Enchondromatoses – Ollier Disease and Maffucci Syndrome

Group of bone dysplasias defined by multiple enchondromas; Ollier disease and Maffucci syndrome result from mosaic postzygotic variants in IDH1 or IDH2, with a high risk of chondrosarcoma and other IDH-associated neoplasms, whereas the remaining members of the class are Mendelian (PTPN11, ACP5, NKX3-2, COL2A1, PTHLH duplication) or of unknown molecular basis.

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition of the class and scope

An enchondroma is a benign cartilaginous tumour that forms inside bone, usually in the metaphysis of the tubular bones, and may be solitary or multiple; the presence of multiple enchondromas defines enchondromatosis [13, 44]. The enchondromatoses form a heterogeneous class: Ollier disease is the most frequent form and Maffucci syndrome the second, and both result from mosaic postzygotic variants in IDH1 or IDH2; the remaining subtypes are extremely rare and, in part, Mendelian [13, 17, 45]. Spranger’s bone dysplasia atlas places the enchondromatoses in the group of disorders caused by disorganised development of skeletal components, alongside multiple exostoses, metachondromatosis, genochondromatosis and dysplasia epiphysealis hemimelica [2, 46–48]. This article treats the class uniformly, with in-depth coverage of the two IDH-related entities and of their generalised form (MC-HGA); dysspondyloenchondromatosis, a type II collagenopathy, multiple cartilaginous exostoses and metachondromatosis, as a PTPN11 loss-of-function disorder related to the RASopathies, enter the differential diagnosis.

1.2. Founding descriptions and clinical milestones

Louis Ollier described “dyschondroplasia” in 1900, in Lyon Médical, the name then given to cases of multiple enchondromas with unilateral predominance; the association with multiple angiomas became known as Maffucci syndrome, a name proposed by Carleton and colleagues in 1942 in honour of the Italian pathologist who had described the first patient in 1881 [2, 19]. The Spranger atlas considers the unilateral form only a topographical variant of enchondromatosis, and not a separate entity, and groups under the same heading the designations dyschondroplasia, Ollier disease and Maffucci syndrome [2]. The clinical literature of the 20th century accumulated small series and long follow-up cases: Cleveland and Fielding documented in 1959 a patient followed for 38 years, Shapiro analysed in 1982 angular deformity, shortening and pathological fractures in 21 patients, Schwartz and colleagues discussed in 1987 the malignant potential of enchondromatosis and Kaplan and colleagues reviewed Maffucci syndrome in 1993 [2]. In 2006, Silve and Jüppner published the Orphanet review that established the estimated prevalence of 1/100,000, stressing that until then only isolated, non-familial cases were known [12]. In 2011, the European multicentre study of Verdegaal and colleagues, with 161 patients, quantified the risk of chondrosarcoma and identified pelvic location and long bone involvement as risk factors [15]. In 2020, El Abiad and colleagues, at Johns Hopkins University, combined a review of 359 patients from the literature with a survey of 162 patients and proposed the first structured follow-up recommendations, which served as the basis for the AACR consensus published in 2025 [13, 14].

1.3. Molecular discovery

The first molecular hypothesis involved the parathyroid hormone and parathyroid hormone-related protein receptor (PTH1R, also written PTHR1): Hopyan and colleagues described in 2002 the heterozygous variant p.R150C (published designation; = NM_000316.3:c.448C>T p.(Arg150Cys)) in the enchondromas of 2 of 6 patients with Ollier disease, with abnormal signalling in vitro and enchondroma-like lesions in transgenic mice; in one of the two men the variant was germline and inherited from the father, in the other it was absent from adjacent normal bone and was interpreted as somatic [49, 50]. Rozeman and colleagues studied 31 patients with Ollier disease or Maffucci syndrome from three European countries: receptor expression in the tumours was normal on immunohistochemistry, the variant was not present in the tumours of 26 patients and sequencing of PTH1R in 11 patients revealed no other variants; they concluded that the receptor was not the cause of enchondromatosis and considered that the variant might be a founder variant in the Canadian population studied by Hopyan or specific to a rare form of enchondromatosis [7, 50]. Couvineau and colleagues described in 2008 three new loss-of-function missense variants (p.G121E, p.A122T and p.R255H; published protein designation, = NP_000307.1 [NM_000316.3] p.(Gly121Glu), p.(Ala122Thr) and p.(Arg255His)) in patients with Ollier disease, in a total of deleterious variants in 5 of 31 enchondromas [51]. According to the OMIM summary, the study analysed PTH1R, IHH, PTHLH and GNAS in leucocyte or tumour DNA from 61 patients with Ollier disease and 23 with Maffucci syndrome; no patient with Maffucci syndrome had a deleterious variant, the p.G121E and p.A122T variants were present only in the enchondroma and p.R255H was also present in leucocytes; because 3 of the 5 patients with a variant in the tumour did not have it in blood, the authors considered mosaicism and concluded that the PTH1R variant alone would not be sufficient to form enchondromas [9, 11]. In 2010, Collinson and colleagues associated a symmetrical, generalised form of enchondromatosis with a de novo 12p11.23–p11.22 duplication that includes PTHLH, the gene encoding the receptor ligand [36]. The decisive milestone came in November 2011, with the simultaneous publication, in Nature Genetics, of the work of Amary and colleagues (London) and of Pansuriya and colleagues (EuroBoNet consortium), who identified heterozygous somatic variants in IDH1 (mainly NM_005896.4:c.394C>T p.(Arg132Cys)) and, more rarely, in IDH2 (NM_002168.4:c.516G>C or c.516G>T p.(Arg172Ser)) in most enchondromas and spindle cell haemangiomas of these patients [17, 18]. In the same year, Vissers and colleagues identified mosaic IDH1 variants in MC-HGA by exome sequencing, and Bowen and colleagues showed that loss of function of PTPN11 causes metachondromatosis but not Ollier disease or Maffucci syndrome [47, 52]; the gene had been pointed to in 2010 by Sobreira and colleagues, who, by genome sequencing of a single proband from a five-generation family combined with linkage analysis, identified a heterozygous 11 base pair deletion in PTPN11 that segregated with the disease [28]. In 2015, Hirata and colleagues reproduced enchondroma-like lesions in mice with conditional expression of mutant Idh1 in chondrocytes, demonstrating that the variant is sufficient to initiate the disease [53].

1.4. Current classifications and nomenclature

Spranger’s historical classification numbers the enchondromatoses by type; Orphanet retains it in the synonyms, with Ollier disease as type I, Maffucci syndrome as type II and cheirospondyloenchondromatosis (generalised enchondromatosis with platyspondyly) as type VI [1, 3, 26]. In the original 1978 version, reproduced by OMIM, the six types were Ollier disease (I), Maffucci syndrome (II), metachondromatosis (III), spondyloenchondrodysplasia (IV), enchondromatosis with irregular vertebral lesions (V) and generalised enchondromatosis (VI); Halal and Azouz added three provisional categories in 1991, and Pansuriya and colleagues proposed a new classification in 2010 [9, 30]. Pansuriya and colleagues counted seven main subtypes (Ollier, Maffucci, metachondromatosis, genochondromatosis, spondyloenchondrodysplasia, dysspondyloenchondromatosis and cheirospondyloenchondromatosis), of which only the first two are frequent [17, 45]. Superti-Furga, Spranger and Nishimura proposed in 2012 a molecularly based reclassification, cited by the Spranger atlas as the reference for the group [2]. The nosology of genetic skeletal disorders of the International Skeletal Dysplasia Society, revised in 2023, is the current nosological classification [54]. In terms of mechanism, the class divides into three groups: the forms due to somatic IDH1/IDH2 mosaicism (Ollier, Maffucci and MC-HGA, which the atlas considers the same disease with different degrees and distributions of mosaicism); the Mendelian forms with a known gene (metachondromatosis due to PTPN11, SPENCD due to ACP5, dysspondyloenchondromatosis due to COL2A1, symmetrical enchondromatosis due to PTHLH duplication and spondylo-megaepiphyseal-metaphyseal dysplasia due to NKX3-2, which enters the differential diagnosis); and the dominant forms without an identified gene (genochondromatosis, carpotarsal osteochondromatosis and Upington disease) [14, 17, 27, 36, 41, 43].

Two nomenclature systems outside genetics are of direct practical relevance. The first is that of the World Health Organization (WHO) for bone tumours, which designates low-grade cartilaginous lesions of the appendicular skeleton as atypical cartilaginous tumour (ACT) and reserves the designation grade 1 chondrosarcoma for the axial skeleton, including the scapula, pelvis and skull [20, 55]. The second is that of the International Society for the Study of Vascular Anomalies (ISSVA), which defines Maffucci syndrome as enchondromas with venous malformations, with or without spindle cell haemangiomas; a 2026 systematic review found that more than half of the publications on Maffucci syndrome still use the non-specific term “haemangioma” and that only two recognise the ISSVA definition [16].

1.5. Operational definitions

In the absence of consensus diagnostic criteria, El Abiad and colleagues used as an operational definition the presence of at least three enchondromas for Ollier disease and of at least three enchondromas with vascular anomalies for Maffucci syndrome [14]. MC-HGA is defined by the association of generalised enchondromatosis, with short stature, severe metaphyseal dysplasia and mild vertebral involvement, with elevated urinary levels of D-2-hydroxyglutaric acid and mild developmental delay [25, 27]. Between Ollier disease, with mosaicism restricted to the lesions, and MC-HGA, with variants detectable in blood and aciduria, an intermediate phenotype has been described: disseminated metaphyseal enchondromatosis with IDH1 mosaicism in blood and without aciduria [56]. Solitary enchondroma, although it does not belong to enchondromatosis, shares the mechanism, because about 40% of solitary central cartilaginous tumours have IDH1 or IDH2 variants [17, 57].

2. Molecular Genetics and Pathophysiology

2.1. IDH1 and IDH2: structure and normal function

IDH1 (2q34; OMIM 147700; HGNC:5382) encodes the cytosolic and peroxisomal NADP⁺-dependent isocitrate dehydrogenase, a homodimer that oxidatively decarboxylates isocitrate to 2-oxoglutarate (α-ketoglutarate) and is an important source of NADPH in the cytoplasm [4]. The protein has 414 amino acids and a C-terminal peroxisomal targeting signal; the gene has 10 exons over 18.9 kb, the first two of which are untranslated [58]. IDH2 (15q26.1; OMIM 147650; HGNC:5383) encodes the mitochondrial matrix isoenzyme, with the same reaction; the protein has 419 amino acids and the NADPH it produces supplies the antioxidant enzymes of the mitochondrion [5, 6, 59]. The MANE Select transcripts confirmed in VariantValidator are NM_005896.4 for IDH1 and NM_002168.4 for IDH2 [6]. The residues affected in enchondromatosis, Arg132 in IDH1 and Arg172 in IDH2, lie in the active site of the enzyme; Arg132, conserved in evolution, binds through hydrophilic interactions to the α-carboxylate group of isocitrate at the substrate binding site [4, 58, 60].

2.2. Neomorphic mechanism: D-2-hydroxyglutarate and epigenetics

Substitutions of Arg132 of IDH1 and of Arg172 (or Arg140) of IDH2 are neomorphic gain-of-function variants: the mutant enzyme loses part of its ability to convert isocitrate to 2-oxoglutarate and acquires a new activity, the reduction of 2-oxoglutarate to D-2-hydroxyglutarate (D-2-HG), which accumulates in tumour tissue and, in forms with widespread mosaicism, in urine [2, 4, 60]. Biochemical studies in 2009 described the two sides of the effect: the subunit with substituted Arg132 loses affinity for isocitrate and forms catalytically inactive heterodimers with the normal subunit, which dominantly reduces production of 2-oxoglutarate (Zhao and colleagues), and acquires the ability to reduce 2-oxoglutarate to D-2-HG in an NADPH-dependent manner (Dang and colleagues) [58]. D-2-HG competitively inhibits the 2-oxoglutarate-dependent dioxygenases, including histone and DNA demethylases, which leads to hypermethylation and blocked cell differentiation [61]. In enchondromas, Pansuriya and colleagues found a CpG island methylator phenotype (CIMP) in all tumours with an IDH1 variant except one: 797 CpG sites were differentially methylated, 710 (89.1%) hypermethylated in the mutant tumours, and 32 of 33 differentially expressed genes were underexpressed; DLX5 was among the most methylated, which suggested delayed hypertrophic differentiation of chondrocytes [17]. Amary and colleagues showed that 2-HG levels in central cartilaginous and vascular tumours, syndromic or not, correlate with the presence of an IDH1 variant [18].

The mouse model of Hirata and colleagues clarified the histogenesis: expression of Idh1 p.R132Q in chondrocytes from development onwards (Col2a1-Cre) is lethal in the neonatal period, but post-weaning induction with tamoxifen (Col2a1-Cre/ERT2) produces multiple enchondroma-like lesions; the mechanism is persistence of hypertrophic growth plate chondrocytes (positive for collagen X), which are retained as remnants within the bone [53]. This explanation is consistent with the clinical observation that lesions appear and grow until puberty and stop appearing after closure of the growth plates [2].

2.3. Postzygotic somatic mosaicism

In 37 of 40 individuals with Ollier disease or Maffucci syndrome studied by Amary and colleagues, at least one tumour had an IDH1 or IDH2 variant, 65% of which were p.Arg132Cys; in 18 of 19 individuals with more than one tumour analysed, all tumours shared the same Arg132 variant, and in 2 of 12 low-level mutant DNA was detected in non-neoplastic tissue [18]. The full-text description in OMIM details these figures: 90.5% of the 74 tumours had a variant (62 of the 68 cartilaginous tumours in IDH1 and 1 in IDH2); of the 19 individuals with several tumours, 15 had the same variant in all, 3 had both tumours analysed without a variant and 1 had p.R132S (= NM_005896.4:c.394C>A p.(Arg132Ser)) in one tumour and normal sequence in the other, so the figure of 18 of 19 corresponds to concordance between tumours and not to the presence of a variant in all; the p.R132C variant (= NM_005896.4:c.394C>T p.(Arg132Cys)) in non-lesional tissue (bone marrow in one patient, blood in another) was detected only by TaqMan and MassARRAY, not by capillary sequencing; complete sequencing of IDH1, IDH2 and PTH1R in the three tumours without a variant revealed no changes; and tumour 2-HG levels followed the presence of a variant, with exceptions (two tumours without a variant from a patient with Maffucci syndrome with elevated 2-HG) [9, 11]. Pansuriya and colleagues sequenced lesional tissue from 43 patients with Ollier disease and 13 with Maffucci syndrome: Sanger sequencing detected variants in 33 patients with Ollier disease (78%) and in 7 with Maffucci syndrome (54%), and a hydrolysis probe assay with a detection limit of 1% mutant allele confirmed 7 more of 8 tumours with subthreshold peaks, for a total of 35 of 43 (81%) and 10 of 13 (77%); 98% of the variants were in IDH1 and 2% in IDH2, and 14 of 16 patients (88%) had identical variants in separate lesions [17]. By tumour, there was a variant in 87% of enchondromas and in 70% of spindle cell haemangiomas; immunohistochemistry for p.R132H (= NM_005896.4:c.395G>A p.(Arg132His)) was positive in 17 of 68 tumours from patients with Ollier disease (25%) [9]. The variants were not present in DNA from blood, muscle or saliva; immunohistochemistry for IDH1 p.R132H revealed 50–95% positive cells within positive tumours (“intraneoplastic mosaicism”) and a very low fraction (on average <1%) of positive osteoblasts, osteocytes, adipocytes and fibroblasts in adjacent normal tissue, absent in bones resected for other reasons and in normal growth plates [17]. In 13 enchondromas from 8 children in Geneva, all had an IDH variant, with variant allele fractions (VAF) from 14% to 45%, which corresponds to intratumoral mosaicism at the lower values [62].

The presence of the same variant in tissues of mesodermal (cartilage, vessels, bone marrow), ectodermal (glia) and endodermal (parathyroid) origin indicates a very early postzygotic event, before gastrulation [63, 64]. A Belgian case published in 2026 documented the same variant NM_005896.4(IDH1):c.394C>T p.(Arg132Cys) in an enchondroma (VAF 41%), in acute myeloid leukaemia (AML) cells (37%) and in a parathyroid adenoma (44%), absent from cultured skin fibroblasts [64]. Mandonnet and colleagues proposed the “triple-hit theory” to explain why the tumour spectrum is restricted despite widespread mosaicism: negative selection of the clone in some tissues, absence of IDH1 expression or a cellular state without D-2-HG accumulation, and inherited predisposition through organ-specific polymorphisms, by analogy with the G allele of rs55705857 at 8q24.21 in IDH-mutant glioma in the general population [63]. The hypothesis does not yet have its own validation data [63].

The degree and distribution of mosaicism modulate the phenotype. In MC-HGA, the IDH1 variants p.(Arg132His) and p.(Arg132Ser) were detected in blood (and, in one patient, also in saliva, but not in fibroblasts), which corresponds to more widespread, presumably earlier, mosaicism with systemic production of D-2-HG [2, 52]. In the intermediate phenotype described in 2023, a 9-year-old boy with disseminated metaphyseal enchondromatosis and a spared spine had IDH1 c.395G>A p.(Arg132His) in 22% of blood reads, without aciduria [56]. The Spranger atlas reports that, in a few patients with Ollier disease, the same variant as in the enchondromas was found in blood DNA [2].

2.4. Variant spectrum and nomenclature

The variants described in enchondromatosis are concentrated in two codons. The data normalised in VariantValidator and ClinVar (GRCh38 and GRCh37) are summarised in the following table [6, 65].

In ClinVar, the IDH1 Arg132 variants have germline classifications of pathogenic or likely pathogenic, an “oncogenic” oncogenicity classification and a tier I somatic classification (tier II for p.Arg132Ser); the germline entry for IDH2 c.516G>C is recorded as a “risk factor”, which reflects submissions from an oncological context and not a Mendelian disease [65]. Exon numbering varies with the transcript: Pansuriya and colleagues place the IDH1 hotspot in exon 4, whereas Brown and colleagues, with transcript NM_001282386.1, describe it in exon 5; VariantValidator confirms that NM_001282386.1:c.394C>T and NM_005896.4:c.394C>T correspond to the same genomic position, so they are the same variant [6, 17, 19]. Hirata and colleagues described the p.R132Q variant in human enchondromas and chondrosarcomas, and Akiyama and colleagues a deletion-insertion p.Gly131_Arg132delinsAlaLeu in a woman with Maffucci syndrome and AML; the material read does not provide the c. notation of these two variants, which were therefore not normalised [53, 64]. Nyhan’s atlas of metabolic diseases gives, for patients with skeletal dysplasia and D-2-hydroxyglutaric aciduria, the IDH1 notation “p.Arg143Ser”; the primary article (Vissers 2011) describes p.R132S, which is the variant normalised above, and the atlas notation does not correspond to any known hotspot [52, 60].

The distribution of variants differs between contexts: in the central and periosteal cartilaginous tumours of a series of about 1200 mesenchymal tumours, the IDH1:IDH2 ratio was 10.6:1, about 40% were p.R132C and there were no IDH2 Arg140 variants, unlike in AML [57]. The variants were exclusive to central and periosteal cartilaginous tumours and were absent in osteochondromas, peripheral chondrosarcomas, osteosarcomas and the other mesenchymal tumours studied [17, 57].

2.5. Genotype–phenotype correlations

There is no established correlation between the specific variant and the type of enchondromatosis: p.Arg132Cys is the most frequent in both Ollier disease and Maffucci syndrome [17, 18]. The spindle cell haemangiomas of Maffucci syndrome have an IDH variant in about 70% of cases and share the variant of the enchondromas of the same patient [17, 19]. In solitary central cartilaginous tumours, variants were more frequent in the hands and feet (11 of 14) than in the long and flat bones (28 of 84; p=0.006), a difference that did not exist in Ollier disease (20 of 22 versus 28 of 34; p=0.5); the presence of a variant had no prognostic value in solitary central tumours, unlike in glioma [17]. In about 20% of patients no IDH1/IDH2 variant is found; in the five negative tumours sequenced across all exons, Pansuriya and colleagues considered intralesional mosaicism below the detection limit or involvement of another gene [17].

2.6. Germline basis: hypotheses and evidence

There is no established germline Mendelian disease for IDH1; ClinGen has no gene–disease validity assertion and OMIM lists, for the gene, only somatic susceptibility to glioma (OMIM 137800), referring enchondromatosis to the phenotypic entries for Ollier disease (166000) and Maffucci syndrome (614569), described as somatic, both marked with the “%” prefix for a phenotype without an assigned Mendelian basis, as is MC-HGA (614875) [9, 11, 24]; the IDH2 entry makes the same cross-reference and associates with the gene, as a germline disease, only D-2-hydroxyglutaric aciduria type II [4, 58, 59]. A GenCC entry submitted by a commercial laboratory classifies Maffucci syndrome as autosomal dominant with limited evidence, a classification incompatible with the mosaic mechanism [4]. Candidate germline cases are scarce: one family in which the mother and two children shared the heterozygous IDH1 variant NM_005896.4:c.299G>A p.(Arg100Gln), with grade 1 chondrosarcoma of the mastoid (unilateral in the mother, bilateral in the children), presentation between 9 and 12 years of age with headache, facial paresis and conductive hearing loss, and D-2-HG not increased in urine or plasma; the authors called for more cases to confirm the association, and the variant has no ClinVar record [65, 67]. A fetus with growth restriction and skeletal, cerebral and vascular anomalies had a de novo IDH1 variant, and germline IDH1 variants are associated with a distinct, exceptionally rare severe developmental syndrome [4, 64]. Hirabayashi and colleagues described constitutional IDH1 abnormalities combined with secondary variants in a child with Maffucci syndrome and acute lymphoblastic leukaemia [68].

Poll and colleagues sequenced the exome or genome from blood or saliva of 94 unrelated probands (71 with Ollier disease and 23 with Maffucci syndrome; 68 trios) and found rare variants (allele frequency <1%) in six genes of the hypoxia-inducible factor 1 (HIF-1) pathway — HIF1A, VHL, IDH1, IDH2, KDM4C and CDKN2A — in 21 of the 94 (about 20% of those with Ollier disease and 30% of those with Maffucci syndrome) [8]. Two probands with glioma had de novo mosaic IDH1 p.(Arg132His) in saliva (VAF of 37% and 39%), and burden analysis against 2054 controls showed enrichment in HIF1A, VHL and IDH1 [8]. Most of the HIF1A, VHL and IDH2 variants were, however, inherited from an unaffected parent and several have gnomAD frequencies of the order of 10⁻³ (for example, IDH2 NM_002168.4:c.1304C>T p.(Thr435Met), 3.61×10⁻³, in two probands), so they do not demonstrate causality; the AACR considers that these findings require further validation [8, 13]. None of the 94 probands had variants in PTPN11, ACP5, NKX3-2 or PTH1R [8].

2.7. The PTH1R controversy

Sources differ on the role of PTH1R (3p21.31; OMIM 168468). Orphanet associates Ollier disease with germline loss-of-function variants in this gene, and the AACR mentions them among the germline findings reported [1, 13]. The Spranger atlas considers its pathogenic role uncertain, and GeneGuidance does not attribute Ollier disease to the gene [2, 69]. OMIM describes the findings of Hopyan and of Rozeman in the text of the gene entry, but does not include Ollier disease in the PTH1R gene–phenotype relationship table, which contains only Blomstrand chondrodysplasia (AR), Eiken syndrome (AR), primary failure of tooth eruption (AD) and Jansen metaphyseal chondrodysplasia (AD) [50]. The primary evidence favours the second position: the original variant, NM_000316.3(PTH1R):c.448C>T p.(Arg150Cys), was not confirmed in 26 patients and is classified in ClinVar as benign or likely benign [7, 65]; Couvineau’s loss-of-function variants appeared in 5 of 31 enchondromas, two of them only in the tumour [51]; the Pansuriya series, which cites a previous frequency of about 8% of PTH1R variants in Ollier disease and none in Maffucci syndrome, found no PTH1R variants in exons 4, 5 and 9 in 35 patients, nor gains or losses of the gene on high-resolution arrays [17]; and Poll found no PTH1R variants in 94 probands [8]. The reading these sources support is that PTH1R is not an established cause of IDH-related enchondromatosis, although it may possibly modulate growth plate signalling in a small subgroup; the well-established germline diseases of the gene are others: Jansen metaphyseal chondrodysplasia (activating variants), Blomstrand chondrodysplasia (biallelic loss), primary failure of tooth eruption (heterozygous loss) and Eiken syndrome (biallelic hypomorphic variants) [50, 69].

2.8. Allelic disorders and IDH-associated somatic tumours

The same substitutions occur as somatic events in several sporadic neoplasms. IDH1 codon 132 variants are present in more than 70% of grade 2 and 3 astrocytomas and oligodendrogliomas and of secondary glioblastomas, with a better prognosis [4]; in the 2021 WHO classification of central nervous system tumours (CNS5), IDH status separates IDH-mutant astrocytoma (grades 2–4, often with loss of ATRX; homozygous deletion of CDKN2A/B confers grade 4), IDH-mutant, 1p/19q-codeleted oligodendroglioma (grades 2–3) and IDH-wildtype glioblastoma [70]. A 2026 review estimates the frequency of mutant IDH at about 73% of gliomas, 56% of chondrosarcomas, 13% of cholangiocarcinomas and a fraction of AML, and recognises a definitive prognostic impact only in glioma [61]. In intrahepatic cholangiocarcinoma, IDH1 variants appear in 8–20% of tumours depending on the series [71]. The OMIM entry on glioma susceptibility brings together data useful for interpreting the gliomas of enchondromatosis: Yan and colleagues (2009), in 445 central nervous system tumours, found IDH1 codon 132 variants in more than 70% of grade II and III astrocytomas and oligodendrogliomas and in the glioblastomas derived from them; De Carli and colleagues (2009) observed IDH1 variants in 38% of adult gliomas (155 of 404) and in 5% of paediatric gliomas (4 of 73); and, in 764 gliomas, Labussière and colleagues (2010) found that almost 90% of the variants were p.R132H, unlike in enchondromas, in which p.R132C predominates [18, 72]. The low frequency of IDH1 variants in sporadic paediatric gliomas contrasts with the occurrence of gliomas at a young age in patients with enchondromatosis [14, 72].

Germline IDH2 variants cause a different disease. The heterozygous gain-of-function substitution at Arg140 (NM_002168.4:c.419G>A p.(Arg140Gln), VCV000014716) causes D-2-hydroxyglutaric aciduria type II (OMIM 613657), autosomal dominant and almost always de novo, with mosaic cases [5, 65, 73, 74]. In 15 patients with type II aciduria, all had this substitution or another at position 418 [60]. The study that defined type II, by Kranendijk and colleagues (2010), sequenced IDH1 and IDH2 in 17 unrelated patients with D-2-hydroxyglutaric aciduria without a D2HGDH variant: none had an IDH1 variant, and 15 had a heterozygous IDH2 variant, 14 p.(Arg140Gln) and 1 NM_002168.4:c.418C>G p.(Arg140Gly) [6, 59, 74]. The variant was not found in 8 of 9 parent pairs studied; in one family, the mother, with normal urinary D-2-hydroxyglutaric acid and somatic mosaicism in blood, had germline mosaicism, and three affected pregnancies were diagnosed by the increase in the acid in amniotic fluid [74]. Nota and colleagues described in 2013 a patient with de novo mosaicism for p.(Arg140Gln) and a patient who inherited the variant from an unaffected mother who was a mosaic carrier [59]. The same p.(Arg140Gln) substitution occurs as a somatic event in AML [59]. Type I aciduria results from biallelic D2HGDH variants (2q37.3) [73]. A germline IDH2 variant does not imply hereditary cancer risk, and a somatic variant found in a tumour is not a hereditary finding [5].

2.9. Genes of the remaining members of the class

PTPN11 (12q24.13) encodes the SHP2 phosphatase; germline gain-of-function variants cause Noonan syndrome and Noonan syndrome with multiple lentigines, whereas loss-of-function variants and intragenic or splicing deletions cause metachondromatosis, which is autosomal dominant; some patients have no variant identified, which indicates heterogeneity [47, 75]. In the series of Bowen and colleagues (2011), the variant was identified in 11 of 17 families (5 frameshift, 2 nonsense, 3 splicing and a 15 kb deletion spanning exon 7, detected only by copy number analysis), each family with a different variant, scattered across the gene; the microdissected lesions of 2 patients had loss of heterozygosity of the normal allele, which points to a somatic second-hit mechanism, typical of a tumour suppressor gene; one family and 5 sporadic cases remained without an identified variant [28]. OMIM classifies metachondromatosis as autosomal dominant with incomplete penetrance [28]. ACP5 (19p13.2) encodes tartrate-resistant acid phosphatase (TRAP); biallelic loss impairs resorption of calcified cartilage in the growth plate and dysregulates osteopontin phosphorylation, with skeletal and immune consequences, which explains SPENCD [76, 77]. NKX3-2 (4p15.33) encodes a homeodomain transcription factor; biallelic loss produces spondylo-megaepiphyseal-metaphyseal dysplasia, with a severe defect of vertebral ossification and abnormal differentiation of the epiphyses of the tubular bones [38, 39]. The gene, homologous to Drosophila bagpipe (former symbol BAPX1), has 2 exons and encodes a protein of 333 amino acids; it is expressed in the mesenchymal condensations of the axial skeleton and limbs in the fetus and, in adults, mainly in chondrocytes and the intestine; in the mouse embryo it is one of the earliest markers of the sclerotome, the precursor of the vertebrae [78]. The variants described in SMMD are homozygous and inactivating: three frameshift variants in exon 1 in three consanguineous families (Hellemans and colleagues, 2009) and a 2 base pair deletion in exon 2, NM_001189.4(NKX3-2):c.507_508del p.(Gly171CysfsTer55), with a premature stop codon, in a Turkish newborn (Simsek-Kiper and colleagues, 2019), classified in ClinVar as pathogenic or likely pathogenic (VCV000522597) [37, 65, 78]. COL2A1 (12q13.11) is the gene for dysspondyloenchondromatosis, which the Spranger atlas treats as a peculiar manifestation of the type II collagenopathies [2, 79]. The de novo 12p11.23–p11.22 duplication that includes PTHLH (12p11.22), the PTH1R ligand, causes a generalised, symmetrical enchondromatosis with dominant transmission [36]. Genochondromatosis, carpotarsal osteochondromatosis and Upington disease still have no known molecular basis [41, 43, 46].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and what they measure

The natural history of Ollier disease and Maffucci syndrome rests on four types of data, with different biases. The European cohort of Verdegaal and colleagues gathered 144 patients with Ollier disease and 17 with Maffucci syndrome from 13 musculoskeletal oncology centres and a national database, all members of the European Musculoskeletal Oncology Society (EMSOS), which favours patients referred for suspected tumour [15]. The literature review of El Abiad and colleagues (160 Ollier and 199 Maffucci patients described up to 2017) tends to overestimate complications, because severe cases are more often published, whereas the survey by the same group (162 respondents from 27 countries, recruited from private patient groups on social media between 2017 and 2018) tends to underestimate them, because the respondents were young (median 17.6 years in Ollier disease and 39.7 years in Maffucci syndrome) and the data were self-reported, without review of imaging or histology [14]. The survey of Colello and colleagues, published in 2026 (123 evaluable responses, 109 Ollier and 14 Maffucci), has the same limitations [80]. Almost all these patients underwent surgery, so the figures describe the disease under usual orthopaedic care and not a natural history without intervention.

3.2. Age at presentation

Lesions usually appear between the 2nd and 10th years of life and may be visible at birth [2]. In the literature review, the median age at diagnosis of enchondroma was 7 years in Ollier disease (range 0–58; mean 11.6) and 11 years in Maffucci syndrome (0–68; mean 15.6) (p=0.029); the diagnosis was made before 20 years of age in 83.8% and 71.8%, and before 1 year in 8.1% and 7.5%, respectively [14]. In the survey, the medians were 4.8 years (0.2–61.4) and 6.0 years (0.67–54), without a significant difference; 86% of patients with Ollier disease and 71% of those with Maffucci syndrome were diagnosed before 10 years of age [14]. Verdegaal and colleagues recorded mean ages at diagnosis of 12 years in Ollier disease and 11 years in Maffucci syndrome [14]. Lesions appear and grow sporadically until puberty; thereafter, new lesions are exceptional and the cartilage is partly replaced by mature bone [2].

3.3. Skeletal manifestations

Enchondromas affect the metaphyses of the tubular bones and the flat bones, with expansion and cortical thinning, sparing the bones of the skull in the classical form described by the Spranger atlas [2]. The distribution is highly variable and typically asymmetric. In the literature review, lesions were unilateral in 57.8% of patients with Ollier disease and in 46.3% of those with Maffucci syndrome (p=0.045), and the upper limb was involved in 75.7% and 84.6% (p=0.046) [14]. In Ollier disease (location known in 135 of the 160 patients), the most affected sites were the femur (46.6%), tibia (30.4%), humerus (27.2%) and pelvis (20.8%), with the hands (43.7%) more affected than the feet (18.5%), skull in 11.9%, ribs in 7.4% and spine in 1.5%; in Maffucci syndrome (175 of 199), femur 29.1%, tibia 25.7%, humerus and ulna 19.4% each, hands 62.9% and feet 28.6% [14]. In the survey, 63.4% of patients with Ollier disease had five or more enchondromas and 40.4% ten or more, and the hands were involved in 76% [14]. Verdegaal and colleagues classified the 161 patients into three distribution groups, which have prognostic value: group I, hands and feet only (18%); group II, long bones only, including scapula and pelvis (39%); group III, small and long or flat bones (43%); 59% of patients with Ollier disease had unilateral disease and 62.5% of those with Maffucci syndrome bilateral disease [14, 15]. A columnar radiological pattern of the lesions has been described in children [81].

Non-malignant complications are the main cause of morbidity in childhood: multiple swellings of the hands and feet, periarticular deformity and joint limitation, bone shortening with limb length discrepancy and altered gait, scoliosis, pain, loss of function and pathological fractures; facial asymmetry and cranial nerve palsies have also been described [2, 13, 14]. Asymmetric shortening, joint deformity and massive swelling of the digits may cause considerable disability, and residual defects in adults include deformity, asymmetric shortening of the long bones and foci of incompletely calcified cartilage in the metaphyses [2]. In the Colello survey, 89% of patients had undergone surgery at least once, with a mean age of 9.1 years at first surgery and a mean of 7.6 operations per patient; the most common indications were correction of limb length discrepancy or deformity of the lower limbs and resection of symptomatic enchondromas [80]. A systematic review of chronic pain and fatigue in multiple osteochondromas and Ollier disease (63 studies, 1252 participants, mainly case reports, no randomised trials) found quantitative data almost only for multiple osteochondromas (chronic pain in 80–95% of adults and 54–64% of children) and limited evidence for Ollier disease [82].

3.4. Vascular manifestations of Maffucci syndrome

The vascular lesions of Maffucci syndrome are soft, dark, irregularly shaped nodules in the skin and subcutaneous tissue, often with phleboliths visible on radiographs; Orphanet also mentions lymphangiomas, which are less frequent [3, 19]. In ISSVA terminology, the diagnostic lesions are venous malformations and spindle cell haemangiomas; in the systematic review of Fang and colleagues, of the 220 patients described in 183 primary reports, only 36 (16%) had a vascular diagnosis compatible with a specific ISSVA label: 9 (4%) venous malformations and 23 (11%) spindle cell haemangiomas without venous malformation, which shows that either lesion can support the diagnosis [16]. In the El Abiad review, the vascular anomalies were unilateral in 57.9%, involved the upper limb in 70.2% and the lower limb in 51.5%, and were visceral in 15.8% (only visceral in 2%, diagnosed by MRI or autopsy); lesions of the meninges, tongue and oral mucosa have been described [14]. The vascular anomalies were diagnosed before 1 year of age in 13.1% (literature) and 14.2% (survey), with a median age at diagnosis of 13 and 9 years; they preceded the enchondromas in 8.7% and 26.9%, and appeared a median of 2 to 3 years after them, which means that many patients with Maffucci syndrome are initially classified as having Ollier disease [14]. These figures contradict the idea, cited in earlier literature, that a quarter of Maffucci cases would be recognised at birth [14]. Malignant transformation of vascular lesions was recorded in 8.5% of patients with Maffucci syndrome in the literature review and in none in the survey [13, 14]. In a Korean girl with histologically confirmed haemangiomas on the palm, sole and face, investigation of mild anaemia and faecal occult blood revealed haemangiomas of the hypopharynx and ascending colon, an uncommon location in Maffucci syndrome (Lee and colleagues, 1999) [11]. A 2024 report described type B aortic dissection with rupture of a thoracoabdominal aneurysm in the postpartum period of a woman with Maffucci syndrome and a negative aortic disease genetic panel; the authors themselves consider the association conjectural [83].

3.5. Secondary chondrosarcoma

Transformation of an enchondroma into chondrosarcoma is the most feared complication. In the Verdegaal cohort, the overall incidence of chondrosarcoma was 40% (n=161): 4 patients (15%) in group I, 27 (43%) in group II and 26 (46%) in group III; pelvic location was associated with a higher risk (odds ratio 3.8; p=0.001) and the authors stressed that the lifetime risk may be higher, because it depends on age [15]. The same cohort recorded chondrosarcoma in 40% of patients with Ollier disease and 53% of those with Maffucci syndrome, at median ages of 33 and 30 years; of the 89 chondrosarcomas, the locations were the femur (20%), phalanges of the feet (15.8%), pelvis (12.4%), humerus and tibia (11% each) and phalanges of the hands (10%) [14]. In the El Abiad review, chondrosarcoma affected 30.6% of patients with Ollier disease and 31.7% of those with Maffucci syndrome, and in the survey 22.2% and 30.5% [14]. Older rates ranged from 20% to 45.8% in Ollier disease and from 52% to 57.1% in Maffucci syndrome, and Liu and colleagues estimated in 1987 the mean age at transformation at 40.5 years [14]. In Maffucci syndrome, Sun and colleagues (1985) described 9 Mayo Clinic patients with chondrosarcoma and estimated, from the English-language literature published since 1973, an incidence of 17.8%; Kaplan and colleagues (1993), from 2 of their own patients and 63 published cases, proposed 30%, and concluded that the syndrome is not hereditary and affects both sexes and all ancestries; OMIM considers these estimates subject to selection bias, because patients with malignant transformation more readily come to attention and publication [11]. The AACR consensus summarises transformation as occurring in about 30% of patients, in any bone, mainly the femur, tibia, humerus, pelvis and scapula, at a median age of 30–52 years and with cases from 10 years of age [13]. In the Colello survey, 19% of patients had developed chondrosarcoma, 35% of them at the site of previous surgery, and 4 had metastatic disease, two of whom had previously had an intramedullary nail placed [80]. Local pain is typical but not constant: there are asymptomatic chondrosarcomas and painful benign enchondromas, and an increase in the size of a lesion should also raise concern; reactivation of growth in an adult should be considered malignant transformation until proven otherwise [2, 13]. Secondary chondrosarcomas are usually low grade and rarely metastasise [13].

3.6. Other neoplasms

IDH mosaicism extends to non-skeletal tissues, and the tumour spectrum goes beyond chondrosarcoma. In the literature review, the prevalence of any malignant neoplasm was 53.1% in Ollier disease and 48.7% in Maffucci syndrome (p=0.409), at a median age at diagnosis of 25 and 30 years [14]. In the survey, the prevalences were 25.4% and 36.1% [14]. The table summarises the non-chondral neoplasms described.

Leukaemia is rare in these patients, despite the frequency of IDH1/IDH2 variants in sporadic AML [13]. The association with juvenile granulosa cell tumour was described in 1984 (Tamimi and Bolen) and in 1986 (Vaz and Turner), the latter with precocious pseudopuberty; OMIM also records a case of fibromuscular dysplasia of the intracranial arteries in a patient with Ollier disease (Slagsvold and Larsen, 1977) [9]. The Spranger atlas, in 2018, reported that in Maffucci syndrome the incidence of intra- and extraskeletal tumours, including intracranial neoplasms, had been described as up to 30%, and that the true incidence of central nervous system tumours remained to be determined [2].

3.7. Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria

MC-HGA manifests in the first year of life, with swelling of the finger joints and, sometimes, mild psychomotor delay; mild to moderate short stature (height between the 3rd and 10th centiles), short hands and feet with “beaded” fingers, prominent large joints, high forehead, narrow palate and, in some patients, scoliosis appear later; final height is not known [27]. Radiographs show mild to moderate generalised platyspondyly, generalised, symmetrical enchondromatosis with marked involvement of the hands, feet and knees, and small ilia with eroded iliac crests and acetabular roofs [27]. Spondyloenchondromatosis with D-2-hydroxyglutaric aciduria was initially described in three patients born to consanguineous unions, which suggested recessive inheritance before IDH1 mosaicism was identified [52, 60]. The first patients described show the breadth of the phenotype. Talkhani and colleagues (2000) described an English girl with macrocephaly, short stature, global developmental delay, alopecia, abnormal tooth eruption, large corneas, thoracic and thoracolumbar scoliosis, rhizomelic shortening, lateral subluxation of the femoral heads and bulbous distal femoral metaphyses with islands of unossified cartilage; Honey and colleagues (2003), a South African infant with shortening of the long bones of the lower limbs, severe speech delay, hypotonia, cutaneous hyperpigmentation in whorls and streaks, extensive metaphyseal radiolucencies at 17 months and brain anomalies on MRI (ventriculomegaly, cavum septi pellucidi and cavum vergae, small posterior fossa); and Bayar and colleagues (2005), a 17-month-old boy with a waddling gait, swollen joints, severe metaphyseal ossification defects and normal mental development, with normal calcium, phosphate and alkaline phosphatase and repeated excretion of 2-hydroxyglutaric acid, authors who proposed the designation metaphyseal enchondrodysplasia with 2-hydroxyglutaric aciduria [24]. Among Vissers’ patients, the carrier of p.R132H had growth retardation, macrocephaly, facial dysmorphism, shield chest, lumbar scoliosis and a lymphangioma of the base of the tongue at 6 months; the carrier of p.R132S had an ostium secundum atrial septal defect and a ventricular septal defect, left renal agenesis, joint contractures, hypotonia, severe psychomotor delay, nystagmus, microcephaly, white matter and cerebellar anomalies and marked tortuosity of the intracerebral vessels [24]. The molecular diagnosis may take decades, as in a case published in 2024, resolved 22 years after investigation began [93].

3.8. Remaining members of the class

Metachondromatosis combines enchondromas, often striated, in the long tubular bones, the iliac crests and above all the short tubular bones, with exostoses that point towards the neighbouring joint; the spine is normal, as is stature, most lesions regress by the end of adolescence with little or no residual deformity and severity varies within the same family; peroneal nerve palsy due to lesions of the fibular head and aseptic necrosis of the femoral head may occur [47]. Maroteaux named it in 1971, from two families with radiological features of multiple exostoses and Ollier disease [28]. The reports of Kennedy (1983) and of Bassett and Cowell (1985) add that the exostoses, unlike those of hereditary multiple exostoses, do not cause shortening or bowing of the long bone, joint deformity or subluxation; that the enchondromatous lesions affect the iliac crest and the metaphyses of the long bones of the lower limbs, with metaphyseal striations; and that, in a 9.5-year-old child with swellings of the hands, feet and knees from 5 years of age, some lesions grew and others appeared while some regressed, with a mother with a milder course (a single exostosis of the wrist) [28]. In another family, the mother of two patients had had exostoses in childhood that regressed, and in adulthood radiographs showed only a widened proximal humerus and a thin first metatarsal, which illustrates how a carrier parent may go unnoticed [28]. Genochondromatosis type 1 is characterised by small, bilateral, symmetrical lesions in the clavicle (with widening of the medial end), proximal humerus and distal femur; type 2 has normal clavicles and symmetrical, generalised metaphyseal enchondromas, mainly in the distal femur, proximal humerus, wrists, hands and feet; in both, the lesions regress in adulthood, stature is normal and the course is benign, with intermittent knee pain in some patients [33, 34, 46]. Type 1 was described by Le Merrer and colleagues (1991) in a mother, a daughter and two sons, and the name alludes to the knee; type 2 was proposed by Kozlowski and Jarrett (1992) in a dominant family without clavicular involvement, with abnormally shaped radius and ulna, coxa vara and square vertebral bodies; Isidor and colleagues (2007) described a 12-year-old boy with metaphyseal lesions in bands parallel to the long axis of the bone, parents with normal radiographs (which suggests a de novo variant), and considered that the three-generation family with “expansile bone lesions” of Dinulos and colleagues (1999; OMIM 603439) might represent a variable form of the same disease [32, 94]. SPENCD combines short stature, platyspondyly, short, broad ilia and small enchondromas in the metaphyses of the long bones or in the pelvis, without secondary deformities, with neurological involvement (spasticity, intellectual disability, cerebral calcifications) or autoimmune involvement (immune thrombocytopenic purpura, systemic lupus erythematosus, haemolytic anaemia, thyroiditis); the course depends mainly on the immune and neurological manifestations, which are highly variable even within the same family and do not correlate with radiological severity [31, 76]. Roifman and Melamed (2003) described the association of combined immunodeficiency, autoimmunity and spondylometaphyseal dysplasia in 4 patients, two of them siblings, children of first cousins of Portuguese ancestry, with recurrent infections, immune thrombocytopenic purpura, hypothyroidism, pulmonary fibrosis and, in the brother, fatal encephalitis at 3.5 years; Renella and colleagues (2006), in 10 patients from 6 families, found neurological manifestations in 7 and autoimmune manifestations in 6, in different combinations within the same family [30]. In the compilation of Briggs and colleagues (2016), with 26 patients from 18 families, 22 had autoimmune disease, age at onset ranged from birth to 15 years and severity ranged from death in infancy due to autoimmune thrombocytopenia to an isolated skeletal dysplasia in a 36-year-old woman; all ACP5 variants were presumed null, with no TRAP expression in blood [30]. The extremes of the spectrum include a 9-year-old girl with spasticity, multisystem inflammation, autoimmunity and immunodeficiency and minimal metaphyseal changes (Girschick and colleagues, 2015) and two Turkish siblings with dysplasia without immune or neurological dysfunction (de Bruin and colleagues, 2016); Bilginer and colleagues (2016) gathered 12 cases of systemic lupus erythematosus associated with SPENCD and recommended that the disease be considered in the presence of lupus with short stature and skeletal changes [30]. Vertebral lesions may regress with cartilage maturation: in a mother followed up to 42 years of age, the lytic lesions disappeared, leaving mild platyspondyly (Bhargava and colleagues, 2005) [30]. Dysspondyloenchondromatosis combines anisospondyly and vertebral and metadiaphyseal enchondromas of the long bones, with kyphoscoliosis and asymmetry of the lower limbs [35]. Symmetrical enchondromatosis due to PTHLH duplication affects the tubular bones in a generalised, symmetrical manner [36]. Carpotarsal osteochondromatosis combines dysplasia epiphysealis hemimelica, intracapsular or periarticular chondromas of the knee, extraskeletal chondromas and osteochondromas, with deformity, swelling and joint locking, and Upington disease, described in a single family in 1971, combines Perthes-like pelvic changes, hip and knee arthralgia, enchondromas and ecchondromas [41, 43]. Hensinger and colleagues (1974) described these lesions, in variable combinations, in 7 members of two generations of one family; Maroteaux and colleagues (1993) observed the same picture in a mother and son, with swelling and stiffness of the ankle at 16 years, a palmar mass of the wrist and locking of the knee, and in the mother deformity of the wrist since adolescence; the authors considered it distinct from dysplasia epiphysealis hemimelica, which is usually sporadic, which changes counselling [40]. The Upington disease family, from the Upington district in the Cape Province (South Africa), had affected members in 5 sibships and 3 generations, with father-to-son transmission (Schweitzer and colleagues, 1971) [42].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In an infant, symmetrical swelling of the finger joints, “beaded” fingers that spare the thumb, short stature and mild psychomotor delay raise the possibility of MC-HGA, which is confirmed by D-2-hydroxyglutaric aciduria and generalised radiological changes [27]. In a child between 2 and 10 years of age, the typical picture of Ollier disease is that of swellings of the hands or feet, progressively worsening lower limb length discrepancy, angular deformity or pathological fracture through a radiolucent metaphyseal lesion; asymmetric or unilateral distribution is a strong clue [2, 14]. The presence of soft, dark nodules in the skin or subcutaneous tissue, mainly on the hands, with phleboliths on radiographs, indicates Maffucci syndrome; because the vascular lesions appear a median of 2 to 3 years after the enchondromas, a diagnosis of Ollier disease in a child should be reviewed if they appear [14, 19]. In adults, the initial presentation may be late, as in the 36-year-old man with palmar nodules and phalangeal enchondromas described by Brown and colleagues, or occur through a neoplastic complication [14, 19].

4.2. Warning signs

The AACR recommends that patients and families be taught to seek care in the event of rapid growth of a mass, persistent pain or other unexplained symptoms, and that a high index of suspicion be maintained at any age [13]. There is no newborn screening for any enchondromatosis.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical and radiological criteria

There are no validated formal diagnostic criteria. The diagnosis is clinical and radiological, and the AACR recommends that alternative diagnoses be considered systematically [12, 13]. The most widely used operational criteria are those of El Abiad and colleagues: at least three enchondromas for Ollier disease; at least three enchondromas and vascular anomalies for Maffucci syndrome [14]. In Maffucci syndrome, the vascular lesion should be characterised according to the ISSVA (venous malformation or spindle cell haemangioma), since either supports the diagnosis [16]. The Spranger atlas describes the cardinal radiological findings: oval, linear or pyramidal radiolucent defects in the metaphyses of the tubular bones and in the flat bones, often with expansion and cortical thinning and asymmetric location, sparing the bones of the skull; shortening and secondary deformities of the affected bones; and, occasionally, slightly irregular vertebral bodies [2]. The atlas figures illustrate the typical lesions: in a 6-year-old child, diaphyses of the short tubular bones expanded by sharply marginated radiolucent swellings, with thinned or absent cortex and an asymmetric distribution that spares the right hand, and shortening of the left femur and tibia with cystic metaphyseal masses and calcified inclusions; in an 11-year-old child, chondromas with irregular calcifications in the metacarpals and phalanges; and, in a 4-year-old child with Maffucci syndrome, ovoid vertebral bodies with anterior beaking and cystic lesions in the iliac crests, ischium and proximal femora [2]. Histology has a limited role in the diagnosis of enchondromatosis and is mainly needed when malignancy is suspected [12].

5.2. Imaging: staging and detection of transformation

Whole-body MRI is the recommended baseline examination to map the bone lesions and vascular anomalies, with targeted MR angiography when the latter are present; bone scintigraphy, with focused radiographs of each enchondroma, is the alternative where whole-body MRI is not available [13]. A 2026 paediatric report compared positron emission tomography with 18F-sodium fluoride and with 18F-fluorodeoxyglucose for baseline mapping [95]. MRI is the examination of choice to distinguish enchondroma from low-grade chondrosarcoma, computed tomography (CT) helps in difficult regions such as the pelvis and scapula, and needle biopsy may be necessary [14]. In a study from the Royal National Orthopaedic Hospital (Stanmore) of 59 lesions from 41 patients with enchondromatosis (43 low grade, including enchondromas and grade 1 chondrosarcomas, and 16 high grade), bone oedema, periosteal reaction and soft tissue oedema were associated with high-grade transformation; cortical destruction and a soft tissue mass were predictors in the larger long bones, and there were no discriminating features in the hands and feet [96]. The UK bone sarcoma guideline states that needle biopsy is less accurate in grading chondral tumours and that dynamic contrast-enhanced MRI can identify the high-grade areas to be sampled [20]. The SELNET (Sarcoma European and Latin American Network) guideline points out that grading of chondrosarcoma is difficult and requires radiopathological correlation, and that pain in a cartilaginous lesion should raise suspicion of malignancy [55].

5.3. Molecular tests: material, techniques and limitations

The material of choice is lesional tissue: enchondroma, spindle cell haemangioma or associated tumour. Blood is usually negative, because the variants are absent or below the detection limit outside the lesions; therefore, a negative result in blood does not exclude the disease [4, 17, 18]. The exceptions are the forms with widespread mosaicism, MC-HGA and the intermediate phenotype, in which the variant may be detected in blood [52, 56]. Sensitivity depends on the technique: Sanger sequencing missed variants in eight Ollier tumours that showed only subthreshold peaks, seven of which were confirmed by a hydrolysis probe assay with a 1% mutant allele limit [17]; NGS detected VAFs of 14% to 45% in paediatric enchondromas [62]; and digital PCR (ddPCR), with a lower limit of 0.1%, quantified p.(Arg132Cys) at 17.3% in a haemangioma and confirmed the absence of the variant in blood [19]. Immunohistochemistry with the H09 antibody detects only IDH1 p.R132H (with cross-reactivity with p.R132L, = NM_005896.4:c.395G>T p.(Arg132Leu)) and is negative for p.R132C, the most frequent variant; in the Pansuriya series only 25% of the 68 Ollier tumours were positive, so negative immunohistochemistry does not exclude an IDH variant [17, 62]. About 20% of patients remain without an identified variant even with sensitive techniques, because of mosaicism below the limit or another cause [13, 17]. SELNET accepts testing for IDH variants as an option when imaging suggests chondrosarcoma, because these variants distinguish central cartilaginous tumours from other lesions (level of evidence III, grade of recommendation C) [55, 57]. In practice, the test is little used: in the El Abiad survey, only 17 of the 162 patients had been tested [14]. Germline IDH1 testing does not guide the use of IDH inhibitors, which requires tumour testing [4].

The report should state the tissue studied, the gene, the transcript with its version (NM_005896.4 or NM_002168.4), the variant in HGVS c. and p. notation, the VAF, the detection limit of the technique and the somatic classification according to the standards of the Association for Molecular Pathology, American Society of Clinical Oncology and College of American Pathologists (AMP/ASCO/CAP), in which IDH1 Arg132 variants are tier I [65]. An IDH1/IDH2 variant in somatic mosaicism has no germline zygosity or Mendelian classification according to the American College of Medical Genetics and Genomics and the AMP (ACMG/AMP), and the report should avoid suggesting a hereditary risk [5]. When the variant is found in blood, the VAF helps to distinguish mosaicism (for example, 22% in blood in the intermediate phenotype and 37–39% in saliva in two of Poll’s probands) from a heterozygous germline variant, and confirmation in another tissue, such as cultured fibroblasts, is useful when the blood has been altered by transplantation [8, 56, 64].

5.4. Biochemistry: D-2-hydroxyglutarate

D-2-hydroxyglutaric aciduria supports the diagnosis of MC-HGA [4, 25]. Conventional gas chromatography–mass spectrometry detects 2-hydroxyglutarate but does not separate the D and L enantiomers, which requires chiral derivatisation or a chiral stationary phase [73]. The reference method is liquid chromatography–tandem mass spectrometry with isotope dilution after derivatisation with diacetyl-L-tartaric anhydride, with inter- and intra-assay coefficients of variation of 3.4–6.2% and a detection limit of 20 pmol in 20 µL of urine [5]. D-2-HG may also be increased in multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type II) and, rarely, in glutaric aciduria type I and succinic semialdehyde dehydrogenase deficiency, which can be distinguished by the organic acid profile [73]. A normal level does not exclude an IDH1 variant, as shown by the family with germline p.(Arg100Gln) [4, 67]. In Ollier disease without widespread mosaicism, urinary measurement is exploratory: in the Belgian patient with previous AML, total 2-HG was 160 mmol/mol creatinine (about 10 times the reference range of 6–17 mmol/mol), 93.8% in the D form, in a single sample collected after transplantation [64].

5.5. Exclusion of genetic differential diagnoses

El Abiad and colleagues recommend, depending on the type of lesions, the associated findings and the family history, sequencing of PTPN11, EXT1, EXT2, ACP5 and/or NKX3-2 to exclude metachondromatosis, multiple exostoses, SPENCD and spondylo-megaepiphyseal-metaphyseal dysplasia; an array for deletions and duplications (which detects, for example, the 12p11 duplication with PTHLH); and urinary organic acid analysis for hydroxyglutaric aciduria [14, 36]. In metachondromatosis, PTPN11 sequencing should be complemented by testing for intragenic deletions, because a 15 kb deletion of exon 7 was only detected by copy number analysis; even so, 6 of 17 families remained without a variant in the Bowen series, so a negative result does not exclude the diagnosis [28]. The recommendation applies mainly to symmetrical or familial forms or those with vertebral, immune or neurological involvement, since typical Ollier disease, asymmetric and sporadic, has a reliable clinical and radiological diagnosis.

5.6. Algorithm

5.7. Prenatal and preimplantation diagnosis

Ollier disease and Maffucci syndrome have no indication for prenatal or preimplantation diagnosis, because there is no germline variant to test for and no documented familial recurrence in the series with molecular study [8, 17]. MC-HGA manifests in the first year of life [27]. In the Mendelian members of the class, prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known (PTPN11, ACP5, NKX3-2, COL2A1) [44]; in spondylo-megaepiphyseal-metaphyseal dysplasia, the disease may already manifest on prenatal ultrasound [39].

6. Differential Diagnosis

6.1. Comparative table

6.2. Differential diagnosis within the class

The distinction between Ollier disease and MC-HGA is one of distribution and chronology: MC-HGA is the same disease in a more generalised and symmetrical form, recognised in infancy and accompanied by platyspondyly and aciduria, whereas Ollier disease has isolated, asymmetric, non-systemic lesions, with later onset [2, 27]. Genochondromatosis is distinguished by less severe, symmetrical and regressing lesions, a normal spine and dominant transmission; in Ollier disease the lesions are asymmetric or unilateral, inhibition of limb growth is common and the lesions do not regress [46]. Metachondromatosis combines enchondromas and exostoses pointing towards the joint, with a normal spine and spontaneous regression [27, 47]. In SPENCD, the metaphyseal lesions are more subtle and the platyspondyly, often more severe, shows central depression of the end plates; autoimmunity and cerebral calcifications guide the diagnosis; axial spondylometaphyseal dysplasia and the Kozlowski type are additional differential diagnoses [27, 76]. The cases with relatively symmetrical lesions and mild vertebral irregularities, formerly grouped as dysspondyloenchondromatosis, are manifestations of COL2A1 variants [2, 79].

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is included in the differential diagnosis proposed by the AACR and by El Abiad, but the sources assign it different OMIM numbers: the AACR gives number 609616 and El Abiad number 613330 [13, 14]. The Spranger atlas, the GeneGuidance database and Orphanet (ORPHA:228387) use number 613330 for this autosomal recessive dysplasia due to NKX3-2, and the OMIM index confirms that entry 613330 corresponds to SMMD, whereas 609616 is another entity, spondylo-megaepiphyseal dysplasia with upper limb mesomelia, punctate calcifications and deafness, described in a single patient by Agarwal and colleagues (2005), without molecular study, with marked mesomelic shortening of the upper limbs, punctate calcifications of the distal ulnar epiphysis and the pubis, megaepiphyses, platyspondyly, progressive sensorineural hearing loss and retinal detachment [99]; OMIM entry 613330 describes SMMD as autosomal recessive due to NKX3-2 (4p15.33), so this number is adopted [10, 37–39]. SMMD is rare in the practice of the differential diagnosis of enchondromatosis, because it is recognised at birth or on prenatal ultrasound by the severe defects of vertebral ossification and because the ossification pattern of the hand, with multiple pseudoepiphyses, is almost pathognomonic from 2–3 years of age; its own differential diagnoses are cleidocranial dysplasia (which has hypoplastic clavicles and a normal spine) and achondrogenesis type 2 (with short tubular bones) [39]. The resemblance to enchondromatosis comes from the original description by Silverman and Reiley (1985), in 8 patients: the striations of the femoral metaphyses resembled those of enchondromatosis and the costochondral junctions of the 5th to 7th ribs had enchondroma-like widening; the hand showed markedly delayed carpal centres, enlarged and advanced metacarpal and phalangeal centres and large, multiple pseudoepiphyses [37]. The short stature is of the short-trunk type, with relatively long limbs, a short, stiff neck and flexion contractures of the distal joints; the vertebrae have preserved pedicles and neural arches, often unfused posteriorly, ossification of the pubis is late, the triradiate cartilage is wide and there is coxa vara with large femoral epiphyses [37]. In the patients described up to 2009, intelligence was normal, with the exception of one boy [37]. In a Turkish newborn whose parents were from the same village, presentation was perinatal and lethal: respiratory failure with immediate intubation, relative macrocephaly, micrognathia, talipes equinovarus, absent ossification of the vertebral bodies, pubis and ischia and duodenal atresia, with death at 14 days from sepsis and respiratory failure after surgical correction; the authors attributed the neuromuscular respiratory failure to early cervical cord compression, without confirmation by neuroimaging [37].

6.3. Differential diagnosis with multiple exostoses

Multiple cartilaginous exostoses form sessile or pedunculated outgrowths on the bone surface, pointing away from the joint, whereas enchondromas are well-defined intraosseous radiolucencies [2, 47]. Transmission is dominant, with about 10% de novo cases, penetrance close to 100% in men and 96% in women, and the risk of chondrosarcoma, 0.2–5.9%, is much lower than in the enchondromatoses [13]. The distinction has direct consequences for counselling and surveillance, which in multiple exostoses does not include regular radiographs of all lesions [13].

6.4. Differential diagnosis of vascular lesions and overgrowth

In Maffucci syndrome, the vascular nodules may be confused with isolated venous malformations, glomuvenous malformations (GLMN), familial angiolipomatosis and the vascular malformations of PTEN hamartoma tumour syndrome, which are also associated with lipomas [44]. Proteus syndrome, due to a mosaic AKT1 variant, causes asymmetric overgrowth of bone and soft tissues and was confused with Maffucci syndrome in one child [44, 98]. Isolated giant extraskeletal chondroma of the hand is another differential diagnosis of a large cartilaginous mass without enchondromatosis [100]. The presence of multiple intraosseous enchondromas and, on histology, of spindle cell haemangioma with an IDH1 variant separates Maffucci syndrome from these entities [17, 19].

6.5. Metabolic differential diagnosis of D-2-hydroxyglutarate

When 2-hydroxyglutarate is elevated in urinary organic acids, the first step is to determine the enantiomer (D or L); in the D form, D2HGDH and IDH2 are studied, and combined D,L-2-hydroxyglutaric aciduria (SLC25A1) and glutaric aciduria type II are considered [5, 60, 73]. Type I aciduria is recessive and has a variable phenotype, from developmental delay to asymptomatic forms; type II, due to germline IDH2 variants, often presents in the neonatal period with epileptic encephalopathy, severe hypotonia, cortical blindness and dilated cardiomyopathy, and about half of the children die in childhood [73]. In the Kranendijk series, 9 of the 15 patients with an IDH2 variant had died between the first months of life and 14 years of age, and those alive were between 3 and 22 years old; the spectrum ranged from asymptomatic forms to developmental delay, epilepsy, hypotonia, cardiomyopathy and dysmorphism, and mean urinary excretion of D-2-hydroxyglutaric acid was 2153 mmol/mol creatinine in 14 type II patients, versus 969 mmol/mol in 20 type I patients [74]. None of these forms has enchondromas; the combination of aciduria and enchondromatosis is specific to MC-HGA [25].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no approved aetiological treatment for any enchondromatosis. In Ollier disease and Maffucci syndrome, treatment is surgical and directed at complications (limb length discrepancy, deformity, large or symptomatic lesions, pathological fractures and malignant transformation), and oncological surveillance is the main risk management strategy [12–14]. The AACR recommends that orthopaedic surgeons take part in monitoring and treatment, and that patients be followed in centres with experience in bone lesion syndromes [13]. When a chondrosarcoma appears, diagnosis and treatment should be discussed in a bone sarcoma multidisciplinary team [20]. Mutant IDH inhibitors, approved for other neoplasms, are being studied in chondrosarcoma and have been used in isolated cases of enchondromatosis, always outside the approved indications [66, 101, 102].

7.2. Orthopaedic surgery

Excision of enchondromas is indicated for severe functional disability, mainly in the hands and feet, and for suspected malignant change; orthopaedic management includes correction of deformities and limb lengthening, historically by the Ilizarov method with external fixators [2, 103]. Surgery is the only treatment available for limb length discrepancy, large enchondromas and vascular overgrowths, and most patients undergo several operations during their lives (89% with at least one operation and a mean of 7.6 operations in the Colello survey) [14, 80].

Motorised intramedullary lengthening nails are a recent alternative to external fixators. In a retrospective series from four French centres over nine years, eight patients with a mean age of 13.3 years (11–16) underwent lengthening of 8 femora and 2 tibiae, with a mean follow-up of 53.8 months; mean lengthening was 6.44 cm in the femur over 76.8 days and 3.75 cm in the tibia over 44 days, the goal was achieved in all, without mechanical complications, and the authors observed improvement or healing of the medullary canal in 8 of the 10 segments, which they interpreted as a therapeutic effect of reaming on the enchondromas [103]. The series is small and non-comparative. On the other hand, in the Colello survey, 35% of chondrosarcomas arose at the site of previous surgery and two of the four patients with metastatic disease had previously had an intramedullary nail placed; the authors recommend caution in the choice of type of surgery and implants, although the data are self-reported and without centralised histological confirmation [80]. These data do not allow the conclusion that the implant causes transformation.

7.3. Treatment of secondary chondrosarcoma

Secondary chondrosarcoma is treated according to bone sarcoma guidelines, which have no specific recommendations for enchondromatosis. The 2024 UK guideline of the British Sarcoma Group (published in 2025) and the 2022 SELNET guideline agree on the essentials, but differ on the initial approach to atypical cartilaginous tumour of the extremities [20, 55]. The 2021 joint ESMO–EURACAN–GENTURIS–ERN PaedCan guideline on bone sarcomas is the European medical oncology reference, but its text was not accessible in this review [23].

Sources: [20, 55].

Conventional chondrosarcoma is resistant to conventional chemotherapy and radiotherapy, and surgery is the mainstay of treatment [66, 104]. The targets under investigation include IDH, the DR5 apoptotic pathway, the Hedgehog pathway, Src, PI3K-Akt-mTOR, histone deacetylation and angiogenesis [104]. In enchondromatosis, the lesions are multiple and the patient is at risk of new tumours throughout life, which makes it particularly important to preserve function and plan resections in a reference centre.

7.4. Vascular lesions of Maffucci syndrome

Symptomatic venous malformations and spindle cell haemangiomas are treated mainly by surgical excision, as in the patient of Brown and colleagues, operated on for functional impairment of the hand [14, 19]. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used off-label with conflicting results, only in case reports: there was success in combination with surgery in one patient and in one child [105, 106]; in a 23-year-old woman treated with 2 mg/day (0.04 mg/kg/day), pain improved but the colour and size of the nodules did not change, and the drug was stopped at 6 months because of oral aphthae and a mild rise in transaminases [107]; and another report described treatment failure in multiple haemangiomas [108]. There is no established dose for this indication. The reference dose by analogous condition is that of the phase 2 trial of Adams and colleagues in complicated vascular anomalies: oral sirolimus starting at 0.8 mg/m² per dose twice daily, adjusted by pharmacokinetics to serum trough concentrations of 10–15 ng/mL, with no maximum dose defined in the source, assessed after 6 and 12 cycles of 28 days [109]. In that trial, 47 of the 57 evaluable patients had a partial response after 6 cycles and grade 3 or higher toxicity attributable to the drug was mainly haematological (27%), with gastrointestinal and metabolic toxicity in 3% each [109]. Spindle cell haemangioma of Maffucci syndrome was not among the lesions studied, so the extrapolation is stated. For comparison, the US label for oral sirolimus approves it for prophylaxis of kidney transplant rejection from 13 years of age and for lymphangioleiomyomatosis in adults (starting dose 2 mg/day, adjusted to troughs of 5–15 ng/mL; the label limits the daily dose to 40 mg, including the loading dose), with a boxed warning on immunosuppression, infections and lymphoma; in the European Union, Rapamune® has the same systemic indications and Hyftor® (gel) is approved for facial angiofibroma of tuberous sclerosis from 6 years of age [110, 111]. No label includes vascular anomalies or Maffucci syndrome, and the paediatric dose of the Adams trial is outside the conditions of the label.

7.5. Pain

Pain is frequent and multifactorial (growing lesions, deformity, joint overload, fractures, chondrosarcoma) and the first obligation in the presence of new pain is to exclude malignant transformation [13, 82]. The strategies described include surveillance, surgery, physiotherapy and analgesia, without randomised trials [82]. Winston and colleagues treated two children with benign cartilaginous tumours and pain refractory to analgesics, one of them with Ollier disease, with intravenous bisphosphonates, with pain relief and improvement in daily activities; the abstract does not give the doses [112]. The analogous condition with published dose recommendations is fibrous dysplasia of bone, also a mosaic bone lesion disease, whose international consensus proposes intravenous bisphosphonates for persistent bone pain: in children, pamidronate 1 mg/kg on two consecutive days (up to 90 mg in total), repeated at week 8 if there is no response and stopped if there is no response after two cycles, or zoledronic acid 0.025 mg/kg, repeated at week 8 and followed by 0.05 mg/kg at week 24 if there is no response, stopped if there is no response after three doses; the consensus suggests considering calcitriol 20–30 ng/kg/day or alfacalcidol 30–50 ng/kg/day (up to 1 µg/day) and calcium supplements during the four days after the first infusion [113]. Transposing these doses to enchondromatosis is a stated extrapolation, without efficacy data beyond Winston’s case. The labels do not include paediatric use: pamidronate is approved in the United States for hypercalcaemia of malignancy (60–90 mg as a single dose), Paget disease, osteolytic metastases of breast cancer and osteolytic lesions of multiple myeloma, with a maximum single dose of 90 mg because of renal risk; zoledronic acid (Reclast®, 5 mg/year in osteoporosis, single dose in Paget disease) is not indicated in children, and its label records, in a paediatric trial in osteogenesis imperfecta, fever (61%), arthralgia (26%), hypocalcaemia (22%) and headache (22%), mainly in the three days after the first infusion [114, 115].

7.6. Mutant IDH inhibitors

Mutant IDH inhibitors block the neomorphic activity of the enzyme and reduce the production of D-2-HG. Three are approved in the United States with IDH1 as a target: ivosidenib (Tibsovo®), first approved in July 2018 and now indicated in newly diagnosed and relapsed or refractory AML, relapsed or refractory myelodysplastic syndromes (MDS) and previously treated cholangiocarcinoma; olutasidenib (Rezlidhia®), approved in December 2022 in relapsed or refractory AML; and vorasidenib (Voranigo®), an IDH1 and IDH2 inhibitor with central nervous system penetration, approved in August 2024 in grade 2 astrocytoma and oligodendroglioma with an IDH1 or IDH2 variant after surgery [4, 116–119]. Enasidenib (Idhifa®) inhibits mutant IDH2 and is approved in the United States in relapsed or refractory AML with an IDH2 variant [5, 120]. None of these drugs has an approved indication in Ollier disease, Maffucci syndrome or chondrosarcoma, and all require demonstration of the variant in the tumour [4].

The relevance of these drugs to enchondromatosis is twofold. First, patients with enchondromatosis develop tumours with an approved indication: IDH-mutant grade 2 glioma, for which vorasidenib significantly prolonged progression-free survival in the phase 3 INDIGO trial, and, more rarely, AML [4, 70, 121]. Second, IDH-mutant chondrosarcoma is the subject of trials. In the phase 1 trial of ivosidenib in solid tumours (NCT02073994; 168 patients), 21 had chondrosarcoma, 13 of which were conventional; with an expansion dose of 500 mg/day and database lock in March 2024, the objective response rate in conventional chondrosarcomas was 23.1% (95% CI 5.0–53.8%), with one complete response (skull base, 1200 mg/day) and two partial responses, a median duration of response of 53.5 months and median progression-free survival (PFS) of 7.4 months (95% CI 2.0–61.3); 3 patients (23.1%) remained on treatment after more than 7 years [101, 122]. In the phase 1b/2 trial of olutasidenib (NCT03684811; published in January 2026), in 23 patients with advanced IDH1-mutant chondrosarcoma treated with 150 mg twice daily, there were no objective responses (primary endpoint not met): 52% had stable disease and 38% progression, with median PFS of 2.0 months (95% CI 1.7–4.7) and median overall survival (OS) of 16.0 months; in conventional chondrosarcomas, stable disease reached 63% and median PFS 3.5 months [66]. The phase 3 CHONQUER trial (NCT06127407; Servier) compares ivosidenib 500 mg once daily with placebo in adults with locally advanced or metastatic and unresectable grade 1–3 IDH1-mutant conventional chondrosarcoma with documented progression; it has been recruiting since July 2024, plans 156 patients, has a primary endpoint of PFS by independent central review in grades 1–2, allows crossover and includes centres in Brazil and several European countries [21]. A phase 2 trial at Memorial Sloan Kettering (NCT04278781) included 6 patients with grade 2–3 conventional chondrosarcoma and is no longer recruiting [123]. In Portugal, a series of two cases of metastatic or recurrent IDH1-mutant grade 2 chondrosarcoma treated with ivosidenib recorded stable disease for 12 months (a 70-year-old woman, second line) and 16 months (a 63-year-old man, first line), without relevant toxicity [124].

In enchondromatosis itself, the evidence comes down to one case: a patient with Maffucci syndrome treated with ivosidenib for recurrent IDH1-mutant glioma had stabilisation of the glioma and, as a collateral effect, firmer and less painful enchondromas and a marked change in radiographic mineralisation [102]. There is no registered trial of IDH inhibitors specifically in Ollier disease or Maffucci syndrome; the records found on ClinicalTrials.gov are observational [125]. Use in benign enchondromas is controversial because of cost, the need for prolonged treatment in children and adverse effects: cytopenias, elevated liver enzymes, QT interval prolongation, gastrointestinal symptoms, musculoskeletal pain, peripheral neuropathy and, in AML, differentiation syndrome [64]. Brown and colleagues discussed this option with their patient and decided not to start it [19]. The AACR accepts that the impact of early diagnosis combined with targeted therapies may need to be studied and reviewed in the future [13].

7.7. Dosing of the drugs mentioned

7.8. Comparative regulatory status

In Portugal, centrally authorised medicines (Tibsovo® and Voranigo®) follow the European Commission decision; the national SmPC (Infomed) and registration with the Brazilian National Health Surveillance Agency (ANVISA) were not consulted, and none of these drugs has an indication in enchondromatosis in any jurisdiction.

7.9. Interventional trials and studies

None of these studies is a randomised trial in patients with enchondromatosis. The trials of IDH inhibitors in chondrosarcoma include sporadic and secondary tumours without separate analysis of patients with Ollier disease or Maffucci syndrome in the material read, and the wide confidence intervals reflect very small samples. Indirect comparison between the ivosidenib trial (23.1% responses, median PFS 7.4 months) and the olutasidenib trial (no responses, median PFS 2.0 months) is not legitimate, because the populations, histological types and periods differ; the negative result of olutasidenib does show, however, that IDH1 inhibition is not uniformly effective in chondrosarcoma. The response of benign enchondroma to these drugs is unknown, except for the isolated case of Funck-Brentano [102].

7.10. Developments in the last 12 months

Between October 2025 and October 2026 the following data emerged, with different levels of evidence. Published trials: the phase 1b/2 trial of olutasidenib in chondrosarcoma, negative for the primary endpoint (January 2026) [66]. Observational studies and reviews: the Colello survey on surgery and malignancy, with the signal of chondrosarcomas at operated sites [80]; Fang’s systematic review on the terminology of the vascular lesions of Maffucci syndrome [16]; Kwiet’s systematic review on pain and fatigue [82]; and the review on IDH as a tumour-agnostic target [61]. Case reports: primary hyperparathyroidism due to an adenoma with an IDH1 variant in two patients with Ollier disease [64, 88], AML and a parathyroid adenoma with the same variant as an enchondroma [64], juvenile granulosa cell tumour with IDH1 and TENT5C variants [86] and the Portuguese series of ivosidenib in chondrosarcoma [124]. Regulation: European authorisation of vorasidenib (September 2025) and variation decision of August 2026, new US label for vorasidenib (June 2026) and Commission decision on ivosidenib (February 2026) [118, 126, 127]. Ongoing research: CHONQUER recruiting, a genomic and phenotypic study by the National Institute of Child Health and Human Development (NICHD) in 100 patients with Ollier disease and Maffucci syndrome (2025–2030), and a survey by the Istituto Ortopedico Rizzoli on transition from paediatric to adult care (91 participants, completed, no published results) [21, 129, 130]. None of these data changes, for the time being, the surveillance recommendations.

7.11. Risk management: recommendations and discrepancies

Oncological surveillance is the risk management intervention with the greatest potential impact, and its complete table is given in section 11. The reference is the consensus of the 2023 AACR Childhood Cancer Predisposition Workshop, published in 2025: baseline whole-body MRI, deferred until about 6–8 years of age to avoid general anaesthesia if there are no symptoms or worrying lesions; musculoskeletal and neurological physical examination every 6–12 months until adulthood and every 12–24 months in adults; radiographs of known lesions at least every 2–3 years; dedicated annual MRI of lesions >5–6 cm or located in the pelvis or scapula; contrast-enhanced brain MRI in early adolescence, in some centres; and whole-body MRI with dedicated brain MRI every 1–2 years from 20 years of age [13]. The earlier proposal of El Abiad, adapted from Herget, differs on one main point: it starts periodic whole-body MRI (every 2 years) at 25 years in Ollier disease and at 30 years in Maffucci syndrome, the median ages of malignancy in the literature review, and proposes annual whole-body MRI for lesions of the pelvis or scapula or >5–6 cm [14, 131]. Other proposals, cited by Brown, included annual whole-body MRI with dilated ophthalmoscopy twice a year, or cranial MRI every 1–3 years for skull base chondrosarcoma and glioma [19]. The AACR acknowledges that the risk may be inflated by ascertainment bias, as argued by Diezi and colleagues, but considers it high enough to justify surveillance, and calls for studies on the ideal methods and intervals [13, 132]. A Danish programme of annual whole-body MRI (62 patients, 5 with enchondromatosis; 253 examinations) showed feasibility and detected three asymptomatic chondrosarcomas, one of them in a patient with enchondromatosis, with no undetected chondrosarcomas during the period, but did not demonstrate a survival benefit [133]. After treatment of a low-grade chondrosarcoma, the UK guideline proposes visits every 4–6 months for 2 years and then annually, with annual chest surveillance up to 5 years, and SELNET visits every 6 months for 2–5 years and then annually; neither defines a stopping point, because there are recurrences after 10 years [20, 55].

7.12. Other members of the class

In MC-HGA, treatment is symptomatic, as in the other enchondromatoses [27]. In metachondromatosis, surgery is reserved for exostoses that compress nerves (for example, peroneal nerve palsy due to lesions of the fibular head), interfere with function or cause significant deformity, and for some cases of aseptic necrosis of the femoral head; spontaneous regression of the lesions justifies a conservative approach in the others [47]. In SPENCD, treatment is directed at the autoimmune disease and the neurological manifestations, by a multidisciplinary team [76]. In spondylo-megaepiphyseal-metaphyseal dysplasia, treatment is symptomatic and prognosis depends on the cervical myelopathy [39]. Genochondromatosis requires no specific treatment, given its benign and regressive course [46].

7.13. Interactions and drugs to avoid

During treatment with ivosidenib, strong CYP3A4 inducers, sensitive CYP3A4 substrates and other drugs that prolong the QT interval should be avoided; with an unavoidable strong CYP3A4 inhibitor, the adult dose is reduced from 500 mg to 250 mg/day with QT monitoring; ivosidenib may reduce the efficacy of hormonal contraceptives, so alternative methods are recommended [116]. Olutasidenib should not be combined with strong or moderate CYP3A inducers or with sensitive CYP3A substrates [117]. With vorasidenib, effective non-hormonal contraception is recommended [118]. The sources consulted do not identify drugs to be avoided because of enchondromatosis itself.

7.14. Pregnancy, lactation, perioperative care and transition

The sources consulted do not describe series of pregnancy in women with Ollier disease or Maffucci syndrome. One report described type B aortic dissection with rupture in the postpartum period of a woman with Maffucci syndrome; the authors consider that aortic surveillance may be appropriate, but this is a single case and a conjectural association [83]. The three IDH inhibitors can cause fetal harm based on animal studies; the ivosidenib label recommends not breastfeeding during treatment and for 1 month after the last dose, and the olutasidenib label for 2 weeks after the last dose [116–118]. Oncological treatment may compromise fertility: in the Belgian patient, chemotherapy and allogeneic transplantation caused premature ovarian insufficiency, and ovarian tissue was cryopreserved before consolidation [64].

In the perioperative context, the main documented concern is the choice of type of surgery and implants [80]. The AACR recommends deferring the initial whole-body MRI to avoid general anaesthesia in young children [13]. The sources consulted do not provide specific anaesthetic recommendations for patients with the vascular lesions of Maffucci syndrome.

Transition from paediatric to adult care is a weak point: the Belgian patient with AML lost orthopaedic follow-up after transition and had never had whole-body or brain MRI [64]. ERN BOND and the Italian patient association A.C.A.R. devoted a conference in 2023 to a multidisciplinary, shared approach to transition, and the Istituto Ortopedico Rizzoli completed in 2026 a survey of 91 adults with multiple osteochondromas or enchondromatoses on this phase [22, 130]. Because oncological surveillance intensifies from 20 years of age, when the patient has already left paediatric care, transition should include explicit transfer of the surveillance plan [13].

8. Reproductive Options and Family Counselling

8.1. Ollier disease, Maffucci syndrome and MC-HGA

These three entities are sporadic. The Spranger atlas states that no hereditary factor has been demonstrated, the review by Silve and Jüppner described only isolated, non-familial cases, and Poll and colleagues, in the largest germline study (94 probands), recorded no evidence of familial recurrence [2, 8, 12]. The Oxford Desk Reference mentions a few cases of familial occurrence of Ollier disease, without demonstration of Mendelian transmission [44]. OMIM lists these reports, all predating the identification of IDH1/IDH2: two brothers (Steudel, 1892), three siblings (Lamy and colleagues, 1954), a brother and sister whose paternal grandfather was also said to be affected (Rossberg, 1959) and a brother and sister (Carbonell Juanico and Vineta Teixido, 1962), and accepts the possibility of dominant inheritance with reduced penetrance [9]. These cases have no molecular confirmation and may correspond to other members of the class; the family of Halal and Azouz (1991), with a boy with generalised enchondromatosis and a short father with isolated platyspondyly, both children of consanguineous unions, also corresponds to a generalised type and not to typical Ollier disease [9]. The OMIM summary on Maffucci syndrome describes it as sporadic [11]. The mechanism, a postzygotic variant restricted to a somatic cell lineage, does not predict transmission: the risk for siblings and for the offspring of an affected individual is, on current data, considered close to that of the general population [17, 18]. The sources do not provide a validated numerical value for this risk, and the absence of documented cases does not amount to zero risk.

Lopez Delhoulle and colleagues point out that, if the variant arises before gastrulation, the primordial germ cells may be affected, so gonadal involvement and potential transmission cannot be excluded in theory; they therefore propose genetic counselling and discussion of preimplantation genetic diagnosis, a proposal that is not based on any documented case of transmission [64]. The same authors note that germline IDH1 variants are associated with a distinct developmental syndrome, with severe skeletal, cerebral and metabolic anomalies, exceptionally rare, and not with an enchondromatosis [4, 64]. The family with germline IDH1 p.(Arg100Gln) and chondrosarcoma of the mastoid transmitted from mother to children constitutes a distinct phenotype, not an enchondromatosis [67]. The rare HIF1A and VHL variants identified by Poll were mostly inherited from unaffected parents and do not support a recurrence risk [8]. The GenCC entry that assigns dominant inheritance to Maffucci syndrome contradicts the mechanism and should not guide counselling [4].

El Abiad and colleagues recorded that the lack of guidelines led, in many patients, to misdiagnosis and incorrect reproductive counselling [14]. Counselling should therefore explain the postzygotic nature of the disease, the absence of documented familial recurrence, the theoretical uncertainty about gonadal mosaicism and the fact that a negative blood test has no value to exclude or confirm the disease. There is no cascade testing applicable to relatives, because there is no germline variant to test for, and prenatal diagnosis is not indicated [8, 17].

8.2. Mendelian members of the class

The recurrence risks of the remaining members of the class depend on the mode of transmission and should be calculated after molecular confirmation. In metachondromatosis, which is autosomal dominant, each child of an affected individual has a 50% chance of inheriting the PTPN11 variant, with highly variable severity within the same family [47]. Penetrance is incomplete and the lesions regress with age, so a carrier parent may have no apparent lesions; molecular testing of the parents, when the proband’s variant is known, clarifies the origin [28]. Genochondromatosis is also dominant, although without a known gene [46]. SPENCD (ACP5) and spondylo-megaepiphyseal-metaphyseal dysplasia (NKX3-2) are recessive, with a 25% risk for each pregnancy of a carrier couple [39, 76]. In SPENCD, OMIM also records an affected mother and son, with a normal father and non-consanguineous parents, and accepts dominant transmission; in the heterozygous parents of one patient, TRAP activity was markedly reduced, without disease [30]. Carpotarsal osteochondromatosis and Upington disease were described in families with vertical transmission (from mother to son in one, and from father to son in the other), compatible with dominant inheritance [40, 42]. In spondylo-megaepiphyseal-metaphyseal dysplasia, recessive inheritance was suggested by recurrence in siblings and parental consanguinity and confirmed by the identification of homozygous NKX3-2 variants; the parents studied were heterozygous [37]. Dysspondyloenchondromatosis, due to COL2A1, is dominant, and Orphanet also records cases in which inheritance is “not applicable”, compatible with de novo or mosaic occurrence [35, 79]. The 12p11 duplication with PTHLH arose de novo, with a 50% risk for the carrier’s offspring [36]. In these forms, cascade testing of relatives, prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known [44]. In D-2-hydroxyglutaric aciduria type II, a metabolic differential diagnosis, the IDH2 variant is dominant and almost always de novo, with mosaic cases [5].

8.3. Minors

In Ollier disease and Maffucci syndrome, questions of predictive testing in siblings or children do not arise, because there is no germline variant. Counselling of affected children focuses on the risk of complications and on adherence to surveillance, which lasts throughout life and intensifies after 20 years of age, when responsibility passes from the paediatrician to the patient [13].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The prevalence of 1/100,000 is repeated by the AACR and by recent reviews without a new population source; El Abiad and colleagues consider it lower than 1/100,000 [13, 14, 102]. The Orphanet figures for Ollier disease and Maffucci syndrome refer to sporadic mosaic diseases due to IDH1 or IDH2 and cannot be read as frequencies of germline variants [4]. The sex distribution is balanced in the literature (50.6% women in Ollier disease and 50.1% in Maffucci syndrome); the female predominance in the surveys (63.5% and 77.8%) reflects a response bias, and the earlier idea of a 2:1 male predominance in Ollier disease has not been confirmed [14].

9.2. Geographical distribution and populations

The available series come mainly from Europe and North America: the Verdegaal cohort gathered 13 European EMSOS centres and a national database; the Pansuriya series, tissue from the European EuroBoNet consortium, the de Duve Institute (Brussels) and Boston Children’s Hospital; and the El Abiad survey, respondents from 27 countries in Europe, North and South America, Asia and Africa [14, 15, 17]. The sources consulted do not identify founder populations or differences in prevalence between ancestry groups in Ollier disease and Maffucci syndrome, which is consistent with a sporadic postzygotic disease; the review of Kaplan and colleagues concluded that Maffucci syndrome occurs in all ancestries and in both sexes [11]. Among the Mendelian members of the class, Upington disease has been described in only one South African family from the Cape Province, and SPENCD has been described in consanguineous families of various origins, including Iraqi Jews, Turkish and Arab families and a family of Portuguese ancestry [30, 42]. In Italy, the Istituto Ortopedico Rizzoli has maintained since 2017 the ROM registry (Registry of Ollier Disease and Maffucci Syndrome), retrospective and prospective, with 400 patients planned up to 2032, restricted to residents of Italy [134]. In the United States, the NICHD is conducting a genomic and phenotypic study with 100 patients planned, which includes in-person assessment with MRI, densitometry, radiographs and positron emission tomography in adults [129].

In Portugal, the only publication identified in the sources is the series of two patients with IDH1-mutant chondrosarcoma treated with ivosidenib, without reference to enchondromatosis [124]; in SPENCD, the two siblings described by Roifman and Melamed were children of first cousins of Portuguese ancestry [30]. In Brazil, the CHONQUER trial includes Brazilian centres, and the SELNET bone sarcoma guideline was developed with the participation of Latin American centres, including the A.C.Camargo Cancer Center in São Paulo [21, 55]. The sources consulted contain no epidemiological data on enchondromatosis in Portugal or Brazil.

9.3. Special populations

Young children require adaptation of surveillance to avoid general anaesthesia [13]. Girls and women with Ollier disease are at risk of juvenile granulosa cell tumour, and lower abdominal pain should be investigated [13]. Patients with Maffucci syndrome have an additional risk of malignant transformation of the vascular lesions [14]. Young adults in transition are the group at greatest risk of loss to follow-up at a time when the risk of chondrosarcoma is increasing [13, 64].

9.4. European Reference Networks and patient organisations

The relevant European Reference Network is ERN BOND (rare bone diseases), coordinated by the Istituto Ortopedico Rizzoli in Bologna (https://ernbond.eu) [22]. For the complications, EURACAN (rare adult cancers, including sarcomas), ERN PaedCan (paediatric cancer), ERN GENTURIS (tumour predisposition syndromes) and VASCERN (rare vascular diseases) are relevant; the first three endorsed the 2021 European bone sarcoma guideline [23]. The sources consulted did not identify an ERN BOND consensus specific to Ollier disease or Maffucci syndrome. Patient organisations include A.C.A.R. Aps, the Italian association of patients with multiple osteochondromas, Ollier disease and Maffucci syndrome, which organises annual conferences with ERN BOND [22, 135], and the Association Ollier Maffucci Europe, founded in France in 1998 [136]. The Oxford Desk Reference indicates Contact a Family (United Kingdom) as a starting point for support groups [44]. Private patient groups on social media were the recruitment route for the two largest published surveys [14, 80].

10. Illustrative Clinical Case

10.1. Adult-onset Maffucci syndrome with a somatic IDH1 variant

Brown and colleagues, from Austin Health (Melbourne), described in 2021 a 36-year-old man referred by plastic surgery for multiple soft nodules on the palm of the right hand, slowly growing and increasing in number over the previous 3–4 years, with three more palpable lesions on the volar aspect of the wrist and one above the olecranon [19]. He was healthy, had normal intellectual development, three healthy children and an unremarkable family history [19]. A radiograph of the right hand showed multiple enchondromas of the 3rd, 4th and 5th fingers and soft tissue masses with phleboliths; MRI revealed masses isointense on T1 and hyperintense on T2 relative to muscle and cartilaginous replacement of the marrow of several phalanges, with expansion, and in the forearm changes of the ulna (expansion, bowing and shortening) and radius [19]. The palmar lesions were resected because of increasing functional impairment and for diagnosis: histology showed a benign vascular tumour with vascular spaces lined by endothelium without atypia and a spindle cell proliferation, diagnostic of spindle cell haemangioma (ISSVA group of benign vascular tumours), which, together with the enchondromas, established the diagnosis of Maffucci syndrome [19].

Sanger sequencing of all IDH1 exons in DNA from the haemangioma identified the variant described by the authors as NM_001282386.1:c.394C>T p.(Arg132Cys), equivalent to NM_005896.4:c.394C>T in the MANE transcript [6, 19]. The chromatogram suggested mosaicism, and ddPCR, with a lower detection limit of 0.1%, quantified the variant in 17.3% of alleles in the haemangioma, with no detection in blood DNA, which confirmed somatic mosaicism [19]. The team discussed with the patient the risk of malignancy and the possibility of an IDH1 inhibitor; it considered that, in a systemically healthy man, the justification for using these drugs was insufficient given the risk of differentiation syndrome and other adverse effects, decided not to offer it and referred the patient to a specialist orthopaedic tumour unit, with imaging surveillance of the bone lesions and regular clinical review [19]. Figure 1 of the article (radiograph, MRI, clinical photographs and histology) is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC8751415/figure/MCS006127BROF1/ and Figure 2 (chromatograms and ddPCR) on the same article page, at https://pmc.ncbi.nlm.nih.gov/articles/PMC8751415/ [19].

The case illustrates four points: diagnosis may be late when the lesions are distal and cause few symptoms; spindle cell haemangioma is diagnostic of the syndrome; molecular testing should be performed on lesional tissue, because blood is negative; and the decision not to use IDH inhibitors in benign disease is consistent with the absence of an approved indication. The surveillance plan in the report does not specify intervals and should be read in the light of the AACR consensus, published later [13].

10.2. Ollier disease with acute myeloid leukaemia and parathyroid adenoma

Lopez Delhoulle and colleagues, from Liège, published in 2026 the case of a young woman diagnosed with Ollier disease in 2016, because of bone pain and multiple right-predominant enchondromas confirmed histologically in two resected lesions, followed annually with radiographs in paediatric orthopaedics [64]. After transition to adult care in 2022 she had a single visit and never had whole-body or brain MRI [64]. At 18 years of age (December 2022) she presented with fatigue and pancytopenia (haemoglobin 8.6 g/dL, platelets 31×10⁹/L, leucocytes 0.73×10⁹/L with 14% blasts), with 76% blasts in the marrow: AML with a complex karyotype 49,XX,−7,+8,+8,+9,+21, of adverse risk according to European LeukemiaNet 2022 [64]. NGS of the blasts detected NM_005896.4(IDH1):c.394C>T p.(Arg132Cys) with a VAF of 37%, in addition to variants in DNMT3A, CEBPA and EZH2 [64]. She received induction with daunorubicin and cytarabine (“7+3”), achieved complete remission and received an allogeneic transplant from an unrelated donor, complicated by premature ovarian insufficiency and possible cardiotoxicity [64]. After the transplant, severe hypercalcaemia due to primary hyperparathyroidism appeared; the right inferior adenoma was resected with normalisation of calcaemia, and a hereditary hyperparathyroidism gene panel was negative [64]. The same IDH1 variant was present in the adenoma (VAF 44%) and in an enchondroma (41%) and absent from cultured skin fibroblasts; the fibroblast exome and chromosome fragility study were negative [64]. The case, the third of Ollier disease with AML and the first with the same variant in enchondroma, blasts and parathyroid, documents the pre-gastrulation origin of the mosaicism and the risk of loss to follow-up at transition; the figure in the article is a hypothetical developmental model, and not a clinical image (https://pmc.ncbi.nlm.nih.gov/articles/PMC13690521/figure/F1/) [64].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Functional prognosis depends on the burden and location of the enchondromas: lesions stop appearing after puberty, but deformities, limb length discrepancy and surgical sequelae persist into adulthood [2, 80]. Vital prognosis depends on the neoplasms. The risk of chondrosarcoma was 40% in the European Verdegaal cohort (n=161), 30.6% in Ollier disease and 31.7% in Maffucci syndrome in the El Abiad literature review, and about 30% in the AACR summary, which refers to a risk of malignant neoplasm that may reach 50%; the probability is higher with lesions in the long bones and axial skeleton, especially the pelvis (odds ratio 3.8), and lower when the lesions are limited to the hands and feet (15%) [13–15]. Cumulative risk increases with age, and the cohort figures, collected in patients of different ages, are not equivalent to a lifetime risk [15]. Secondary chondrosarcomas are usually low grade, rarely metastasise and have a 5-year survival above 90% [13, 14]. In the Colello survey, 4 of 123 patients had metastatic disease [80]. Gliomas, more frequent in Ollier disease, arise at younger ages than sporadic gliomas and may be multifocal [13, 14]. In MC-HGA, final height is unknown [27]; in metachondromatosis and genochondromatosis the lesions regress and the prognosis is benign [46, 47]; in SPENCD, prognosis is determined by the immune and neurological manifestations [76]; in spondylo-megaepiphyseal-metaphyseal dysplasia, by cervical myelopathy, which may lead to tetraplegia and death in childhood [39].

11.2. Surveillance in Ollier disease and Maffucci syndrome

The El Abiad proposal, which served as the basis for the AACR, differs in the start of periodic whole-body MRI (every 2 years from 25 years of age in Ollier disease and from 30 years in Maffucci syndrome) and in annual whole-body MRI, instead of dedicated MRI, for lesions of the pelvis or scapula or >5–6 cm [14]. Lopez Delhoulle and colleagues, building on the AACR and El Abiad, propose baseline brain MRI in early adolescence repeated every 1–2 years, more frequent than the single examination of the AACR [64]. Verdegaal and colleagues identified patients with enchondromas in the long bones or axial skeleton, especially the pelvis, as the population most in need of regular screening [15]. A single report suggested aortic surveillance in Maffucci syndrome, without constituting a recommendation [83]. The sources consulted do not recommend haematological, ovarian or parathyroid surveillance in asymptomatic patients; these neoplasms are detected by symptom-directed assessment.

11.3. Follow-up of the other members of the class

In MC-HGA, the sources consulted do not define a specific protocol; the scoliosis and mild developmental delay described make regular clinical assessment necessary, in addition to the surveillance common to the IDH-related enchondromatoses [27]. In metachondromatosis, lesions of the fibular head may cause peroneal nerve palsy and aseptic necrosis of the femoral head is a described complication [47]. In SPENCD, follow-up is immunological and neurological, by a multidisciplinary team [76]. In spondylo-megaepiphyseal-metaphyseal dysplasia, MRI of the cervical spine is the examination that best shows myelopathy secondary to vertebral collapse [39]; the authors of the lethal neonatal case argued that early diagnosis may prevent the neurological complications of cervical cord compression [37]. The sources consulted do not describe a risk of chondrosarcoma or oncological surveillance protocols for these Mendelian forms.

12. Summary and Final Considerations

The enchondromatoses are bone dysplasias defined by multiple enchondromas and bring together entities with very different mechanisms. Ollier disease and Maffucci syndrome, the most frequent, result from mosaic postzygotic variants in IDH1 (mainly p.(Arg132Cys)) or, more rarely, IDH2 (p.(Arg172Ser)), present in the lesions in about 80% of patients and usually absent from blood; MC-HGA is the form with widespread mosaicism, with D-2-hydroxyglutaric aciduria [17, 18, 52]. The mutant enzyme produces D-2-hydroxyglutarate, which alters the epigenome and retains remnants of hypertrophic growth plate chondrocytes within the bone [17, 53]. The other members of the class are Mendelian, with genes such as PTPN11, ACP5, COL2A1, NKX3-2 or the PTHLH duplication, or still without a known molecular basis, and are distinguished by the symmetry of the lesions, vertebral involvement, associated exostoses, spontaneous regression and family history [2, 36, 47, 76]. The role of PTH1R in Ollier disease, still recorded by Orphanet, is not supported by the largest series [7, 8, 17].

The diagnosis of Ollier disease and Maffucci syndrome is clinical and radiological; molecular testing, when needed, is performed on lesional tissue, and a negative blood result does not exclude the disease [13, 17]. The vascular lesions of Maffucci syndrome should be classified according to the ISSVA, and may appear years after the enchondromas [14, 16]. Orthopaedic complications dominate childhood and lead to repeated surgery; in adulthood, the main concern is transformation into chondrosarcoma, observed in 30–40% of the cohorts, more frequent with lesions of the pelvis and long bones, alongside gliomas, juvenile granulosa cell tumours and other IDH-associated neoplasms [13–15, 80]. The 2025 AACR consensus is the reference for surveillance: baseline whole-body MRI in childhood, periodic clinical examination and radiographs, annual MRI of high-risk lesions and whole-body MRI with brain MRI every 1–2 years from 20 years of age [13]. Chondrosarcoma is treated according to bone sarcoma guidelines [20, 55]. Mutant IDH inhibitors have modest and heterogeneous activity in chondrosarcoma, are being evaluated in a phase 3 trial and have no indication in benign disease [21, 66, 101]. Counselling should convey the non-hereditary nature of Ollier disease and Maffucci syndrome, with the theoretical caveat of gonadal mosaicism, and distinguish it from the Mendelian forms of the class [8, 64]. Transition to adult care should ensure continuity of surveillance, at a time when tumour risk increases [13, 64].

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