Oculodentodigital Dysplasia and Cenani-Lenz Syndrome

Disorders related to GJA1 (connexin 43) and to LRP4: dominant and recessive oculodentodigital dysplasia, syndactyly type III, recessive craniometaphyseal dysplasia, connexin 43 keratodermas and Cenani-Lenz syndactyly syndrome

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

Two syndactyly syndromes with distinct molecular bases

Oculodentodigital dysplasia (ODDD) and Cenani-Lenz syndactyly syndrome (CLSS) share syndactyly as the presenting sign in clinic and the fact that each belongs to an allelic family of a single gene. ODDD is the main disease caused by variants in GJA1, the gene for connexin 43 (Cx43), the most widely expressed gap junction protein in the body; the same protein underlies a recessive form of ODDD, isolated syndactyly type III, a recessive craniometaphyseal dysplasia and two keratodermas [6, 22]. CLSS is the most severe of the classical non-syndromic syndactylies and results from loss of function of LRP4, a receptor that antagonises canonical Wnt signalling in the developing limb and that, in other contexts, is a co-receptor for agrin at the neuromuscular junction and a facilitator receptor for sclerostin in bone [8, 9, 23]. This article covers the two classes in parallel, with ODDD in the foreground because of its multisystem and progressive nature.

Historical overview of oculodentodigital dysplasia

The first probable description of ODDD is owed to Lohmann, in 1920, in a paper on "pure" microphthalmia [2, 11]. In 1939 Mohr described, under the name dominant acrocephalosyndactyly, a father and five children with craniofacial deformity and complete syndactyly of the 4th and 5th fingers, probably the same condition [2]. The name "oculodentodigital dysplasia" was proposed by Meyer-Schwickerath, Gruterich and Weyers in 1957, and Gorlin, Meskin and St. Geme characterised the full pattern in 1963; in 1964 Gillespie described two siblings with microphthalmia, small nose, hypotrichosis, dental anomalies, camptodactyly of the 5th finger, 4–5 syndactyly and absent phalanges of the toes [2, 7, 11]. Renwick noted in 1967 that absence of the middle phalanx of toes 2 to 5 is a constant sign, Jones and colleagues documented in 1975 a paternal age effect in new mutations, and Fara and Gorlin described in 1981 bony orbital hypotelorism in about 40% of cases, with normal inner canthal distance [2]. The neurological dimension was recognised later: in 1980 Opjordsmoen and Nyberg-Hansen described a family from northern Norway with nine affected members over three generations in whom spastic paraplegia coexisted with syndactyly type III and began with neurogenic bladder; Gutmann and colleagues reported diffuse white matter changes on MRI in 1991; and Loddenkemper and colleagues reviewed the 243 published cases in 2002 and concluded that the neurological manifestations were underestimated [2, 15].

Molecular discovery and nomenclature

In 1997 Gladwin and colleagues mapped the locus to 6q22–q24 in six families, including the Brueton family with syndactyly type III without other signs (maximum lod score 9.37) [2]. In 2003 Paznekas and colleagues found heterozygous GJA1 variants in all 17 families studied, 16 missense and one codon duplication, and found that all carriers had craniofacial and limb dysmorphism, which established complete penetrance [6, 36]. The recessive form, proposed by Beighton in 1979 and by Traboulsi in 1986, received molecular confirmation in 2006, with the premature termination variant p.(Arg33Ter) in the homozygous state in two sisters born to consanguineous parents [10, 37]. The designation "syndactyly type III" was retained in OMIM as a separate entry (186100), but family and molecular data show that it corresponds to the mildest end of the ODDD spectrum [1, 3]. Dysmorphology textbooks still list GJA1 as a cause of Hallermann-Streiff syndrome and of hypoplastic left heart syndrome; these associations have not been confirmed: the "Hallermann-Streiff" patient with a homozygous GJA1 variant was reclassified as recessive ODDD, six classical cases of Hallermann-Streiff had no GJA1 variants, and the variant associated with hypoplastic left heart was reclassified as of uncertain significance [1, 6, 7, 10].

Historical overview of Cenani-Lenz syndrome

In 1967 Cenani and Lenz described two siblings with total syndactyly similar to that of Apert syndrome, but with severe shortening and fusion of the radius and ulna, fusion of the metacarpals and "disorganisation" of the phalanges, with the feet less affected; they identified similar cases published by Liebenam (1938), Borsky (1958) and Yelton (1962) [4]. There followed reports of siblings born to consanguineous parents, of quasidominant inheritance (Temtamy, 2003) and of associated anomalies such as renal hypoplasia (Bacchelli, 2001) and congenital hypothyroidism (Jarbhou, 2008), which led to the proposal to reclassify the condition as a syndromic syndactyly [4]. In 2010 Li and colleagues mapped the locus by homozygosity to 11p11.2–q13.1 (lod score 7.46) and identified biallelic LRP4 variants in 12 of 14 families, adding the renal anomalies to the picture [4, 9]. Since then, similar phenotypes have been described due to rearrangements of the GREM1–FMN1 locus and to an APC splicing variant, which are treated as differential diagnoses within the clinical spectrum of Cenani-Lenz [20, 21, 38].

Current classifications

The classical classification of syndactylies by Temtamy and McKusick, reproduced in the Oxford Desk Reference, defines five types by the digits involved; type III corresponds to syndactyly of the 4th and 5th fingers caused by GJA1 and present in ODDD [39]. Malik (2012) reorganised the non-syndromic syndactylies into nine types, most of them AD; only types VII (Cenani-Lenz) and IX are AR, and type VII is the most severe [5]. Harpf and colleagues distinguished two broad phenotypes within CLSS, the "spoon hand" type and the oligodactyly type, with carpal, metacarpal and digital synostoses and syndactyly of the toes as constant findings, and radioulnar synostosis, brachymesomelia and metatarsal synostoses as inconstant findings [24]. In the approach to leukodystrophies, ODDD is classified among the hypomyelinating leukodystrophies with brainstem involvement, a criterion that has diagnostic value in its own right [19].

Operational definitions and scope

ODDD denotes the picture caused by pathogenic GJA1 variants with at least one of the craniofacial, ocular, dental, digital or neurological manifestations described, including oligosymptomatic forms and predominantly neurological adult forms [7, 40]. CLSS denotes the distal limb malformation with oligosyndactyly, metacarpal synostoses and phalangeal disorganisation, with or without involvement of the forearm and kidneys, caused by biallelic LRP4 variants [4, 38]. Sclerosteosis 2 and congenital myasthenic syndrome 17, also caused by LRP4, belong respectively to the sclerosing bone dysplasias and to the congenital myasthenic syndromes; Ellis-van Creveld syndrome, sometimes grouped in lists of syndactylies and polydactylies, belongs to the short-rib thoracic dysplasias; and the syndactylies have their own general classification within the anomalies of the digits.

2. Molecular Genetics and Pathophysiology

Table of all types and genes in the class

Connexin 43 and gap junctions

GJA1 lies at 6q22.31 (GRCh38 6:121,435,646–121,449,727) and has two exons separated by an intron of about 11 kb; the entire coding region is in exon 2 [6, 7]. There is an intronless pseudogene on chromosome 5 with about 96% identity to the cDNA, which must be excluded when designing primers and which explains spurious published findings: the variants described in 2001 as a cause of hearing loss in African American patients and the changes associated with hypoplastic left heart were in the pseudogene or were identical to its sequence [6, 7]. Cx43 (NP_000156.1, 43 kD) is one of about 20 human connexins and has four transmembrane domains, two extracellular loops with three conserved cysteines each, one intracellular loop and cytoplasmic amino and carboxyl termini [7]. Six connexins form a connexon or hemichannel; two connexons from neighbouring cells dock to form a channel that allows the passage of ions and molecules up to about 1 kD, such as Ca2+, inositol phosphates and cyclic nucleotides, and thousands of channels aggregate into plaques [6, 7]. Mouse and human share 97% of the sequence; Cx43 is abundant in the heart, where it couples cardiomyocytes together with Cx40 (GJA5), and is expressed in bone (osteoblasts, osteocytes, osteoclasts and chondrocytes), skin, lens and ciliary body, cochlea, astrocytes, bladder and limb bud [6, 31, 42]. In the central nervous system, astrocytic Cx43 forms heterotypic channels with oligodendrocytic Cx47 (GJC2), a coupling that contributes to myelin maintenance and explains the phenotypic proximity to the GJC2 hypomyelinating leukodystrophies [22, 40].

Mechanism of the dominant form

Most ODDD variants are missense variants distributed across the domains of Cx43; the mutant protein associates with the normal protein and causes abnormal assembly, failure of trafficking to the membrane or altered conductance, so that coupling is lost despite a normal allele — a dominant-negative effect [22, 36]. The genetic proof came from the recessive form: heterozygous carriers of NM_000165.5:c.97C>T p.(Arg33Ter), who produce no protein from one allele, are clinically normal, which excludes haploinsufficiency as the mechanism of the dominant form [22, 37]. Some ODDD variants also increase hemichannel activity, and the keratoderma variants are either hemichannel gain-of-function variants (c.23G>T p.(Gly8Val), with greater Ca2+ entry and keratinocyte apoptosis) or Golgi retention variants (erythrokeratodermia 3), which explains how restricted skin diseases and multisystem ODDD arise from the same gene [6, 22, 34]. In animal models, the c.389T>C p.(Ile130Thr) variant reduces cardiac Cx43 and its phosphorylated forms, lowers junctional conductance, slows conduction and increases spontaneous and induced ventricular tachyarrhythmias; c.412G>C p.(Gly138Arg) and conditional ablation cause syndactyly through reduced SHH and BMP2 and lack of interdigital apoptosis; and c.178G>A p.(Gly60Ser) reproduces microphthalmia, angle closure and separation of the ciliary body epithelia [2, 6].

Mechanism of the recessive forms

The recessive variants are loss-of-function variants, but not uniformly so: NM_000165.5:c.97C>T p.(Arg33Ter) truncates the protein in the first transmembrane domain, forms no channels and is diffusely distributed in the cell, including the nucleus; c.227G>A p.(Arg76His) reaches the membrane and forms functional channels, behaving as a hypomorph [6, 41]. Subsequently described were homozygous c.442C>T p.(Arg148Ter) (third recessive family, 2018), a compound heterozygosity with a severe and progressive phenotype, homozygous c.604C>T p.(Arg202Cys) with normal carrier parents and, in 2025, homozygous c.565del p.(Arg189Glufs*35) in a Brazilian girl [43–46]. Smith's Recognizable Patterns counts 12 patients from 7 recessive families, 3 with molecular confirmation, and considers the phenotype clinically indistinguishable from the dominant one; Bone Dysplasias and the Brazilian series describe the recessive form as more severe, with marked hyperostosis of the calvaria and mandible [1, 11, 45]. The same Brazilian family showed that a proband with two heterozygous variants of undetermined cis or trans phase, c.752G>C p.(Ser251Thr) and c.848C>T p.(Pro283Leu), had a mild phenotype [45].

Variant spectrum and genotype-phenotype correlation in ODDD

Paznekas's 2009 review compiled 62 Cx43 alterations: 53 (85%) dominant missense variants, two codon duplications (NM_000165.5:c.145_147dup p.(Gln49dup), c.154_156dup p.(Phe52dup)), one codon deletion (c.507_509del p.(Phe169del)), two frameshifts with C-terminal truncation, one recessive nonsense and one recessive missense variant, and one GJA1/GJB2 compound heterozygosity [7]. Eighty-five per cent of the alterations lie before amino acid 192; the extracellular and transmembrane domains account for half and the intracellular domains for the other half; eleven fall in the calmodulin-binding domain (amino acids 136–158); the carboxyl terminus, the largest domain, has only the two truncations [7]. There are eight recurrent variants, none with more than five cases, and ten codons with two or three different variants [7]. In the 2020 review, with 165 genotyped individuals and 73 variants, the most frequent were c.605G>A p.(Arg202His) (11%), c.389T>C p.(Ile130Thr) (10%) and c.119C>T p.(Ala40Val) (10%), and the variants clustered in extracellular domain 1 and cytoplasmic domain 1 [16]. The correlations are weak: the phenotype varies within the same family and with the same variant; the most consistent exceptions are the marked palmoplantar keratoderma associated with C-terminal truncations, uveitis associated with c.581A>C p.(His194Pro) in a single Italian family, and isolated syndactyly type III associated with some variants of the first transmembrane domain and with c.427G>A p.(Gly143Ser) [2, 3, 7, 16].

Normalised reference variants

The historical numbering of GJA1 variants coincides with the HGVS numbering of the MANE Select transcript, because the count starts at the ATG and the protein has no cleaved signal peptide; this was confirmed in VariantValidator [47].

LRP4 and the Wnt pathway in the developing limb

LRP4 (11p11.2; GRCh38 11:46,856,717–46,918,550) encodes a transmembrane receptor of the low-density lipoprotein receptor family, with class A ligand-binding repeats, EGF repeats, four YWTD-type β-propeller domains, a transmembrane domain and cytoplasmic NPXY and tSXV motifs [8]. In the developing limb, LRP4 is expressed in the apical ectodermal ridge and antagonises LRP6-mediated activation of Wnt/β-catenin signalling; Lrp4-/- mice have fully penetrant polysyndactyly, expansion of the apical ectodermal ridge, ectopic expression of Fgf8, Shh, Bmp2, Bmp4 and Wnt7a and dental anomalies, and loss of Lrp4 delays the ureteric bud and may prevent kidney formation [8, 9]. In bone, LRP4 in osteoblasts and osteocytes binds sclerostin and potentiates inhibition of the Wnt pathway; at the neuromuscular junction, it binds neural agrin through the first β-propeller and activates MuSK, leading to clustering of acetylcholine receptors [8, 35].

Mechanism of Cenani-Lenz syndrome

CLSS variants are mainly missense variants in conserved extracellular regions (class A repeats, calcium-binding EGF repeats and YWTD domain), together with splicing and truncating variants [5, 9]. In reporter assays, four of five missense mutants completely lost antagonism of LRP6-mediated activation of the Wnt pathway and NM_002334.4:c.409G>A p.(Asp137Asn) retained residual function; all failed to traffic efficiently to the plasma membrane [9]. The proposed mechanism is complete or near-complete loss of LRP4 function, with excessive activation of LRP6/Wnt-β-catenin signalling in the autopod and kidney [9]. The location of the variants separates the allelic phenotypes: sclerosteosis 2 variants affect the central cavity of the third β-propeller and abolish the sclerostin-facilitating function without affecting MuSK; congenital myasthenic syndrome 17 variants affect blades 5 and 6 of the third propeller and reduce binding to agrin and MuSK without affecting the Wnt pathway; no CLSS variant described up to 2011 lay in the third propeller [8]. Bone Dysplasias summarises the mechanism of sclerosteosis 2: LRP4 binds sclerostin and facilitates its inhibitory action on the canonical Wnt pathway, so hypomorphic LRP4 variants increase bone formation [50]. Homozygous c.1820A>G p.(Tyr607Cys) in the first β-propeller reduced agrin binding by 80% and agrin-induced acetylcholine receptor clustering by 85% in myotubes from the patient, who had CLSS and congenital myasthenic syndrome [35].

Founder variants and genotype-phenotype correlation in CLSS

NM_002334.4:c.1585G>A p.(Asp529Asn) was found in three Turkish families with a common haplotype, and c.409G>A p.(Asp137Asn) in two Egyptian families with an identical haplotype, which defines them as founder variants in these populations [8, 9]. There is a correlation between the amount of residual function and severity: missense variants cause syndactyly, oligodactyly and minor renal malformations; homozygous nonsense c.289G>T p.(Glu97Ter) caused a severe phenotype with short limbs, humeral deformity, supernumerary nipples and unilateral renal agenesis; and combinations of two truncating variants (c.2401A>T p.(Lys801Ter) with NP_002325.2:p.(Ser1020Glnfs*27), a designation published at protein level; c.2710del p.(Trp904Glyfs*5) in the homozygous state) caused lethal prenatal forms with mesomelic reductions, tetraphocomelia and bilateral renal agenesis [5, 17, 18, 51]. At the other extreme, homozygous c.1348A>G p.(Ile450Val) caused only bilateral postaxial oligodactyly of the upper limbs with fusion of the 4th and 5th metacarpals, without renal involvement, and c.2858T>C p.(Leu953Pro) a form restricted to the upper limbs and kidneys in a Pakistani family with nine affected members [52, 53].

Locus heterogeneity of CLSS

In 2 of Li's 14 families there were no LRP4 variants nor homozygosity in the region, which indicated locus heterogeneity [9]. A homozygous 263 kb deletion of FMN1, which also removes limb-specific GREM1 regulatory sequences, caused oligosyndactyly, radioulnar synostosis, hearing loss and renal defects, as in the limb deformity mouse; a 1.7 Mb duplication including GREM1 and FMN1 caused isolated Cenani-Lenz-like oligosyndactyly with dominant transmission [20]. An APC splicing variant that reduces the normal transcript by about 80% caused typical CLSS with scoliosis in a consanguineous Saudi family, with increased Wnt/β-catenin signalling; patients with this phenotype had no polyposis, and OMIM keeps APC as an association pending confirmation [4, 21, 38]. LRP4 and APC act in the canonical Wnt pathway and GREM1 and FMN1 in the BMP antagonist pathway, which places the four causes on a common axis controlling interdigital apoptosis and distal differentiation [38].

Penetrance, expressivity, modifiers and mosaicism

ODDD has complete penetrance for the craniofacial and limb signs in the 2003 families, but expressivity is highly variable, to the point that there are families with syndactyly type III only, families with microphthalmia without syndactyly (NM_000165.5:c.581A>C p.(His194Pro)) and families with an almost exclusively neurological phenotype (c.659C>T p.(Ser220Phe)) [2, 36, 40]. c.758C>T p.(Ala253Val) (published designation A253V) was suggested as a modifier, because in a family with FOXC1 Axenfeld-Rieger syndrome the carriers of this variant had later-onset glaucoma [7]. In 2026, c.443G>A p.(Arg148Gln) was described as a modifier that brings forward SPG4 spastic paraplegia (SPAST) by destabilising the deubiquitinase VCPIP1 and lowering spastin, whereas relatives carrying p.(Arg148Gln) alone had no neurological signs — a finding that coexists with the description of p.(Arg148Gln) as a cause of de novo spastic paraparesis in an adult and that has been the subject of critical commentary [48, 49, 54]. In sporadic ODDD cases the sex ratio is 6 males to 15 females, compared with 73/79 in familial cases, and there is a paternal age effect in new mutations [2, 7]. The sources consulted do not describe germline or somatic mosaicism in classical ODDD.

3. Clinical Spectrum and Manifestations by System

Common description of ODDD and reference cohorts

ODDD combines a characteristic face with ocular, dental and digital anomalies present from birth and, in a proportion of patients, a progressive white matter neurological disease [1, 11]. The frequencies come from three types of data with different denominators, which should not be mixed. The Paznekas cohort (2009) brought together 177 individuals from 54 genotyped families, with 31 families (57%) having two or more affected generations, 21 (39%) with sporadic cases and 2 recessive; the per-family percentages (face 92%, eye 68%, teeth 70%, digits 80%, neurological 30%, conductive hearing loss 26%, slow-growing hair 26%; 78% of families with more than two categories) were reproduced in Bone Dysplasias and in OMIM [1, 2, 7]. Kumar's systematic review (2020) gathered 295 individuals from 91 reports published between 1963 and 2019, 165 of them with a confirmed variant, and described the ocular manifestations [16]. Jones's surgical series (2011) re-evaluated 38 children from 31 families followed for syndactyly in a paediatric orthopaedic hospital in Texas between 1980 and 2009 [55]. All are series of published or referred patients, biased towards recognisable forms, and none measures the frequency in the carrier population.

Face and skull

The typical face has a long, thin, "pinched" nose with hypoplastic alae nasi, small anteverted nostrils, a prominent columella and narrow nasal bridge, marked epicanthic folds, short palpebral fissures and, in about 40%, bony orbital hypotelorism with normal inner canthal distance [1, 2, 56]. The features become more evident after 3–4 years of age [11]. There is occasionally microcephaly, cleft lip and palate (cleft palate in 3% of the 177 patients, compared with 0.05% in the general population) and fine, dry, sparse or curly, slow-growing hair; in a Danish family with NM_000165.5:c.286G>A p.(Val96Met), 7 of 9 affected members had curly hair and none of the 8 unaffected relatives did [2, 7, 11].

Eye

In the review of 295 cases, the most frequent ocular manifestations were microcornea (111; 38%), microphthalmia (110; 37%), short palpebral fissures (56; 19%), glaucoma (51; 17%), epicanthus (36; 12%), strabismus (27; 9%), hypotelorism (24; 8%), hypertelorism (22; 7%), madarosis (19; 6%), cataracts (17; 6%), myopia (16; 5%), persistent pupillary membranes (13; 4%), shallow anterior chamber (12; 4%) and uveitis (10; 3%) [16]. In the 2009 cohort, microphthalmia and microcornea affected 22% and 27% of individuals, and glaucoma 16%, about eight times the population frequency (1.86%); glaucoma occurred in 16 families (30%), and four patients with glaucoma became blind (14% of those with glaucoma), about three times the rate observed in glaucoma in general [7]. Cataract (3%) and strabismus (5%) did not differ from the general population in that cohort [7]. Glaucoma may be angle-closure, owing to a small anterior segment or ciliary body cysts, or open-angle, described as a late complication [11, 16, 57]. Other findings described are a thin and porous or atrophic iris, persistent fetal vasculature, retinal and optic nerve dysplasia, choroidal thinning and, in 2026, incipient keratoconus in a patient with NM_000165.5:c.226C>T p.(Arg76Cys) [2, 11, 58]. The recessive form tends to have more severe ocular involvement, with persistent hyperplastic primary vitreous, childhood-onset cataract and synechiae [10, 46].

Teeth

Enamel hypoplasia, often with extensive caries, and microdontia affected 40% and 21% of the 177 patients; tooth loss was described in at least 10% (in some cases with extraction of all teeth), dental agenesis (7%), amelogenesis imperfecta, pulp stones and delayed eruption (2% each) and malocclusion (3%), and 15% of families had no dental anomaly [7]. Other reports add taurodontism and enlarged pulp chambers, and generalised enamel hypomineralisation of the primary dentition with early fractures and wear [2, 59]. The mandible is wide, with a thick alveolar ridge and an obtuse angle [1].

Hands and feet

Syndactyly of the 4th and 5th fingers, unilateral or bilateral, with or without other digits, was present in 72% of the 177 patients; 43% had the isolated bilateral 4–5 form (syndactyly type III), 14% unilateral forms and 16% additional involvement, mainly of the 3rd finger [7]. The syndactyly is usually cutaneous, sometimes with bony fusion of the terminal phalanges, and is associated with camptodactyly and clinodactyly of the 5th finger (70% of families) and hypoplasia or aplasia of the middle phalanx of the 5th finger [1, 7]. Twenty per cent of individuals had no syndactyly of the hands, which hinders recognition [7]. In the feet, syndactyly occurred in 25% of individuals and 40% of families; Smith's Recognizable Patterns describes it between the 3rd and 4th toes, and the 2009 cohort recorded 2–3 forms in five families and 4–5 forms in three; absence of the middle phalanx of the lateral toes is a constant radiological sign [1, 7, 11]. In the Texas series, 32 of 38 children had bilateral syndactyly, symmetrical in 31, and the severity of syndactyly was associated with dental and urological severity, but not with ophthalmological or neurological severity [55].

Skeleton

Radiographs show mild to moderate widening of the long and short tubular bones, ribs and clavicles, a wide mandible and, in some patients, cranial and vertebral hyperostosis; adult stature is normal [1, 11]. The recessive cases of Afrikaner origin had marked cranial hyperostosis, mandibular overgrowth and, in two, spinal cord compression at the skull base [10]. MRI in six dominant patients showed no stenosis of the craniocervical junction [19].

Hearing

Conductive hearing loss affected 10% of individuals and 26% of families, more than ten times the population frequency (0.8%), and ear infections occurred in 10% [7]. One patient lacked an ossicle [7].

Nervous system: hypomyelinating leukodystrophy

Neurological manifestations affect about 30% of families and, in the Texas series, 29% of children [7, 55]. The dominant picture is a slowly progressive spastic paraparesis, often preceded or accompanied by neurogenic bladder with incontinence and recurrent cystitis; ataxia, dysarthria, tibialis anterior weakness, paraesthesiae and posterior column changes, nystagmus, gaze palsy and seizures are added [2, 11, 19]. The 2002 review of 243 cases described spasticity (25), gaze palsy or strabismus (28), bladder and bowel disturbances (21), visual loss (20) and blindness (4), hearing loss (15), ataxia (11), nystagmus (9), weakness (5) and paraesthesiae (3) [15]. In the 2009 cohort, urinary incontinence affected 12% and faecal incontinence 2%, and symptoms often appeared only from the second decade [7]. In an Italian family of ten carriers of NM_000165.5:c.416T>C p.(Ile139Thr), five had central nervous system manifestations, most often isolated ataxia or ataxia with spasticity, and sphincter disturbances were the first manifestation in most; all those examined had subclinical visual evoked potential abnormalities [60]. Intellectual performance is usually normal; mild intellectual disability, memory problems in adults and basal ganglia calcification have been described [10, 11, 61].

MRI shows a characteristic pattern, described in six patients from four families with 12 scans between 5 and 52 years of age: diffuse supratentorial hypomyelination (mildly increased T2 signal with normal T1), involvement of the posterior limb of the internal capsule and the corpus callosum, T2 hypointensity of the rolandic cortex and primary visual cortex, and symmetrical involvement of the middle cerebellar peduncle, pyramidal tract and medial lemniscus in the pons [19]. The pallidum and dentate nucleus were hypointense in two patients each; spectroscopy showed increased creatine and myo-inositol, normal or slightly reduced NAA and normal or low choline, a hypomyelination profile; there was no restricted diffusion [19]. The changes were present regardless of whether there were symptoms or syndactyly, and progressed with age, with loss of the normal subcortical white matter and involvement of the anterior limb of the internal capsule in older patients [19]. In some adults the leukodystrophy is extensive, with atrophy and ventriculomegaly [61]; in others, MRI shows only cerebral and spinal atrophy without white matter lesions, despite severe paraparesis [48]. Saudubray includes ODDD (GJA1) among the hypomyelinating leukodystrophies due to defects of cellular trafficking, alongside the GJC2 connexinopathies resembling Pelizaeus-Merzbacher disease, which places it in the metabolic differential diagnosis of hypomyelination [62].

Adult neurological forms without evident dysmorphism

An Italian family of five siblings with the NM_000165.5:c.659C>T p.(Ser220Phe) variant had an almost exclusively neurological picture: three siblings with spastic paraparesis beginning between 30 and 60 years of age, one asymptomatic sister aged 68 with white matter changes, and subtle dysmorphic features recognised only after the molecular diagnosis [40]. Other adults reached the diagnosis through spastic paraparesis (a 38-year-old man with de novo c.443G>A p.(Arg148Gln), wheelchair-dependent since 2012), a spastic-ataxic syndrome with tremor and parkinsonism (a 32-year-old Indian woman with c.317T>C p.(Leu106Pro)) or adult leukodystrophy with gait and memory impairment (c.413G>A p.(Gly138Asp)) [48, 61, 63].

Heart

Smith's Recognizable Patterns records cardiac defects in 3%, cardiomyopathy and arrhythmias as occasional manifestations, and sudden death related to cardiac anomalies [11]. In the cohort of 177 patients, the only electrocardiographic findings were right bundle branch block (2) and ventricular extrasystoles (1) [64]. A family with NM_000165.5:c.175C>T p.(Pro59Ser) had progressive conduction system disease and dilated cardiomyopathy over three generations: the father had conduction block at 5 years, a pacemaker at 8, ventricular tachycardia, stroke and heart failure (ejection fraction 11%), received a transplant at 9 years and died at 24; the elder daughter had high-grade atrioventricular block and dilated cardiomyopathy and died at 14 months after cardiac arrest; the younger daughter, with a normal electrocardiogram and echocardiogram at birth, had second-degree block and an ejection fraction of 36% at 4 months [64]. Congenital heart disease has also been described in two patients with de novo variants: pulmonary atresia with intact septum, right ventricular hypoplasia and tricuspid stenosis [c.226C>T p.(Arg76Cys)] and ventricular septal defect [c.145C>G p.(Gln49Glu)] [65]. The original family with c.389T>C p.(Ile130Thr) had a higher incidence of arrhythmias, and the corresponding mouse model develops ventricular tachyarrhythmias [2, 6].

Skin, hair, nails and lymphatics

Palmoplantar keratoderma, follicular hyperkeratosis, trichorrhexis nodosa and brittle nails are often overlooked; marked keratoderma is associated with variants that truncate the carboxyl terminus [2, 48]. In 2026 hereditary leukonychia (porcelain-white nails) associated with a GJA1 variant was described [66]. Primary lymphoedema of the lower limbs segregated with NM_000165.5:c.617A>G p.(Lys206Arg) in a three-generation family, with onset at 14 and 30 years and abnormal drainage on lymphoscintigraphy [2]. The Oxford Desk Reference includes ODDD with lymphoedema (GJA1, missense, AD) in the gene table for lymphatic anomalies [67].

Other manifestations

Omphalocele, central apnoea and microaspiration in infancy, mitral valve prolapse, kyphoscoliosis, hip dislocation and cubitus valgus have been described [11, 16, 48, 59]. In the 2026 Italian family, two brothers had infertility or oligospermia, an association that remains speculative, supported by male subfertility in the mouse model [40].

Other allelic disorders of GJA1

Isolated syndactyly type III consists of complete bilateral syndactyly of the 4th and 5th fingers, sometimes with fusion of the distal phalanges, a short 5th finger with an absent or rudimentary middle phalanx, and spared feet; some families with this phenotype have a face similar to that of ODDD, and there are sporadic patients with variants in the first transmembrane domain [3]. Recessive craniometaphyseal dysplasia due to p.(Arg239Gln) causes progressive craniofacial hyperostosis with narrowing of the foramina, visual loss, mixed hearing loss, facial palsy, prognathism and sometimes truncal ataxia due to posterior fossa compression; it has been described in Brazilian, Portuguese and Indian families; the Oxford Desk Reference places cranial nerve compression, with optic atrophy and facial palsy, between 2 and 12 years of age [6, 31, 68, 69]. Palmoplantar keratoderma with congenital alopecia combines severe palmoplantar hyperkeratosis, hypotrichosis or alopecia and nail dystrophy; erythrokeratodermia variabilis et progressiva 3 has transient figurate erythema, scaling and keratoderma, without systemic signs of ODDD [22, 34].

Cenani-Lenz syndrome: limbs

CLSS is defined by complex syndactyly of the hands with fusion and disorganisation of the metacarpals and phalanges, oligodactyly, shortening of the radius and ulna and radioulnar synostosis; the feet are less affected, with cutaneous syndactyly, oligodactyly and metatarsal synostoses [4, 9]. The spectrum ranges from the "spoon hand", with total syndactyly, absent thumbs and bony masses in place of the metacarpals, to bilateral postaxial oligodactyly of the upper limbs with fusion of the 4th and 5th metacarpals and, at the other extreme, to the lethal prenatal form with mesomelic reductions and tetraphocomelia [4, 17, 18, 52]. A 31-year-old Chinese man homozygous for p.(Asn94Lys) had only four metacarpals in each hand, absent distal phalanges, asymmetrical syndactyly and syndactyly of the right 2nd and 3rd toes, with normal kidneys and no dysmorphism [5].

Cenani-Lenz syndrome: kidney and other systems

In the 2010 series, more than half of families had renal agenesis or hypoplasia; the Pakistani family with NM_002334.4:c.2858T>C p.(Leu953Pro) had left renal hypoplasia in 3 of 9 affected members, and later reports include horseshoe kidney and unilateral or bilateral renal agenesis [5, 9, 35, 53, 70]. In 2026, in a family of four affected members with c.3830G>T p.(Arg1277Leu), the 2-year-old proband had a horseshoe kidney and the 6-year-old cousin right renal agenesis, and craniofacial and renal anomalies were estimated in about half of published cases [70]. Facial dysmorphism, when present, is mild: high, prominent forehead, hypertelorism, depressed nasal bridge, downslanting palpebral fissures, short nose and micrognathia [4, 9]. Also described are scoliosis, hemivertebrae, diastematomyelia and mixed hearing loss; congenital hypothyroidism, laryngomalacia and hip dislocation; genital anomalies and cleft palate; cataract; and, in two siblings with c.4910G>A p.(Cys1637Tyr), recurrent ketotic hypoglycaemia [4, 71]. Cognitive development is usually normal [52, 70].

Cenani-Lenz syndrome with congenital myasthenia

A 42-year-old Algerian woman, born to consanguineous parents and homozygous for p.(Tyr607Cys), was born with syndactyly and brachydactyly more severe in the hands and a horseshoe kidney, and from the age of 19 developed progressive proximal weakness with neck fatigability, without ophthalmoparesis or bulbar signs; anti-acetylcholine receptor and anti-MuSK antibodies were negative and 3 Hz repetitive stimulation showed a 25–28% decrement in the accessory nerve [35]. The case shows that the same LRP4 variant can affect both the limb and the neuromuscular junction, a possibility already anticipated in 2010 for alleles with lower residual function [9, 35].

Natural history and treated disease

The sources describe the natural history of patients receiving symptomatic treatment, without studies comparing treated and untreated groups. In ODDD, life expectancy, intelligence and adult stature are generally normal, and morbidity depends on glaucoma (with a risk of blindness), tooth loss, neurological progression and, rarely, conduction disease and cardiomyopathy [1, 7, 64]. In CLSS, hand function depends on the underlying anatomy and the reconstruction, vital prognosis depends on renal involvement, and forms with biallelic truncating variants can be lethal before birth [9, 17, 24].

4. Clinical Recognition and Warning Signs

When to suspect, by age and context

In the prenatal period, ultrasound allows visualisation of the digits from the second trimester; isolated syndactyly is difficult to document, but the severe forms of CLSS present with mesomelic reductions, symmetrical oligosyndactyly of the hands and feet, tetraphocomelia and renal agenesis [17, 18, 39]. In the newborn and infant, ODDD should be considered in the presence of syndactyly of the 4th and 5th fingers with camptodactyly of the 5th finger, microphthalmia or microcornea and a thin nose with hypoplastic alae; the Oxford Desk Reference includes looking for microphthalmia and a "pinched nose" in the examination of any child with syndactyly [11, 39]. Hand surgeons are often the first specialists to see these children, because of ulnar-sided syndactyly [55]. In the child, enamel hypoplasia with early caries, tooth loss and conductive hearing loss are clues, and the face becomes more evident after 3–4 years [7, 11]. In adolescents and adults, ODDD should be sought in the presence of unexplained spastic paraparesis, ataxia or neurogenic bladder, especially with a history of syndactyly surgery, small teeth or microphthalmia, and in the presence of an MRI pattern of hypomyelination with brainstem involvement [19, 40, 48]. CLSS is recognised at birth by the hand malformation, which resembles that of Apert syndrome but without craniosynostosis and with forearm shortening [39].

Warning signs that change management

Newborn screening

There is no newborn screening for ODDD or CLSS; early diagnosis depends on the physical examination of the newborn with syndactyly and on ophthalmological assessment [39].

5. Diagnosis: Criteria, Tests and Algorithms

Clinical criteria

There are no formal published diagnostic criteria for ODDD or for CLSS. In practice, the 2009 cohort considered a family positive when it had features in more than two of the categories face, eyes, teeth and limbs (78% of families) [7]. The diagnosis rests on a clinical pattern confirmed by the identification of a pathogenic variant in GJA1 or of biallelic variants in LRP4 [22, 23]. Non-molecular investigations characterise the phenotype, but none establishes the diagnosis on its own [22, 23].

Targeted assessment

The MRI pattern as a diagnostic criterion

The pattern of supratentorial hypomyelination with involvement of the middle cerebellar peduncle, pyramidal tract and medial lemniscus distinguishes ODDD from other hypomyelinating leukodystrophies with brainstem involvement: Pelizaeus-Merzbacher-like disease affects the basis pontis more, 4H syndrome spares the medial lemniscus, hypomyelination of early myelinating structures affects the medulla and caudal pons more, and none of them affects the middle cerebellar peduncles [19]. It is also distinguished from the dominant leukodystrophy due to LMNB1 duplication, from fragile X premutation tremor/ataxia syndrome and from leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), which are not hypomyelinating [19]. Recognition of this pattern should prompt testing of GJA1 even in the absence of syndactyly [19, 40].

Molecular tests and their order

In a child with clinical ODDD, sequencing of GJA1 (single gene or a syndactyly or ocular malformation panel) identifies most variants, all of which are point variants or small insertions and deletions in the coding region of exon 2 [7, 36]. In adults with a neurological presentation, spastic paraplegia, ataxia and neuromuscular disease panels may not include GJA1; in the 2026 Italian family, two panels of 160–170 genes were non-diagnostic and the diagnosis came from an exome analysed with a white matter disease panel [40]. In CLSS, sequencing of LRP4 is the first step; if negative, it is followed by copy number analysis by array or genome (deletions and duplications of GREM1–FMN1) and by sequencing of APC, ideally by exome or genome [9, 20, 21, 38]. Exome sequencing has been the preferred method in recent syndactyly series [5]. In associated fatigable weakness, a congenital myasthenic syndrome panel includes LRP4 [35].

Limitations of the tests

The GJA1 pseudogene on chromosome 5, with about 96% identity to the cDNA, can be amplified instead of the gene, producing false variants or masking real ones; laboratories should use primers that exclude it, and variants that coincide with the pseudogene sequence should be interpreted with caution [6, 7]. ODDD has no predominant recurrent variants, so targeted variant tests are not appropriate [7]. A negative sequencing result does not exclude the diagnosis: the sources do not describe the clinical sensitivity of GJA1 sequencing, and the authors of the 2009 cohort allow for variants in regulatory regions and atypical cases yet to be explained [7]. In CLSS, about 2 of 14 families in the original series had no LRP4 variants, which reflects locus heterogeneity rather than technical failure; deletions and duplications of GREM1–FMN1 are not detected by panel sequencing without copy number analysis [9, 20]. Low-level mosaicism has not been described in the sources consulted.

Report content and interpretation

The report should state the gene, the transcript with version (GJA1 NM_000165.5; LRP4 NM_002334.4, both MANE Select), the variant in HGVS c. and p. notation, zygosity and classification according to the ACMG/AMP criteria [5, 40, 47]. In the 2026 Italian family, p.(Ser220Phe) was classified as likely pathogenic with criteria PM1, PM2, PP2, PM5 and PP3, and in the 2024 Chinese CLSS case p.(Asn94Lys) with PM2, PM3, PP3 and PP4 [5, 40]. A variant of uncertain significance in GJA1 gains weight with segregation in the family, with reverse phenotyping (targeted examination of eyes, teeth, hands and MRI in carriers) and with the occurrence of another pathogenic variant at the same codon [40]. In LRP4, interpretation depends on phase: two variants must be in trans, which requires parental testing [9]. The associations of GJA1 with non-syndromic hearing loss (ClinGen: disputed, 2022) and with isolated congenital heart disease (ClinGen: limited, 2024) do not allow these isolated phenotypes to be attributed to a variant on the basis of the gene alone [22].

Diagnostic algorithm

Prenatal and preimplantation diagnosis

The Oxford Desk Reference states that prenatal genetic testing is available for several syndactyly syndromes; when the familial variant is known, it can be sought in fetal material or in embryos [39]. Second-trimester ultrasound can show the hand malformation and limb reductions in severe forms of CLSS, and bilateral renal agenesis in lethal forms [17, 18]. In ODDD, ultrasound does not predict the severity of neurological or ocular disease, because expressivity varies within the same family [7].

6. Differential Diagnosis

Comparative table

Hallermann-Streiff and ODDD

Hallermann-Streiff syndrome shares microphthalmia, a small thin nose and hypotrichosis with ODDD, and some textbooks still associate it with GJA1 [1, 72]. It is distinguished by thin tubular bones and a thin calvaria with wormian bones (in ODDD, wide bones and sometimes hyperostosis), by the absence of syndactyly type III, by almost constant cataract (94%), by proportionate short stature (mean final height 152 cm in women and 155–157 cm in men) and by its always sporadic occurrence [1, 72]. Six classical cases had no GJA1 variants, and the only patient published as Hallermann-Streiff with a homozygous GJA1 variant was reinterpreted as recessive ODDD [7, 10].

Neurological ODDD and other causes of spastic paraparesis and leukodystrophy

In adults, ODDD with little dysmorphism is confused with hereditary spastic paraplegias and adult leukodystrophies; the combination of early neurogenic bladder, visual evoked potential abnormalities and hypomyelination with brainstem involvement points to GJA1 [19, 60]. A search for minor signs, such as syndactyly corrected in childhood, small teeth with hypoplastic enamel, microcornea and absent middle phalanges of the toes, supports reverse phenotyping [40, 61]. Coexistence with variants in other genes, such as SPAST, should be considered in the light of the modifier role proposed for p.(Arg148Gln) [49, 54].

CLSS, Apert and other complex syndactylies

The CLSS hand resembles that of Apert syndrome, but the absence of craniosynostosis, forearm shortening with radioulnar synostosis, metacarpal fusion and phalangeal disorganisation distinguish it [4, 39]. Within the clinical spectrum of Cenani-Lenz, inheritance and the presence of hearing loss or of normal kidneys point towards FMN1 (AR with hearing loss and renal defects), the GREM1–FMN1 duplication (AD, isolated hands) or APC (AR, scoliosis), but radiology is not gene-specific and diagnosis requires molecular confirmation [20, 21, 23].

7. Treatments and Risk Management Strategies

General principles and guidelines

There are no published clinical guidelines or consensus statements for ODDD or for CLSS, and no drug has an approved indication for any disease related to GJA1 or LRP4 [22, 23]. Management is symptomatic, organ-directed and multidisciplinary, and the available recommendations come from reference textbooks, curated databases and case series and reports [1, 11, 22]. For congenital myasthenic syndrome 17, the GeneReviews review of the congenital myasthenic syndromes, cited by GeneGuidance, makes no specific recommendation for LRP4 and notes that data on the response to acetylcholinesterase inhibitors are absent or limited [23]. The surveillance recommendations that follow are therefore of a low level of evidence (expert opinion and case series).

Eye

Smith's Recognizable Patterns recommends periodic ophthalmological assessment because of the risk of open-angle glaucoma as a late complication, and Bone Dysplasias includes glaucoma treatment among the three therapeutic measures for ODDD [1, 11]. GeneGuidance proposes lifelong ophthalmological follow-up with attention to glaucoma, microphthalmia, microcornea and refractive error [22]. In a 6-year-old girl with chronic angle-closure glaucoma due to ciliary body cysts, the pressure was controlled with a Baerveldt drainage implant in each eye, with timolol 0.5% and latanoprost 0.005% in the interval and timolol with brimonidine when the pressure rose; trabeculectomy was avoided because of the risk of endophthalmitis with antimetabolites (0.2–1.5% per year) in a single functional eye, cyclocryotherapy was reserved for end-stage disease and angle procedures were considered contraindicated in angle closure [57]. The authors recommend ultrasound biomicroscopy to screen for ciliary body cysts and serial gonioscopy, which in the fellow eye detected progressive narrowing of the angle over three and a half years [57]. In a previously published case of open-angle glaucoma, the pressure was controlled with trabeculotomy and cyclocryotherapy [57]. Amblyopia, strabismus and refractive errors are treated according to usual paediatric ophthalmology practice [16].

Teeth

Bone Dysplasias and GeneGuidance recommend comprehensive restorative and prosthetic dental care for a small, hypoplastic and caries-prone dentition [1, 22]. In a 3-year-old child with generalised enamel hypomineralisation of the primary dentition, full conservative restoration was performed under general anaesthesia, but there was renewed breakdown of the unrestored enamel within 6 months, which shows the limitations of conservative techniques and the need for surveillance every 3 months [59].

Hand

Surgical correction of syndactyly is the first-line measure for function and growth of the digits [1, 22]. In the Texas series, ulnar-sided syndactyly was the reason for referral to the hand surgeon, and the authors stress that the frequency of ophthalmological, dental and neurological abnormalities justifies referral to those specialties [55]. In CLSS, reconstruction depends on the anatomy: in a case of the oligodactylous variant, bilateral separation of the digital rays with tendon transfers allowed grasp function to be obtained [24]. Three-dimensional computed tomography helps to plan surgery on complex hands [71]. The sources consulted do not define an optimal age for surgery in these two syndromes.

Neurological disease

Treatment of spasticity and neurogenic bladder follows the principles applied to spastic paraplegia and neurogenic bladder of other causes [22]. Intrathecal baclofen has been reported as effective in controlling spastic paraparesis in one patient with ODDD [22]. In a 38-year-old man, tizanidine, baclofen, gabapentin, amitriptyline and clonazepam were used, the last being the most effective; botulinum toxin increased weakness, because of the extent of the musculature involved, and was not repeated [48]. The sources do not report specific doses of these drugs in ODDD, and their use is extrapolated from other causes of spasticity. Motor rehabilitation, walking aids and urological assessment with a urodynamic study are part of management [22].

Heart

Cardiac assessment at diagnosis is recommended, because congenital heart defects are rare but do occur, and because syndactyly type III associated with heart disease should prompt study of GJA1 [65]. In the family with p.(Pro59Ser), progressive conduction disease led to a pacemaker at 8 years in the father and to epicardial biventricular pacing with metoprolol in the 2.5-year-old daughter, and end-stage dilated cardiomyopathy led to heart transplantation; biventricular pacing was preferred to right ventricular pacing so as not to worsen the cardiomyopathy [64]. The authors of a 2025 report recommend cardiological monitoring because of the arrhythmias associated with ODDD [48]. These approaches are individual and follow the general indications for pacing and heart failure.

Hearing, lymphoedema and skin

Conductive hearing loss is assessed by audiometry and tympanometry and treated as usual; in a child with otitis media with effusion, ventilation tubes improved hearing and language [22, 59]. Primary lymphoedema of the lower limbs, described with p.(Lys206Arg), warrants lymphoscintigraphy and decongestive treatment according to the practice for primary lymphoedema [2]. The keratodermas are treated with emollients and keratolytics [22].

Kidney and other systems in CLSS

Renal ultrasound is required in all children with CLSS, because of the frequency of renal agenesis and hypoplasia, and renal function should be followed when there is a single or hypoplastic kidney [9, 23]. In cases with fatigable weakness, confirmation of a neuromuscular junction defect leads to a specialised neuromuscular assessment; there are no LRP4-specific data on therapeutic response [23, 35]. The ketotic hypoglycaemia described in one family warrants attention to fasting during intercurrent illness [71].

Recessive craniometaphyseal dysplasia

Early decompression of the optic canal can delay or prevent visual loss, but is not always effective; hearing loss should be diagnosed and treated, posterior fossa compression requires foramen magnum decompression, and cosmetic surgery can reduce mandibular overgrowth [31]. GeneGuidance recommends surveillance of hearing and of the facial nerve and neurosurgical assessment [22].

Regulatory status

Clinical trials and recent developments

The absence of trials means that there are no controlled efficacy data for any intervention, and that the approaches described rest on individual reports without a comparison group; a negative search in one registry does not prove that no studies exist in other registries [73]. The developments of the last twelve months are all descriptive or preclinical: an Italian family with a predominantly neurological phenotype (p.(Ser220Phe); family report, 2026) that leads to the recommendation to include GJA1 in neurological and neuromuscular disease panels [40]; a study in organoids derived from induced pluripotent stem cells proposing the GJA1–VCPIP1–spastin pathway as a modifier of SPG4 and a possible therapeutic target (preclinical study with one proband, 2026), followed by a commentary questioning the isolated pathogenicity of p.(Arg148Gln) [49, 54]; incipient keratoconus and leukonychia as new findings (case reports, 2026) [58, 66]; and, in CLSS, a new variant p.(Arg1277Leu) with horseshoe kidney and renal agenesis in a family with four affected members (family report, 2026) [70].

Agents to avoid, pregnancy, perioperative care and transition

The sources consulted do not identify contraindicated drugs specific to ODDD or CLSS. In cases with a neuromuscular junction defect associated with CLSS, the general precautions for myasthenic syndromes apply [35]. The sources consulted do not describe pregnancies in women with ODDD or CLSS or specific anaesthetic recommendations; the complications with implications at these times are the conduction disease and cardiomyopathy described in some families with ODDD and the renal agenesis or hypoplasia of CLSS [9, 64]. Transition to adult care is critical in ODDD, because neurological disease often appears from the second decade onwards and may be the first reason for consultation in adulthood, and because glaucoma is a late complication; ophthalmological, dental and neurological follow-up should continue throughout life [7, 11, 40].

8. Reproductive Options and Family Counselling

Recurrence risks by inheritance and scenario

Counselling in ODDD

Counselling must take into account that the variant does not predict severity: members of the same family may have only syndactyly type III, only microphthalmia or an adult spastic paraparesis [2, 7, 40]. Before a case is considered sporadic, the parents should be examined for minimal signs — corrected syndactyly, a short or curved 5th finger, small teeth, microcornea — as the Oxford Desk Reference recommends for all syndactylies, and preferably tested for the variant [39, 40]. Reverse phenotyping of carrier relatives, including brain MRI and ophthalmological examination, identifies oligosymptomatic carriers who benefit from surveillance for glaucoma and conduction disease [19, 40]. In de novo cases, the recurrence risk for siblings is low; the sources consulted do not quantify the risk of germline mosaicism in ODDD.

Counselling in CLSS

In CLSS, most families are consanguineous and the parents are heterozygous carriers without signs; confirmation that two variants are in trans requires parental testing [9]. The variant type guides prediction: biallelic truncating variants are associated with severe or lethal forms, and missense variants with non-lethal forms of variable severity [5, 17, 18]. In populations with founder variants (p.(Asp529Asn) in Turkey, p.(Asp137Asn) in Egypt), targeted testing of partners may be considered [9].

Cascade testing, minors and reproductive options

Cascade testing of relatives at risk of ODDD has clinical utility, because it identifies people who need ophthalmological, cardiological and neurological surveillance; in at-risk children, clinical and ophthalmological examination complements the test [22, 40]. In CLSS, carrier testing of healthy siblings has no clinical consequence in childhood. Reproductive options include prenatal diagnosis by targeted molecular testing, preimplantation genetic testing and second-trimester ultrasound, which can show the hand malformations and limb reductions in severe forms of CLSS and bilateral renal agenesis in lethal forms [17, 18, 39].

9. Special Considerations: Population Diversity and Epidemiology

What the available figures measure

There is no population-based estimate of the prevalence or incidence of ODDD or CLSS; Orphanet places both in the class <1/1,000,000 without a point value, on the basis of counts of published cases (243 ODDD cases in the 2002 review; about 30 CLSS cases by expert estimate) [12, 14, 15]. The later counts — 177 individuals from 54 genotyped families in 2009 and 295 individuals in 91 reports up to 2019 — measure published cases and not frequency in the population [7, 16]. The statement that fewer than 1000 people have been diagnosed worldwide is an author's estimate without a source [57]. The oligosymptomatic and adult neurological forms, which are only now beginning to be diagnosed with exome sequencing, suggest that the counts underestimate the true frequency [19, 40].

Geographical distribution and founder populations

The 2009 cohort was almost entirely of Indo-European ancestry, and the authors hypothesised that GJA1 variants might be expressed atypically in other ancestries; this impression is contradicted by later reports of patients from India, South Africa and Pakistan [2, 7, 37, 63]. In the United States, the Texas paediatric series brought together 73 children from 47 families diagnosed in a single orthopaedic hospital between 1980 and 2009, which corresponds to a referral series and not to a prevalence [55]. In Europe, there are families published in Denmark, Norway, the Netherlands, Italy and the United Kingdom, and the Heidelberg and Amsterdam MRI series [2, 19, 40, 60]. CLSS has been described mainly in consanguineous families from Turkey (founder variant p.(Asp529Asn) in three families), Egypt (p.(Asp137Asn) in two), Pakistan, Jordan, Saudi Arabia, Algeria, Sri Lanka, the Maldives and China, and in an Orthodox Jewish family from the United Kingdom [5, 9, 18, 21, 35, 52, 53, 71, 74].

Portugal and Brazil

The recessive GJA1 variant p.(Arg239Gln) causing AR craniometaphyseal dysplasia was identified in a Portuguese family, a Brazilian family and a sporadic Brazilian patient, as well as in an Indian family [6]. In Brazil, two families with ODDD have been published, one with the homozygous variant p.(Arg202Cys) and the other with two heterozygous variants, and a girl from Recife with recessive ODDD due to homozygous c.565del [45, 46]. The sources consulted contain no frequency data for ODDD or CLSS in Portugal or Brazil. The EUROCAT registry gives for Portugal a birth prevalence of hypoplastic left heart syndrome of 5.5 per 100,000 (2009), a figure unrelated to GJA1, whose association with this heart defect has not been confirmed [6, 75].

Special populations

Adults with undiagnosed spastic paraparesis and leukodystrophy, and patients followed in adult neurology with negative panels, are the population in which the diagnosis of ODDD is made latest [40, 48]. Children with ulnar-sided syndactyly referred for hand surgery are the population in which the diagnosis can be made earliest [55]. Patients with childhood glaucoma and microcornea are another point of entry [16].

European reference networks and patient organisations

10. Illustrative Clinical Case

Oculodentodigital dysplasia with syndactyly and microphthalmia in an infant

In 2020 Kumar, Couser and Pandya published the case of an 8-month-old girl born to healthy non-consanguineous parents aged 37 (mother, of Native American ancestry) and 30 (father, of German and Irish ancestry) [16]. During pregnancy, second-trimester ultrasound detected an omphalocele and, later, possible syndactyly of the hands; she was born at 39 weeks weighing 3.552 kg, with a length of 50 cm and head circumference of 34.5 cm, and Apgar scores of 9 [16]. At birth she had a 4 cm omphalocele with bowel in the sac, operated on day 2, sparse fine hair, a small nose with hypoplastic alae and prominent columella, small palpebral fissures, microcornea, microphthalmia, a wide anterior fontanelle and retrognathia, complete syndactyly of the 4th and 5th fingers and webbing between the 3rd and 4th fingers of both hands; the echocardiogram showed a mild patent ductus arteriosus and patent foramen ovale [16]. At 4 months, ophthalmological examination showed deep anterior chambers, bilateral nasolacrimal duct obstruction, microphthalmia, 8 mm corneas, blond fundi and moderate hypermetropia [16]. Sequencing of GJA1 (NM_000165.3) identified the heterozygous variant c.65G>A p.(Gly22Glu), previously described in other patients with ODDD and with syndactyly type III, and deletion/duplication analysis was negative [6, 16]. At 8 months she still had feeding difficulties, with weight on the 9th centile and length on the 12th centile, and cognitive and motor delay [16]. The published figures, which were consulted, show the face (beaked nose with hypoplastic alae and prominent columella, microphthalmia, microcornea, small palpebral fissures, retrognathia; https://pmc.ncbi.nlm.nih.gov/articles/PMC7165356/figure/fig1/) and complete syndactyly of the 4th and 5th fingers of the right hand (https://pmc.ncbi.nlm.nih.gov/articles/PMC7165356/figure/fig2/) [16]. The case illustrates neonatal recognition through the association of ulnar-sided syndactyly, a characteristic nose and microphthalmia, and adds omphalocele, not previously described in ODDD [16]. The measures described — repair of the omphalocele, early ophthalmological assessment and GJA1 testing — match the approach recommended in the reference sources; the report does not describe brain MRI or an electrocardiogram, which are part of the surveillance proposed for ODDD [19, 22, 65].

Cenani-Lenz syndrome in a mild adult form

In 2024 Fu and colleagues described a 31-year-old Chinese man, born to non-consanguineous parents, with asymmetrical malformation of both hands: four metacarpals in each hand, a right first metacarpal that was distally slender, absent distal phalanx, disorganisation of the remaining phalanges, fusion of several phalanges and soft tissues and absent digits; in the right foot, syndactyly of the 2nd and 3rd toes [5]. The hands were more affected than the feet, the kidneys were normal on ultrasound, and there was no facial dysmorphism or cognitive impairment; the parents and sister had no phenotype [5]. The exome identified the homozygous variant c.282C>A p.(Asn94Lys) in LRP4 (NM_002334.4), absent from databases and classified as likely pathogenic [5]. Photographs and radiographs of the hands and a photograph of the foot are available at https://pmc.ncbi.nlm.nih.gov/articles/PMC10767612/figure/mgg32319-fig-0002/ [5]. The case shows that CLSS can occur without known consanguinity and without renal involvement, and that the diagnosis of a mild form may only be made in adulthood by exome sequencing [5].

11. Prognosis and Long-Term Follow-Up

Prognosis

In ODDD, life expectancy, intelligence and adult stature are generally normal [1, 11]. Morbidity has three main determinants. Glaucoma affects 16–17% of patients and led to blindness in 14% of the patients with glaucoma in the 2009 cohort [7, 16]. Neurological disease affects about 30% of families, usually begins from the second decade onwards and progresses slowly; some patients lose independent walking, such as the patient who needed a wheelchair from adulthood after gait disturbance since the age of 6 [7, 48]. Dental disease leads to tooth loss in at least 10% [7]. Sudden death and cardiomyopathy are rare but serious, with deaths at 14 months and at 24 years in one family [11, 64]. In CLSS, vital prognosis depends on renal involvement and on the variant type (biallelic truncating forms lethal in the prenatal period), and functional prognosis depends on the anatomy of the hand and the reconstruction; cognitive development is usually normal [9, 17, 24, 70].

Surveillance table

The following intervals derive from the recommendations of the reference textbooks and clinical curation and from the approaches described in series and reports; no guideline fixes them, and the frequency of assessments without a published interval is set by the treating team.

Lifelong follow-up

Follow-up of ODDD should continue into adulthood, because glaucoma and neurological disease are late complications and because oligosymptomatic carriers may have white matter changes without symptoms [11, 19, 40]. In CLSS, surveillance focuses on hand function and the kidney [9, 23].

12. Summary and Final Considerations

Oculodentodigital dysplasia is the main disease caused by variants in GJA1, the connexin 43 gene, and is defined by the association of a thin nose with hypoplastic alae, microphthalmia and microcornea, enamel hypoplasia, syndactyly of the 4th and 5th fingers and, in a proportion of patients, hypomyelinating leukodystrophy with spastic paraparesis and neurogenic bladder. Inheritance is almost always dominant, with high penetrance, highly variable expressivity and a dominant-negative mechanism; the recessive form results from loss of function and heterozygotes are healthy. The same gene causes isolated syndactyly type III, recessive craniometaphyseal dysplasia and two keratodermas, whereas the associations with Hallermann-Streiff syndrome, hypoplastic left heart syndrome and non-syndromic hearing loss have not been confirmed and, in part, resulted from the chromosome 5 pseudogene. Diagnosis rests on sequencing of GJA1 with exclusion of the pseudogene and, in adults with a neurological presentation, on recognition of an MRI pattern of hypomyelination with involvement of the middle cerebellar peduncle, pyramidal tract and medial lemniscus, which should prompt testing even without syndactyly. There is no targeted therapy or guideline; treatment is symptomatic and the priorities are lifelong ophthalmological surveillance for glaucoma, dental care, hand surgery, neurological and urological follow-up and cardiac assessment, because of the conduction disease and cardiomyopathy described in some families. Cenani-Lenz syndactyly syndrome results from biallelic loss of function of LRP4, which no longer antagonises LRP6-mediated Wnt signalling, and manifests as complex oligosyndactyly with metacarpal synostoses and phalangeal disorganisation, forearm shortening and, in more than half of families, renal agenesis or hypoplasia. The variant type is related to severity, from mild postaxial forms to lethal prenatal forms with truncating variants, and locus heterogeneity includes rearrangements of GREM1–FMN1 and an APC variant. Management includes hand reconstruction, renal surveillance and, in the rare patients with fatigable weakness, assessment for an associated congenital myasthenic syndrome. In both conditions, genetic counselling depends on the family's mode of inheritance and does not allow severity to be predicted from the variant.

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