Disaccharidase Deficiencies, Acrodermatitis Enteropathica, Trichohepatoenteric Syndrome and Very-Early-Onset Monogenic IBD

Monogenic enteropathies with targeted treatment: sacrosidase and diet, oral zinc and haematopoietic stem cell transplantation

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

This article brings together four groups of autosomal recessive diseases that present mainly as chronic diarrhoea in infancy and share one decisive clinical feature: each has a specific intervention that radically changes the course of the disease, namely avoidance of the carbohydrate and enzyme replacement in the disaccharidase deficiencies, oral zinc in acrodermatitis enteropathica, nutritional and immunological support in trichohepatoenteric syndrome (THES), or allogeneic haematopoietic stem cell transplantation (HSCT) in defects of the interleukin-10 (IL-10) pathway, which cause monogenic inflammatory bowel disease (IBD). The following table summarises the reference data for each entity; the prevalence figures are those of the sources cited and measure different things (point prevalence, birth prevalence or estimates from allele frequency; section 9).

Table sources: Orphanet and Orphadata [1–7], OMIM [8–15], GeneReviews [16], gene records [17], allele-frequency estimates [18], Inuit founder [19], Danish incidence and zinc dose [20], IL-10 axis patients [21], sacrosidase label and orphan designation [22, 23], French CSID PNDS [24] and European networks [25–28].

1. Introduction

1.1. Scope and rationale for the grouping

Congenital diarrhoeas and monogenic enteropathies form a class of more than fifty diseases; within this class, four groups stand out because establishing the diagnosis leads to a specific therapy with a very large effect. The congenital disaccharidase deficiencies (sucrase-isomaltase and lactase) are enzyme defects of the enterocyte brush border whose expression depends on the carbohydrate ingested; acrodermatitis enteropathica is a defect of apical zinc transport that is corrected by oral supplementation; trichohepatoenteric syndrome is a disease of the SKI complex of ribonucleic acid (RNA) surveillance that combines enteropathy, hair abnormalities, liver disease and combined immunodeficiency; and IL-10 pathway defects are inborn errors of immunity that cause the most severe and earliest form of monogenic IBD, curable by HSCT [16, 29, 30]. In the reference textbooks these entities appear mainly in tables on the approach to chronic diarrhoea and dehydration in infancy, where sucrase-isomaltase deficiency is placed under acidic diarrhoea beginning with the introduction of complementary foods, lactase deficiency under neonatal diarrhoea, and acrodermatitis enteropathica under diarrhoea with periorificial skin lesions after weaning [29].

Very-early-onset monogenic IBD (VEO-IBD, very early-onset inflammatory bowel disease) is in turn a syndromic class with more than one hundred known genetic causes [31]. The IL10, IL10RA and IL10RB genes are covered in depth because they were the first identified, have complete penetrance of intestinal inflammation and are the paradigm of treatment by HSCT; the remaining genes of the class are presented in a table, with the clinical feature and the test that distinguish them [30, 32, 33].

1.2. Historical overview

Congenital lactose intolerance was first described by Durand in 1958, and the first siblings with congenital lactase deficiency were reported by Holzel and colleagues in 1959; in 1983, Savilahti and colleagues collected 16 Finnish cases diagnosed over 17 years, all with watery diarrhoea after the first feed or, at the latest, by the tenth day of life [9]. The locus was assigned to 2q21 by linkage studies in 19 Finnish families in 1998, and in 2006 Kuokkanen and colleagues identified five variants in the coding region of LCT, including the founder nonsense variant «Fin-major», showing that the congenital form results from structural damage to the enzyme and not from the regulatory element responsible for adult hypolactasia [34]. The latter had been explained in 2002 by Enattah and colleagues, who located the C/T-13910 variant about 14 kb upstream of LCT [35].

Sucrase-isomaltase deficiency was first described by Weijers and van de Kamer in 1959 and recognised as an entity during the 1960s [24]; the symptomatic late-onset adult form was described by Jansen in 1965, and in 1967 Peterson and Herber identified sucrase deficiency as a cause of diarrhoea in adults and documented the efficacy of an enzyme of fungal origin, the direct forerunner of current enzyme replacement [8]. In 1987, Harms and colleagues showed that oral freeze-dried yeast corrected the symptoms, and in 1988 Naim and colleagues showed, with monoclonal antibodies, that the disease results from at least three cellular phenotypes of retention or missorting of the protein [8]. Sacrosidase, an invertase purified from baker's yeast, was approved by the Food and Drug Administration (FDA) on 9 April 1998 [36]. The term «genetic sucrase-isomaltase deficiency» (GSID) is now proposed to encompass the spectrum from the severe congenital form to mild late-onset forms [37].

Acrodermatitis enteropathica, known by the eponym Danbolt-Closs, was for decades treated empirically with diiodohydroxyquinoline, whose efficacy was later understood to be linked to zinc; Moynahan reported the response to oral zinc in 1974, confirmed by Neldner and Hambidge in 1975 [10]. Zinc therapy, introduced in 1975, became universal, and the SLC39A4 gene was identified in 2002 by two independent groups [38, 39].

Trichohepatoenteric syndrome was described by Stankler and colleagues in 1982, in two siblings who died at 33 and 87 days with severe diarrhoea and trichorrhexis nodosa; Girault and colleagues described in 1994 eight children with severe secretory diarrhoea and woolly hair under the name phenotypic diarrhoea, and Verloes and colleagues coined the term «tricho-hepato-enteric syndrome» in 1997 [11]. Hartley and colleagues identified TTC37 variants in 2010 in 12 children from 11 families, and Fabre and colleagues found SKIV2L variants in 2012 in six patients without TTC37 variants; the two genes were later renamed SKIC3 and SKIC2 under the nomenclature of the «superkiller» complex [11, 12, 16].

The first monogenic cause of IBD was described in 2009 by Glocker and colleagues, who identified homozygous variants in IL10RA and IL10RB in four of nine children with early-onset colitis and successfully treated one of them by HSCT [40]. Deficiency of the IL10 ligand itself was described in 2010, and in 2012 Kotlarz and colleagues showed, in 66 children with IBD before the age of 5 years, that IL-10 pathway defects explained 16 cases and that HSCT induced sustained remission [17, 41].

1.3. Current nomenclature and classifications

The age classification of paediatric IBD distinguishes paediatric-onset IBD (Montreal classification A1, before 17 years), early-onset IBD (Paris A1a, before 10 years), very-early-onset IBD or VEO-IBD (before 6 years), infantile IBD (before 2 years) and neonatal IBD (first 28 days) [32]. The 2024 classification of the International Union of Immunological Societies (IUIS) places IL-10 deficiency and IL-10R deficiency in the «immune dysregulation with colitis» subgroup of the diseases of immune dysregulation, and THES among the combined immunodeficiencies with syndromic features, alongside immunodeficiency with multiple intestinal atresias due to TTC7A [42]. The 2025 European consensus on malabsorption classifies congenital lactase and sucrase-isomaltase deficiencies among the disorders of epithelial enzymes and metabolism [43]. In gene nomenclature, SKIC3 and SKIC2 replace TTC37 and SKIV2L; both names coexist in the literature after 2020 [16, 44].

1.4. Definition of the entities

Congenital sucrase-isomaltase deficiency is the absence or marked reduction of sucrase activity, with variable isomaltase activity, caused by biallelic variants in SI, which prevents the digestion of sucrose and of part of the starch dextrins [8, 22]. Congenital lactase deficiency is the absence of lactase-phlorizin hydrolase activity from birth due to biallelic variants in the coding region of LCT, distinct from adult-type lactase non-persistence, which is a regulated trait and not a disease [34, 45]. Acrodermatitis enteropathica is systemic zinc deficiency due to biallelic variants in SLC39A4, which encodes the apical transporter ZIP4 [38]. THES is the disease caused by biallelic variants in SKIC3 or SKIC2, with intractable diarrhoea, hair abnormalities and, in variable proportion, IUGR, dysmorphism, immunodeficiency and liver disease [16]. IL-10 pathway defects are the diseases caused by biallelic loss-of-function variants in IL10, IL10RA or IL10RB, which cause enterocolitis beginning in the first months of life with complete penetrance [32, 42].

2. Molecular Genetics and Pathophysiology

2.1. Sucrase-isomaltase (SI)

The SI gene, at 3q26.1, encodes a bifunctional α-glucosidase anchored in the apical membrane of the enterocyte; the protein is synthesised as a single precursor, glycosylated and cleaved in the lumen by pancreatic proteases into sucrase and isomaltase subunits, which remain associated as a heterodimer [17]. Sucrase hydrolyses the α-1,2 bond of sucrose into glucose and fructose, isomaltase hydrolyses the α-1,6 bonds of isomaltose and of starch limit dextrins, and the complex also contributes to the digestion of maltose; activity is concentrated in the distal duodenum and the jejunum [17, 22]. In humans, the complex accounts for 60–80% of intestinal maltase activity and almost all sucrase activity, which makes it indispensable for the digestion of sucrose, maltose and isomaltose, present in most diets [24]. In the typical congenital form almost all sucrase activity is absent, isomaltase activity is markedly reduced and maltase activity moderately decreased, although isomaltase ranges from absent to nearly normal [8, 22].

Most pathogenic variants do not abolish transcription; they act after translation, through misfolding with retention in the endoplasmic reticulum, missorting to the basolateral membrane, aberrant processing or delivery to the membrane of a catalytically defective protein, which explains the biochemical heterogeneity described since 1988 [8, 17]. Unhydrolysed sucrose and starch draw water by osmotic effect and are fermented by the colonic microbiota, producing hydrogen, methane and organic acids; the result is acidic diarrhoea, gas, bloating, cramps and, in young children, poor weight gain [22]. Lactic acid, normally absent or present only in traces in the colon, acidifies the stool and reduces colonic absorption of sodium and water, and short-chain fatty acids can cause metabolic acidosis [24]. In a given patient, symptoms are proportional to the amount of malabsorbed sugar, and small amounts are often tolerated thanks to adaptation of the gut and microbiota; as this is not a food allergy, accidental ingestion of an excluded food carries no vital risk and is treated symptomatically only [24].

The spectrum of severity is continuous. Hypomorphic alleles and possibly some isolated heterozygous variants reduce activity without abolishing it, giving later-onset presentations that overlap with IBS [17, 37]. In patients with IBS, four rare loss-of-function variants typical of CSID are more frequent in the heterozygous state than in controls, and the hypomorphic variant NM_001041.4:c.43G>T p.(Val15Phe) has been studied with respect to the response to sucrose challenges and to low-starch, low-sucrose diets [46–50]. This line of research does not by itself establish a dominant disease: the interpretation of SI variants is hampered by variable penetrance and expressivity, a possible dominant-negative effect, inconsistent terminology and heterogeneous functional data [51]. In an Australian cohort of 72 patients with IBS, 54% had at least one hypomorphic variant (85% as simple carriers), and their presence was not associated with the response to the low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet or with long-term symptom control [52].

Outside Arctic populations, at least 80% of published patients carry one of three common variants, all in the sucrase domain and with a demonstrated effect on intracellular trafficking and on the abolition of sucrase and isomaltase activities: NM_001041.4:c.1730T>G p.(Val577Gly), NM_001041.4:c.3218G>A p.(Gly1073Asp) and NM_001041.4:c.5234T>G p.(Phe1745Cys) [24, 50]. In a patient of European ancestry with clinical suspicion, it is exceptional not to find any of these three variants on at least one allele. Analysis of gnomAD added more than 40 presumed loss-of-function variants, among which NM_001041.4:c.2789A>G p.(Gln930Arg) is relatively frequent [18, 24, 50]. Published data show no major phenotypic differences between genotypes, despite distinct effects on trafficking and function, but they rest on few studies [24].

In Inuit populations, the variant NM_001041.4:c.273_274del, p.(Gly92LeufsTer8), described in the literature as c.273_274delAG or p.Gly92Leufs*8, predicts absence of functional protein and accounts for practically all pathogenic alleles; in the Canadian Arctic the observed allele frequency was 17.2% (95% confidence interval, CI: 12.6–21.8%), which predicts, by Hardy-Weinberg equilibrium, a homozygote prevalence of 3.0% [19, 50]. In Greenland, homozygous adults without gastrointestinal disease showed lower glycaemic variability on a Western sucrose-rich diet and lower fasting insulin than non-carriers, which links this variant to a more favourable metabolic profile [53].

The frequency of the Arctic variant made it possible to study the consequences of complete loss of function at population level. In Greenland, in a case-control study using electronic health records of 80 homozygotes and 80 non-carriers matched for sex, age, residence and European genetic admixture, the homozygotes, who were unaware of their genotype (only one had the diagnosis recorded), had 19% more consultations for gastrointestinal symptoms (incidence rate ratio, IRR, 1.19; 95% CI 1.02–1.40) and 41% more gastrointestinal diagnostic procedures (IRR 1.41; 95% CI 1.05–1.92) than non-carriers [24, 54]. Homozygous adults had a body mass index about 2 kg/m² lower, weight about 5 kg lower, a more favourable lipid profile and higher serum acetate, a phenotype reproduced in Si-knockout mice fed sucrose; no effect was observed on glucose homeostasis, type 2 diabetes or cardiovascular disease in the small group studied, and the effect appeared independent of lower intake of added sugar [24]. SI is also expressed in taste cells carrying the sweet taste receptors T1R2 and T1R3, which supports the hypothesis, not yet demonstrated, of reduced sensitivity to the taste of sucrose in patients [24].

2.2. Lactase-phlorizin hydrolase (LCT) and regulation by MCM6

The LCT gene, at 2q21.3, encodes lactase-phlorizin hydrolase, a two-domain brush-border enzyme: one domain hydrolyses lactose into glucose and galactose and the other acts on hydrophobic β-glycosides such as phlorizin and glycosylceramides; the protein is synthesised as a pre-proprotein of 1927 amino acids and processed to the mature form [17, 34]. In the congenital deficiency, biallelic variants in the coding region produce a structurally abnormal enzyme that is inactive from birth [34]. The Finnish founder variant NM_002299.4:c.4170T>A, p.(Tyr1390Ter), known as Fin-major or Y1390X, was homozygous in 27 of 32 patients (84%) of the original series and accounts for about 90% of Finnish alleles; the other variants in that series were two frameshift deletions and the substitutions Q268H and G1363S [17, 34, 50]. Outside Finland, S688P with E1612X in an Italian girl, homozygous G1363S in Turkish siblings and homozygous c.3448delT in a newborn of Turkish origin in Germany have been described, among others [55, 56]. All produce a similar phenotype, regardless of the position or type of variant [55]. Recent functional studies have described LCT missense variants with a dominant-negative effect in vitro, through the formation of hetero-complexes with the normal enzyme that impair intracellular trafficking, a laboratory finding still without established clinical translation [57].

Adult hypolactasia has a different mechanism. The protein is normal, and it is transcription that declines after weaning, under the control of a cis element located in an intron of the neighbouring gene MCM6; the C/T-13910 variant, normalised as NM_005915.6:c.1917+326C>T (NC_000002.12:g.135851076G>A), is completely associated with biochemically verified non-persistence in Finnish families and in four populations, and sequencing of the coding region and promoter of LCT shows no variants correlated with the trait [17, 35, 50]. Lactase persistence behaves as a dominant trait and non-persistence is the ancestral state of most adults in the world, which is why OMIM considers the designation «hereditary persistence of lactase» more appropriate [17, 45].

2.3. Zinc and the ZIP4 transporter (SLC39A4)

Zinc is a cofactor of more than one hundred enzymes and essential for nucleic acid metabolism, protein synthesis and gene regulation by zinc-finger proteins; cellular homeostasis depends on two families of transporters with opposing roles, SLC30 (ZnT), which lower cytosolic zinc by promoting efflux, and SLC39 (ZIP), which raise it by promoting influx [38]. The SLC39A4 gene, at 8q24.3, encodes ZIP4, the main intestinal zinc importer, with eight transmembrane domains, expressed on the apical membrane of duodenal and jejunal enterocytes; its activity and its trafficking to the surface are regulated by zinc availability [17, 38]. Variants are scattered throughout the gene, are of several types and have been described mainly in families from Europe, the Middle East and North Africa; missense variants can abolish transport and cause protein mistrafficking [17, 38, 39]. Systemic zinc deficiency mainly affects rapidly renewing tissues such as the skin, the gut and lymphoid tissue [38].

In more than half of patients with clinically confirmed AE no variants are found in the coding region of SLC39A4, and some have only one variant; proposed explanations include dysregulated transcription through metal response elements, modifier genes or another as yet unidentified gene [38, 39]. No genotype-phenotype correlation has been established [20]. The same family of transporters explains other zinc disorders: maternal heterozygous variants in SLC30A2 (ZnT2), at 1p36.11, reduce zinc in breast milk and cause transient neonatal zinc deficiency, with maternal dominant inheritance; SLC39A13 causes a spondylodysplastic form of Ehlers-Danlos syndrome and SLC30A9 a cerebrorenal syndrome described in one family [38, 58].

2.4. The SKI complex and trichohepatoenteric syndrome

The human SKI complex is a cytoplasmic heterotetramer that acts as a cofactor of the RNA exosome in the surveillance and degradation of normal and non-functional mRNA [16]. SKIC3 (5q15; transcript NM_014639.4, 43 exons, the first three non-coding) encodes a protein of 1564 amino acids with 20 tetratricopeptide repeats that mediate protein-protein interactions; SKIC2 (6p21.33, in the class III region of the major histocompatibility complex; transcript NM_006929, 28 exons) encodes a DEAD-box family RNA helicase with ATPase activity, of 1246 amino acids [16, 17]. THES results from loss of function of either protein; SKIC3 variants are missense, nonsense or splicing variants and reduce, abolish or mislocalise the protein, whereas SKIC2 variants are mainly nonsense or small insertions/deletions [16]. Cells from patients with SKIC2 variants show a type 1 interferon signature, unlike those from patients with SKIC3 variants, which suggests partly independent functions and provided the rationale for the isolated use of a Janus kinase 1 and 2 (JAK1/2) inhibitor [16, 59].

In the GeneReviews series of 52 patients, SKIC2 accounted for 31% and SKIC3 for 69% of cases; in the mutation update of 96 patients from 85 families, about two thirds had TTC37 variants and one third SKIV2L variants, and in 8 (8.3%) only one variant was found [11, 16]. There are no hotspots, most variants are private and all those described up to 2018 were detectable by sequencing; in Saudi Arabia, by contrast, 89.6% of 30 patients had SKIV2L variants [16, 60, 61]. Some cases escape exome and genome sequencing, such as a Brazilian patient whose diagnosis required RNA and protein analysis because of hidden aberrant TTC37 transcripts [62]. The recurrent SKIC3 variant NM_014639.4:c.2808G>A p.(Trp936Ter), described in the homozygous state in Indian and Pakistani families, did not show a distinct phenotype [16, 50, 63]. The two genes produce similar clinical pictures, but liver disease was more frequent with SKIV2L (88%) than with TTC37 (51%) and IUGR occurred in 86% and 70%, respectively, whereas in the Saudi cohort liver involvement was more common in the TTC37 form [11, 61]. The immunodeficiency combines hypogammaglobulinaemia due to near absence of class-switched memory B cells, reduced interferon gamma (IFN-γ) production by T cells and natural killer (NK) cells, reduced NK degranulation and, in some patients, abnormal T-cell proliferation [42, 64].

2.5. The interleukin-10 pathway

IL-10 is the main anti-inflammatory cytokine; it is produced by dendritic cells, NK cells, eosinophils, mast cells, macrophages, B cells and subsets of CD4 T cells, including regulatory T cells, and binds to a tetrameric receptor formed by two IL-10R1 (α, IL10RA) and two IL-10R2 (β, IL10RB) chains [30]. Binding activates the kinases JAK1 and TYK2 (tyrosine kinase 2), which phosphorylate STAT3; STAT3 induces suppressor of cytokine signalling 3 (SOCS3) and anti-inflammatory genes that suppress the production of tumour necrosis factor (TNF), IL-1β, IL-6 and IL-8 and the expression of major histocompatibility complex (MHC) class II molecules [17, 21]. Without IL-10 signalling, intestinal macrophages shift towards an inflammatory M1 phenotype and produce IL-1β through caspase-8-dependent non-canonical inflammasome activation, and IL-23, which recruits Th17 cells; the result is a hyperinflammatory enterocolitis directed against the microbiota [21, 32]. The defect resides in cells of the haematopoietic lineage, which explains cure by HSCT [17, 65].

IL10RB is also a chain shared by the receptors for IL-22, IL-26 and the type III interferons (IL-28A, IL-28B and IL-29), so its deficiency abolishes more pathways than IL10RA deficiency [17, 42]. In ligand deficiency, cells do not secrete functional IL-10 but respond to exogenous IL-10; in receptor deficiency, leucocytes do not respond to IL-10 [42]. The penetrance of intestinal inflammation is 100%, unlike many other defects of the class [32]. ClinGen classified the gene-disease relationship as definitive for IL10RA and IL10RB and as moderate for IL10 [17].

IL10RA variants cluster in the extracellular domain (26 of 27 missense variants between amino acids 22 and 235 of 578) and accumulate in East Asia: 99.1% of patients with NM_001558.4:c.301C>T, p.(Arg101Trp), and 97.0% of patients with c.537G>A, p.(Thr179=), described in the literature as p.T179T and with an effect on splicing, are from East Asia; the former has an allele frequency of 0.0635% in China and is absent in Japan, and the latter 0.12% in Japan and 0.0096% in China [50, 66]. The existence of 12 independent pathogenic variants in that region, with a partly increased response to IL-10 in heterozygotes, supports the hypothesis of balancing selection, possibly by Schistosoma japonicum, rather than an isolated founder effect [66]. Patients with IL10RB deficiency are mainly from Central and South Asia and Europe and come from consanguineous families; the most frequent variants are NM_000628.5:c.139A>G, p.(Lys47Glu), and c.611G>A, p.(Trp204Ter) [50, 66, 67]. In Portugal, a founder deletion of exon 3 of IL10RB (NM_000628.5:c.174-1467_331+1354delinsCT, p.?) has been described, with a haplotype shared by three unrelated families and a common ancestor estimated at about 400 years ago, as well as a duplication of about 6 kb of exon 6 that preserves surface expression but abolishes signalling [50, 68]. Copy-number variants account for 19% (deletions) and 3.8% (duplications) of patients with IL10RB defects reported up to 2018 [68]. A 333 bp deletion spanning exon 1 of IL10RA and cases of paternal uniparental disomy of chromosome 11 with apparent homozygosity for c.301C>T show that the exome can fail or mislead the interpretation of zygosity [21, 69].

High-titre neutralising anti-IL-10 autoantibodies produce a phenocopy of the disease in children without pathogenic variants, with a normal response of the cells after washing [21].

2.6. The class of very-early-onset monogenic IBD

Monogenic defects explain about 15–20% of VEO-IBD and disrupt intestinal homeostasis through five main mechanisms: disruption of the epithelial barrier, failure of bacterial clearance by phagocytes, hyperinflammation or autoinflammation, defects of tolerance (regulatory T cells and IL-10 signalling) and defects in the development or function of adaptive immunity [30, 32]. The 2021 European consensus proposed a panel of 75 genes, and the 2026 therapeutic atlas counted 102 known genetic causes [31, 33]. The table summarises the genes of the class by mechanism, with the inheritance, the distinguishing feature and the discriminating test; OMIM numbers are from the OMIM catalogue. In the table, LPS denotes lipopolysaccharide; TREC, T-cell receptor excision circles; SCID, severe combined immunodeficiency; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; HLH, haemophagocytic lymphohistiocytosis; EBV, Epstein-Barr virus; XIAP, X-linked inhibitor of apoptosis; and PLAID/APLAID, the PLCG2-associated antibody deficiency and immune dysregulation syndromes.

Table sources: genes, inheritance and phenotypes [30, 32, 33, 42]; glycogen storage disease Ib [70, 71]; XIAP deficiency [72]; ADA2 deficiency [73]; Hermansky-Pudlak [74, 75]; OMIM numbers [76].

2.7. Normalised reference variants

The table uses Human Genome Variation Society (HGVS) nomenclature and the MANE Select transcript (Matched Annotation from NCBI and EMBL-EBI), normalised in VariantValidator.

The conversion of the published SKIC2 description (c.3112_3140del) to c.3113_3141del results from the 3′ alignment rule applied by VariantValidator and does not change the protein consequence [50].

2.8. Allelic disorders and modifiers

No allelic phenotypes other than THES are known for SKIC2 or SKIC3 [16]. For IL10, OMIM records only susceptibility associations (protection against graft-versus-host disease, susceptibility to HIV-1 and progression of rheumatoid arthritis), with no Mendelian IBD phenotype entry [15]. For LCT, the same chromosomal region harbours the congenital disease and the persistence trait, with distinct mechanisms [34, 35]. For SLC39A4, maternal heterozygosity may reduce zinc in breast milk and bring forward symptoms in breastfed infants, which can be confused with transient deficiency due to SLC30A2 [20, 58].

3. Clinical Spectrum and Manifestations by System

3.1. Congenital sucrase-isomaltase deficiency

In the classic form, the child is asymptomatic while receiving breast milk or sucrose-free formula and becomes ill when sucrose enters the diet, with the introduction of complementary foods, a sweetened formula, fruit or juice; watery, explosive and acidic diarrhoea, abdominal distension, cramps, excoriated nappy rash, vomiting and, if exposure continues, faltering growth appear [17, 29]. The stools contain reducing substances and are acidic, and symptoms follow the sucrose and starch load rather than a fixed course [17, 29]. Free fructose is well tolerated, which distinguishes the disease from hereditary fructose intolerance and fructose malabsorption [80]. Many children improve in later childhood as colonic salvage capacity and eating habits change, and many are never recognised as having a genetic disease [17]. Starch intolerance, dependent on isomaltase, is the component that persists under sucrase replacement and maintains residual symptoms [17, 22].

In late-onset forms, older children and adults present with chronic abdominal pain, bloating, flatulence and loose stools indistinguishable from IBS or other disorders of gut-brain interaction [17, 37]. In adults, disaccharidase deficiency is more common than previously thought, and simultaneous deficiency of all four disaccharidases is associated with greater weight loss [81]. In a Turkish series, 10% of 148 children with disorders of gut-brain interaction tested for SI had symptomatic GSID, compared with 0.3% of 980 patients who underwent exome sequencing for other indications [82]. A qualitative North American study of 43 patients (8 adults and 35 children or adolescents) described a prolonged diagnostic journey, with confusion with common gastrointestinal diseases, and considerable improvement in symptoms and quality of life with sacrosidase, but with persistent symptoms [83]. Extraintestinal symptoms such as headache, vertigo, memory problems and lethargy occur in fewer than 20% of patients with carbohydrate maldigestion [43].

The timing of onset depends on the carbohydrate offered. Exclusive breastfeeding does not cause symptoms, because human milk contains neither sucrose nor maltose, and the same applies to formulas whose only sugar is lactose; formulas, cereals and thickeners containing dextrin-maltose or starch can trigger the disease as early as the first month, and improvement after switching to a lactose-only formula supports the hypothesis [24]. Severity depends on the amount of carbohydrate ingested, the rate of gastric emptying, the fermentative activity of the microbiota, residual SI activity, associated enzyme deficiencies (such as lactase deficiency) and coexisting intestinal disease or inflammation, and tolerance generally improves by adolescence [24]. Metabolic acidosis and, in two patients, nephrocalcinosis and urolithiasis have been described; the French patient association reports fatigue, thirst and a symptom latency that varies with the food, data not yet systematically studied [24]. No routine laboratory test guides the diagnosis: it is the detailed dietary history, linking sucrose intake to symptoms, that raises suspicion [24]. In the North American series of 43 patients, the signs that led to diagnosis were diarrhoea (65%), failure to gain weight (37% of children), abdominal pain (50% of adults and 17% of children), reflux (31% of children) and bloating (20% of children); most were diagnosed before 5 years of age, 39% received the diagnosis in less than one year and 30% between one and two years [24, 83]. Aversion to sweet foods, frequent in hereditary fructose intolerance, appears less common, although the patient association describes it [24].

3.2. Congenital lactase deficiency

Profuse watery diarrhoea begins in the first days of life, as soon as the newborn receives breast milk or lactose-containing formula; in the 1983 Finnish series, the mother usually noticed diarrhoea after the first feed and always by the tenth day [9, 17]. Without treatment, dehydration, weight loss and faltering growth ensue, usually requiring hospital admission; breastfeeding becomes impossible [17, 84]. Sucrose, maltose and starch are tolerated [9]. Hypercalcaemia, hypercalciuria and nephrocalcinosis are known complications: a newborn of Turkish origin, admitted on day 17 with hypertonic dehydration and metabolic acidosis, had hypercalcaemia, hypercalciuria and nephrocalcinosis that resolved only months after the lactose-free diet, and an Indian infant referred for hypercalcaemia normalised calcium within one week without lactose [56, 85]. With a lactose-free diet, symptoms and growth normalise [17].

Adult hypolactasia, by contrast, produces bloating, cramps, flatulence and osmotic diarrhoea proportional to the lactose load and is a trait of most of the world's adult population; secondary lactase deficiency is transient and accompanies mucosal damage due to infection, coeliac disease, Crohn's disease or bacterial overgrowth [17, 43].

3.3. Acrodermatitis enteropathica

Children are healthy at birth. Symptoms usually begin between 4 and 10 weeks in non-breastfed infants and around weaning in breastfed infants, because zinc in breast milk is more bioavailable; in breastfed infants of heterozygous mothers onset may be earlier [20, 38]. Anorexia, weight loss and faltering growth appear before the skin lesions and alopecia [29]. Dermatitis, present in almost all, is located in acral, periorificial and anogenital regions; it begins as scaly erythematous and eczematous plaques, which become pustular, vesiculobullous, psoriasiform or crusted, and after the first year pustular and hyperkeratotic changes predominate; superinfection with Candida albicans or Staphylococcus aureus is frequent [20, 38]. Diarrhoea is intermittent and may become watery and intractable [38].

Mood changes are an early sign: apathy and irritability in infants and depression later. Further features include alopecia of the scalp, eyebrows and eyelashes, Beau's lines, paronychia, nail dystrophy, blepharitis, conjunctivitis, photophobia, erythematous oral mucosa, hypogeusia, anaemia, poor wound healing, male hypogonadism and delayed puberty; infections can be fatal [20, 38]. In a Tunisian series of 29 patients, onset occurred between 15 days and 12 months (mean 6.86 ± 3.25 months) and presentation to a doctor was late (mean 2.8 months after onset); at presentation, 66% had mucosal signs, 52% complete alopecia of the scalp, eyelashes and eyebrows, 52% diarrhoea and 45% neuropsychiatric disturbances, and the gastrointestinal and psychiatric signs depended on the delay in presentation [20, 86].

Without treatment, a significant fraction has a progressive course; in a historical review of 179 cases, most without confirmation of hereditary disease, 34 of 51 untreated patients and 2 of 128 treated patients died, and most deaths occurred before 12 years of age [20, 38]. Atypical presentations include late onset, as in a boy breastfed until 2 years of age who presented at 8 years in septic shock, absence of hypozincaemia and acneiform lesions [77, 87].

3.4. Trichohepatoenteric syndrome

THES begins before birth: most children are born below the 10th centile for weight or length, and in the second trimester severe fetal growth restriction of non-placental cause, hyperechogenic bowel and dolichocephaly may be observed [16, 88]. Intractable diarrhoea, present in practically all patients, usually begins in the first days of life, with median onset at 31 days in a French series, and sometimes only at the end of the first year; it is watery, rarely bloody, persists with bowel rest and leads to malabsorption and faltering growth [16, 64]. Endoscopy is often normal and biopsy shows mild to severe villous atrophy [16].

The hair is woolly, poorly pigmented, brittle and impossible to comb, changes that may not be evident in the first months or may be masked by cultural practices [16]. Final height is below the 3rd centile in more than half of patients despite adequate nutrition; the three adults with data measured 148 cm (−2.36 standard deviations, woman aged 27), 171 cm (−0.74, man aged 18) and −5 standard deviations (woman aged 17) [16]. Liver disease ranges from hepatomegaly and raised transaminases to fibrosis and cirrhosis, with iron overload and sometimes haemochromatosis, including neonatal haemochromatosis; one hepatoblastoma has been described [16, 79].

The immunodeficiency manifests as viral (respiratory syncytial virus, Epstein-Barr virus, EBV) and bacterial infections, hypogammaglobulinaemia or poor vaccine response and sometimes monoclonal hyper-IgA; in a French cohort, 4 of 9 patients had EBV infection and 4 transient haemophagocytosis [16, 64]. Café-au-lait spots predominate on the lower limbs, and a subgroup from the Arabian Peninsula has hyperpigmentation of the pelvis, waist and lower limbs; xerosis and rubbery-textured skin appear later [16]. Heart disease includes ventricular septal defect, atrial septal defect, tetralogy of Fallot, bicuspid aortic valve and aortic sinus dilatation; platelets may be large without a functional defect [16]. Occasional findings include hypothyroidism (3/15), conical or dysplastic teeth, inguinal hernia, small or polycystic kidneys, glaucoma, radioulnar synostosis, osteoporosis, nephropathy and renal and hepatic cysts [16, 44].

The natural history has changed with long follow-up. In a United Kingdom cohort of 13 patients followed between 1996 and 2020, all received PN, 6 were weaned off it, all had endoscopic gastrointestinal inflammation and almost half developed refractory monogenic IBD by 11 years of age; diarrhoea with intestinal failure improved over time in all, and respiratory complications contributed substantially to morbidity and mortality [89]. Recent cases describe chronic active colitis with crypt abscesses and an inverted CD4/CD8 ratio, a VEO-IBD-like picture [90].

3.5. Monogenic IBD of the IL-10 axis

In the Kotlarz series, the 16 patients with IL-10 or IL-10R deficiency developed refractory colitis in the first three months of life; all had perianal disease, 11 folliculitis and 4 arthritis [41]. In a systematic review of 286 patients, the median age at onset was 1.0 month (0.3–4.0) and at genetic diagnosis 16.0 months; the first manifestation was prolonged diarrhoea in 45.7%, bloody diarrhoea in 17.8% and colitis in 15.5%, and patients with receptor deficiency had dermatological manifestations (50.5%) and faltering growth (60.5%) that were absent in patients with ligand deficiency [67]. About 70% begin in the neonatal period and almost all before 2 years of age; 94.2% (131 of 139) have multiple perianal lesions, including fissures, skin tags, abscesses and perianal, rectovaginal and rectourethral fistulae [21]. The enterocolitis is extensive, with ulcers and enterocutaneous fistulae that historically led to multiple resections and stomas [13, 30].

Extraintestinal manifestations include folliculitis, arthritis, oral ulcers, recurrent respiratory disease, infections and, without HSCT, B-cell lymphoma, especially diffuse large B-cell lymphoma, more associated with IL10RB deficiency [21, 30, 42]. Basic immunology is normal in most [67]. There is no significant difference between the three genes in age at onset, perianal disease or mortality; 10-year survival was higher in ligand deficiency than in receptor deficiency in the systematic review [21, 67].

3.6. Clinical spectrum of VEO-IBD in general

VEO-IBD accounts for 6–15% of paediatric IBD and may be mild or more extensive and severe than later-onset IBD; about 40% of children with infantile or very-early-onset IBD have pancolitis at presentation, the extent may progress to the small bowel, histology may evolve towards granulomas or duodenal atrophy, and IBD unclassified is more frequent (11–22%) than in later-onset IBD (4–10%) [30]. Other defects of the class have their own markers: about 20% of patients with XIAP deficiency present with fistulising IBD with a risk of EBV-associated HLH; up to 40% of patients with CGD have Crohn-like intestinal inflammation; Wiskott-Aldrich syndrome causes ulcerative colitis-like colitis in infancy; and IPEX causes enteropathy with villous atrophy [30, 32].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

THES may be suspected on second-trimester ultrasound in the presence of severe, isolated fetal growth restriction without a placental cause, hyperechogenic bowel and dolichocephaly; polyhydramnios and placental hyperplasia were described in the first cases [11, 88]. In the other groups covered by this article there are no characteristic prenatal signs, except for the known risk in a family with an index case, in which prenatal or preimplantation diagnosis is possible [16, 33].

4.2. Newborn and young infant

Watery diarrhoea that begins with the first feed and settles when lactose is withdrawn suggests congenital lactase deficiency; hypercalcaemia or nephrocalcinosis in an infant with diarrhoea should raise the same hypothesis [9, 56, 85]. Intractable neonatal diarrhoea in an infant with IUGR suggests THES, especially if the hair is woolly, light-coloured and brittle [16]. Enterocolitis in the first three months, with perianal disease, fistulae and folliculitis, calls for investigation of an IL-10 pathway defect; early infection, with or without perianal disease, points to CGD or XIAP deficiency [30, 41]. In a boy with infantile IBD and splenomegaly or HLH, XIAP deficiency must be excluded before any potent immunosuppression; when CGD is suspected, anti-TNF therapy is contraindicated [30].

4.3. Introduction of complementary foods and weaning

Acidic diarrhoea with nappy rash and bloating, beginning when sucrose and starch dextrins enter the diet, is the typical pattern of sucrase-isomaltase deficiency [17, 29]. In an infant without effect on weight, chronic diarrhoea is mostly functional (irritable colon of infancy), often associated with a hypercaloric diet or with too much or too little fibre; the French PNDS recommends correcting the diet first and only then, if diarrhoea persists, proposing a trial sucrose-free, low-starch diet for 2 to 3 weeks, with a food and symptom diary, before referral [24]. With faltering growth or malnutrition, coeliac disease and giardiasis must be excluded first and investigation continues at a reference centre [24]. Periorificial and acral dermatitis with alopecia, diarrhoea and irritability appearing weeks after the end of breastfeeding is the pattern of AE; in a breastfed infant, especially a preterm one, the same picture without weaning suggests transient zinc deficiency due to zinc-poor breast milk [38, 91].

4.4. Older child and adult

A child or adult diagnosed with IBS, functional abdominal pain or functional diarrhoea whose symptoms are triggered by ingestion of sucrose or starch should be tested for sucrase-isomaltase deficiency, and lack of response to a low-FODMAP diet also justifies investigating disaccharidase deficiencies [17, 81]. Severe perianal disease, folliculitis, arthritis, atypical infections, HLH, associated autoimmunity, early tumours and a consanguineous or X-linked family history are warning signs of monogenic IBD at any age [32, 33].

4.5. Warning and emergency signs

In CSID, accidental ingestion of sucrose is not an emergency: there is no risk of anaphylaxis and treatment is symptomatic [24].

4.6. Newborn screening

None of the entities in this article is part of biochemical newborn screening programmes. Combined immunodeficiency due to TTC7A, a differential diagnosis of THES and VEO-IBD, can be detected by low TREC in newborn screening for severe combined immunodeficiency [42]. Registered genomic newborn screening studies include extended panels, but the sources consulted do not describe the inclusion of these diseases in public health programmes [95].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Initial assessment of chronic diarrhoea in infancy

The first distinction is between osmotic diarrhoea, which settles with fasting or with withdrawal of the offending carbohydrate, and secretory or inflammatory diarrhoea, which persists with bowel rest [16, 29]. Neonatal acidic watery diarrhoea with reducing substances in the stool points to glucose-galactose malabsorption or lactase deficiency; the same diarrhoea after the introduction of complementary foods, to sucrase-isomaltase deficiency; non-acidic diarrhoea with hypochloraemic alkalosis, to congenital chloride diarrhoea; and diarrhoea with periorificial lesions and low plasma zinc, to AE [29]. Diarrhoea that persists on PN, with IUGR, abnormal hair or blood, points to THES or immune enteropathy; enterocolitis with perianal disease, to the VEO-IBD class [16, 30].

5.2. Sucrase-isomaltase deficiency

The reference standard is the disaccharidase assay on a duodenal biopsy homogenate, which measures sucrase, isomaltase (palatinase), maltase and lactase; the typical profile is absent or reduced sucrase, reduced isomaltase and normal lactase, with normal duodenal histology [17, 37]. Because acquired brush-border damage (coeliac disease, giardiasis, enteritis, Crohn's disease, bacterial overgrowth) reproduces the same enzyme deficiency, the result can only be interpreted together with histology, and confirmation of the genetic form in practice requires biallelic variants in SI [17]. Biopsy may overestimate the diagnosis: in a series of 25 children with low disaccharidases and normal villi, only 7 of 21 (33.3%) with low sucrase had a 13C-sucrose breath test compatible with CSID, and 9 of 15 (60%) had a breath test suggestive of bacterial overgrowth that responded to antimicrobials; the authors proposed an algorithm combining biopsy and breath tests [96]. In a Scottish series of 245 biopsied patients, 38% had some low disaccharidase activity, with sucrase, maltase and lactase deficiencies in 19.4%, 25.0% and 29.9% of cases, a frequency that mainly reflects secondary or partial deficiencies [97].

Non-invasive tests include the hydrogen and methane breath test after sucrose, the 13C-sucrose breath test and the symptom test after a sucrose challenge; they are useful but not fully validated, so a negative result does not exclude the disease [17, 37]. In a home-based study of 45 adults with confirmed CSID and 118 controls, ingestion of 50 g of fasting sucrose worsened all six symptoms assessed over the following two hours, and the best diagnostic variable was the worsening of the global symptom score at 1 and 2 hours (11.7 in patients versus 3.2 in controls) [98]. Improvement with a sucrose- and starch-free diet and the response to a sacrosidase trial supported the diagnosis in all variant carriers in a Turkish paediatric series [82].

SI sequencing identifies biallelic variants in the congenital form and, in the Inuit, targeted testing for c.273_274del is a simple and minimally invasive means of diagnosis [19]. The interpretation of isolated heterozygous variants and hypomorphic variants requires caution, because of variable penetrance and inconsistent variant terminology in the literature [51].

The 2025 French PNDS proposes a three-step sequence that reserves endoscopy for after indirect evidence has been gathered: an oral sucrose challenge, sensitive but of low specificity; when the challenge is positive or equivocal, or when clinical suspicion is strong from the outset, genetic analysis of SI; and the enzyme assay on biopsies, as third line, for genetically equivocal cases or when definitive confirmation is needed, discussed at a multidisciplinary meeting [24]. This order differs from the one that treats the disaccharidase assay as the first test [17, 37]; the justification given is that the genetic test is more accessible, non-invasive and less costly and that, if negative, it allows other causes of chronic diarrhoea to be sought in the same DNA [24].

Source: [24].

The hydrogen breath test follows a standardised protocol: 24 hours of low-residue diet, 12 hours of fasting (6 hours below 6 months of age) and 1 g/kg of sucrose (up to 2 g/kg in some studies, not exceeding 50 g) in a 10 g/100 mL solution; a rise of 20 parts per million (ppm) above baseline within the following two hours is abnormal [24]. Altered intestinal transit, small intestinal bacterial overgrowth, partial malabsorption in some healthy controls and production of methane instead of hydrogen limit the result, so ESPGHAN does not recommend the breath test alone for diagnosis; the 13C-sucrose test (about 20 mg of sucrose) was not available in France in 2025 [24].

The pre-analytical phase of the enzyme assay determines the result. Disaccharidase activities are about 40% lower in the duodenum than in the proximal jejunum, so sites closest to the jejunum are preferred (third or fourth part of the duodenum, or jejunum), ideally two sites with 1 to 3 fragments each, one cryotube per site without mixing fragments, and immediate freezing on dry ice or in liquid nitrogen; enzyme samples are taken before histology samples, because forceps contaminated with formalin destroy activity, and transport delays and freeze-thaw cycles must be avoided (in the Nancy laboratory protocol, samples taken from Thursday to Sunday or on the eve of a public holiday are kept frozen at −20 °C and sent at the start of the following week) [24]. One biopsy is for histology, which distinguishes primary deficiency, with normal mucosa, from secondary deficiency. The Dahlqvist method measures the glucose released from each substrate in a homogenate; since two biopsies may give different values, several are taken, and the full panel is measured (lactase, maltase, sucrase, isomaltase and sometimes trehalase and glucoamylase), because lactase and trehalase, preserved in CSID, serve as same-day positive controls [24]. A sucrase/lactase ratio of 1.0 or less has been proposed as a guide, but hypolactasia, frequent after 6 years of age in many populations, may invalidate it, and trehalase then becomes the most useful control [24]. Owing to the difficulty of internal and external quality control, the assay was performed in only two French laboratories (Lyon and Nancy), and the final diagnosis rests on the concordance of several lines of evidence [24].

5.3. Congenital lactase deficiency

The diagnosis of the congenital deficiency is made by genetic testing; the hydrogen breath test documents lactose malabsorption and a validated symptom test documents intolerance, but a lactose load should not be used in a symptomatic newborn, in whom it is dangerous [17, 43]. Before genetics, the diagnosis was based on the clinical picture and very low lactase activity on biopsy, with normal histology and other disaccharidases, which separates the disease from secondary deficiency [17, 55]. Low faecal pH and reducing substances support the osmotic nature, and a therapeutic trial with withdrawal and reintroduction of lactose is informative; in a newborn in whom glucose-galactose malabsorption was suspected first, tolerance of maltodextrin and immediate diarrhoea after lactose pointed to lactase, and detection of homozygous c.3448delT made biopsy unnecessary [17, 56]. In Finland, targeted testing for c.4170T>A is the first step [17]. Genotyping of MCM6 c.1917+326C>T describes a common trait and has no Mendelian implication [17].

5.4. Acrodermatitis enteropathica

Serum zinc is usually low (5.8 ± 3.2 µmol/L in patients versus 12.6 ± 2.3 µmol/L in normal individuals) but may be normal; zinc in hair, erythrocytes or leucocytes does not improve accuracy, and chronic diarrhoea of other causes also lowers zinc, so the diagnosis never rests on serum zinc alone [38]. In the Tunisian series, plasma zinc ranged from 14 to 88 µg/100 mL and was not related to clinical severity [86]. Low urinary zinc, low alkaline phosphatase, changes in the fatty acid profile, hypobetalipoproteinaemia, low vitamin A and depressed humoral and cellular immunity support the diagnosis; intestinal biopsy shows partial to subtotal villous atrophy and inclusions in Paneth cells on electron microscopy [38]. Skin biopsy may show compact hyperkeratosis, acanthosis and a subcorneal pustule with neutrophils [77].

The practical approach is to start zinc on clinical suspicion; improvement should occur within one week [38]. When the clinical picture is equivocal, temporary withdrawal of zinc after some time, causing rapid relapse, distinguishes true AE from acquired deficiency; this is the clinical criterion used in the reference series [20, 38]. Sequencing of SLC39A4 is theoretically superior and distinguishes AE from transient deficiency, but more than half of patients with clinically confirmed AE have no variants in the coding region, so a negative result does not exclude the disease [38, 91].

5.5. Trichohepatoenteric syndrome

No published diagnostic algorithm exists. The diagnosis is established by identification of biallelic pathogenic or likely pathogenic variants in SKIC2 or SKIC3; biallelic variants of uncertain significance (VUS), or one pathogenic variant with a VUS, neither establish nor exclude the diagnosis [16]. When the phenotype is suggestive, serial sequencing may be performed, starting with SKIC3, or preferably a very-early-onset IBD panel that includes both genes, bearing in mind that some diarrhoea, liver disease or immunodeficiency panels do not include them; when the phenotype is non-specific, the exome is the best option [16]. Light microscopy of the hair shows trichorrhexis nodosa in about 80% of patients [16]. Immunological assessment should include immunoglobulins, vaccine antibodies, class-switched memory B cells, NK cells and T-cell proliferation [64]. In 8.3% of patients in the mutation update only one variant was found, and some cases were solved only by RNA analysis, which shows the limits of the exome and genome [11, 62].

5.6. Very-early-onset monogenic IBD

The diagnosis of IBD requires upper endoscopy and complete ileocolonoscopy with ileal intubation, even in young children; capsule endoscopy is limited by size, and intestinal ultrasound by an experienced radiologist often replaces magnetic resonance enterography [30]. Histology may suggest a monogenic cause when it shows eosinophilic infiltrates, villous atrophy, graft-versus-host disease-like apoptosis (dyskeratosis congenita, TTC7A, SCID), intraepithelial lymphocytosis, atrophy with a lymphocytic infiltrate that does not respond to gluten withdrawal (IPEX, common variable immunodeficiency) or granulomas with pigmented macrophages (CGD, Hermansky-Pudlak) [30]. Endoscopic classification into Crohn's disease or ulcerative colitis has limited value [33].

The initial immunological screen, which the gastroenterologist can perform, includes a full blood count (neutropenia; leucocytosis in leucocyte adhesion deficiency, LAD), biochemistry, inflammatory markers, IgG, IgA, IgM and IgE immunoglobulins, vaccine titres, the DHR respiratory burst test for CGD (which requires viable neutrophils, with a half-life of 18 hours and sensitivity to transport) and XIAP expression by flow cytometry in all infantile IBD, especially in boys; lymphocyte subsets, memory B cells, CD107a cytotoxicity and specific assays are performed together with immunology [30]. The IL-10 axis assay measures the absence of IL-10 inhibition of the response of mononuclear cells to lipopolysaccharide (LPS) or the absence of STAT3 phosphorylation after IL-10, with an IL-6 control; it confirms receptor defects but does not validate ligand defects, and does not identify which of the genes is affected [17, 30, 99]. Flow cytometry of receptor surface expression may be normal in patients with a functional deficiency [17, 68].

The recommendations of the Porto group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) converge on the essentials and differ in emphasis, as summarised in the table [30, 33].

The diagnostic yield depends on selection: 13–41% in infantile IBD, 0–33% in VEO-IBD and 0–38% between 6 and 18 years of age, depending on pre-selection, and 3% in all paediatric IBD at one centre [33]. In a multicentre Middle Eastern study with trio exome sequencing, the yield was 76.9% in congenital diarrhoeas and 7.1% in VEO-IBD [100]. In Brazil, the exome gave a conclusive diagnosis in 17% of 100 children up to 4 years of age with suspected inborn error of immunity [101].

5.7. Limitations of genetic tests

The limitations are concrete and explain many late diagnoses. In the IL-10 axis, the 333 bp deletion of exon 1 of IL10RA is not captured by routine exome sequencing, deletions and duplications of IL10RB account for about one fifth of the alleles described, the exon 6 duplication in the Portuguese family was detected only by complementary DNA (cDNA) sequencing and locus capture, and uniparental disomy can mimic homozygosity [21, 68, 69]. In THES, a single variant in 8.3% of patients and hidden aberrant transcripts require RNA analysis [11, 62]. In AE, more than half of clinical cases have no coding variant [38]. In silico prediction tools may classify as tolerated IL10RA variants with a demonstrated functional defect [32]. In all groups, the proportion of variants detectable by a method is not equivalent to the clinical sensitivity of the test.

5.8. Report content, VUS and segregation

The report should state the gene, the versioned reference transcript (for example, NM_001558.4 for IL10RA), the HGVS description at cDNA and protein level, the zygosity, the classification according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria and the parental origin when studied [16, 33]. In recessive diseases, confirmation that two variants are in trans requires study of the parents; trio analysis increases the yield, and deposition of VUS in ClinVar or sharing through Matchmaker Exchange facilitates their characterisation [30, 33]. In consanguineous families more than one plausible defect may exist [33].

5.9. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible in THES; in IL10RA defects they have been performed as preimplantation testing after in vitro fertilisation or by amniocentesis or chorionic villus sampling, with requests reported by centres in 4 of 10 countries surveyed [16, 33]. Prenatal trio exome sequencing can identify THES in fetuses with severe growth restriction [88].

6. Differential Diagnosis

6.1. Comparative table

Sources: differential of the diarrhoeas and disaccharidase deficiencies [17, 29, 43, 56, 80], of zinc and AE [38, 91–94, 102–108], of THES [16, 75, 76, 109] and of VEO-IBD [30, 32, 42, 70–74].

6.2. Differential of the disaccharidase deficiencies

Acidic diarrhoea with reducing substances is common to glucose-galactose malabsorption and the disaccharidase deficiencies. The former begins with any milk and responds to a formula in which fructose is the only carbohydrate; lactase deficiency tolerates maltodextrin; and sucrase-isomaltase deficiency begins with sucrose and starch, while free fructose is tolerated [29, 56, 80]. In hereditary fructose intolerance, ingestion of fructose, sucrose or sorbitol causes systemic symptoms and not just diarrhoea, and this disease must be excluded before any fructose challenge [80]. The most frequent distinction in practice is from secondary deficiency: low disaccharidase activity with abnormal histology, or with simultaneous deficiency of all four enzymes, suggests mucosal damage, and bacterial overgrowth may explain low sucrase with a normal 13C-sucrose test [17, 81, 96]. In adults, the differential diagnosis with IBS is central, and disaccharidase deficiencies should be sought when the low-FODMAP diet fails [81]. The French PNDS adds graft-versus-host disease to the causes of secondary deficiency in older children and adults, and identifies functional diarrhoea of infancy without effect on weight, often linked to dietary imbalance, as the most frequent differential when growth is normal [24]. Adult hypolactasia and lactose intolerance are common traits and do not justify LCT testing [17, 43].

6.3. Differential of acrodermatitis enteropathica

Transient zinc deficiency in breastfed infants, especially preterm infants, has an identical skin picture, but is due to the low zinc content of breast milk caused by a maternal SLC30A2 variant, occurs only during breastfeeding, involves no intestinal absorption defect and does not relapse after weaning [38, 58]. In a preterm girl of Yi ethnicity, the condition responded to 3 mg/kg/day of zinc, maintenance at 1 mg/kg/day was stopped at 8 months without recurrence, and SLC39A4 sequencing was normal in the child and parents [91]. Organic acidurias (propionic and methylmalonic) and maple syrup urine disease produce, in late severe decompensations or under excessively prolonged protein restriction, desquamation, alopecia and diarrhoea, described as an AE-like syndrome unrelated to zinc deficiency and attributed to acute protein malnutrition, especially isoleucine deficiency; in these cases zinc is often ineffective [94, 103, 104]. In ornithine transcarbamylase deficiency, protein restriction with benzoate or phenylbutyrate and essential amino acid deficiency may lead to kwashiorkor, and AE-like skin lesions have been described [110]. In biotinidase deficiency, the skin lesions are patchy, erythematous or exudative and typically periorificial, with alopecia, but may appear late or be absent, and one patient was mistaken for years for AE; in holocarboxylase synthetase deficiency, the rash is erythematous and scaly, most marked in the nappy area and skin folds; all patients with biotinidase deficiency and most with holocarboxylase synthetase deficiency respond to biotin [92, 105]. Lysinuric protein intolerance may give perianal dermatitis typical of AE, but in this disease serum zinc is often raised [93, 106]. In Hartnup disease, the pellagra-like skin changes of sun-exposed areas may mimic those of zinc deficiency [107]. Zinc deficiency is also part of the phenotype of IARS1 deficiency, an aminoacyl-tRNA synthetase disorder with intellectual disability, hypotonia, faltering growth and liver dysfunction [108]. A variant of the sodium-dependent multivitamin transporter (SLC5A6) has recently been described as a mimic [102]. Contact dermatitis, the initial diagnosis in the case described in section 10, infectious and inflammatory dermatoses, hyper-IgE syndrome, human immunodeficiency virus (HIV) infection, chronic IBD and Netherton syndrome are differentials that delay diagnosis [77].

6.4. Differential of trichohepatoenteric syndrome

GeneReviews lists as the main differentials tufting enteropathy due to EPCAM, with its own histology; IPEX due to FOXP3, with low regulatory T cells; gastrointestinal defects with immunodeficiency due to TTC7A, with intestinal atresia; and syndromic tufting enteropathy due to SPINT2, with choanal atresia [16]. Woolly, brittle hair with trichorrhexis nodosa distinguishes THES, but trichorrhexis nodosa also occurs in AE, argininosuccinic aciduria and other metabolic diseases, and Menkes disease gives pili torti [11, 29, 111]. In trichothiodystrophy, the hair is brittle and sulphur-deficient, with trichorrhexis nodosa on microscopy, and is associated with short stature, intellectual disability, unusual facies and sometimes ichthyosis; about half of patients are photosensitive, due to variants in XPD, XPB or TTDA [29, 76, 109]. The liver disease of THES enters the differential of neonatal liver diseases and neonatal haemochromatosis; FOCAD, a protein associated with the SKI complex, causes rapidly progressive neonatal cirrhosis without the enteric picture of THES [79, 112].

6.5. Differential within VEO-IBD

Enterocolitis with perianal disease and folliculitis before three months of age is highly suggestive of an IL-10 defect, but CGD and XIAP deficiency can give similar perianal pictures; CGD is distinguished by the DHR test and by granulomas with pigmented macrophages, and XIAP deficiency by flow cytometry and the risk of HLH [30, 32]. XIAP deficiency, or X-linked lymphoproliferative syndrome type 2, manifests as haemophagocytosis, which can be triggered by EBV, but may present as IBD or splenomegaly [72]. In glycogen storage disease Ib, IBD with histology resembling Crohn's disease is frequent and attributed to neutrophil dysfunction; in the European study of 288 patients with glycogen storage disease type I, 57 had type Ib, 54 of whom had neutropenia, 27 perianal infections and 23 prolonged diarrhoea, and IBD was not observed in the absence of neutropenia [70, 71]. The enterocolitis may improve with 5-aminosalicylic acid and with granulocyte colony-stimulating factor (G-CSF), which improves colitis in most patients but causes splenomegaly and has been associated with acute myeloid leukaemia after continuous treatment for many years; adalimumab was beneficial in one refractory patient [70]. Hermansky-Pudlak syndrome combines variable oculocutaneous albinism, a bleeding tendency, progressive pulmonary fibrosis and granulomatous colitis, has ten genetic types and a founder effect in Puerto Rico, with a carrier frequency of 1 in 18, and is diagnosed by the absence of platelet dense bodies on electron microscopy or by genetics [74, 75]. ADA2 deficiency, of recessive inheritance, has gastrointestinal manifestations in one third of patients, with abdominal pain, IBD, raised transaminases, hepatosplenomegaly and portal hypertension, alongside vasculopathy with lacunar infarcts and fever; low or absent plasma ADA2 activity suggests the diagnosis, which is confirmed by genetics [73]. IPEX mainly causes small-bowel enteropathy with villous atrophy, and severe, early, fistulising enterocolitis distinguishes IL-10R deficiency from IPEX [17, 30]. Anti-IL-10 autoantibodies should be considered when the functional assay is abnormal and genetics are negative [21]. Very-early-onset polygenic IBD, without an identified monogenic defect, is the most frequent situation, and treatment is then similar to that of older children [30].

7. Treatments and Risk Management Strategies

7.1. Sources of recommendations

The available recommendations are of different kinds. For VEO-IBD there are two position papers from paediatric societies, the 2020 NASPGHAN paper and the 2021 paper of the ESPGHAN Porto group, both based on literature review and, in the European case, on formal voting [30, 33]. For the disaccharidase deficiencies, the most recent European reference is the 2025 consensus on malabsorption (United European Gastroenterology, ESPGHAN, European Society for Clinical Nutrition and Metabolism and others), complemented by clinical reviews and by the sacrosidase label [22, 37, 43]. For AE, the ClinGen paediatric actionability report summarises the evidence on zinc supplementation and is used as the dose reference, with the reference textbook of metabolic diseases as a comparison [20, 38]. For THES, guidance is that of GeneReviews, without formal consensus [16]. There are no randomised trials in IL-10 deficiencies, THES or AE; the evidence comes from case series, retrospective cohorts and systematic reviews [17, 113]. For CSID there is also the PNDS of the Haute Autorité de Santé (HAS), prepared by the French reference centre for rare digestive diseases (March 2025), which is based on a critical review of the literature (116 references indexed up to 1 June 2024) because there was then no scientific society recommendation; the review ended before publication of the European consensus on malabsorption [24, 43].

7.2. Sucrase-isomaltase deficiency

Diet. The basis of treatment is sucrose restriction, with starch restriction adjusted to each patient's tolerance and symptoms; this approach is effective but difficult to maintain, especially in young children [17, 37]. Historically, treatment required a strictly sucrose-free diet at all times [22]. Sucrose is present in fruit, juices and processed foods, and dietitian support is needed to preserve energy intake.

Initial nutritional assessment. A nutritional assessment is carried out before starting the diet; faltering growth is corrected with calorie supplements free of starch and sucrose and sometimes with temporary nutritional support for a few weeks, and deficiencies of vitamins or trace elements, which are uncommon, are corrected if present [24].

Diet according to the French PNDS. Because isomaltase may be preserved and maltase digests 20–40% of starch, not all patients are starch-intolerant, and tolerance of both varies between individuals; a food diary guides adjustment [24]. In infants, breastfeeding poses no problems; with bottle feeding, a formula is chosen in which lactose is the only carbohydrate, because many contain starch, maltodextrins or sucrose. Complementary feeding begins with purées of non-starchy vegetables and of fruit with less than 2% sucrose, then meat, maintaining breast milk or formula until at least 1 year of age [24]. In children and adults, the starting point is a controlled diet low in sucrose and starch, adjusted to presumed tolerance, increasing food by about 10 g per day to define the tolerance threshold, a value that is only indicative [24]. Starch is reintroduced first; some patients without enzyme activity must avoid it completely, but most tolerate, as a guide, 30–120 g of starch per day. Tolerance improves with double cooking, slow chewing, eating starch with meals and more fibre; the patient association reports better tolerance of fried than boiled potatoes, of semolina than pasta and, contrary to what is recommended, of refined than wholemeal flour, observations without controlled study [24, 37]. Sucrose-containing foods are introduced one at a time, each for 3 to 7 days, starting with those containing up to 2% [24].

Source: [24], following the McMeans (2012) scheme.

The PNDS content tables (French CIQUAL 2020 database, in g of sucrose per 100 g of edible portion) show, for example, high values in mango (8.5 g), banana (7.9 g), melon (6.56 g), pineapple (6.4 g) and orange (3.5 g), and low values in pear (0.95 g), apple (0.82 g), raspberry (0.5 g) and cherry and strawberry (<0.2 g); among vegetables, cooked parsnip (6.2 g), cooked beetroot (5.3 g) and raw carrot (4 g) contrast with lettuce and raw tomato (0 g) [24]. The North American tolerance list reproduced in the same document places apple and guava among poorly tolerated fruits, despite their low content in the French database, which reinforces the need to test each food with the diary [24, 37]. The family learns to read labels and recognise sucrose and starch and receives a list of substitutes: glucose (dextrose), fructose, lactose and aspartame are generally tolerated, whereas table sugar, maple syrup, molasses, coconut, date and icing sugars and caramel are not [24, 37]. Some patients need prolonged restriction and others improve their tolerance over time; at school, an individualised care plan, usually with a meal brought from home, is generally necessary [24].

Sacrosidase. Sacrosidase (Sucraid®) is a β-D-fructofuranoside fructohydrolase obtained from baker's yeast, as an oral solution containing 8500 IU/mL, which hydrolyses sucrose in the lumen into glucose and fructose; it does not contain isomaltase [22]. In the USA it is indicated for the treatment of the sucrase deficiency that is part of CSID, in adults and children from 5 months of age, and was approved by the FDA on 9 April 1998 [22, 36]. There is no guideline with a dose different from that of the label, which is the reference.

Source: [22].

Management of hypersensitivity reactions consists of stopping the drug and seeking immediate care; persistence of symptoms on sacrosidase should lead to starch restriction, and not to regarding the treatment as having failed [17, 22]. The label has not been evaluated in secondary sucrase deficiency [22].

Sacrosidase in the French PNDS and discrepancies with the label. In France, sacrosidase is prescribed under a named-patient compassionate access authorisation, and the PNDS generally proposes it to reduce dietary restrictions, especially to allow fruit and the associated micronutrients [24]. The dose coincides with that of the label (1 mL below 15 kg; 2 mL above 15 kg, with each meal or snack), half before and half midway through the meal; the PNDS, however, states dilution in 100 mL of room-temperature liquid, whereas the label specifies 60 mL for 1 mL and 120 mL for 2 mL, and attributes weak isomaltase and maltase activity to the enzyme, whereas the label states that it contains no isomaltase; both agree that starch intolerance may require additional restriction [22, 24]. For the two randomised double-blind trials, the PNDS reports 81% of patients asymptomatic on a non-restrictive diet (the label describes 86% in children up to 3 years and 77% in older children) and normalisation of the hydrogen and 13C-sucrose breath tests; in a post-marketing surveillance study, 65 of 69 responders (94%) were still on treatment after a median of 3 years, with constipation, headache and sleep disturbance as the most frequently reported adverse effects [22, 24]. Storage in the refrigerator, or in an insulated bag, limits use away from home. Probiotics containing Saccharomyces cerevisiae have intrinsic sucrase activity, but there are few data on their use and dose [24, 37]. The PNDS also notes supply shortages, reports of lack of efficacy and of intolerance and, according to the FDA, the papain used in extraction as a possible cause of allergic reactions [24].

Invertase as an alternative. In a retrospective Glasgow cohort, invertase (a yeast enzyme supplement) was given to nine children with low sucrase on biopsy with normal histology: four had resolution of symptoms, four a partial response and one no response, with resolution or marked improvement of diarrhoea in eight, and an estimated annual cost of 1972 pounds sterling versus 51 938 pounds with sacrosidase oral solution [97]. This is low-level evidence (retrospective series, without controls or described genetic confirmation), relevant in Europe, where sacrosidase has no marketing authorisation. Oral freeze-dried yeast had been used effectively in 1987 [8]. In France, S. cerevisiae invertase and a glucoamylase solution are magistral preparations of the FRIPHARM platform of the Hospices Civils de Lyon, used when sacrosidase fails; invertase, a food enzyme (E1103) qualified for pharmaceutical use under general monograph 2034 of the European Pharmacopoeia, is diluted in water and glycerol (50/50 v/v), stored between 2 and 8 °C and released with a certificate of analysis (total bacterial count <100 CFU/mL, coliforms <30 CFU/mL, absence of Escherichia coli, Salmonella and yeasts, heavy metals, allergens, enzyme activity, density and pH); patient experience was under evaluation in 2025, and the PNDS sets no dose for these preparations [24]. Glucoamylase may complement treatment by improving starch digestion [24]. Enzyme mixtures sold as food supplements, with sucrase and glucoamylase activity (Starchway®), are stored at room temperature but have not been studied in CSID and are neither reimbursed nor recommended; the patient association describes a modest benefit [24].

Regulatory status. In the European Union, sacrosidase has orphan medicinal product designation (EU/3/13/1183, from 2013) for CSID, but is not on the list of medicines authorised by the European Medicines Agency (EMA); in Brazil there is no registration of sacrosidase in the open data of the Agência Nacional de Vigilância Sanitária (ANVISA) [23, 114]. The sources consulted do not describe a sacrosidase medicinal product available in Portugal; access, where it exists, depends on importation or on enzyme supplements without medicinal product status. In France, access is through a named-patient compassionate access authorisation [24].

7.3. Congenital lactase deficiency

In the symptomatic newborn, immediate and complete exclusion of lactose, with lactose-free formula, rehydration and correction of electrolyte and acid-base disturbances, is decisive; the lactose-free diet is maintained for life, with dietary support to ensure adequate calcium and energy intake [17, 84]. With the diet, symptoms and growth normalise; hypercalcaemia normalised within one week in one infant and nephrocalcinosis took months to resolve in another [56, 85]. The European consensus recommends calcium supplementation or fortified foods in children on a lactose-reduced diet, because of the risk of insufficient calcium intake [43]. There is no pharmacological treatment targeting the product of the LCT gene [17].

In secondary lactase deficiency, lactose restriction is needed only for a limited period and if symptoms are attributable to intolerance on validated assessment [43]. In adult hypolactasia, which is a trait, it is sufficient to adjust lactose to tolerance; most tolerate small amounts, fermented dairy products and lactose taken with other foods, and total exclusion of dairy products is neither necessary nor desirable [17].

7.4. Acrodermatitis enteropathica

Oral zinc. Elemental zinc supplementation is lifelong and any interruption causes relapse [20]. The reference dose is that of the series used by ClinGen: 5–10 mg/kg/day of elemental zinc, as zinc sulphate (26 patients) or zinc gluconate (3 patients), with complete healing of skin lesions within three weeks and follow-up of 7 to 24 years without growth or intellectual impairment and without recorded adverse effects [20]. The reference textbook gives a usual dose of 35–90 mg of elemental zinc per day, in divided doses, with clinical improvement within days and normalisation of serum zinc, urinary zinc and alkaline phosphatase; the initial dose is generally maintained throughout childhood, may be increased during the growth spurt and may be reduced after puberty [38]. The drug table of the same book gives, for AE, 1–2 mg/kg/day of elemental zinc in infants and thereafter 30–100 mg/day orally, as sulphate or acetate [115]. In a review of 231 paediatric patients with hereditary or acquired AE, 91.4% of the 174 supplemented patients responded and the most commonly used effective dose was 1–3 mg/kg/day, without consensus on the optimal dose; recent genetically confirmed cases responded to 3 mg/kg/day [77, 94, 116]. The references express the dose in different ways (per kg and as an absolute dose); none defines a maximum specific to AE, and the published upper limits are 10 mg/kg/day in the reference series [20] and 100 mg/day in the book's table [115], and the review shows that lower doses are also effective in many cases [94]; in practice, the dose is adjusted to the clinical response and plasma zinc, increasing it in adolescence, in pregnancy or in inflammatory states, and three patients in the reference series needed higher doses in adolescence despite good adherence [20].

Zinc sulphate may cause gastric intolerance; in that case it may be encapsulated or replaced by gluconate or another salt [38]. In Portugal, the only oral zinc medicinal product with a summary of product characteristics (SmPC) consulted is Wilzin® (zinc acetate), authorised only for Wilson disease, with doses of 25 mg twice daily between 12 months and 6 years, 25 mg three times daily from 6 to 16 years with weight under 57 kg and 50 mg three times daily from 16 years or 57 kg, to be taken on an empty stomach [117, 118]. Use of zinc acetate in AE would be off-label and the label doses have not been established for this disease; they serve only as a comparison with the reference dose. In Brazil, oral zinc sulphate medicinal products are registered, such as Unizinco® and Uni-Z® [114].

Adverse effects and monitoring. Zinc at high, sustained doses induces metallothionein in enterocytes and may cause copper deficiency; the zinc acetate SmPC describes sideroblastic anaemia and leucopenia as early manifestations of this deficiency, reversible on dose reduction, as well as gastric irritation and increases in amylase, lipase and alkaline phosphatase [17, 117]. For this reason, serum copper and zinc should be monitored regularly, reducing zinc or supplementing copper if deficiency develops [20, 38].

Prognosis with treatment. With zinc, the prognosis is excellent; in the historical review 2 of 128 treated patients died versus 34 of 51 untreated patients, and in the reference series the only death occurred after irregular treatment and infection [20, 38]. ClinGen rated AE as having strong actionability in the paediatric context (score 11CC: severity 2, likelihood 3C, effectiveness 3C, nature of intervention 3); there is no assessment for adults [17].

Sepsis of cutaneous origin. Extensive erosive lesions may be a portal of entry for sepsis; management includes empirical broad-spectrum antibiotics, haemodynamic and nutritional support with prevention of refeeding syndrome, and zinc from the outset [77].

7.5. Trichohepatoenteric syndrome

There is no specific treatment; the aims are to maximise weight gain and linear growth, reduce the burden of infections and manage intellectual disability individually [16]. The initial assessment includes a paediatric nutrition consultation; IgG, IgM and IgA, immunophenotyping and specific vaccine antibodies, to detect rapid loss of protective antibodies; liver ultrasound, transaminases and gamma-glutamyl transferase, with paediatric hepatology if abnormal; cardiac assessment for malformations; assessment of cognitive, language and psychosocial development; and a genetics clinic appointment [16].

Nutrition. Most children need PN at diagnosis to achieve weight gain and catch-up growth, combined, according to tolerance, with oral feeding, usually semi-elemental; 30–50% become independent of PN after prolonged PN, and encouraging oral feeding rather than tube feeding helps prevent future feeding disorders [16]. Nine patients did not need PN, three of them on an amino acid formula [16]. In the Saudi series, 83% received PN for a mean of 13.34 months, almost half were weaned off it and PN was associated with a worse prognosis, presumably as a marker of severity; in the British series all received PN and 6 of 13 were weaned off it [61, 89].

Immunity. Immunoglobulin replacement in patients with low immunoglobulins appears to reduce the infection rate, and full immunological assessment also justifies antimicrobial prophylaxis in selected cases [16, 64, 90]. No immunoglobulin dose has been established for THES; by extrapolation from primary humoral immunodeficiency, intravenous immunoglobulin labels give 300–800 mg/kg every 3–4 weeks, adjusted to trough IgG and clinical response, with a warning about thrombosis and renal dysfunction [119]. HSCT had been reported twice by 2018, without success (one death from infection and one slight improvement), and is not an established treatment [16].

Intestinal inflammation. When the presentation is that of IBD, infection must be excluded; corticosteroids, azathioprine and anti-TNF agents may be considered, but improvement is transient or absent, and IBD of later childhood is refractory to conventional treatment [16, 89]. In a 5-year-old boy with SKIV2L variants, baricitinib, a JAK1/2 inhibitor, combined with azathioprine, reduced the symptoms of enteritis, on the rationale of the type 1 interferon signature; this is an isolated report and off-label use [59].

Other aspects. Growth hormone has not shown efficacy in anecdotal reports [16]. Dental abnormalities justify assessment by a dentist, and the fragility and loss of hair have an emotional impact that may benefit from counselling and hairpieces [16]. Respiratory care is an important part of follow-up, given the weight of respiratory complications in morbidity and mortality [89].

7.6. IL-10 pathway defects

Allogeneic HSCT. HSCT is the only curative treatment and is considered the de facto standard in defects of IL-10 signalling; it should be considered early because the defect resides in haematopoietic cells and the colitis resists conventional immunosuppression [33, 65]. Without HSCT, patients are exposed to B-cell lymphoma, and the autologous HSCT used in lymphomas does not correct the defect, so genetic identification points towards allogeneic transplantation [30, 33]. Genetics should precede any HSCT, to exclude purely epithelial defects (such as TTC7A or IKBKG), in which transplantation is of little or no efficacy [33].

These results are not directly comparable with one another: they differ in era, cell source, conditioning, age and severity at the time of transplantation and definition of remission. The Chinese cohort, the largest, showed no significant difference in survival between transplanted and non-transplanted patients, with wide confidence intervals and lower survival in patients with perforation; in that cohort, prior enterostomy and HSCT after 2 years of age were associated with a trend towards better survival, without statistical significance [21, 120]. The most favourable results come from centres with lower-toxicity conditioning and small series [99, 121]. In the Portuguese family with the IL10RB founder deletion, two patients were symptom-free 4.5 and 3 years after HSCT and the third died of severe GVHD at 12 months [68]. Intestinal decolonisation and PN in the peri-transplant period, and vedolizumab before HSCT to prevent intestinal GVHD, are exploratory strategies [21].

Bridging therapies. Anakinra, an IL-1 receptor antagonist, has a rationale in the excess of IL-1β and has been used as a bridge to HSCT in at least four patients (two IL10RA and two IL10RB), with clinical, endoscopic and histological response within 4–7 weeks, including patients with limited response to infliximab, adalimumab and vedolizumab [21, 123]. The reported dose was 2 mg/kg/day subcutaneously [99]. No dose has been established for this disease; the FDA label for neonatal-onset multisystem inflammatory disease (NOMID) and for deficiency of the IL-1 receptor antagonist gives 1–2 mg/kg/day, adjustable in increments of 0.5–1 mg/kg up to 8 mg/kg/day, with a neutrophil count before starting, monthly for 3 months and then quarterly up to 1 year; it should not be started during active infection, combined with anti-TNF agents or given with live vaccines [124]. Use in IL-10R deficiency is off-label; Kineret® has been authorised in the European Union (EU) since 2002 for rheumatoid arthritis, COVID-19 and periodic fever syndromes, and is registered in Brazil [114, 125]. Thalidomide was used in patients with IL-10 defects in a review of 14 studies with 213 children with refractory IBD, 16 of them with IL-10 defects, and is under observational study in VEO-IBD (NCT06382519) [21, 95].

What does not work. Methotrexate, azathioprine, ciclosporin, tacrolimus and mercaptopurine were almost all ineffective, and anti-TNF therapy brought minimal benefit, particularly in IL-10 defects [21, 113].

Surgery. More than half (52.5%) of patients with IL-10 defects underwent intestinal surgery; surgery is not curative because the disease recurs, but enterostomy is a bridge to HSCT and improves quality of life in severe perianal disease [21]. In a Shanghai cohort, 46 patients underwent enterostomy (19 emergency and 27 elective); after 10 years, 35 had undergone HSCT and 25 were alive, 19 had had the stoma closed (mean age 3.9 ± 1.5 years) and the median interval between HSCT and closure was 19.6 months [126].

Gene therapy. Gene therapy and gene editing corrected signalling in macrophages derived from induced pluripotent stem cells of patients with IL10RB deficiency and reduced colitis in the Il10rb-null mouse; there is no clinical trial of gene therapy for IL-10 defects [21]. This level of evidence is preclinical.

7.7. Other forms of the VEO-IBD class

Identification of the gene changes therapy in several forms of the class [30, 31, 33]. Besides IL-10 defects, HSCT is curative in XIAP deficiency, STXBP2 deficiency, IPEX, defects of IL2RB, DOCK8, RAG1/2, gain-of-function STAT1 and PIK3CD, SCID and CGD; CGD, IL-10R and XIAP defects should prompt assessment for HSCT [30]. Abatacept (CTLA4-Fc fusion protein) and rapamycin are used in CTLA4 haploinsufficiency and LRBA deficiency, and as a bridge in IPEX and PIK3CD deficiency; IL-18 blockade combined with IL-1 blockade is effective in NLRC4 defects; IFN-γ is used long term in CGD; and anakinra and canakinumab serve as a bridge in hyperinflammatory defects [30, 33]. The 2026 therapeutic atlas found efficacy of at least one pharmacological intervention in 61% (62 of 102) of monogenic conditions, including eculizumab in CD55 deficiency and empagliflozin in glycogen storage disease Ib [31]. In CGD, anti-TNF therapy is contraindicated because of the risk of severe infection and death [30].

In VEO-IBD without an identified defect, treatment approximates that of later-onset IBD, with pharmacokinetic particularities. With azathioprine at the standard dose of 2–3 mg/kg/day, none of 30 patients with VEO-IBD reached therapeutic 6-thioguanine levels (median 154), and only five reached them with doses above 3 mg/kg/day (up to 5.1 mg/kg/day); thiopurines are associated with hepatosplenic T-cell lymphoma and, in children with IBD between 2007 and 2016, with malignancy or HLH, and their use requires metabolite monitoring [30]. Infliximab persistence in 33 children with VEO-IBD was 36%, 18% and 12% at 1, 2 and 3 years, versus 93%, 78% and 67% in the REACH trial in older children, and 42.9% of 42 children with VEO-IBD stopped it before week 14 versus 7.7% of 130 with later-onset IBD; starting at 10 mg/kg per infusion (no maximum dose defined in the source), shortening intervals and adjusting by drug levels are proposed strategies without prospective validation [30]. There are no published data on vedolizumab, natalizumab or ustekinumab in VEO-IBD, apart from case reports [30].

Surgery is more frequent in VEO-IBD (50% with onset before 1 year and 29% after 1 year in one series); given the difficulty of distinguishing Crohn's disease from ulcerative colitis and the possible progression of disease extent, temporary diverting ileostomy is preferable to colectomy [30].

7.8. Regulatory status

Sources: [22–24, 36, 114, 117–119, 124, 125].

7.9. Trials and interventional studies

None of these studies allows indirect comparison: the sacrosidase trials are old, short and have symptomatic outcomes; the HSCT series are retrospective, single-centre and heterogeneous; and the only recent randomised trial using SI genotype studied a metabolic outcome in healthy adults and not the treatment of the disease [22, 53, 120]. The phase 4 sacrosidase trial ended without reaching its planned recruitment, and there are no randomised treatment trials in AE, THES or IL-10 defects [95, 113]. Registered observational studies include cord blood transplantation in IL-10R deficiency (NCT04170192, status unknown), characterisation and biobanking that includes THES (NCT04499040) and genetics of severe zinc deficiencies (NCT02870166, completed) [95].

7.10. Developments in the last 12 months

In the sources consulted, there was no new regulatory authorisation, Committee for Medicinal Products for Human Use opinion or phase 3 trial for these diseases during the period; the absence of results in a search does not demonstrate that other studies do not exist [23, 95].

7.11. Agents to avoid, pregnancy, perioperative care and transition

Agents and situations to avoid. In CSID, sacrosidase should not be mixed with fruit juice or heated, and is contraindicated in hypersensitivity to yeast or papain; in hereditary fructose intolerance, a differential of CSID, no fructose challenge should be performed before excluding it [22, 80]. In CLD, lactose must also be avoided in medicines and formulas, and the lactose load test should not be used in the newborn [17]. In AE, stopping zinc causes inevitable relapse [20]. In VEO-IBD, anti-TNF therapy is contraindicated in CGD; live vaccines (measles, mumps and rubella, rotavirus, varicella, intranasal influenza, BCG, oral typhoid, yellow fever) should be avoided under immunosuppression, and immunosuppression should be deferred for at least 1 month after a live vaccine for corticosteroids and 3 months for thiopurines and biologics, in coordination with immunology [30]. Anakinra should not be combined with anti-TNF agents or given with live vaccines [124]. In CSID, the excipients of oral medicines (sucrose, maltodextrins) should be checked, although small amounts are well tolerated if the medicine is taken with a meal together with the enzyme, and starch in excipients is generally tolerated; the PNDS lists, as a guide, sucrose-free forms of paracetamol (effervescent, orodispersible, suppository, sugar-free syrup), amoxicillin, metopimazine, phloroglucinol, tramadol, prednisone, loperamide and desloratadine, and magistral preparations when necessary [24]. Infant formulas must be free of sucrose, dextrin-maltose and maltose, and oral rehydration solutions used in intercurrent gastroenteritis must be free of sucrose and maltodextrins, otherwise they may be ineffective or worsen the diarrhoea [24]. Several drugs reduce SI activity and may worsen symptoms: α-glucosidase inhibitors (acarbose, miglitol, voglibose), miglustat, codeine, ranitidine and plant extracts rich in polyphenols [24].

Pregnancy and lactation. In AE, requirements increase in pregnancy and lactation, with 400–500 mg/day of zinc sulphate, and the dose should be adjusted according to levels [20, 38]. Sacrosidase has no animal reproduction studies and is not expected to cause fetal harm; it should be used only if needed [22]. No patient with THES had had children by 2018 [16]. In women with CLD on a lactose-free diet, calcium intake must be ensured [43].

Perioperative care. In IL-10 defects, diverting enterostomy has a high complication rate and should be planned as a bridge to HSCT; stoma closure takes place a median of 19.6 months after HSCT [17, 126]. In AE, wound healing depends on correction of zinc deficiency [38]. In diseases with prolonged PN, such as THES, central venous access and the associated liver disease constrain surgery [16].

Therapeutic education and daily life in CSID. In France there was, in 2025, no accredited therapeutic education programme for CSID; the proposed objectives are to understand the disease, identify foods containing sucrose and starch and their approximate content, know substitutes, recognise medicines and rehydration solutions containing sucrose, use enzyme replacement and know how to act in intercurrent infectious diarrhoea [24]. The diet weighs on communal meals (school, parties, family meals), and many patients keep symptoms that cause absence from school and sport, stress and a feeling of being different [24, 83]. In a cross-sectional study of 49 patients on sacrosidase (mean dose 5 ± 3 mL/day), there were 1.3 ± 0.9 stools per day and fewer symptoms with higher doses; mean energy intake was 1500 ± 400 kcal/day in children, 1900 ± 800 kcal/day in adolescents and 1900 ± 500 kcal/day in adults, with 44% carbohydrate, 39% fat and 17% protein, and carbohydrates were 35% starch, 8% fibre and 59% sugars; sucrose and fructose were not associated with symptoms, lactose was associated with diarrhoea and maltose with nausea, bloating and reflux [24].

Transition. AE and CLD require lifelong treatment and adherence in adolescence, when zinc requirements may increase [20]. In CSID, symptoms may lessen in later childhood, but starch intolerance persists in many patients [17]. In THES, transition involves gastroenterology, immunology, hepatology and psychosocial support, in a context in which IBD may appear in later childhood [89]. After HSCT for an IL-10 defect, long-term follow-up includes chimerism, immune function and surveillance for late complications of transplantation [99, 121].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All the main entities in this article are autosomal recessive. The parents of an affected child are, as a rule, obligate heterozygotes and asymptomatic; in each pregnancy, the risk of a sibling being affected is 25%, of being an asymptomatic carrier 50% and of being neither affected nor a carrier 25% [16]. The offspring of an affected person are obligate carriers, and the risk of having an affected child depends on the carrier status of the other parent; each sibling of the proband's parents has a 50% probability of being a carrier [16]. In populations with founder variants or consanguinity, the probability that the partner is a carrier increases: in the Inuit of the Canadian Arctic, the allele frequency of SI c.273_274del is 17.2%, and a carrier frequency of about 1 in 4 is cited in the Inuit of Nunavut; in Nilsiä, in north-eastern Finland, the carrier frequency of LCT c.4170T>A is 1 in 35, a local figure that cannot be extrapolated to the country [17, 19]. Consanguinity was present in all assessable patients with IL10 deficiency, in 22.9% of those with IL10RA defects and in 79.4% of those with IL10RB defects [67]. In CSID, the French PNDS recommends looking for signs of the disease in siblings, whose risk is 25%, and notes that the parents and offspring of patients are generally not affected [24].

Transient neonatal zinc deficiency is an exception: the infant's disease results from a maternal heterozygous SLC30A2 variant that reduces zinc in breast milk, inheritance is dominant on the maternal side and the risk recurs in breastfed infants of the same mother, without an absorption defect in the child [38, 58].

8.2. Heterozygotes

Heterozygotes for THES and IL-10 defects are asymptomatic and are not at risk of developing the disease [16]. Heterozygotes for East Asian pathogenic IL10RA variants have a partly increased response to IL-10, without disease [66]. In carriers of SI variants, heterozygosity and hypomorphic alleles have been associated with IBS-like symptoms in some studies, but not with clinical course in others, and counselling should reflect this uncertainty [46, 51, 52]. In a prospective study at 18 North American centres of 308 non-Hispanic white children with idiopathic chronic loose stools, the cumulative prevalence of 37 genotyped hypomorphic SI variants was higher than in ExAC data of the same ethnic origin, used as the reference population (4.5% versus 1.3%; odds ratio 3.5; 95% CI 2.0–6.1), with clinically more marked diarrhoea in carriers [127]; the French PNDS describes this reference as «unmatched», whereas the study matched it for ethnicity, although not for age or symptoms [24]. Heterozygous variants have also been associated with IBS in adults; confirmation requires studies of elimination diets and of relatives [24]. A heterozygous SLC39A4 mother may produce milk with less zinc, which brings forward symptoms in the affected child [20].

8.3. Cascade testing

Carrier testing in at-risk relatives requires prior identification of the variants in the index case [16]. In IL-10 defects, testing of siblings is also clinical: an affected sibling may be diagnosed before perianal disease develops, and a healthy non-carrier sibling may be assessed as an HSCT donor. In Inuit with chronic diarrhoea, targeted testing for the SI founder variant is rapid and minimally invasive [19]. In Finland, testing for c.4170T>A is the first step in a newborn with suspected disease [17].

8.4. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible [16]. In IL10RA defects, both have been performed in families with an index case, and a survey of tertiary centres in 10 countries found requests for prenatal testing in 4; these decisions require specific genetic counselling and raise ethical questions about embryo selection and termination of pregnancy [33]. In THES, prenatal trio exome sequencing identified compound heterozygosity in SKIC2 in a fetus with severe growth restriction [88]. In diseases with simple and effective treatment, such as CLD and AE, prenatal diagnosis is valuable mainly for preparing neonatal treatment. The ideal time to clarify risks and discuss options is before pregnancy, and DNA banking is useful in probands without a molecular diagnosis [16]. In CSID, a disease without vital risk and controllable by diet, the French PNDS considers that the diagnosis does not imply prenatal screening or discussion of termination of pregnancy for medical reasons [24].

8.5. Counselling

Counselling should distinguish Mendelian disease from common traits: an MCM6 genotyping result for «lactose intolerance» describes a trait and a dietary preference, not a disease, and has no reproductive implications [17]. In late-onset and mild forms of sucrase-isomaltase deficiency, the implications for offspring depend on the genotype and are less predictable than in the congenital form [51]. In IL-10 defects, counselling includes discussion of HSCT, lymphoma risk and reproductive options [33]. Testing of asymptomatic minors is justified when it has a direct benefit, as in siblings of patients with an IL-10 defect or AE, and not merely to determine carrier status. Young adults who are affected, carriers or at risk of being carriers should receive counselling on risks to offspring and reproductive options [16]. In France, genetic counselling in CSID takes place at the reference centres for rare digestive diseases, and the diagnosis is communicated by a paediatric or adult gastroenterology team that includes a dietitian, complemented by the patient association [24].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available figures measure

The figures refer to different quantities and cannot be compared directly. Allele-frequency estimates assume complete penetrance and correct variant classification; the old clinical prevalences of CSID probably include secondary deficiencies and do not distinguish genetic forms; and the case count of an ultra-rare disease depends on the awareness of centres [18, 51, 96]. The absence of data for a region, in the sources consulted, does not mean the absence of patients. The European clinical estimate cited by the PNDS (0.05–0.2%) differs from that of GeneGuidance and OMIM (0.02%), which illustrates the imprecision of clinical estimates, and the Inuit allele frequency of 20% cited by the PNDS and the 17.2% measured in the Canadian Arctic come from different samples [17, 19, 24].

9.2. Founder populations and geographical distribution

Sucrase-isomaltase deficiency is common in the indigenous populations of the Arctic (Greenland, Alaska, Canada), owing to a single founder variant [17, 19]. The absence of signs of positive selection around the variant suggests that its frequency results from genetic drift in small, isolated populations, and the traditional Inuit diet, rich in protein and fat and poor in carbohydrate, probably kept homozygotes asymptomatic until the introduction, a few decades ago, of Western foods rich in sucrose and starch [24]. CLD belongs to the Finnish disease heritage, with the Fin-major variant in about 90% of alleles, but has been described in Italian, Turkish, German patients of Turkish origin and Indian patients [17, 55, 56, 85]. AE has been described mainly in families from Europe, the Middle East and North Africa, and appears more common in north-western Tunisia, sub-Saharan Africa and South-East Asia; recent series from China include Han, Yi, Tibetan and Xinjiang minority patients [20, 38, 87, 116]. THES has been described worldwide and is more frequent in consanguineous populations; in Saudi Arabia, the great majority of patients have SKIV2L variants [16, 61]. IL10RA defects are concentrated in East Asia (China 40.7% of patients in the systematic review, South Korea 8.5%), with probable balancing selection; IL10RB defects predominate in consanguineous families from Central and South Asia and Europe; Italy contributed 13.9% of the patients in the review [66, 67]. In the Middle East, consanguinity explains very high diagnostic yields in congenital diarrhoeas (76.9%) but not in VEO-IBD (7.1%), similar to that in North America [100].

9.3. United States and Europe

In the USA, sacrosidase has been available since 1998 and the journey of patients with CSID has been studied qualitatively [36, 83]. The incidence of VEO-IBD has increased over recent decades and NASPGHAN published the American reference position paper [30]. In Europe, the ESPGHAN consensus guides the genomics of monogenic IBD, the French cohort underpins the prevalence estimate for THES, the British cohort describes its later course and the European consensus on malabsorption guides the disaccharidase deficiencies [16, 33, 43, 89]. Scandinavian, British and German studies are investigating the role of SI variants in IBS [46, 47, 95].

9.4. Portugal and Brazil

In Portugal, a founder deletion of exon 3 of IL10RB has been described in three unrelated families, with a common ancestor estimated at about 400 years ago, which may increase the risk of IL-10Rβ deficiency in the Portuguese population, whether in the homozygous or compound heterozygous state, even in non-consanguineous families; its population frequency has not been assessed [68]. In Brazil, a patient with THES whose diagnosis required RNA and protein analysis of TTC37 has been described, a national cohort of 100 children with suspected inborn error of immunity had a conclusive molecular diagnosis in 17% by exome sequencing, and the Brazilian dermatological literature has discussed the distinction between AE and transient zinc deficiency [62, 101, 128]. The sources consulted do not provide prevalences for Portugal or Brazil.

9.5. Special populations

Breastfed preterm infants are at increased risk of transient zinc deficiency, owing to greater requirements and lower absorptive capacity [38, 91]. In adults, sucrase-isomaltase deficiency should be considered in patients with refractory IBS [81]. In Inuit populations, the SI genotype has dietary and metabolic implications beyond gastrointestinal disease [53]. Greenlandic adults homozygous for the Arctic variant have a more favourable metabolic profile (lower body mass index and more favourable lipids), but also more consultations and tests for gastrointestinal symptoms [24].

9.6. European reference networks and patient associations

ERN RITA (immunodeficiency, autoinflammatory, autoimmune and paediatric rheumatic diseases) is the relevant network for IL-10 defects, THES and the rest of monogenic VEO-IBD; ERNICA (congenital and inherited digestive diseases, including intestinal failure) for congenital diarrhoeas and THES; ERN RARE-LIVER for the liver disease of THES; and ERN-Skin for AE [25–28]. Among the associations, CSID Cares provides information on CSID in the USA; the International Patient Organisation for Primary Immunodeficiencies (IPOPI) represents patients with primary immunodeficiencies; and the European Federation of Crohn's & Ulcerative Colitis Associations (EFCCA) and the Associação Portuguesa da Doença Inflamatória do Intestino (APDI) support patients with IBD [129–132].

In France, CSID is followed in the network of the reference centre for rare digestive diseases (MaRDi), coordinated at the Robert Debré Hospital (Paris), with paediatric and adult competence centres where functional challenges and breath tests are performed; genetic testing is carried out mainly in Marseille (La Timone), Paris (Necker-Enfants Malades) and Bordeaux, under the genetic pre-indication «congenital enteropathies of the young child», with multidisciplinary consultation meetings accessible at any age, and the disaccharidase assay in Lyon and Nancy, the latter a biological reference centre linked to the reference centre for rare metabolic diseases [24]. The disease can be recognised as a long-term condition (ALD 17, «metabolic disease»), with exemption from co-payment, and the Association Française de la Déficience Congénitale en Saccharase et Isomaltase (AFDCSI) supports families, collaborates in education and is developing an app to estimate the sugar content of meals [24].

10. Illustrative Clinical Case

10.1. Late-diagnosed acrodermatitis enteropathica with septic shock

Foroughi and colleagues described in 2025 an 8-year-old Iranian boy, the fourth child of consanguineous parents, with three healthy sisters, born at term weighing 2900 g and with normal development [77]. He was exclusively breastfed until 2 years of age; after weaning, pustules, erosions and genital ulcers appeared, followed by facial lesions. The initial diagnosis was allergic contact dermatitis and an elimination diet brought no improvement; a course of zinc and multivitamins partly improved the lesions, but the ulcers did not heal. At 7 years the family stopped the supplements and turned to Chinese herbal medicine, and a year later the lesions worsened, the child stopped interacting socially and was admitted in septic shock [77].

On admission he had a blood pressure of 70/40 mmHg, heart rate of 180/min, respiratory rate of 30/min, oxygen saturation of 94% in room air and temperature of 36.5 °C, with weak pulses and oliguria. He had generalised haemorrhagic and erosive dermatitis, predominantly in the perioral-facial, genital and limb regions (Fig. 1 of the article), generalised alopecia of the scalp, eyelashes and eyebrows and inability to walk without arthritis; he weighed 15 kg (z-score −5.11), measured 121 cm (z −1.25) and had a body mass index of 10.25 [77]. Tests showed haemoglobin 10.8 g/dL, albumin 2.5 g/dL, total cholesterol 48 mg/dL, triglycerides 43 mg/dL, vitamin A 12.9 µg/dL, sodium 130 mEq/L, C-reactive protein 86 mg/L, erythrocyte sedimentation rate 121 mm/h, procalcitonin 2.2 ng/mL, IgE 1055 U/mL and IgG 2178 mg/dL; blood culture grew Staphylococcus epidermidis. Plasma zinc was 60 µg/dL (reference 78–105) on the second day and alkaline phosphatase was normal [77].

The child received fluids, ceftriaxone (100 mg/kg/day) and vancomycin (60 mg/kg/day) for 14 days and adrenaline up to 0.3 µg/kg/min for 48 hours. On the second day he started zinc sulphate at a dose of 3 mg/kg/day of elemental zinc and a progressive high-calorie, high-protein diet, starting at 75 kcal/kg because of the risk of refeeding syndrome [77]. Skin biopsy showed compact hyperkeratosis, acanthosis, mild spongiosis and a neutrophil-rich subcorneal pustule (Fig. 2), and hair biopsy showed pigment dilution of the shaft (Fig. 3). Exome sequencing identified the variant NM_130849.4:c.1465_1474+4del in the homozygous state in SLC39A4, a deletion that alters the reading frame and the canonical donor site of intron 9, with a frequency of 0.0034% in gnomAD, no homozygotes, and already described in patients with AE [50, 77]. The article mistakenly refers to an autosomal dominant hypothesis; the homozygous genotype described is consistent with the recessive inheritance of the disease.

He was discharged on day 14 with zinc and iron. Serum zinc normalised at two months and, at four months, all lesions had disappeared, weight was 23 kg (z −0.78), height 123 cm and body mass index 15.2, with regrowth of hair, eyebrows and eyelashes and marked psychological improvement (Fig. 4, showing the appearance at discharge, at 3 weeks, at 2 months and at 4 months) [77]. The figures cited are in the original article: https://pmc.ncbi.nlm.nih.gov/articles/PMC12560606/.

10.2. Lessons from the case

The case brings together several points of this article. Prolonged breastfeeding delayed onset, as predicted by the greater bioavailability of zinc in breast milk; the initial diagnosis of contact dermatitis and partial treatment with zinc delayed recognition; and stopping zinc caused a severe relapse, corresponding to the withdrawal test described in the clinical criteria, here without diagnostic intent [20, 38, 77]. Normal alkaline phosphatase and only moderately low zinc, already on treatment, show that biochemical markers can mislead and that genetic confirmation is useful [38, 87]. The dose used (3 mg/kg/day) is lower than that of the ClinGen reference series (5–10 mg/kg/day) and coincides with the range most used in the recent paediatric literature; it was effective in this patient, which does not make it a routine dose [20, 94]. The authors acknowledge that they did not exclude coeliac disease, Crohn's disease or HIV infection [77].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by entity

CSID. The prognosis is good with diet and, when available, sacrosidase, which made 86% of children up to 3 years and 77% of older children asymptomatic in the label trial; many children improve spontaneously in later childhood, but starch intolerance and residual symptoms may persist, with an impact on quality of life [17, 22, 83]. Faltering growth is reversible once the diagnosis is made [22]. With an adapted diet, symptoms tend to decrease with age and the risk of malnutrition becomes low [24].

CLD. Without treatment, dehydration can be severe; with a lactose-free diet, growth and development are normal, and hypercalcaemia and nephrocalcinosis resolve within weeks to months [17, 56, 85].

AE. Without zinc, 34 of 51 patients died in a historical review, most before 12 years of age; with lifelong zinc, the prognosis is excellent, without growth or intellectual impairment over follow-up of up to 24 years, provided there are no interruptions [20, 38].

THES. Infection was the cause of death in 7 of 21 patients and liver disease in 7 of 17 with a known cause; 20% of patients described in the literature died of infection despite immunoglobulin replacement [16, 64]. Diarrhoea with intestinal failure tends to improve over time and 30–50% come off PN, but refractory IBD may appear in later childhood, final height is low in more than half and respiratory complications weigh on mortality [16, 89]. A Balkan patient with SKIV2L variants, on PN since birth, died at 3 years of age [78].

IL-10 defects. Without HSCT, the disease is severe and refractory, with multiple operations and a risk of B-cell lymphoma; overall survival in the largest cohort was 64.2% with HSCT and 47.5% without HSCT, and recent series with lower-toxicity conditioning report survival of 80–100% and medication-free remission in the great majority [99, 120–122]. Ten-year survival was higher in ligand deficiency than in receptor deficiency [67].

11.2. Surveillance table

12. Summary and Concluding Remarks

Congenital disaccharidase deficiencies, acrodermatitis enteropathica, trichohepatoenteric syndrome and IL-10 pathway defects are autosomal recessive diseases that present mainly as chronic diarrhoea in infancy and whose identification changes treatment. The timing of onset guides diagnosis: diarrhoea with the first feed suggests lactase deficiency, diarrhoea with the introduction of sucrose suggests sucrase-isomaltase deficiency, periorificial dermatitis after weaning suggests AE, intractable diarrhoea with IUGR and woolly hair suggests THES, and enterocolitis with perianal disease before three months suggests an IL-10 defect.

In the disaccharidase deficiencies, diet is effective; sacrosidase, approved in the USA since 1998 and without authorisation in the European Union, replaces sucrase but not isomaltase, and invertase is emerging as a low-cost alternative with limited evidence. In France, the 2025 PNDS proposes a stepwise investigation (sucrose challenge, SI genetics, enzyme assay as third line), a gradual diary-guided dietary reintroduction and compassionate access to sacrosidase [24]. Diagnosis of the genetic form requires attention to secondary deficiency, which biopsy alone may confound, and the interpretation of hypomorphic SI variants in adults with IBS symptoms remains under investigation. The distinction between congenital lactase deficiency, a rare disease enriched in Finland, and adult hypolactasia, a trait regulated by MCM6, is essential to avoid medicalising normal variation.

In AE, lifelong oral zinc transforms a historically fatal disease into a condition with an excellent prognosis, provided there is adherence and copper monitoring; serum zinc may be normal, more than half of clinical cases have no identified coding variant, and transient deficiency of the breastfed infant, acrodermatitis dysmetabolica and other metabolic diseases are important differentials.

THES is a multisystem disease of the SKI complex, with combined immunodeficiency, liver disease and a risk of IBD in later childhood, managed with nutritional support, immunoglobulin and annual surveillance, without established curative therapy. IL-10 defects are the paradigm of monogenic IBD: genetics and the functional assay should be performed early, because allogeneic HSCT is curative, conventional immunosuppression fails and there is a risk of lymphoma. European and North American recommendations advocate sequencing in all infantile IBD and in much of VEO-IBD, functional validation of variants and assessment by multidisciplinary teams, in liaison with the European reference networks.

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