GRACILE and Other BCS1L Disorders, Transaldolase Deficiency, Aagenaes Syndrome and Other Rare Causes of Neonatal Cholestasis

BCS1L-related complex III deficiency (GRACILE, mitochondrial complex III deficiency nuclear type 1, Björnstad syndrome), transaldolase deficiency (TALDO1), lymphoedema-cholestasis syndrome 1 (Aagenaes, UNC45A) and osteo-oto-hepato-enteric syndrome, with brief sections on Donnai-Barrow syndrome (LRP2), Nance-Horan syndrome (NHS) and complex lymphatic anomalies

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

Definition and scope

Infantile cholestasis, defined by elevation of conjugated (direct) bilirubin above 1.0 mg/dL (17 μmol/L), is always pathological and affects about 1 in every 2500 term newborns; biliary atresia accounts for 25 to 40% of cases and a group of individually rare monogenic disorders for about 25% [55]. This article brings together three of these monogenic disorders, with distinct mechanisms, which share presentation as cholestasis or liver failure in the neonatal period and the absence of targeted therapy: the BCS1L disorders, with GRACILE syndrome at the severe end, transaldolase deficiency, an inborn error of the pentose phosphate pathway, and Aagenaes syndrome, or lymphoedema-cholestasis syndrome 1 (LCS1), caused by a regulatory variant of the UNC45A gene [1, 5, 7]. The article also covers, in brief sections, three entities with no mechanistic relationship to these: Donnai-Barrow syndrome, caused by the LRP2 gene, which shares proximal tubular dysfunction; Nance-Horan syndrome, caused by the NHS gene, which enters the differential diagnosis of congenital cataracts; and the complex lymphatic anomalies, which enter the differential diagnosis of the lymphoedema and chylous effusions of Aagenaes syndrome [35, 36, 38]. Early-onset mitochondrial encephalomyopathies, monogenic recurrent and neonatal acute liver failure, progressive familial intrahepatic cholestases, hereditary primary lymphoedemas and monogenic congenital diarrhoeas, which include osteo-oto-hepato-enteric syndrome, are the neighbouring groups in the differential diagnosis.

Historical overview

In 1998, Fellman and colleagues, from the Children's Hospital in Helsinki, described 17 newborns from 12 Finnish families with severe fetal growth restriction, lactic acidosis, aminoaciduria and iron overload with hepatic haemosiderosis, all of whom died in the neonatal period or within the first four months, and proposed the criteria for a previously unrecognised autosomal recessive disorder [29]. The acronym GRACILE summarises these criteria. It was proposed by Fellman in 2001, from the cardinal findings [16]. In 2002, Visapää and colleagues, working from a 1.5 cM interval at 2q33-37, identified in the Finnish patients the homozygous missense variant S78G in BCS1L, which encodes a chaperone required for assembly of respiratory chain complex III, and described five other variants in three British infants [56]. The same gene had been associated a year earlier, by de Lonlay and colleagues, with complex III deficiency with neonatal proximal tubulopathy, liver disease and encephalopathy in six patients from four families [57]. In 2007, Hinson and colleagues showed that Björnstad syndrome, with sensorineural hearing loss and pili torti, is also a BCS1L disorder [58]. The association between pili torti and sensorineural deafness had been noted by Björnstad in 1965, who found it in 5 of 8 cases of pili torti [18]. The multinational cohort of Hikmat and colleagues (2021), with 33 patients from 10 countries, led to the BCS1L disorders being described as a continuum of manifestations, ordered mainly by age at onset, rather than as separate syndromes [26].

Transaldolase deficiency was described in 2001 by Verhoeven and colleagues in an infant with cirrhosis and hepatosplenomegaly, with elevated ribitol, D-arabitol and erythritol in urine and plasma and a homozygous three-base-pair deletion that removes serine 171 of the enzyme [59]. The patient, the first daughter of consanguineous Turkish parents, had undergone surgery for coarctation of the aorta soon after birth and at 10 years still had cutaneous telangiectasias, hepatosplenomegaly, clitoromegaly and persistent thrombocytopenia [20]. In 2006, Valayannopoulos and colleagues recognised it as a cause of fetal hydrops and neonatal multiorgan disease in a sibship of four [60]. The 2026 systematic review gathers 51 confirmed patients [25].

Aagenaes syndrome was described in 1968 by Aagenaes, van der Hagen and Refsum as hereditary recurrent intrahepatic cholestasis from birth, in 16 Norwegian patients who later developed lower-limb oedema [7, 61]. The same author published new cases in 1998 and follow-up from childhood to adulthood [62]. Bull and colleagues mapped the locus to a 6.6 cM interval at 15q in 2000, with a haplotype shared by 30 of 36 chromosomes from affected individuals [63]. In 2023, Almaas and colleagues identified in all 26 patients studied the c.-98G>T variant in the 5' untranslated region (5'UTR) of UNC45A [7]. Five years earlier, Esteve and colleagues had associated biallelic loss-of-function coding variants in the same gene with a syndrome of cholestasis, congenital diarrhoea, hearing loss and bone fragility, now called osteo-oto-hepato-enteric syndrome (O2HE) [8].

Donnai-Barrow syndrome was described in siblings in 1993 and recognised as allelic with the facio-oculo-acoustico-renal (FOAR) syndrome of Holmes and Schepens (1972) when Kantarci and colleagues identified LRP2 variants in both, in 2007 [64, 65]. Nance-Horan syndrome was described in 1974 by Horan and Billson and by Nance and colleagues; the NHS gene was identified in 2003 by Burdon and colleagues [36, 39].

Current nomenclature and classifications

OMIM distinguishes three BCS1L phenotypes: GRACILE (603358), mitochondrial complex III deficiency nuclear type 1 (MC3DN1, 124000) and Björnstad syndrome (262000) [16–18]. Orphanet classifies GRACILE as ORPHA:53693, tubulopathy-encephalopathy-liver failure syndrome (equivalent to MC3DN1) as ORPHA:254902 and Björnstad as ORPHA:123, all within isolated complex III deficiency (ORPHA:1460) [1–3, 23]. The review by Čunátová and Fernández-Vizarra (2024) adds the designation “BCS1L mitopathy” for the continuum of intermediate forms and isolated hypertrophic cardiomyopathy as a fifth presentation [4]. Complex III deficiency in turn belongs to the class of oxidative phosphorylation (OXPHOS) deficiencies, classified by mechanism [66].

OMIM designates Aagenaes syndrome as “lymphedema-cholestasis syndrome 1” (%214900); the designation LCS1 implies the existence of other forms of lymphoedema with cholestasis, such as that described in a Serbian Roma family without linkage to the 15q locus and the phenocopies due to CCBE1 [14, 67, 68]. The OMIM entry, consulted in October 2026, still maps the disorder to 15q with no associated gene, despite identification of the UNC45A variant in 2023 [7, 14]. O2HE has entry 619377 [22].

The classification of the International Society for the Study of Vascular Anomalies (ISSVA), revised in 2025, divides lymphatic malformations into isolated forms, complex lymphatic anomalies and lymphoedemas; the complex lymphatic anomalies include GLA, KLA, GSD and CCLA, isolated or syndromic [38].

The term “gracile bone dysplasia” designates osteocraniostenosis (ORPHA:2763; OMIM 602361), a lethal skeletal dysplasia unrelated to BCS1L [69, 70].

Definition of the entities in scope

GRACILE syndrome is the lethal neonatal form of BCS1L-related complex III deficiency, defined by fetal growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death [1]. MC3DN1 encompasses the more variable and less severe forms with tubulopathy, encephalopathy and liver failure [2]. Björnstad syndrome is the form limited to congenital sensorineural hearing loss and pili torti [3]. Transaldolase deficiency is an inborn error of the non-oxidative branch of the pentose phosphate pathway, with prenatal or neonatal presentation with hydrops, hepatosplenomegaly, liver dysfunction, thrombocytopenia, anaemia and renal and cardiac abnormalities [5]. Aagenaes syndrome combines neonatal intrahepatic cholestasis, which becomes intermittent with age, with severe chronic lymphoedema, mainly of the lower limbs [6]. Donnai-Barrow syndrome is a malformation syndrome with typical facial dysmorphism, myopia, hearing loss, agenesis of the corpus callosum, low-molecular-weight proteinuria and variable intellectual disability [47]. Nance-Horan syndrome is an X-linked syndrome with congenital cataracts and microcornea, dental anomalies and facial dysmorphism [48].

2. Molecular Genetics and Pathophysiology

BCS1L and complex III

Complex III (ubiquinol-cytochrome c reductase or bc1 complex) transfers electrons from reduced coenzyme Q10 to cytochrome c and pumps protons from the matrix into the intermembrane space; of its 11 subunits, 10 are nuclear-encoded and cytochrome b is encoded by mitochondrial DNA [26]. BCS1L (2q35) encodes an AAA-family ATPase of the inner mitochondrial membrane that forms a homoheptamer and, in an ATP-dependent manner, translocates the Rieske iron-sulphur protein (UQCRFS1) from the matrix to the nearly complete complex, in the last step of assembly [4, 9]. Fernandez-Vizarra and colleagues showed in patient cells that lack of BCS1L produces a catalytically inactive and unstable complex III, devoid of the Rieske protein [71]. All variants studied by Hinson and colleagues disrupted respirasome assembly, reduced electron transport chain activity and increased reactive oxygen species production; only those of complex III deficiency increased mitochondrial content, and clinical severity tracked reactive oxygen species production [58]. The complex III assembly factors linked to human disease are BCS1L, LYRM7, TTC19, UQCC2 and UQCC3; the structural subunits are CYC1, UQCRB, UQCRC2, UQCRFS1, UQCRQ and UQCRH, in addition to mitochondrially encoded MT-CYB [4, 66]. BCS1L is the most frequent cause of complex III deficiency [4].

In the Finnish patients with GRACILE, complex III activity in muscle was within the normal range, unlike in the British and Turkish patients, which led Visapää and colleagues to propose an additional role for BCS1L in iron metabolism [56]. In the liver, kidney and heart of GRACILE patients, Kotarsky and colleagues later found reduced BCS1L, Rieske protein and complex III quantity and activity, with cirrhosis and iron deposition; of the iron proteins, only ferritin was elevated, and in the placenta of an affected fetus ceruloplasmin and hephaestin were increased, linking the iron overload to placental dysfunction [72]. The mouse carrying the c.232A>G variant reproduces the human disease from three weeks of age: growth failure, hepatic glycogen depletion, steatosis, fibrosis and cirrhosis, tubulopathy and lactic acidosis, with complex III activity of 20% in the liver and 40% in the heart and kidney; in young animals the complex is correctly assembled, indicating another assembly factor in early ontogeny [73].

Structural modelling in the Hikmat cohort showed that p.Ser78Gly affects the interface between chains of the heptamer (+2.6 kcal/mol) without global destabilisation, suggesting weaker oligomerisation; p.Gly230Arg and p.Cys252Tyr (published protein designations), with predicted destabilisation greater than +20 kcal/mol, occurred only in compound heterozygosity with milder alleles, and complete loss of function is probably embryonic lethal, as in the knockout mouse [26]. According to Čunátová, variants in the BCS1-specific region, at the protomer interface, are associated with the most severe forms (GRACILE and mitopathy), whereas those in the AAA region affect activity without destabilising the complex [4]. Hinson and colleagues had proposed that Björnstad variants alter protein-protein interaction residues and those of complex III deficiency alter ATP-binding residues [58]. In the nuclear gene-encoded Leigh spectrum, BCS1L accounts for less than 1% of cases, with sensorineural hearing loss, proximal tubulopathy, liver involvement and pili torti [24].

TALDO1 and the pentose phosphate pathway

Transaldolase (EC 2.2.1.2), encoded by TALDO1 (11p15.5), catalyses in the reversible, non-oxidative branch of the pentose phosphate pathway the transfer of three carbons between sedoheptulose-7-phosphate and glyceraldehyde-3-phosphate, forming erythrose-4-phosphate and fructose-6-phosphate; together with transketolase, it recycles pentose phosphates into glycolysis [11, 13]. The deficiency leads to accumulation of polyols (erythritol, arabitol, ribitol, sedoheptitol, perseitol), erythronic acid and seven-carbon sugars [13]. Transaldolase does not produce NADPH directly, but blocked carbon recycling restricts the return of substrate to the oxidative phase and reduces available NADPH; in the Taldo1−/− mouse model there is depletion of NADPH and glutathione, altered mitochondrial membrane potential, susceptibility to paracetamol-induced liver failure and hepatocarcinogenesis, prevented by N-acetylcysteine [25]. In experimental models, aldose reductase consumes NADPH when producing polyols and contributes to oxidative stress and to progression from cirrhosis to hepatocellular carcinoma, and mTOR activation reduces paraoxonase-1 secretion and generates antiphospholipid antibodies and immune-mediated cirrhosis; these mechanisms have not been validated in patients [25]. Elevated urinary 2-oxoglutarate and fumarate point to disturbed mitochondrial metabolism [11, 33]. The functional gene lies at 11p15.5-p15.4, and there is a pseudogene locus (TALDOP1) on chromosome 1 with a truncated segment of exon 5 [19].

UNC45A, myosin Vb and canalicular trafficking

UNC45A (15q26.1) encodes a UCS-domain co-chaperone that acts with HSP70 and HSP90 in folding myosin motors, including non-muscle myosin II and myosin Vb (MYO5B), which is responsible for apical trafficking in enterocytes and canalicular trafficking in hepatocytes [7, 12]. The protein has 944 amino acids, with an N-terminal triple TPR motif and a C-terminal UCS domain, is expressed in many tissues and also binds the progesterone receptor and HSP90 [21]. In O2HE, the biallelic variants abolish expression or alter the conformation of the protein; myosin Vb, a client identified by mass spectrometry, is misfolded, and intestinal cells develop microvillus inclusions with Rab11 and mislocalised apical transporters, as in microvillus inclusion disease [74]. In the liver, the recurrent variant p.(Arg98Trp) (published protein designation) weakens the interaction with HSP70 chaperones and retains the bile salt export pump (BSEP, ABCB11) in MYO5B+/RAB11A+ endosomes that do not reach the canalicular membrane [75].

In Aagenaes syndrome, the c.-98G>T variant reduces UNC45A mRNA in the blood of homozygotes by about 50% and the protein to 57% of control values; in compound heterozygotes with an exonic loss-of-function allele, mRNA falls to 37% and protein to 17%, and the same effect is reproduced in HEK293T cells edited by CRISPR/Cas9 [7]. Healthy carriers of an exonic allele have less protein (39%) than patients homozygous for the 5'UTR variant, so the baseline level does not explain the disease; Almaas and colleagues propose that patients sit at a UNC45A threshold, with an inability to respond to cholestatic triggers [7]. Biopsies show mislocalised BSEP and multidrug resistance-associated protein 2 (MRP2), as in MYO5B disease and O2HE [7]. Aagenaes is thus the third cholestatic disorder of the UNC45A-myosin Vb axis, distinguished by the presence of lymphoedema and the absence of diarrhoea; patients with two coding alleles (O2HE) do not have lymphoedema [7]. The mechanism of the lymphoedema is not elucidated in the sources consulted.

LRP2 and megalin

LRP2 (2q31.1; about 236 kb, 79 coding exons) encodes megalin, an endocytic receptor of 4655 amino acids (600 kDa) of the low-density lipoprotein receptor family, expressed in absorptive epithelia (proximal tubule, brain, eye, lung, intestine, reproductive tract, yolk sac) and with more than 50 ligands [35]. In the proximal tubule, together with cubilin, it retrieves filtered proteins such as retinol-binding protein (RBP) and vitamin D-binding protein (VDBP), and it is required for activation of 25-hydroxyvitamin D by CYP27B1 [35]. In the embryonic neuroepithelium, endocytosis of sonic hedgehog and BMP4 explains the agenesis of the corpus callosum and the ocular malformations [76]. DBS variants cause loss of function; the splice variant NM_004525.3:c.2639+1G>A abolishes megalin in the proximal tubule [35].

Missense variants show that loss of function does not always mean absence of protein. In cells derived from induced pluripotent stem cells from a family with the variant NM_004525.3:c.9575G>A p.(Arg3192Gln), mutant megalin reached the membrane but did not release its ligand in the endosome; the receptor-ligand complex was routed to lysosomes and degraded, which depleted the receptor in the presence of ligand [77]. The variant NM_004525.3:c.4198T>C p.(Cys1400Arg), studied in a CRISPR-edited mouse model, produces a megalin that dimerises and localises to the apical membrane of the proximal tubule, but both fluid-phase and receptor-mediated endocytosis are impaired, with mislocalised RAB11+ and TFR1+ recycling compartments and enlarged lysosomes; structural modelling suggests that the substitution is tolerated at the cell surface and creates steric clashes at endosomal pH [78]. In urinary proteomics of 9 patients with DBS, the profile of the patient with p.(Cys1400Arg) could not be distinguished from that of patients with splice, nonsense or frameshift variants; this patient had the variant on a single allele detected by exome, and compound heterozygosity with an as yet unidentified second allele is presumed [78]. In a study of six families with DBS/FOAR, kidney biopsies from two families showed no megalin in the brush border, whereas the two patients from a third family, with a variant altering a YWTD repeat of a class B LDL domain, had reduced, normally localised megalin, with residual uptake of RBP and albumin and, even so, proteinuria [79].

The allelic spectrum extends beyond the full picture. Two children presenting as Dent disease, with low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis or nephrolithiasis, associated with hearing and visual loss, had biallelic LRP2 variants, which led the authors to propose that some cases with a Dent phenotype and no variant in CLCN5 or OCRL correspond to mild forms of DBS/FOAR or to a continuum between the two conditions [80]. In three families with sensorineural hearing loss and retinal dystrophy, without the other signs of DBS, exome sequencing identified compound heterozygous LRP2 variants (for example, NM_004525.3:c.5005A>G p.(Asn1669Asp) with c.149C>G p.(Thr50Ser)); abundant expression of Lrp2 in the marginal cells of the stria vascularis of the murine cochlea suggests that the deficiency impairs the endocochlear potential [81]. In non-syndromic pathological myopia, vitreous LRP2 levels and its expression in the neural retina and retinal pigment epithelium were reduced in patients with high myopia and posterior staphyloma; this expression study, with a mouse model and human cells, did not identify germline variants and does not establish LRP2 as a gene for isolated myopia [82].

NHS

NHS (Xp22.13; about 650 kb) encodes a protein of 1630 amino acids with four nuclear localisation signals, an actin regulator with a WAVE homology domain, required for development of the lens, teeth, brain and face [36, 39]. Nance-Horan syndrome variants are truncating variants or loss-of-function deletions, distributed throughout the gene, more frequent in exon 1/intron 1 and exon 6; the allelic CTRCT40 results from rearrangements that alter transcription [36, 37].

The spectrum of mechanisms includes balanced X-autosome translocations that disrupt the gene at Xp22.13 and, more recently, copy number gains: in a family with a t(X;19)(p22.13;q13.1) translocation, the mother and half-sister of the proband, carriers of the balanced form, had congenital cataract and a clinical diagnosis of Nance-Horan, whereas the proband, with the unbalanced form (partial Xp monosomy and partial 19q trisomy), had intellectual disability, short stature, primary amenorrhoea, cleft palate and horseshoe kidney, without the ocular phenotype [83]. In 2026 the first case attributed to a partial duplication restricted to NHS was described, in a 10-year-old boy with sutural cataract, bilateral microcornea and learning difficulties; until then only two duplications involving the locus had been published, without a conclusive phenotype [84]. The distribution of cases points to a dosage effect: complete loss of function in hemizygous males produces the syndrome, variants that alter regulation produce isolated cataract, and in females severity depends on the proportion of cells expressing the mutant allele after X inactivation [83, 85]. Functional studies in cell lines suggest different cellular mechanisms between variants (extracellular matrix disruption and oxidative stress in one, mitochondrial dysfunction in another), without an established clinical correlation [86].

Inheritance

The BCS1L disorders, transaldolase deficiency, Aagenaes syndrome, O2HE and DBS are autosomal recessive [7, 9, 13, 35]. In Aagenaes, the combination of alleles determines the phenotype: two 5'UTR alleles or one 5'UTR allele with an exonic loss-of-function allele cause LCS1, and two coding alleles cause O2HE [7]. DBS can result from paternal uniparental isodisomy of chromosome 2 [35]. In lymphoedema-cholestasis syndrome, OMIM also mentions an affected mother and daughter in a non-consanguineous British family, interpreted as a possible de novo dominant variant at the same or another locus; the molecular basis in this family is not elucidated in the sources consulted, and autosomal recessive inheritance is what has been demonstrated for the UNC45A variant [7, 14]. Nance-Horan syndrome is X-linked semidominant, with high penetrance in males and variable expression in females, which can be severe when X inactivation is highly skewed [36].

Recurrent and founder variants

The UNC45A c.-98G>T variant lies upstream of the start of the MANE transcript in the VariantValidator reference system, which recommends the genomic description; ClinVar records it as NM_018671.5:c.-98G>T [10, 87]. The allele frequency is 0.000014 in gnomAD v3.1.2 and 0.0011 to 0.002 in Scandinavian databases, 50 to 100 times higher [7]. In gnomAD v3.1.1, the summed frequency of confirmed pathogenic BCS1L variants is about 1:750, with an estimated disease risk of 1:561,890 [26].

Genotype-phenotype correlations, penetrance and allelic disorders

In the Hikmat cohort, all 9 p.Ser78Gly homozygotes presented at birth and died in the first year (median 4 days, range 1 day to 3 months); the 4 compound heterozygotes for this variant had symptom onset in the first month, and the 20 patients with other variants had onset between birth and 7 years; survival was significantly worse with p.Ser78Gly (p<0.001) [26]. A BCS1L 5'UTR variant (c.-122G>T, published designation, upstream of transcript NM_001079866.2) that maintains residual expression of the normal allele, in trans with p.(Leu280Phe) (published protein designation), attenuated the phenotype to central nervous system disease and axonal neuropathy [93]. In transaldolase deficiency there is no predictive genotype: in the family homozygous for p.Ser171Phe (published protein designation), siblings ranged from asymptomatic to cirrhosis with hepatocellular carcinoma, and the genotype serves mainly as an aetiological and family marker [25, 94]. In Aagenaes, compound heterozygotes (5'UTR with an exonic allele) more often required liver surgery (4/7 transplants and 1 shunt) than 5'UTR homozygotes (3/19 transplants and 1 shunt; p=0.03), with no difference in upper-limb lymphoedema (6/7 vs 13/19) [7]. In DBS there are no clinically relevant genotype-phenotype correlations [35]. In Nance-Horan syndrome there is no clear correlation; a higher frequency of intellectual disability with variants in exons 2, 6 or 8 has been speculated [36]. The relevant allelic disorders are Björnstad and MC3DN1 (BCS1L), O2HE (UNC45A) and CTRCT40 (NHS) [7, 9, 37]. TALDO1 heterozygosity has been associated with greater susceptibility to paracetamol-induced liver injury, suggesting a haploinsufficiency effect not yet clinically confirmed [13].

3. Clinical Spectrum and Manifestations by System

Common description: multisystem neonatal cholestasis or liver failure

The three core disorders of this article present, in their most frequent form, in the first month of life, with cholestatic jaundice or liver failure in a newborn who often already had intrauterine growth restriction. They are distinguished by their extrahepatic features: lactic acidosis, proximal tubulopathy and iron overload in BCS1L disease; hydrops, cytopenias, cutis laxa, heart disease and, later, hypogonadism in transaldolase deficiency; lymphoedema and recurrent pruritus in Aagenaes syndrome [7, 26, 30]. A child with fetal growth restriction, lactic acidosis after birth, hypoglycaemia, coagulopathy and cholestasis, especially with neurological signs or tubulopathy, should prompt consideration of mitochondrial disease, and a normal lactate does not exclude a respiratory chain defect [95].

GRACILE and other BCS1L disorders

In Fellman's original series, the 17 newborns were born close to term (mean 37.8 weeks) but with a mean weight of 1690 g, −3.8 standard deviations for gestational age; at 24 hours, mean pH was 7.00, lactate 12.2 mmol/L and pyruvate 121 μmol/L; all had aminoaciduria and poor weight gain, nine died between 2 and 12 days and eight between 1 and 4 months [29]. Despite intensive care, about half of patients die in the first days and the rest by 4 months; the British patients described have, in addition to the Finnish picture, complex III deficiency and neurological signs [16]. In the four studied, there was hepatic haemosiderosis with 2.8 to 5.5 mg of iron per gram of dry weight, ferritin of 1260 to 2700 μg/L, transferrin saturation of 61 to 100% and low transferrin (0.54 to 0.76 g/L) [29]. Hypoglycaemia, elevated ferritin and conjugated bilirubin and aminoaciduria reflect mitochondrial liver disease and tubulopathy; acidosis develops on the first day [96]. Massive bicarbonaturia can make the acidosis refractory [97].

The Hikmat cohort (33 patients from 15 centres in 10 countries, data up to December 2020) describes the natural history beyond classic GRACILE [26]. Twenty-four patients (73%) had symptom onset at birth or in the first month; 19 of 30 (63%) were small for gestational age; nine had a symptom-free interval of 3 months to 7 years. The most frequent manifestations were lactic acidosis (27), failure to thrive (27), proximal tubulopathy (24), liver disease (24), death in the first year (14), sensorineural hearing loss (12), iron overload (10), movement disorders (9), cholestasis (7) and epileptic seizures (6); there was also global developmental delay (9), attention deficit hyperactivity disorder (3), cataract (3), optic atrophy (1) and hypertrophic cardiomyopathy (1). Thirteen patients (39%) met the criteria for GRACILE and two (6%) those for Björnstad; the remaining 18 (55%) had intermediate combinations [26].

Source: Hikmat and colleagues, 2021, table 2 [26].

In late-onset patients neurological manifestations predominate: dystonia, athetosis, tremor, ataxia and seizures; a boy with hearing loss at 8 months developed an unsteady gait and, at 18–20 months, paroxysmal episodes lasting about 5 minutes, four to five times a day, triggered by exertion and relieved by rest, with normal magnetic resonance imaging [26]. MRI showed abnormalities in 8 of 10 patients studied, mainly T2/FLAIR hyperintensities in the deep white matter, thalamus and dentate nucleus; only 12% had basal ganglia lesions, and a Leigh-like phenotype occurred in 2 of 33 [26]. Progressive encephalopathy with spasticity, seizures and basal ganglia lesions, without liver disease, is another presentation [71]. Björnstad syndrome is limited to congenital sensorineural hearing loss and pili torti, with occasional hypogonadism and intellectual disability [3]. The hearing loss is congenital and of variable severity; in pili torti, the hair shafts are flattened at irregular intervals and twisted 180 degrees on their axis, which makes them brittle, and they are usually recognised in early childhood [18]. Ólahová described an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties [88]. Isolated hypertrophic cardiomyopathy is the most recently described presentation [4].

Transaldolase deficiency

In Williams's series of 34 patients, 22 presented before birth or in the first month and 12 between 3 months and 9 years; an older sibling of two affected children was asymptomatic at 9 years, and hepatomegaly was only noted after the molecular diagnosis [27]. The most frequent initial signs are intrauterine growth restriction, oligohydramnios and fetal hydrops before birth, and hepatosplenomegaly with portal hypertension, coagulopathy, cholestasis, anaemia and thrombocytopenia in the newborn; most have dysmorphic features (downslanting palpebral fissures, low-set ears, hypertrichosis), skin changes (cutis laxa, spider telangiectasias, multiple haemangiomas), neonatal oedema and congenital heart disease (septal defects, cardiomyopathy, tetralogy of Fallot) [13]. In Eyaid's 12 Saudi patients, all had heart disease, wrinkled skin and a facies with a triangular face, low-set ears, prominent philtrum, infraorbital creases, wide mouth and thin lips [20]. Psychomotor development is normal in most, and brain magnetic resonance imaging and spectroscopy are normal, unlike in ribose-5-phosphate isomerase deficiency [13].

Scaglione's European cohort (16 patients, 12 boys, followed between 1999 and 2025 in Paris, Rennes, Lille, Bordeaux, Stockholm and Warsaw, with up to 20 years of follow-up) quantifies the natural history [30]. Twelve patients came from consanguineous families, with five sibling pairs; median age at diagnosis was 8 months (1 month to 22 years). The first signs were intrauterine growth restriction (13; 81%), facial dysmorphism (12; 75%), cutis laxa or wrinkled skin (13; 81%), telangiectasias (6; 38%) and hypertrichosis (5; 31%).

The authors distinguish four hepatic trajectories: a severe form with death before transplantation, a rapidly progressive form with early transplantation, a slow course with transplantation before 20 years, and a slow course without organ failure, the most frequent (10 of 16) [25, 30]. In the systematic review of 51 patients, the minimum documented counts were hepatomegaly or hepatosplenomegaly in 42, cytopenia in 37, anaemia in 32, fibrosis or cirrhosis in 16, portal hypertension in 15, coagulopathy in 14, renal involvement in 19, endocrine or gonadal involvement in 11 and cardiac anomaly in at least 20; three patients had confirmed hepatocellular carcinoma and eight died [25]. These counts describe published reports, not frequencies in the affected population [25]. Hepatocellular carcinoma can arise early: a 16-month-old boy with cirrhosis and hepatocellular carcinoma had a 30-month-old brother with cirrhosis and an asymptomatic 8-year-old brother, all homozygous for p.Ser171Phe [94].

Renal involvement, present in 7 of 9 patients in the first nephrological series, includes low-molecular-weight proteinuria, hypercalciuria, generalised aminoaciduria, renal phosphate wasting, hyperchloraemic metabolic acidosis and moderate chronic kidney disease in older patients [98]. In adulthood, hypergonadotrophic hypogonadism, osteopenia and slowly progressive renal and liver disease predominate; in Horvath's three adults, symptomatic since the neonatal period, the genetic diagnosis was made only at 17, 26 and 32 years [28].

Aagenaes syndrome (LCS1)

In Almaas's Norwegian cohort (26 patients from 24 families, median age 19 years), birthweight was normal (median 3824 g) and all had cholestasis in infancy, with severity ranging from a few self-limiting episodes to persistent cholestasis with disabling pruritus [7]. Biopsies from the first 4 months show neonatal hepatitis with giant cell transformation in 40 to 90% of hepatocytes (median 75%, up to 30 nuclei per cell), cholestasis, portal inflammation, fibrosis (7 of 8), bile duct paucity (5 of 6 assessable, with a mean of 0.2 ducts per portal tract) and iron deposition (7 of 8) [7]. The cholestasis gradually decreases in most, but cholestatic episodes with elevated bile acids and intense pruritus persist, similar to benign recurrent intrahepatic cholestasis; pregnancy, hormonal contraceptives and the menstrual cycle are described triggers [7]. Of the 19 patients not transplanted in childhood, 15 had intermittent cholestasis, one mild chronic pruritus and two severe chronic pruritus [7].

Lower-limb lymphoedema appeared at a median of 2.5 years (from congenital to 15 years), was present in all except two infants and affected the upper limbs in 19; some had scrotal, trunk and facial oedema, and two required pleurodesis for chronic pleural effusion [7]. The lymphoedema worsens at puberty, and erysipelas is a frequent complication [7]. In 17 adults assessed by examination, ultrasound and segmental bioimpedance, the lymphoedema was more extensive than in other hereditary lymphoedemas (arms, face and trunk), with limited tissue fibrosis, and about one third had severe forms (grades III–IV) [34]. Cognition is normal and hearing loss is absent [7]. Cirrhosis occurs in about 25% during childhood or later, and fat malabsorption can cause fat-soluble vitamin deficiency with bleeding, rickets and neuropathy [6]. In adulthood, mild elevations of alkaline phosphatase, gamma-glutamyltransferase (GGT) and bile acids persist, with lower albumin and alpha-tocopherol than in controls [99]. In 15 adults, all those older than 35 years had marginal periodontitis and 87% had dental discolouration [100]. Health-related quality of life was reduced in three of eight SF-36 domains (physical role functioning, general health and mental health), and severe lymphoedema correlated with pain and poorer mental health [101].

Osteo-oto-hepato-enteric syndrome

O2HE combines cholestasis, often with low GGT and intense pruritus, congenital diarrhoea of the microvillus inclusion disease type, hearing loss and bone fragility, with mild developmental delay in some patients [8, 102]. In the original description, a European girl had intractable secretory diarrhoea requiring parenteral nutrition from day four and severe bilateral deafness, without liver disease or bone fragility, and two Tunisian sisters had neonatal cholestatic jaundice that resolved by 3 years, persistently elevated bile acids with intractable pruritus treated by partial internal biliary diversion, multiple fractures, bilateral deafness and mild intellectual disability [22]. In Duclaux-Loras's series of six patients, watery diarrhoea began in the first days or weeks, one infant developed hypovolaemic shock at 3 weeks and underwent total enterectomy at 20 months, another required intestinal transplantation, and in a third the diarrhoea stopped at 10 years [12, 74]. The facies may resemble that of Alagille syndrome [102].

Donnai-Barrow syndrome

The dysmorphism includes a large anterior fontanelle and wide metopic suture in infants, widow's peak, marked hypertelorism, enlarged eyes, downslanting palpebral fissures, posteriorly rotated ears, depressed nasal bridge and a short nose with a broad or bifid tip [35]. High myopia (−6 dioptres or worse) is universal and retinal detachment occurs in about 30%, with progressive visual loss up to legal blindness; childhood-onset sensorineural hearing loss is present in all and is often profound [35]. Congenital diaphragmatic hernia (or eventration) and omphalocele (or umbilical hernia) each occur in about 40%, rarely together; agenesis of the corpus callosum, complete or partial, is present in most, sometimes with periventricular nodular heterotopia [35, 64]. Intellectual disability is mild to moderate, high birthweight (about 4 kg) and macrocephaly are frequent, and final stature is normal [35]. Low-molecular-weight proteinuria is asymptomatic in most; hypercalciuria, nephrocalcinosis, nephrolithiasis and focal segmental glomerulosclerosis have been described, and end-stage kidney disease is rare but severe, mainly in adults [35].

The ocular phenotype extends beyond myopia. In a consanguineous family from the United Arab Emirates, four homozygous children had myopia of −15 to −22 dioptres (spherical equivalent), hypertelorism and downslanting palpebral fissures; three had spontaneous retinal detachment, with a complicated postoperative course, and the eyes without detachment showed optic disc dysplasia with fine emerging vessels and multiple rings of peripapillary depigmentation, which the authors consider distinctive among the vitreoretinopathies with high myopia [90]. In two British children, myopia exceeded 20 dioptres, with iris transillumination, ciliary body hypoplasia, optic nerve hypoplasia and giant ectopic posterior vortex veins, a finding that helps distinguish DBS from other causes of high myopia in childhood [103]. The 2026 ophthalmological review adds iris coloboma and optic nerve head anomalies to the spectrum [53]. In a literature review published with a case of bilateral detachments due to giant retinal tears at 24 months, 10 of the 38 patients with DBS who survived the first year had had retinal detachment (26.3%), a figure close to the approximately 30% given by GeneReviews [35, 104].

Renal involvement is not limited to tubular proteinuria. In six families with nine patients, the urinary protein/creatinine ratio ranged from 166 to 704 mg/mmol (normal <15 mg/mmol) and the albumin/creatinine ratio from 7 to 33 mg/mmol (normal <3 mg/mmol), with intact IgG in the urine of all patients, indicating glomerular leakage; four had a reduced glomerular filtration rate, and the biopsy of one patient showed focal glomerulosclerosis, interstitial fibrosis, inflammation and tubular atrophy, with IgA deposits [79]. In the mouse model with renal megalin inactivation, the number of nephrons was 19% lower in early adulthood, with more glomeruli disconnected from the tubule, and a reduced filtration rate [79]. The authors conclude that megalin dysfunction increases the risk of early-onset chronic kidney disease, contradicting the earlier description of a benign tubulopathy [79]. The spectrum of tubular dysfunction also includes hypercalciuria, nephrocalcinosis and nephrolithiasis, in a pattern overlapping with Dent disease [80].

Nance-Horan syndrome

In males, the bilateral congenital cataracts are dense, nuclear or stellate, and require early surgery; they are associated with microcornea, microphthalmia, glaucoma, strabismus and nystagmus, and visual acuity often remains low despite surgery [36]. Dental anomalies (screwdriver-shaped incisors, bud-shaped molars, supernumerary teeth or agenesis) are present in both dentitions in all affected males and are characteristic in type and clustering [36, 105]. The face is long, with a prominent nose and pointed chin. Heterozygous females have opacities centred on the posterior Y sutures, rarely requiring surgery in childhood, and sometimes only mild facial dysmorphism [36]. The frequency of intellectual disability in males differs between sources: about 80% according to the Oxford Desk Reference, “a minority, up to about 30%” according to GeneGuidance, and 4 of 6 with developmental delay in the 2026 series [36, 37, 40].

The extraocular phenotype includes less frequent manifestations. In three Turkish families with five affected males and three carriers, one boy had bilateral cataract, iris heterochromia, microcornea, mild intellectual disability, Hutchinson incisors, supernumerary teeth and bud-shaped molars; another, with a 22-gene deletion that included NHS, had global delay, microphthalmia, cataract and a ventricular septal defect; two half-brothers and a maternal uncle had mild to moderate intellectual disability, and one of them autistic traits [106]. The authors emphasise that the dentist may be the first to suspect the diagnosis [106]. Microcornea is part of the differential diagnosis of anterior segment malformations [107]. In a Sicilian family, the affected boy had late regression of cognitive, motor, language and adaptive skills, with behavioural changes, corpus callosum anomalies and periventricular leukoencephalopathy on magnetic resonance imaging [92]. Congenital diaphragmatic hernia has been described in a fetus with a novel NHS nonsense variant, and expression of the gene in the murine fetal diaphragm suggests a possible causal relationship, still based on a single case [108]. Congenital heart disease occurs in a proportion of patients [92].

In heterozygous females, expression ranges from no signs to cataract requiring early surgery. In a Swiss family, the grandmother underwent surgery at 61 years, the mother at 3 months and the proband had dense posterior cataract with microcornea; in another, a sister underwent surgery at 21 and 27 months, the female proband did not require surgery and a carrier maternal aunt had no cataract [85].

Complex lymphatic anomalies

GLA is characterised by multifocal dilated lymphatic vessels in several organs, presenting mainly in childhood, with morbidity dominated by deterioration of pulmonary function [50]. KLA has malformed lymphatic channels lined by spindle-shaped endothelial cells, with a predilection for the thorax, pericardial and pleural effusions, haemorrhage and fractures, and a generally poor prognosis [51]. GSD is a massive osteolysis associated with proliferation and dilatation of lymphatic vessels, mono- or polyostotic, presenting with localised pain or pathological fracture [52]. It was described by Gorham and Stout in 1955 as massive osteolysis (“vanishing bone”); OMIM includes it in the entry for diffuse cystic angiomatosis of bone, which also describes a family with 12 affected individuals over four generations with asymptomatic lytic bone lesions [46]. CCLA, isolated or syndromic, completes the group in the ISSVA classification [38]; in Adams's sirolimus trial, the three patients with central conducting lymphatic anomalies progressed [54]. The hereditary generalised lymphatic dysplasias and the complex lymphatic anomalies enter the differential diagnosis.

Treated disease and natural history

Fellman's and Hikmat's data on GRACILE reflect natural history with intensive supportive care, without disease-modifying therapy [26, 29]. In transaldolase deficiency, the 2026 series include transplanted patients and patients on hormonal and renal treatment, and survival into adulthood of 13 of 16 patients should not be read as untreated natural history [30]. In Aagenaes, all Norwegian patients received ursodeoxycholic acid, colestyramine or rifampicin, and 7 of 26 were transplanted at 5–8 months, so the course described is that of treated disease [7].

4. Clinical Recognition and Warning Signs

When to suspect cholestasis

The joint guideline of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN/ESPGHAN) recommends measuring total and conjugated bilirubin in every formula-fed infant who is jaundiced after 2 weeks of age; a breastfed infant who looks well may be reassessed at 3 weeks, in accordance with local practice (recommendation 1A) [55]. Bilirubin should always be fractionated, and a conjugated bilirubin above 1.0 mg/dL (17 μmol/L) mandates investigation (1A); direct observation of stool colour and examination for hepatomegaly, splenomegaly and ill appearance are part of the minimum assessment (1A) [55]. The history should include consanguinity, ethnic origin, prolonged neonatal jaundice in siblings, an affected maternal half-sibling (neonatal haemochromatosis), cholestasis of pregnancy in relatives, pruritus and fluctuation of jaundice, failure to thrive and steatorrhoea [109].

Signs pointing to each entity

The combination of severe fetal growth restriction, lactic acidosis on the first day, aminoaciduria, cholestasis and elevated ferritin in a newborn points to GRACILE, especially in families of Finnish origin [29, 96]. Beyond the neonatal period, proximal tubulopathy, sensorineural hearing loss, pili torti, movement disorders or seizures with lactic acidosis suggest other BCS1L disorders; the diagnosis may be missed when the presentation is neurological, late or limited to tubulopathy [26]. Fetal hydrops, growth restriction, hepatosplenomegaly with thrombocytopenia and anaemia, lax and wrinkled skin and congenital heart disease in a newborn with liver dysfunction suggest transaldolase deficiency [13, 110]. Unexplained liver disease with low-molecular-weight proteinuria should prompt measurement of urinary polyols [98]. In an adolescent or adult, “cryptogenic” cirrhosis, renal dysfunction, cytopenia and hypergonadotrophic hypogonadism justify the same test [28, 30]. Neonatal haemochromatosis with cardiomyopathy, attributed to gestational alloimmune liver disease (GALD), may be transaldolase deficiency [111]. Neonatal cholestasis with giant cell hepatitis in Scandinavian families, especially from south-western Norway, or the later appearance of limb oedema, point to Aagenaes syndrome; genetic diagnosis allows it to be recognised before the lymphoedema becomes evident [7]. Cholestasis with low GGT and pruritus, associated with congenital diarrhoea, hearing loss or fractures, suggests O2HE [8, 102].

Emergency signs

Neonatal liver failure with coagulopathy, hypoglycaemia and metabolic acidosis requires transfer to a paediatric hepatology centre with transplantation and intensive care capability [13, 32]. In transaldolase deficiency, liver failure at birth without recovery before the first month, or deterioration of liver function in the first 6 months, is associated with mortality close to 100% and should prompt immediate consideration of transplantation [13]. The severe intracranial haemorrhages described in transaldolase deficiency and the vitamin K deficiency of cholestasis justify early correction of coagulation [30, 109].

Newborn screening

None of these disorders is included in newborn screening programmes. Sedoheptulose-7-phosphate is elevated in dried blood spots in transaldolase deficiency, which makes screening feasible in theory [13]. A bile acid assay by ultra-high-pressure liquid chromatography with tandem mass spectrometry detected elevated bile acids and distinct profiles in newborn screening samples from children with Alagille syndrome, Aagenaes syndrome and alpha-1 antitrypsin deficiency [112]. None of these methods is validated for population screening.

5. Diagnosis: Criteria, Tests and Algorithms

Initial assessment of cholestasis

Abdominal ultrasound excludes choledochal cyst and lithiasis and may suggest biliary atresia, without diagnosing it (1A); hepatobiliary scintigraphy lacks the specificity to serve as a stand-alone test (1B); liver biopsy interpreted by an experienced paediatric pathologist is the most useful investigation in prolonged conjugated hyperbilirubinaemia (1B); and intraoperative cholangiography with histology of the remnant is the gold standard for biliary atresia (1A) [55]. Percutaneous biopsy had a complication rate of 1.7% in children and 4.6% (3 of 65) in a series of infants [55]. When an inborn error is suspected, the guideline recommends blood gases, electrolytes, glucose, ammonia, uric acid, lactate and pyruvate (lactate/pyruvate ratio), ketone bodies and, in urine, ketones, 2-keto acids, reducing substances, acylglycines, pH and sulphites [55]. Low or normal GGT points to progressive familial intrahepatic cholestasis types 1 and 2, ARC syndrome and bile acid synthesis defects, and it is elevated in most other causes [109]. In advanced liver failure of any cause, non-specific secondary abnormalities appear, such as hyperlactataemia, hypertyrosinaemia above 200 μmol/L and hypermethioninaemia, which can mimic an inborn error [113].

BCS1L disorders

Fellman's criteria for GRACILE are fetal growth restriction, severe lactic acidosis, aminoaciduria and iron overload (hepatic haemosiderosis, elevated ferritin, hypotransferrinaemia and elevated transferrin saturation) [29]. The Hikmat cohort defined proximal tubulopathy by the presence of at least two of generalised aminoaciduria, glycosuria, low-molecular-weight proteinuria, bicarbonate wasting with tubular acidosis and renal salt wasting [26]. Lactate was elevated in 26 of 30 patients, hypoglycaemia in 13 of 25 and hypoalbuminaemia in 10 of 17 [26]. According to the Mitochondrial Medicine Society (MMS), a plasma lactate above 3 mmol/L in a correctly collected sample suggests primary or secondary mitochondrial dysfunction; elevated lactate has a sensitivity of 34 to 62% and a specificity of 83 to 100% for primary mitochondrial disease, and the lactate/pyruvate ratio is only useful when lactate is elevated (sensitivity 31%, specificity 100%) [31]. Sampling with a tourniquet or from an agitated child falsely elevates lactate [31].

Respiratory chain enzymology showed complex III deficiency (isolated or with complex II) in muscle in 10 of 12 patients, in liver in 3 of 4 and in fibroblasts in 1 of 3, and was normal in five patients [26]. In the Finnish patients with GRACILE complex III activity in muscle was normal [56], and Ólahová described normal activity in the muscle of two patients with reduced assembly or a combined defect in fibroblasts [88]. Normal enzymology does not exclude the disease; analysis of complex III assembly by blue native gel electrophoresis (BN-PAGE) and respirometry in lymphocytes are complementary [4, 9]. Hair microscopy detects pili torti, and audiometry with auditory evoked potentials documents the hearing loss [9]. Confirmation is molecular: biallelic BCS1L variants by exome or genome sequencing, which have made muscle biopsy unnecessary in most cases [4, 24]. BCS1L 5'UTR regulatory variants (c.-122G>T and NM_001079866.2:c.-50+358G>A) lie outside the coding region and may escape an exome [26, 93].

Transaldolase deficiency

The biochemical diagnosis rests on increased urinary excretion of sedoheptulose, mannoheptulose, sedoheptitol, perseitol and sedoheptulose-7-phosphate and of the polyols erythritol, arabitol and ribitol, by gas chromatography-mass spectrometry or proton nuclear magnetic resonance; the elevations are most marked in the neonatal period and subtler later, and in plasma and cerebrospinal fluid they are minimal or absent [11, 13]. Erythronic acid is a major abnormal metabolite [11]. Transaldolase activity in fibroblasts, lymphoblasts, erythrocytes or liver and TALDO1 sequencing are the gold standard [13]. Today, the diagnosis is often molecular, by exome, genome or liver disease panels, with biochemical confirmation; mild or adult forms may be missed if polyols are not measured and the genomic result is interpreted without knowledge of the disease [25]. Sedoheptulokinase deficiency produces very high urinary sedoheptulose and erythritol but low-normal sedoheptulose-7-phosphate [114]. In Rodan's infant, urinary sedoheptulose was 12,012 (normal <95), ribitol 1398 (52–158), erythritol 3257 (450–1572) and arabitol 3335 (210–578), in the units of the reporting laboratory [33].

Aagenaes syndrome

The clinical diagnosis rests on neonatal cholestasis with giant cell hepatitis followed by lymphoedema; liver biopsy shows giant cell transformation, duct paucity and mislocalised BSEP and MRP2 [7]. The molecular test must include the 5'UTR region of UNC45A: in Almaas's study, exome sequencing of four probands and one sibling, focused on the 15q locus, did not identify the cause, which only genome sequencing revealed [7]. In patients with a single 5'UTR variant, a second loss-of-function allele should be sought, including splice variants [7]. Dried blood spot bile acid profiles distinguish Aagenaes from Alagille and alpha-1 antitrypsin deficiency [112].

Donnai-Barrow syndrome

There are no formal criteria and no pathognomonic sign [35]. The diagnosis is established by the characteristic clinical picture with the low-molecular-weight proteinuria pattern and/or by biallelic LRP2 variants; urinary protein electrophoresis (or Coomassie staining of a spot urine) shows loss of RBP and VDBP in 100% of patients, and the dipstick is not suitable for this purpose [35]. Loss of RBP and VDBP is not specific and occurs in other tubulopathies [35]. LRP2 sequencing identified the variants in 17 of 17 families; if only one or no variant is found, deletion and duplication analysis should be performed [35]. LRP2 is one of the longest genes in the genome, with many private benign variants, which requires careful interpretation according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [35].

Proteinuria can be present from 2 months of age, before myopia and hearing loss are recognised, and a child with early-onset high myopia can be the first presentation of atypical DBS [91]. Exome sequencing may fail to detect the second allele: in a patient with clinical DBS and a typical urinary profile, only one missense variant was found [78]. In a Dent phenotype without a variant in CLCN5 or OCRL, especially if there is hearing loss or myopia, LRP2 should be included in the analysis [80]. The combination of sensorineural hearing loss and retinal dystrophy without other signs also justifies its inclusion in panels [81]. Prenatal ultrasound can identify diaphragmatic hernia, agenesis of the corpus callosum and omphalocele, and molecular testing confirms the diagnosis [53].

Nance-Horan syndrome

Slit-lamp biomicroscopy of the mother and of at-risk women, looking for opacities on the posterior Y sutures, and dental examination with orthopantomography (screwdriver-shaped incisors, bud-shaped molars) support the diagnosis [37, 105]. NHS sequencing should detect copy number variants, because microdeletions are a recognised mechanism; in a woman with the phenotype and a negative test, the karyotype may show an X-autosome translocation disrupting the gene [36, 37]. In a Brazilian family, the disorder was diagnosed as isolated hereditary cataract until exome sequencing [115].

In a Swiss cohort of 20 families with congenital cataract studied by exome, likely causal variants were identified in 10, two of them in NHS; in both families, the syndrome had been classified as isolated cataract, because the systemic signs are variable and late [85]. Panel or exome sequencing may not detect partial NHS duplications, which should be sought when suspicion persists [84]. In a woman with the phenotype and negative sequencing, karyotype and fluorescence in situ hybridisation (FISH) can identify an X-autosome translocation [83].

Diagnostic algorithm

Test limitations and report content

Exome sequencing does not, as a rule, detect variants in untranslated and deep intronic regions (such as the UNC45A and BCS1L 5'UTR variants), larger deletions and duplications, repeat expansions or epigenetic changes, and the false-negative rate varies by genomic region [7, 116]. A negative result does not exclude the diagnosis when the clinical picture is suggestive. Identification of biallelic variants of uncertain significance, or of one pathogenic variant with one of uncertain significance, neither establishes nor excludes the diagnosis [35]. The report should state the gene, the versioned transcript, the HGVS nomenclature, zygosity, phase (parental testing) and the ACMG/AMP class. For UNC45A it is advisable also to give the genomic coordinate NC_000015.10:g.90935227G>T [10].

Prenatal and preimplantation diagnosis

When the familial variants are known, prenatal diagnosis on chorionic villi or amniocytes and preimplantation genetic testing are possible for all the entities [13, 35]. In transaldolase deficiency, sedoheptulose and ribitol were elevated in the amniotic fluid of an affected fetus, which also allows a biochemical diagnosis [13]. Without a prior diagnosis, the ultrasound findings of transaldolase deficiency (severe growth restriction, echogenic bowel and liver, placentomegaly, hypertrichosis, raised umbilical artery pulsatility index, late oligohydramnios) are not specific, and chromosomal microarray does not detect the disease; the incremental yield of prenatal exome over microarray is about 4% in isolated growth restriction and 30% when there are multisystem anomalies, according to the literature cited by Adeniji [111]. In DBS, fetal ultrasound or MRI may show agenesis of the corpus callosum, diaphragmatic hernia, omphalocele, hypertelorism and prominent eyes, but a normal scan does not exclude an affected fetus [35].

6. Differential Diagnosis

Comparative table of causes of neonatal cholestasis or liver failure

Main differentials

Neonatal haemochromatosis is the differential most often confused with GRACILE and transaldolase deficiency, because all three can present with neonatal liver failure and iron overload. Most cases of neonatal haemochromatosis result from gestational alloimmune disease, and maternal intravenous immunoglobulin from 14 weeks prevents recurrence in many subsequent pregnancies [109]. In Adeniji's case, two siblings with neonatal haemochromatosis and hypertrophic cardiomyopathy were treated as GALD, with immunoglobulin in the second pregnancy and postnatal exchange transfusion, without effect; exome sequencing revealed transaldolase deficiency [111]. Cardiomyopathy, which is not typical of GALD, and severe lactic acidosis with aminoaciduria, which defines GRACILE, are the most useful clues [29, 111]. Fellman explicitly distinguished GRACILE from other lactic acidoses, neonatal haemochromatosis and hepatitis [29].

Within complex III deficiency, the other genetic causes (TTC19, LYRM7, UQCRB, UQCRQ, UQCRC2, UQCRFS1, CYC1, UQCC2, UQCC3, UQCRH) mainly produce encephalopathy, leukoencephalopathy or episodic metabolic decompensations, without the visceral picture of GRACILE [4]. Björnstad syndrome, limited to congenital sensorineural hearing loss and pili torti, is recognised by hair microscopy and enters the differential diagnosis of syndromic hearing loss [3, 9].

In transaldolase deficiency, growth failure, dysmorphism, cutis laxa, heart disease, hepatosplenomegaly, pancytopenia and bleeding tendency overlap with many other genetic disorders, which is why none of Eyaid's 12 Saudi patients had a correct initial diagnosis [110]. Ribose-5-phosphate isomerase deficiency, also of the pentose phosphate pathway, has leukoencephalopathy, which is absent in transaldolase deficiency [13].

Aagenaes syndrome is distinguished from the progressive familial intrahepatic cholestases and benign recurrent intrahepatic cholestasis by lymphoedema, which may appear only after the first years; from O2HE by the absence of diarrhoea, hearing loss and bone fragility; and from MYO5B disease, which can cause low-GGT cholestasis and giant cell hepatitis, by lymphoedema and the gene [7]. The CCBE1 phenocopies (Hennekam generalised lymphatic dysplasia) combine cholestasis with lymphoedema or hydrops, and a Romani family with an atypical picture suggests other loci [67, 68]. Primary lymphoedema and the complex lymphatic anomalies, without neonatal cholestasis, enter the differential diagnosis of lymphoedema and chylous effusions [38].

Differential diagnosis of Donnai-Barrow syndrome

Kabuki, Cornelia de Lange and Meacham syndromes also enter the syndromic differential diagnosis of congenital diaphragmatic hernia [117].

Differential diagnosis of Nance-Horan syndrome

Congenital cataract with dental anomalies is distinguished from oculofaciocardiodental syndrome (BCOR), from Lowe syndrome (carriers with punctate rather than sutural opacities) and from isolated X-linked cataracts, including the allelic CTRCT40 [37, 40]. The combination of congenital cataract, screwdriver-shaped incisors and bud-shaped molars is a strong clinical indication of Nance-Horan [105].

7. Treatments and Risk Management Strategies

Principles and quality of evidence

None of the disorders in this article has a disease-modifying treatment that is approved or has been tested in a clinical trial. Management of the BCS1L disorders follows the general MMS recommendations for primary mitochondrial diseases, obtained by Delphi consensus rather than from trials [31, 32]. In transaldolase deficiency and Aagenaes syndrome, the evidence is limited to retrospective cohorts and case reports [7, 25, 30]. A search of ClinicalTrials.gov in October 2026 found no registered trials for BCS1L, GRACILE, transaldolase deficiency, Aagenaes syndrome or UNC45A [118]. Treatment is directed at the affected organs and decided by teams at reference centres, within the European networks MetabERN and ERN RARE-LIVER.

BCS1L disorders

Acute treatment and intercurrent illness

Mitochondrial diseases decompensate with infection, fasting, anaesthesia and surgery, and many patients respond to timely intervention [32]. The MMS recommends that every patient have a written emergency plan, updated at each visit, with baseline symptoms, nutritional requirements, medication and contraindicated therapies [32]. In acute decompensation, it recommends intravenous fluids with dextrose (in limited amounts in disorders of pyruvate metabolism, on a ketogenic diet or if there has been an adverse reaction to glucose), withdrawal of potentially toxic drugs and correction of metabolic derangements; lipids may be used, and nutritional support should preferably start within the first 48 hours [32]. It also recommends measuring sodium, potassium, calcium, magnesium and phosphate (recurrent abnormalities require assessment of tubular and adrenal function), monitoring lactate during introduction of feeding and ventilator weaning, assessing thyroid and adrenal function in critical illness, considering stress-dose corticosteroids in vasopressor-refractory hypotension and excluding hypoglycaemia, hypoalbuminaemia and coagulopathy when there is liver dysfunction [32]. In significant acidosis, the GeneReviews on the Leigh spectrum indicates sodium bicarbonate or sodium citrate, trometamol (THAM) if there is hypernatraemia, and avoidance of lactate-containing solutions, such as Ringer's lactate [24]. The massive bicarbonaturia of the GRACILE tubulopathy can make the acidosis refractory to replacement [97]. In bone marrow failure, red cell or platelet transfusions and granulocyte colony-stimulating factor may be required [32]. In classic GRACILE, with death of most patients in the first year, the care plan includes discussion of palliative care with the family [9, 26]. Fellman and colleagues treated two newborns with intravenous apotransferrin, raising transferrin to 2–5 g/L, followed by exchange transfusion: transferrin saturation normalised in one and free iron decreased reversibly in the other, but both died at 10 and 8 weeks; the approach was not adopted [16].

Drugs to avoid and anaesthesia

The MMS lists as drugs to avoid when possible, or to use with caution, valproic acid, statins, metformin, high-dose paracetamol and some antibiotics (aminoglycosides, linezolid, tetracycline, azithromycin, erythromycin); chronic or frequent paracetamol use can deplete glutathione and cause liver disease, aminoglycosides can worsen hearing loss, topiramate can cause lactic acidosis, and only valproate in POLG disease is an absolute contraindication [32]. In infantile hepatocerebral disease, valproate should be avoided because of the risk of fulminant liver failure [32]. The 2020 Delphi consensus (16 experts from six countries) reached agreement on the safety of 46 drugs or drug classes, emphasising that risk depends on the patient and the drug and that decisions should be individualised; corticosteroids were considered safe in the acutely ill patient [119]. For anaesthesia, it is recommended to minimise preoperative fasting and add glucose to perioperative fluids, to use volatile anaesthetics and muscle relaxants with caution, to avoid propofol or limit it to short procedures because of the risk of propofol infusion syndrome, and to titrate anaesthetics slowly; local anaesthetics are generally well tolerated and there is no established link with malignant hyperthermia [24, 32].

Chronic support and transplantation

Vitamins and cofactors (coenzyme Q10, alpha-lipoic acid, riboflavin, L-carnitine) are used empirically, without proof of efficacy in a Cochrane review; the MMS recommends offering coenzyme Q10 to most patients, alpha-lipoic acid and riboflavin, L-carnitine only with documented deficiency, introducing one supplement at a time and correcting deficiencies [31]. In complex III disorders, current treatment is limited to vitamin cocktails with coenzyme Q10, physiotherapy, nutritional support and management of decompensations [4]. In a mild variant, patient fibroblasts responded moderately in vitro to a coenzyme Q10 analogue, without clinical data [93]. The MMS recommends surveillance for malnutrition at least every six months, gastrostomy when there is dysphagia or failure to thrive, annual transaminases and referral to hepatology if they are elevated [32]. Liver transplantation may be an option in acute or acute-on-chronic liver failure, weighing comorbidities and the natural history of the specific disease; survival of some transplanted mitochondrial patients approaches that of non-mitochondrial patients [32]. The mouse model suggests that isolated hepatic correction improves systemic metabolism, but the deficiency persists in other tissues [120]. Kidney transplantation in mitochondrial patients has survival similar to the national average, and dialysis is considered palliative, so patients on dialysis should be assessed for transplantation [32]. In Björnstad syndrome, treatment is that of sensorineural hearing loss (hearing aids or cochlear implant) [9]; in hyperactivity associated with ataxia, clonidine and guanfacine worsened ataxia and falls in one patient [26].

Preclinical research

In the Bcs1l p.Ser78Gly mouse, expression of the alternative oxidase from Ciona intestinalis prolonged median survival from 210 to 590 days by preventing lethal cardiomyopathy, without correcting the liver disease, growth restriction or lipodystrophy [121]. In 2026, a single intraperitoneal injection of a recombinant adeno-associated viral vector carrying normal Bcs1l, targeted to hepatocytes, restored assembly and activity of hepatic complex III, prevented liver disease, attenuated hypoglycaemia, improved growth and nearly doubled survival [120]. NAD+ repletion had no therapeutic effect in the model [9]. None of these strategies has been tested in humans.

Transaldolase deficiency

Liver transplantation

There is no aetiological therapy or enzyme replacement [11]. Liver transplantation is the only intervention with a demonstrated effect in end-stage liver disease. In the systematic review, seven patients were transplanted: two died shortly afterwards (portal thrombosis with pulmonary infection and respiratory failure; cardiac arrest on the first postoperative day in a child with decompensated cirrhosis, hepatopulmonary syndrome and hepatocellular carcinoma) and five were alive with a functioning graft at last follow-up, from 1 year to young adulthood [25]. In Scaglione's cohort, four patients were transplanted (median age 7 years, range 0.5 to 15 years; median follow-up 5.3 years) for severe neonatal liver failure, progressive dysfunction or suspected hepatocellular carcinoma; one died of postoperative complications at 6 months and one developed Epstein-Barr virus-associated post-transplant lymphoproliferative disease, treated with rituximab and immunoglobulin [30]. Three patients with severe neonatal-onset disease remained below 4 kg despite parenteral nutrition, and two died before transplantation was feasible [30]. The authors recommend considering transplantation early when there is liver failure [30]. Transplantation corrects liver function and improves the cytopenias, but does not correct the deficiency in the kidneys, gonads, haematopoietic cells and other tissues: urinary polyols persist after transplantation, and the renal and endocrine complications continue [25, 30]. In the transplanted Polish siblings, immunosuppression with tacrolimus, mycophenolate mofetil and transient corticosteroids was switched to ciclosporin because of suspected nephrotoxicity [25]. A girl aged 3 years and 4 months received a left lateral segment from her father, with resolution of the coagulopathy and bleeding and a stable graft at 1 year [122].

Kidney, blood, heart and endocrine glands

Tubulopathy with proteinuria was treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 5 of 16 patients, and kidney transplantation was discussed in two adults with progressive chronic kidney disease, without being performed [30]. Monitoring of renal function is mandatory [98]. Severe cases require transfusions and surveillance for bleeding and thrombocytopenia [13]. A neonatal dilated cardiomyopathy improved in the first 4 months with diuretics and digoxin, and only one patient required prolonged heart failure treatment [30]. Hypergonadotrophic hypogonadism was treated with androgens in five boys and with oestrogen-progestogen therapy in one girl; secondary adrenal insufficiency and primary hypothyroidism required replacement [30]. Hormonal abnormalities in the newborn are often transient [13].

N-acetylcysteine and avoidance of paracetamol

In the Taldo1−/− model, N-acetylcysteine prevented paracetamol-induced liver failure and hepatocarcinogenesis [13, 25]. Rodan and Berry treated an Emirati infant homozygous for p.(Arg192Cys), with hepatomegaly and elevated alpha-fetoprotein, with oral N-acetylcysteine for 6 months, under an institutional innovative therapy protocol; alpha-fetoprotein normalised and the course was stable, without adverse effects, but the clinical significance of this normalisation is uncertain [33]. Lee-Barber and colleagues described liver failure attributed to paracetamol in a patient with transaldolase deficiency, with alpha-fetoprotein already falling after paracetamol was stopped and before N-acetylcysteine, and concluded that these patients should avoid paracetamol [123]. Avoidance of paracetamol is the measure with the greatest consensus across sources [13, 33, 123].

The dose of 100 mg/kg/day was extrapolated from that used in ethylmalonic encephalopathy, another disorder with theoretical glutathione depletion, exceeds the mucolytic doses in the SmPC and does not correspond to any approved indication [33, 124]. The most frequent adverse effects of oral acetylcysteine are gastrointestinal; hypersensitivity reactions, including anaphylaxis, bronchospasm and angioedema, are uncommon to very rare [124].

Surveillance for hepatocellular carcinoma

The absolute risk of hepatocellular carcinoma cannot be estimated; in advanced fibrosis, cirrhosis, portal hypertension, nodular disease or changing alpha-fetoprotein, the systematic review suggests, as expert practice, regular imaging and alpha-fetoprotein, with no validated interval, to be set by the hepatology team [25].

Aagenaes syndrome

Cholestasis and pruritus

All 26 patients in the Norwegian cohort received ursodeoxycholic acid, colestyramine and/or rifampicin; two underwent nasobiliary drainage and two partial external biliary diversion, and seven were transplanted at 5–8 months of age [7]. Temporary removal of bile and depletion of the bile acid pool can interrupt the cycle of cholestasis and pruritus [7]. The sources consulted do not describe specific doses of these drugs in Aagenaes syndrome; the dosing used in the progressive familial intrahepatic cholestases serves as a reference by extrapolation. Compound heterozygotes (5'UTR with an exonic allele) more often required liver surgery [7]. More than half of patients can expect a normal life expectancy, and the liver disease has a better prognosis than other hereditary neonatal cholestases [99, 126].

Nutrition and fat-soluble vitamins

During cholestasis, patients need a fat-reduced diet [127]. Outside episodes, the diet of 15 patients older than 10 years was similar to that of controls, with lower intake of saturated fat and fish, lower serum alpha-tocopherol and 25-hydroxyvitamin D below the reference range; the authors recommend counselling on fat quality, carbohydrates and fibre and regular measurements to decide on vitamin D and E supplementation [127]. Fat malabsorption can cause fat-soluble vitamin deficiency with bleeding, rickets and neuropathy [6].

Lymphoedema

The lymphoedema is similar to other hereditary lymphoedemas, but more extensive; about one third of adults have severe forms requiring close follow-up, and more frequent use of compression on the upper limbs is recommended [34]. Erysipelas is frequent and affects quality of life [7]. Chronic pleural effusions led to pleurodesis in two patients [7]. Decongestive therapy and compression follow the general principles of lymphoedema treatment.

Oral health

Because marginal periodontitis occurred in all adults older than 35 years and dental discolouration in 87%, frequent dental visits are recommended [100].

Osteo-oto-hepato-enteric syndrome

Treatment is supportive: parenteral nutrition for the congenital diarrhoea, enterectomy or intestinal transplantation when fluid and electrolyte balance cannot be maintained, and liver transplantation in liver failure [12]. In hepatocytes carrying the p.(Arg98Trp) variant, paracetamol-induced upregulation of HSPA1A restored canalicular localisation of BSEP; this is a cellular result, without clinical application [75]. Intestinal management follows that of the monogenic congenital diarrhoeas.

Donnai-Barrow syndrome

25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are megalin ligands, and megalin is required for renal activation of vitamin D, which explains the hypovitaminosis D and osteomalacia described [35]. There are no investigational therapies; the only study registered on ClinicalTrials.gov is observational (metabolic screening, NCT01509287, completed) [118].

Prevention of retinal detachment is where the sources diverge. GeneReviews accepts that prophylactic peripheral photocoagulation may reduce the risk [35]; the authors of the case of giant tears at 24 months, with redetachment after vitrectomy, advocate early prophylactic laser retinopexy or scleral buckling [104]; the British authors consider the evidence for prophylactic retinopexy inconclusive, propose surveillance with wide-field retinal imaging and recommend avoiding orbital manipulation and hypotony during surgery, because of the risk associated with the ectopic vortex veins [103]. No study has compared the two strategies. For hearing loss, two implanted Saudi cousins progressed in auditory perception, speech and intelligence quotient and attended mainstream school [128]; a Chinese girl used hearing aids from 2 years and received a cochlear implant at 9 [91]. Given the possibility of early-onset chronic kidney disease, renal function and glomerular proteinuria warrant nephrology follow-up from diagnosis; the sources consulted do not evaluate antiproteinuric drugs in this disease [79].

Nance-Horan syndrome

An opacity that obscures the red reflex in a preverbal child is an absolute indication for lensectomy; surgery is generally performed at about 6 weeks for unilateral cataract and at 6–8 weeks for bilateral cataract, to limit deprivation amblyopia, followed by aphakic or pseudophakic refractive correction, amblyopia treatment and surveillance for glaucoma and visual axis opacification [37]. These recommendations come from a narrative review of paediatric cataract in general, not from syndrome-specific data [37]. The dental anomalies require restorative and orthodontic treatment, and intellectual disability, when present, educational support [37].

Developmental assessment should be repeated throughout childhood, because late regression has been described, and cardiological examination belongs in the initial assessment, given the occurrence of congenital heart disease [92, 106]. Heterozygous females may need cataract surgery in childhood or only in adulthood, which justifies ophthalmological examination of carriers [85].

Complex lymphatic anomalies: sirolimus

In the phase 2 trial by Adams and colleagues (NCT00975819), continuous oral sirolimus was started at 0.8 mg/m² per dose, twice daily, adjusted to trough concentrations of 10 to 15 ng/mL, in 28-day cycles, in patients aged 0 to 31 years, with no maximum dose defined in the source beyond the concentration target [54]. Use in complex lymphatic anomalies is off-label in all jurisdictions.

Trials table

The Adams trial had no control group, grouped heterogeneous diagnoses with subgroups of 3 to 22 patients, used an unvalidated composite response measure (imaging, function and quality of life) and had no complete responses, so the results by subtype are descriptive [54]. The lack of response in central conducting lymphatic anomalies contrasts with the response in GLA [54]. There are no clinical trials in the BCS1L disorders, transaldolase deficiency or Aagenaes syndrome, and no indirect comparisons between studies are made [118].

Developments in the last 12 months

No marketing applications, opinions of the Committee for Medicinal Products for Human Use (CHMP) or authorisations for these disorders were identified in the sources consulted; a negative search does not prove absence [118].

Pregnancy, perioperative care and transition

In Aagenaes syndrome, pregnancy and hormonal contraceptives can trigger severe cholestatic episodes, which should be taken into account in contraceptive counselling and obstetric follow-up [7]. In mitochondrial diseases, the MMS recommends avoiding prolonged fasting and giving dextrose-containing fluids before, during and after procedures [32]. Patients with transaldolase deficiency who reach adulthood need continued hepatic, renal, haematological and endocrine follow-up, because the renal, gonadal and bone complications progress slowly and liver transplantation does not correct them [25, 28]. Adults with Aagenaes retain mild hepatobiliary dysfunction, vitamin D and E deficiency and lymphoedema that worsens at puberty [7, 99]. In DBS, renal follow-up is particularly important in adults, in whom end-stage kidney disease is the main concern [35].

Guideline recommendations and divergences

The NASPGHAN/ESPGHAN guideline (2017) provides the basis for detection and assessment of infantile cholestasis [55]. The MMS recommendations (2015 and 2017) apply to the BCS1L disorders; the 2020 Delphi consensus softens the list of drugs to avoid, keeping only valproate in POLG disease as an absolute contraindication [31, 32, 119]. There are no specific guidelines for transaldolase deficiency, Aagenaes syndrome or GRACILE; the recommendations for early transplantation and renal and endocrine surveillance in transaldolase deficiency come from cohorts [28, 30]. In DBS, the GeneReviews recommendations are expert opinion based on 49 described patients [76].

8. Reproductive Options and Family Counselling

Autosomal recessive disorders

The BCS1L disorders, transaldolase deficiency, Aagenaes syndrome, O2HE and DBS are autosomal recessive: when both parents are carriers, each sibling of an affected individual has a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of not being a carrier [13, 35]. Carriers are asymptomatic; in DBS they have no structural defects, dysmorphism or renal dysfunction [35]. In Aagenaes, all 17 parents studied were healthy and heterozygous for the 5'UTR variant (15) or for an exonic allele (2), and none reported cholestasis or lymphoedema [7]. TALDO1 heterozygosity has been associated with greater susceptibility to paracetamol-induced liver injury, without this justifying, in the sources, recommendations for carriers [13].

Intrafamilial variability shapes counselling. In transaldolase deficiency, siblings with the same genotype ranged from asymptomatic to cirrhosis with hepatocellular carcinoma, and a sibling asymptomatic at 8–9 years was diagnosed only through family testing, so testing should be offered to the siblings of a patient [27, 94]. In Aagenaes, two siblings with the same variants had different courses, one with liver transplantation and the other without [89]. In DBS, diaphragmatic hernia or omphalocele in one sibling does not predict its presence in another [35]. By contrast, in the BCS1L disorders, homozygosity for p.Ser78Gly was always associated with GRACILE with onset at birth and death in the first year, which is of value in prenatal counselling [26].

Uniparental isodisomy is a rare mechanism: in a child with DBS, homozygosity for the paternal variant resulted from paternal isodisomy of chromosome 2, and the mother was not a carrier; the recurrence risk for siblings is then very low [35]. Confirming the carrier status of both parents before counselling a 25% risk is therefore important.

Carriers and founder populations

Carrier testing in relatives requires prior identification of the family variants [35]. In Finland, where GRACILE belongs to the Finnish disease heritage and the diagnosis is made by the c.232A>G variant, and in Scandinavia, where the UNC45A c.-98G>T variant has an allele frequency of 0.0011 to 0.002, targeted testing for these variants is useful for the partners of known carriers [7, 96]. In the United Arab Emirates a founder effect has been suggested for the TALDO1 p.(Arg192Cys) variant [33]. Consanguinity is frequent in families with transaldolase deficiency (17 of 21 families in the Williams series; 12 of 16 patients in the Scaglione cohort) [25].

Nance-Horan syndrome

Nance-Horan syndrome is X-linked semidominant. A carrier woman transmits the variant to 50% of her sons, who will be affected, and to 50% of her daughters, who will be carriers with variable expression; an affected man transmits it to all his daughters and to none of his sons [36]. About 5% of carriers have no ocular signs, and de novo microdeletions have been described, so slit-lamp examination of the mother and molecular testing should precede risk estimation [36, 40]. In women with highly skewed X inactivation or with X-autosome translocations, the manifestations can be severe [36, 37]. In a balanced X-autosome translocation, the risk for offspring includes the unbalanced forms, with a phenotype different from the syndrome [83]. Because severity in females cannot be predicted from the genotype, a carrier daughter may have anything from no signs to cataract requiring surgery in the first months [85].

Prenatal and preimplantation diagnosis and minors

With the family variants identified, prenatal diagnosis on chorionic villi or amniocytes and preimplantation genetic testing are possible [13, 35]. The ideal time to determine genetic risk and discuss reproductive options is before pregnancy, and counselling should be offered to young adults who are affected, carriers or at risk of being carriers [35]. In Adeniji's family, the diagnosis of transaldolase deficiency was made only after the death of two children, by trio exome; the mother later had a healthy child with another partner, without immunoglobulin, which illustrates the importance of an aetiological diagnosis before assuming an alloimmune cause with maternal recurrence risk [111]. Testing of asymptomatic minors is justified when it has clinical benefit, as in the siblings of patients with transaldolase deficiency or Aagenaes syndrome, in whom the diagnosis guides hepatic, renal and endocrine surveillance [7, 27]. Carrier testing in minors should, as a rule, wait until adulthood.

9. Special Considerations: Population Diversity and Epidemiology

Prevalence and what each study measures

Numbers of published cases measure the literature, not the frequency in the population, and are subject to ascertainment bias: in transaldolase deficiency, all patients in the Scaglione cohort were diagnosed at paediatric hepatology centres, and forms without liver involvement probably exist [30]. The estimate of 1:561,890 for the risk of BCS1L disease derives from allele frequencies, not from patient counts [26].

Founder populations and geographical distribution

GRACILE is a disorder of the Finnish disease heritage: of Hikmat's 33 patients, 10 were diagnosed in Finland and all p.Ser78Gly homozygotes had a neonatal presentation; the remaining patients came from the United Kingdom, USA, France, Sweden, Austria, Norway, Spain, Italy and Oman, with 23 of European ancestry, 3 from the Middle East, 3 Turkish, 2 Pakistani and 2 African American [26]. Outside Finland, a Turkish variant (NM_001079866.2:c.296C>T p.(Pro99Leu)) and combinations of other variants give a similar phenotype [26]. Aagenaes syndrome is concentrated in south-western Norway, with many patients linked to a common ancestor; Bull found a shared haplotype in 83% of chromosomes from Norwegian patients [7, 63]. The Oxford Desk Reference describes the syndrome as very rare outside Scandinavia [131]. Outside Scandinavia, Turkish patients with another 5'UTR variant and families with phenocopies (Serbian Roma; Mexican with CCBE1) have been described [67, 68, 89]. Transaldolase deficiency has been described in families of Arab (Saudi Arabia, United Arab Emirates), Turkish, European (France, Poland), South Asian, Cambodian and various African origins, often consanguineous [25, 30, 110]. DBS has been described in northern and central Europeans, in the Middle East, in Americans of European origin and in African Americans, without ethnic predominance [35].

Portugal and Brazil

The sources consulted do not mention Portuguese patients with these disorders. In Brazil, a family with Nance-Horan syndrome (variant c.3333del, published designation) initially diagnosed as isolated hereditary cataract has been described [115]. The absence of data in the sources consulted does not demonstrate the absence of patients.

Special populations

Preterm infants and those receiving parenteral nutrition have cholestasis from other causes, which can delay recognition of a genetic disorder [55]. Women with Aagenaes syndrome have cholestatic episodes linked to pregnancy, contraceptives and the menstrual cycle [7]. Female carriers of Nance-Horan may have only mild opacities and go unnoticed [36].

European reference networks and patient organisations

ERN RARE-LIVER (https://rare-liver.eu) covers rare paediatric liver diseases, including genetic neonatal cholestasis; MetabERN (https://metab.ern-net.eu) covers mitochondrial diseases and inborn errors of metabolism; VASCERN (https://vascern.eu) covers vascular and lymphatic anomalies; ERN-EYE (https://www.ern-eye.eu) rare eye diseases; ERKNet (https://www.erknet.org) hereditary kidney diseases; and ERN ITHACA (https://ern-ithaca.eu) malformation syndromes. Patient organisations include the United Mitochondrial Disease Foundation (https://www.umdf.org), the Lymphangiomatosis & Gorham's Disease Alliance (https://www.lgdalliance.org), the Lymphatic Education & Research Network (https://www.lymphnet.org), the Lymphoedema Support Network (https://www.lymphoedema.org), CDH International (https://www.cdhi.org) and the Children's Liver Disease Foundation (https://www.childliverdisease.org) [35, 109].

10. Illustrative Clinical Case

Transaldolase deficiency in two siblings, interpreted as gestational alloimmune liver disease

Adeniji and colleagues described two successive pregnancies of a non-consanguineous couple [111]. In the first, the fetus was referred for being small; at 20 weeks it had echogenic bowel, mild bowel dilatation and mild polyhydramnios; at 32 weeks, asymmetric growth restriction (abdominal circumference below the 5th centile), grade 2 echogenic bowel, dilated transverse colon and thickened placenta; and at 35 weeks and 6 days, estimated weight below the 10th centile and oligohydramnios. The girl was born at 36 weeks weighing 1820 g (5th centile), with platelets of 33,000/µL, prothrombin time of 48.5 s (INR 5.2) and fibrinogen of 147 mg/dL, and required multiple transfusions for disseminated intravascular coagulation; she had no metabolic acidosis. She had little subcutaneous fat, hypotonia, a butterfly vertebra at T5, a small umbilical hernia, hypoplastic lips, hirsute forehead, short palpebral fissures, telecanthus and a broad nasal bridge. Microarray showed trisomy X and a 373 kb duplication at 16p13.3 of uncertain significance, and ferritin was 920 ng/mL. She developed conjugated hyperbilirubinaemia (conjugated bilirubin of 6.5 mg/dL on day 20 and 21 mg/dL on day 32), splenomegaly, ascites and hypertrophic cardiomyopathy, and the family opted for withdrawal of care on day 33. Autopsy showed a micronodular liver with cholestasis and hepatic iron of 6275.9 μg/g (reference 200–1600), and the presumptive diagnosis was neonatal haemochromatosis due to gestational alloimmune liver disease [111].

In the second pregnancy, the mother received weekly intravenous immunoglobulin from 14 weeks. The fetus showed biometric lag at 17 weeks, echogenic bowel, normal microarray and negative screening for congenital infections at 19 weeks, and at 28 weeks retrognathia, scalp hypertrichosis, echogenic bowel and liver and an increased umbilical artery pulsatility index (figures 1 to 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC13588688/figure/FI1/, https://pmc.ncbi.nlm.nih.gov/articles/PMC13588688/figure/FI2/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC13588688/figure/FI3/) [111]. The boy was born at 37 weeks weighing 1605 g (below the 1st centile) and underwent exchange transfusion for a suspected alloimmune process. He had intermittent hypoglycaemia and, on day 30, severe cholestasis (total bilirubin 46.0 mg/dL, direct 26.5 mg/dL, alkaline phosphatase 994 U/L), common bile duct stones, a 1.5 cm subcapsular hepatic mass and hepatic iron of 6.9 to 8.9 mg/g dry weight. A mitochondrial DNA depletion and liver disease panel was negative. After progressive coagulopathy and intracranial haemorrhage, the parents opted for withdrawal of care on day 43; autopsy confirmed neonatal haemochromatosis with hepatic nodularity and fibrosis (figure 4, https://pmc.ncbi.nlm.nih.gov/articles/PMC13588688/figure/FI4/) and hypertrophic cardiomyopathy [111].

Trio exome sequencing after death identified, in trans, NM_006755.1:c.574C>T p.(Arg192Cys), of paternal origin and known to be pathogenic, and c.715C>T p.(Arg239Cys), of maternal origin, novel and located in the phosphate-binding site, conserved down to Escherichia coli (figure 5, https://pmc.ncbi.nlm.nih.gov/articles/PMC13588688/figure/FI5/); Sanger sequencing of the sister's tissue confirmed the genotype [111]. In the current MANE transcript nomenclature, the variants correspond to NM_006755.2:c.574C>T p.(Arg192Cys) and NM_006755.2:c.715C>T p.(Arg239Cys) [10]. Urinary polyols were not measured. The mother later had a healthy daughter with another partner, without immunoglobulin.

The case illustrates three points. First, neonatal haemochromatosis is a phenotype and not an aetiological diagnosis: transaldolase deficiency produced a picture indistinguishable from alloimmune disease, and immunoglobulin and exchange transfusion were ineffective [111]. Second, cardiomyopathy, which is not typical of alloimmune disease, is a clue to transaldolase deficiency [30, 111]. Third, microarray does not detect monogenic disorders, and exome sequencing before assuming an alloimmune mechanism would have changed the counselling, by defining a 25% recurrence risk for the couple instead of a maternal risk [111]. The empirical prenatal immunoglobulin and exchange transfusion described are the management of one report and do not represent the management of transaldolase deficiency, for which there is no targeted therapy.

Donnai-Barrow syndrome presenting as early-onset high myopia

Yuan and colleagues described a 14-year-old Chinese girl, the second of four children of healthy non-consanguineous parents [91]. Proteinuria was detected at 2 months; at 2 years high myopia and sensorineural hearing loss were diagnosed, and she began using hearing aids; she said her first word only at 3 years, with unclear speech, and at 9 years received a cochlear implant in the right ear [91]. On examination she had hypertelorism, exophthalmos, a broad high forehead, depressed nasal bridge, short nose with a broad tip, esotropia and finger hyperextensibility [91]. Axial length was 37.58 mm in the right eye and 37.80 mm in the left, with nystagmus, markedly reduced scotopic and photopic responses on electroretinography, persistent pupillary membrane, severe myopic retinopathy, bilateral posterior staphylomas, vitreous opacities, central and paracentral scotomas and absent foveal reflex; she also had a bicornuate uterus and proteinuria of 2434.95 mg/24 h [91]. Exome sequencing identified NM_004525.3:c.9032G>A p.(Arg3011Lys), de novo, and c.2909-2A>T, inherited from the father; the mother and a sister heterozygous for the paternal variant had a normal ophthalmological examination [10, 91]. The patient attended a special education school, performing well and travelling independently [91].

The case shows that infantile proteinuria, high myopia and hearing loss, considered in isolation, did not lead to the diagnosis for 12 years, and that testing for low-molecular-weight proteinuria in a child with high myopia and hearing loss would have directed investigation towards LRP2 [35, 91]. The phase of the two variants derives from the family segregation described in the article, without direct phasing of the de novo variant [91].

11. Prognosis and Long-Term Follow-Up

Prognosis

In GRACILE in the original series, all 17 patients died by 4 months [29]. In the Hikmat cohort, p.Ser78Gly homozygotes all died in the first year (median 4 days); patients with onset in the first month had a mortality of 15 in 22 (death in the first year in 14), with a median time to death of 27 days, and those with late onset 2 in 9, with a median time of 8 years; multiorgan failure (15 of 17) and sepsis (2 of 17) were the causes of death [26]. The presence of p.Ser78Gly was associated with significantly shorter survival (p<0.001), and age at onset is the main clinical marker of prognosis [26].

In transaldolase deficiency, mortality approaches 100% when liver failure present at birth does not recover in the first month or when liver function deteriorates in the first 6 months [13]. In the Scaglione cohort, 13 of 16 patients were alive at last follow-up (median age 17.6 years); three infants died, two of liver failure before transplantation was feasible and one of post-transplant complications [30]. Ten of 16 patients followed a slow course without the need for transplantation, with stable cirrhosis; chronic kidney disease appeared in five and progressed in the two oldest, and most had good educational and occupational integration [30]. One patient with neonatal liver failure had complete resolution by 15 years [13]. Hepatocellular carcinoma has been described in three patients, one of them at 16 months [25, 94].

In Norwegian Aagenaes syndrome, by 2006 cirrhosis with transplantation or death in early childhood had occurred in 6 of 40 patients, slowly progressive cirrhosis in 3 and possible progression to cirrhosis in 2; more than half can expect a normal life expectancy [126]. For the same 40 patients, OMIM reports that nine died in early childhood, mainly from haemorrhage before vitamin K prophylaxis, four from cirrhosis (at 2, 7, 8 and 50 years) and two from unrelated causes in adulthood, and three of the survivors had been transplanted in childhood [14]. In 13 adults followed for 9 years, liver function remained clinically stable, with low-grade hepatobiliary dysfunction and nutritional status similar to that of controls [99]. Cirrhosis occurs in about 25% [6]. Lymphoedema is the main cause of long-term morbidity, severe in about one third of adults [34].

In DBS, many pregnancies are terminated or end in perinatal death because of malformations; the major risks are retinal detachment in a child who already has hearing loss and progression of renal dysfunction, and only two adults older than 50 years had been described, one with a kidney transplant and the other with renal rickets [35]. Among patients who survived the first year, 26.3% had retinal detachment, and renal series show glomerular proteinuria and reduced filtration already in childhood [79, 104]. In Nance-Horan syndrome, visual acuity often remains low despite early surgery [36].

Surveillance table

Intervals not indicated as specific were not defined in the sources consulted and should be individualised by the reference teams.

12. Summary and Final Considerations

The BCS1L disorders, transaldolase deficiency and Aagenaes syndrome are three rare monogenic causes of neonatal cholestasis or liver failure, without targeted therapy, whose identification depends on recognising the extrahepatic features and on using genetic tests capable of detecting variants outside the coding regions. GRACILE, the lethal Finnish form of BCS1L-related complex III deficiency, combines severe fetal growth restriction, lactic acidosis on the first day, aminoaciduria, cholestasis and iron overload; the 2021 multinational cohort showed that the BCS1L disorders form a continuum, with late neurological, tubular or auditory forms, and that age at onset and the p.Ser78Gly variant determine prognosis. Normal complex III enzymology does not exclude the disease, and treatment follows the general recommendations of the Mitochondrial Medicine Society, with an emergency plan, dextrose-containing fluids, prevention of catabolism and caution with drugs such as valproate and propofol; liver-directed gene therapy is still at the preclinical stage.

Transaldolase deficiency is an inborn error of the pentose phosphate pathway that manifests with growth restriction, hydrops, hepatosplenomegaly, cytopenias, cutis laxa and heart disease, and that can mimic gestational alloimmune liver disease. The diagnosis is made by urinary polyols and seven-carbon sugars and by TALDO1 sequencing. The 2026 cohorts show that most patients survive with stable cirrhosis, that liver transplantation saves those with liver failure but does not correct the renal, endocrine and bone complications, and that the disease should be sought in adolescents and adults with unexplained cirrhosis, cytopenia, kidney disease and hypergonadotrophic hypogonadism. Avoidance of paracetamol has experimental and clinical support, and N-acetylcysteine remains experimental.

Aagenaes syndrome, with an incidence of 1 in 80,980 births in Norway, is due to the c.-98G>T variant in the 5' untranslated region of UNC45A, alone or with a loss-of-function allele; the same gene, with two coding alleles, causes osteo-oto-hepato-enteric syndrome. Exome sequencing may not detect the variant. Neonatal cholestasis with giant cell hepatitis improves in most, but episodes of pruritus, fat-soluble vitamin deficiency and lymphoedema that worsens at puberty persist; more than half of patients can expect a normal life expectancy.

Donnai-Barrow syndrome, Nance-Horan syndrome and the complex lymphatic anomalies share with these disorders only aspects of the differential diagnosis. In the first, low-molecular-weight proteinuria is the diagnostic clue, and surveillance of the retina, hearing and kidney guides follow-up; in the second, congenital cataract with screwdriver-shaped incisors and the mother's sutural opacities guide the diagnosis; in the third group, sirolimus, used off-label, produced partial responses in most patients with generalised lymphatic anomaly and kaposiform lymphangiomatosis in a phase 2 trial without a control group. In DBS, proteinuria of glomerular origin and reduced filtration in childhood indicate a risk of early chronic kidney disease, and prevention of retinal detachment divides the sources between prophylactic retinopexy and surveillance with imaging. In Nance-Horan syndrome, duplications and X-autosome translocations complete the spectrum of mechanisms, and carriers may need surgery from the first months of life.

13. References

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