phenotype, parental carrier status and functional implications. At the molecular level, SCYL1 functions as a scaffolding protein for coat protein complex I-mediated retrograde vesicular transport. Its loss disrupts Golgi-to-ER trafficking, with downstream ER stress and hepatocyte apoptosis, particularly during febrile systemic responses[1,7]. Beyond the hepatocerebellar involvement, defects in vesicular trafficking may also affect haematopoietic precursors during inflammatory stress. This may help explain the pain cytopenia observed in our patient, but it needs to be proven. Prior reports variably reported this feature, as shown in Table 3[1,4,6-14].

Table 3 Reported cases of SCYL1-associated recurrent acute liver failure and neurological manifestations (literature review).

Ref.	Patient (s)	Genotype	Key phenotypic features
Schmidt et al[8]	2 siblings (European), 1 female (Cuban)	Compound heterozygous: P.Val313Cysfs*6, p.Ala504Profs*15; p.Gln546*, c.1230+1G>A	RALF, chronic fibrosis, CVA, intention tremor, neurogenic stutter
Lenz et al[1]	7 pediatric patients	Homozygous nonsense (p.Gln628*, p.Glu86*, p.Gln57*) and missense (p.Asp478Gly, p.Ala105Val)	Named CALFAN. Low-GGT cholestasis, RALF; variable neuro-phenotypes
Incecik et al[6]	10 years male (Turkish)	Homozygous: C.1420C>T (exon 11)	First Turkish case; RALF, delayed motor milestones, axonal neuropathy, CVA
Shohet et al[7]	28 months male, 18 years aunt (Ashkenazi Jewish)	Homozygous synonymous: C.459C>T (exon 4)	Aberrant splicing. RALF, short stature, motor neuropathy
Li et al[4]	7 years male (Han Chinese)	Homozygous frameshift: P.H32Gfs*20 (exon 1)	First East Asian case. RALF, late-onset skeletal disease, mild neuro-impairment
Spagnoli et al[9]	7 years female	Homozygous 1-bp duplication: P.Cys512 Leufs*8	Predominant neurologic phenotype; recurrent respiratory failure
McNiven et al[10]	13 years male, 9 years female (siblings)	Compound heterozygous: P.Asn133 Lysfs*136 and multi-exon deletions (exons 7-8)	Severe hepatic phenotype requiring liver transplantation; later tremor and cognitive dysfunction
Isa et al[11]	5 years male (Bahraini)	Homozygous nonsense: C.895A>T (exon 7)	RALF triggered by fever, global developmental delay, progressive inability to walk
Zare et al[12]	11 years female (Iranian)	Homozygous mutation in exon 11	Recurrent liver failure, compensated cirrhosis, gait disability, dysarthria, clubfoot
Kazem et al[13]	8years female, 9 years male (Kuwaiti Siblings)	Homozygous splice site: C.1386+1G>A	Intrafamilial variability: Girl had RALF; brother remains asymptomatic
Suenera et al[14]	6 years female (Indian)	Homozygous frameshift: P.Lys249ArgfsTer58 (exon 6)	Overlap with PFIC. Also carried LPAR6 mutation explaining brittle hair
Present case	19 months female (Arab)	Homozygous nonsense: C.1420C>T (p.Arg474*) (exon 11)	RALF × 3, low-GGT cholestasis, pancytopenia, tremors, fine motor delay; partial steroid response

RALF: Recurrent acute liver failure; CVA: Cerebellar vermis atrophy; CALFAN: Cholestasis, acute liver failure, and neurodegeneration; GGT: Gamma-glutamyl transferase; PFIC: Progressive familial intrahepatic cholestasis.

Neurologically, the patient exhibited tremors, dysmetria, and truncal ataxia. Despite the fact that a formal neurodevelopmental assessment wasn’t performed, caregivers reported delayed fine motor skills expected from a toddler at this age. Brain MRI was unremarkable, keeping in mind that it is recommended to perform neurological and radiographic assessments periodically, given the evolving nature of neuroimaging changes highlighted in the previous literature. The reports describe structural cerebellar changes, defined as vermis atrophy and optic nerve thinning, typically emerge in mid-childhood or adolescence rather than in infancy[1,6]. The normal MRI findings, therefore, do not exclude the diagnosis; rather, it reflects the age-dependent temporal evolution of neuroimaging abnormalities in this condition.

Before receiving the genetic diagnosis, during our patient’s most severe episode, an empiric short course of corticosteroid was given with an impression of virally (multisystem inflammatory syndrome in children associated with coronavirus disease 2019) propagated ALF. Putting this into perspective of SCYL1- related vesicular transport disorder, no mechanistic rationale for steroid efficacy has been evident. The observed improvement likely reflects the spontaneous recovery phase of a febrile hepatic insult, consistent with previously published cases[1,4].

The absence of complete biochemical normalisation between episodes in our patient, combined with evidence of early fibrosis on biopsy, indicates progressive hepatic injury. This trajectory parallels that of other reported cases and underscores the risk of long-term hepatic remodelling and cirrhosis[1]. Liver transplantation had addressed protracted hepatic disease in prior reports, although its effects on neurological sequelae remains unclear[7].

CONCLUSION

This case illustrates the diagnostic value of WES in resolving unexplained paediatric RALF. SCRA21 should be included in the differential diagnosis of children presenting with fever-triggered ALF accompanied by persistently low GGT and neurological features, even when those features are subtle at an early age. The pancytopenia documented in our patient represents a potentially expanded phenotypic feature of SCYL1-related disease that warrants attention in future case series. Furthermore, the mechanism of biochemical improvement observed in this case following a trial of short course of corticosteroid needs further research to prove its therapeutic potential in disorders of vesicular transport. Early genetic evaluation using WES is essential for establishing a diagnosis, facilitating family counselling, and guiding future care decisions.