Weill–Marchesani Syndrome, Acromelic Dysplasias and Isolated Ectopia Lentis (ADAMTSL4)

Disorders of the extracellular matrix microfibril network sharing fibrillin-1 as a common axis: Weill-Marchesani syndrome (microspherophakia, ectopia lentis, glaucoma, short stature and brachydactyly), geleophysic and acromicric dysplasias (acromelic short stature, with valvular and airway disease in the former) and autosomal recessive isolated ectopia lentis due to ADAMTSL4.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. A class defined by the microfibril

Weill-Marchesani syndrome (WMS), geleophysic (GD) and acromicric (ACMICD) dysplasias and Myhre syndrome form the group of acromelic dysplasias, so called because skeletal shortening mainly affects the distal segments of the limbs, the hands and the feet [5, 9]. The 2023 revision of the Nosology of genetic skeletal disorders retains this set as group 17 and lists in it the forms of GD linked to ADAMTSL2, FBN1 and LTBP3, the forms of ACMICD linked to FBN1 and LTBP3, the four forms of WMS (FBN1, ADAMTS10, ADAMTS17 and LTBP2), Myhre dysplasia (SMAD4), acrocapitofemoral dysplasia (IHH) and the acrodysostoses (PDE4D and PRKAR1A); tricho-rhino-phalangeal dysplasia was removed from the group and moved to the syndromic brachydactylies [5]. The atlas by Spranger and colleagues describes GD, ACMICD, WMS and Myhre syndrome as pathogenetically related members of a family of disorders with altered transforming growth factor β (TGFβ) signalling or altered interaction of TGFβ with fibrillin [29]. The proteins encoded by the genes of the class — fibrillin-1, the latent TGFβ-binding proteins (LTBP2 and LTBP3) and the metalloproteases and related proteins of the ADAMTS family (a disintegrin and metalloproteinase with thrombospondin motifs) — take part in the assembly and function of microfibrils, which form the zonular fibres that suspend the lens and which regulate the bioavailability of TGFβ in the growth cartilage, heart valves and airway [9, 10]. The same protein, fibrillin-1, produces a “tall” phenotype in Marfan syndrome, with ectopia lentis, dolichostenomelia and aortic aneurysm, and a “short” phenotype in the acromelic dysplasias, with short stature, short hands and joint stiffness, which gave rise to the expression “mirror image” of Marfan [30, 31].

This article covers the class in its entirety. It also includes autosomal recessive isolated ectopia lentis due to ADAMTSL4, which is not a skeletal dysplasia but belongs to the same protein family (the ADAMTS-like proteins, without catalytic activity) and is, after FBN1, the most frequent genetic cause of non-syndromic ectopia lentis in Europe [7, 32]. Marfan syndrome, heritable aortopathies and Myhre syndrome appear here in the differential diagnosis. Classic homocystinuria is another cause of ectopia lentis.

1.2. Historical milestones

Georges Weill described the association of lens ectopia with general malformations in 1932, and Oswald Marchesani published the combination of brachydactyly and congenital spherical lens as a systemic disorder in 1939 [1]. Meyer and Holstein reported in 1941 four siblings, children of consanguineous parents, with short stature, spherophakia with glaucoma and brachydactyly, and Probert described in 1953 a family with vertical transmission in which he noted the resemblance to Marfan syndrome [1, 2]. The dominant form was named GEMSS syndrome (glaucoma, ectopia lentis, microspherophakia, stiffness and short stature) by Verloes and colleagues in 1992, based on a family with three affected generations [2]. The historical synonyms “spherophakia-brachymorphia syndrome” and “congenital mesodermal dysmorphodystrophy” still appear in the literature [9].

The molecular basis was clarified in stages. Wirtz and colleagues linked the dominant form to the FBN1 locus in 1996 and Faivre and colleagues identified an in-frame 24-base-pair deletion in this gene in 2003 [2, 33]. The recessive form was mapped to 19p13 in Lebanese and Saudi families (lod score 5.99) and attributed to ADAMTS10 by Dagoneau and colleagues in 2004 [1, 34]. Morales and colleagues described in 2009 biallelic ADAMTS17 variants in Saudi families with a condition they called “Weill-Marchesani-like”, because the patients had neither brachydactyly nor joint stiffness [3, 35]. Haji-Seyed-Javadi and colleagues associated LTBP2 with a consanguineous Iranian family in 2012 [36]. Shah and colleagues proposed in 2014 that the combination of microspherophakia and short stature with variants in a WMS gene suffices for a diagnosis of WMS, without the qualifier “like” [3].

Spranger and colleagues described GD in 1971 in a letter to The Lancet, in which they proposed the name from two Greek terms meaning “happy” and “nature” (physis), because of the “good-natured” facial appearance of the children, and suggested that it was a “focal” mucopolysaccharidosis [4, 37, 38]. Urinary mucopolysaccharide excretion was normal, and later studies showed lysosome-like inclusions staining for neutral glycoprotein in the skin, liver, trachea, cartilage and valves [4, 38]. Spranger's first patient was re-evaluated at 48 years by Legare and colleagues, who documented his ADAMTSL2 variants [4, 39]. Le Goff and colleagues identified ADAMTSL2 in 2008, from four consanguineous families of French Polynesian, Moroccan, Algerian and Pakistani origin, and in 2011 showed that heterozygous variants in the TB5 domain of fibrillin-1 cause both GD and ACMICD [40, 41]. McInerney-Leo and colleagues added LTBP3 in 2016 [42].

Maroteaux and colleagues named ACMICD in 1986, based on six sporadic cases with a mildly dysmorphic face, very short hands and feet and characteristic metacarpal notches; they later observed the disorder in a mother and son [11]. Moore-Federman syndrome, published in 1965 as “familial dwarfism and stiff joints”, is now considered the same entity [5, 6].

Ectopia lentis et pupillae was recognised as a recessive disorder by Siemens in 1920 and by Franceschetti in 1927 [16]. Al-Salem described two Arab families with recessive isolated ectopia lentis in 1990, and Ahram and colleagues identified in 2009, in one of these families, a homozygous nonsense variant in ADAMTSL4 [15, 43]. Christensen and colleagues showed in 2010 that ectopia lentis et pupillae in five Norwegian families resulted from the same 20-base-pair deletion, demonstrating that the isolated form and the form with pupillary displacement are expressions of the same gene [16, 44].

1.3. Operational definitions

Ectopia lentis is defined as displacement of the lens from its normal position due to stretching or rupture of the zonular fibres, with acute or chronic visual disturbance [15]. Microspherophakia is a small, spherical lens, with an increased anteroposterior diameter and a reduced equatorial diameter, whose equator is visible with the pupil maximally dilated [45, 46]. In WMS there are no consensus diagnostic criteria; diagnosis rests on suggestive clinical findings and is confirmed by identification of biallelic variants in ADAMTS10, ADAMTS17 or LTBP2, or of a heterozygous variant in FBN1 [9]. In the largest series assembled, ophthalmological anomalies were described as mandatory for diagnosis [21]. GD and ACMICD also have no published consensus criteria; clinical diagnosis rests on the combination of clinical and radiological findings and molecular diagnosis on the finding of variants in ADAMTSL2, FBN1 or LTBP3 [10]. The Spranger atlas recommends reserving the designation “geleophysic dysplasia” for the originally described recessive form, although OMIM and the Nosology use the term for all three genetic forms [5, 29]. ADAMTSL4-related eye disorders form a continuum ranging from isolated ectopia lentis to ectopia lentis et pupillae and to minor anomalies without pupillary displacement [7].

2. Molecular Genetics and Pathophysiology

2.1. The microfibril, the zonule and TGFβ

Fibrillin-1 is a glycoprotein of about 350 kDa, ubiquitously expressed, which aggregates into microfibrils about 10 nm in diameter [10]. It has a modular structure with 46 to 47 epidermal growth factor (EGF)-like domains, 42 to 43 of which bind calcium, interspersed with seven eight-cysteine modules (TB domains, from TGFβ-binding protein-like), which exist only in fibrillins and LTBPs, and it contains binding sequences for the integrins α5β1, αvβ3 and αvβ6 [10]. Microfibrils are the non-collagenous scaffold of soft and hard matrices and control the storage, distribution, release and activation of locally produced TGFβ and bone morphogenetic proteins (BMPs) [10]. Fibrillin is abundant in the wall of the proximal aorta and in the lens zonules, which explains the convergence of ectopia lentis and aortopathy in Marfan syndrome [47].

In the acromelic dysplasias, alteration of the microfibrillar network and increased TGFβ bioavailability have been demonstrated in patient fibroblasts [10, 26]. In the original ADAMTSL2 study, total TGFβ in the culture medium of fibroblasts from patients with GD was ten times higher than in controls, and the active fraction represented 85% and 92% of the total, versus 7% in controls [10, 40]. Marzin and colleagues proposed that excess TGFβ induces aberrant inflammation and fibrosis in the valves and airway, based on histological analysis of a surgically removed mitral valve, which showed collagen accumulation with severe fibrosis encasing the chordae tendineae and no glycosaminoglycan deposition [26]. This hypothesis was challenged in 2026: in fibroblasts from patients with GD, basal TGFβ1 secretion was reduced, transcriptomic analysis showed no pathway activation and phosphorylation of SMAD proteins did not differ from controls [48]. The exact mechanism therefore remains under discussion; what is consistent across studies is the disorganisation of the microfibrillar network [10, 48]. The 2021 French PNDS (French National Diagnosis and Care Protocol) also links the pulmonary hypertension of these dysplasias to the TGFβ/ALK1/endoglin pathway, based on animal models of pulmonary hypertension unrelated to the acromelic dysplasias and without demonstration in patients [22].

2.2. Weill-Marchesani syndrome genes

ADAMTS10 (19p13.2) and ADAMTS17 (15q26.3) encode zinc metalloendopeptidases of the ADAMTS superfamily, with roles in the formation, remodelling and degradation of the extracellular matrix [9]. The ADAMTS10 protein interacts directly with fibrillin-1 and promotes its deposition in the matrix of cultured fibroblasts [9]. ADAMTS10 is expressed in skin, fetal chondrocytes and the fetal and adult heart [1]. A variant in the ADAMTS10 signal peptide impairs secretion of the complete enzyme, a distant effect described by Kutz and colleagues in an 86-year-old patient [1]. In mice, combined inactivation of Adamts10 and Adamts17 causes postnatal lethality and more severe bone shortening, with narrowing of the hypertrophic zone of the growth plate; fibronectin and collagen VI were identified as potential substrates of ADAMTS17, and in deficient fibroblasts fibronectin deposition was impaired and fibrillin-1 accumulated inside the cell [49]. ADAMTS17 appears to regulate the secretion or pericellular assembly of the matrix, whereas ADAMTS10 would act at later stages [49].

LTBP2 (14q24.3) encodes a matrix protein that associates with fibrillin-1 microfibrils; in fibroblasts from patients with LTBP2-related WMS, the microfibrillar network was disorganised [9]. The association with WMS rests on a single consanguineous Iranian family, homozygous for the missense variant V1177M, and is still flagged as provisional in OMIM [12, 36]. LTBP2 variants more often cause primary congenital glaucoma, isolated microspherophakia and the syndrome of microspherophakia and/or megalocornea with ectopia lentis, with or without secondary glaucoma (#251750) [9, 50].

FBN1 (15q21.1) causes the dominant form of WMS. The first variant identified in the dominant form was an in-frame 24-base-pair deletion, in the family described by Gorlin [2, 33]. In 2020 GeneReviews counted nine probands with FBN1-related WMS, three of them with deletions or duplications detectable only by dosage methods [9]. In the series of 61 patients published in 2024, patients with an FBN1 variant in the TB5 domain were significantly shorter than those with FBN1 variants outside that domain (p = 0.0040) [21].

The precise mechanism of WMS variants has not been elucidated [9]. Mouse data for ADAMTS17 point to failure of microfibril-dependent BMP signalling in the growth plate: in the Adamts17-null mouse the hypertrophic zone is shorter, there is more fibrillin-2 and less phosphorylated SMAD1, and terminal chondrocyte differentiation is restored with BMP [51].

2.3. Genes of geleophysic and acromicric dysplasias

ADAMTSL2 (9q34.2) encodes an ADAMTS-like glycoprotein, without enzymatic activity, whose identified partner is LTBP1, the protein that stores latent TGFβ in the matrix [10]. The mutant proteins are synthesised and maintain normal intracellular levels, but their extracellular concentration is reduced, suggesting misfolding with deficient secretion [10]. The mechanism is loss of function [10]. A patient with two nonsense alleles has never been described, which suggests embryonic lethality; patients have two missense variants or one missense and one nonsense variant, distributed throughout the gene [10, 26]. A 30-base-pair deletion in the N-linked glycan-rich module has been described and is detectable by sequencing [10]. In mice, the patient variant p.D167N reproduces the reduced survival, short stature, growth plate shortening, aortic valve dysplasia and bronchial obstruction of the human disease [52].

In FBN1-related GD and ACMICD, all known variants are missense and lie in exons 41 and 42, which encode the TB5 domain [10, 11, 13]. This domain has eight cysteines joined by four disulphide bridges, essential for protein folding [10]. Half of the variants create or remove a cysteine [10]. The mechanism is dominant negative [10]. Patient fibroblasts have fewer microfibrils and a disorganised microfibrillar network [10]. The same domain can give the opposite phenotype: in a French national laboratory that has studied more than 5000 probands with suspected Marfan since 1996, five patients with classic Marfan had in-frame variants in the TB5 domain, one of them at an amino acid previously implicated in GD [30].

LTBP3 (11q13.1) encodes a protein of the LTBP family, with 13 EGF-like repeats and four TB domains, incorporated into the matrix through fibrillin-1 and involved in the secretion, capture and activation of TGFβ [10]. The heterozygous variants associated with GD disorganise the microfibrillar network, but TGFβ signalling is not increased [10]. LTBP3 has two disorders with different inheritance: the dominant form (GD3 and ACMICD) and the recessive form, with dental anomalies and short stature (#601216), also called brachyolmia with amelogenesis imperfecta [10, 51]. Aortic root dilatation and mitral prolapse have been described in siblings with the recessive form and rare variants in thoracic aortic aneurysm cohorts; this is an association proposed in small series, not curated or included in aortopathy guidelines [51].

2.4. ADAMTSL4 and the zonule

ADAMTSL4 (1q21.2) has several isoforms; the MANE reference transcript is NM_019032.6, whose numbering coincides with that of NM_019032.4 used in GeneReviews, and the longest isoform has 1097 amino acids (NP_061905.2) [7, 53]. The protein has no metalloprotease domain and is therefore catalytically inactive; it contains seven thrombospondin type 1 repeats, a cysteine-rich module, a spacer domain and a PLAC domain, is secreted and glycosylated, co-localises with fibrillin-1 and increases its deposition [7]. In the eye it is expressed in the iris, ciliary body and retinal pigment epithelium; in the mouse, expression is intense at the lens equator, where the zonular fibres insert [7]. The Adamtsl4-null mouse develops zonular detachment and dedifferentiation of the pigment epithelium, and the model explains the human disease by deficient assembly of fibrillin-1 into microfibrils and, above all, deficient anchoring of microfibrils to the lens [7]. Most pathogenic variants introduce a premature stop codon; some are missense in critical regions, such as p.(Arg746His) in the first thrombospondin repeat [7].

2.5. Variant spectrum and founder variants

The Norwegian ADAMTSL4 deletion has a common ancestor estimated at about 150 generations, that is, about 4000 years [16]. In western Norway, 3 of 190 blood donors were heterozygous, corresponding to a homozygote frequency of about 1/16,000, with a wide confidence interval; in a German study, 2 of 360 individuals were carriers [7]. In Bukharian Jews, the c.2594G>A carrier frequency of 1/48 predicts about 1/9000 homozygotes [7].

2.6. Genotype–phenotype correlations

In WMS, the 2020 GeneReviews recognised no genotype–phenotype correlations, owing to the scarcity of cases [9]. The 2024 series showed that the TB5 domain of FBN1 is associated with shorter stature [21]. The review of 128 cases by Faivre and colleagues found differences in frequency between recessive and dominant forms: microspherophakia in 94% and 74%, ectopia lentis in 64% and 84%, joint limitation in 49% and 77% and cardiac anomalies in 39% and 13%, respectively [1, 59]. Among patients with ADAMTS17, microspherophakia and short stature were constant, whereas brachydactyly, stiffness, glaucoma, cataract and cardiac changes were inconstant [3]. In a review of 19 patients with ADAMTS10, microspherophakia and high myopia were present in all, glaucoma in 47.4% and heart disease in 55.6% of the 18 previously published cases [55].

In GD and ACMICD, the Necker Hospital cohort showed that valvular disease was more likely with FBN1 variants involving a cysteine (43% versus 0%, p = 0.0072), that mitral valve dysplasia predominated with FBN1 and pulmonary stenosis with ADAMTSL2, and that the 13 patients with a severe cardiorespiratory outcome had ADAMTSL2 variants, cysteine-involving FBN1 variants or LTBP3 splice or stop-loss variants; no patient with a good outcome had a cysteine-involving FBN1 variant [26]. A Chinese cohort of 14 patients with TB5 variants, integrated with 52 published patients, estimated mortality at 29.6% (95% CI 15.9–48.5%) in GD2 and 4.0% (0.7–19.5%) in ACMICD (p = 0.038), and associated cysteine or aromatic residue substitutions with higher mortality (p < 0.001) [58]. Patients with ADAMTSL2 and with FBN1 do not differ clinically in the main features [10, 26]. In the series by Allali and colleagues, toe walking was recorded in 88% of patients with ADAMTSL2 and in 18% of those without variants in this gene, and facial dysmorphism was more frequent with ADAMTSL2, whereas short stature was more severe in patients without ADAMTSL2 [4, 60]. Patients with LTBP3-related GD have had no valvular disease to date, but two died of respiratory failure in early childhood [10, 14].

In ADAMTSL4-related disease there are no clinically useful correlations; the same variant causes isolated ectopia lentis or ectopia lentis et pupillae, and the phenotype varies within the family and between the two eyes of the same patient [7]. In the 2026 European series, all cases of ectopia lentis et pupillae carried c.767_786del [23].

2.7. Inheritance, penetrance and allelic disorders

FBN1-related WMS, FBN1- or LTBP3-related GD and ACMICD are autosomal dominant; WMS due to ADAMTS10, ADAMTS17 and LTBP2, ADAMTSL2-related GD and ADAMTSL4-related eye disease are autosomal recessive [7, 9, 10]. Penetrance of WMS is considered complete, with variable expressivity within and between families [9]. Reduced penetrance has not been described in dominant GD [10]. Some heterozygotes for recessive forms of WMS have been described with mild manifestations, but carriers are as a rule asymptomatic [1, 9]. Ectopia lentis et pupillae showed apparent dominant transmission in isolated families, more probably explained by pseudodominance [16].

3. Clinical Spectrum and Manifestations by System

3.1. Weill-Marchesani syndrome

Data sources. Clinical knowledge of WMS comes from three types of source: the review of 128 cases published up to 2003 (57 recessive, 50 dominant and 21 sporadic), most without molecular confirmation [1, 59]; the 2020 GeneReviews, which brings together the authors' clinical experience [9]; and the 2024 French series, with 18 new and 43 published patients, all with an identified pathogenic variant (21 ADAMTS17, 19 FBN1, 19 ADAMTS10 and 2 LTBP2) [21]. The frequencies from these sources are not comparable with each other, because inclusion criteria and periods differ.

Eyes. Ocular anomalies are the hallmark of the syndrome and, in the 2024 series, were present in all patients, with spherophakia in 42/61 and ectopia lentis in 39/61 [21]. The eye problem is recognised at a mean age of 7.5 years [9]. Microspherophakia causes lenticular myopia, usually the first finding, which is distinguished from axial myopia by the normal or short axial length of the eye [9, 51, 55]. Ectopia lentis usually displaces the lens downwards [9]. Glaucoma is the most serious complication and can lead to blindness; it results mainly from pupillary block, due to anterior displacement of the spherical lens or dislocation into the anterior chamber [9]. The mechanisms described include anterior displacement of the iris by the spherical lens with peripheral anterior synechiae and angle closure, increased iridolenticular contact with pupillary block, angle dysgenesis and ciliary body hyperplasia [55]. In an Indian series of 159 eyes of 80 patients with microspherophakia (18 with WMS and 3 with Marfan), glaucoma was present in 51% of eyes, mean age was 20 ± 13 years, mean refractive error −13.5 ± 5.5 dioptres and mean intraocular pressure (IOP) 27.7 ± 11.1 mmHg; the angle was closed in 75% and open in 25%, there was subluxation in 53 eyes and dislocation in 14, and about 20% of eyes were blind from glaucoma at presentation and 30% at the last visit [62]. Visual loss is earlier and more severe than in other lens dislocation syndromes, and blunt trauma can precipitate dislocation and pupillary block [9]. Central corneal thickness is increased (622.07 ± 26.13 μm in 14 patients, versus 549.97 ± 25.78 μm in 40 controls), which leads to overestimation of IOP measured by applanation [9, 55]. Isolated cases have been described of presenile vitreous liquefaction in a dominant family, retinal vascular tortuosity, pigmentary retinopathy in a 14-year-old girl and corneal endothelial dysfunction with advanced glaucoma in a 30-year-old woman [9]. Two Chinese siblings aged 32 and 42 years with ADAMTS17 variants had high myopia, ectopia lentis and secondary glaucoma, as well as short stature and brachydactyly [63]. In 2026, posterior lens dislocations in LTBP2-related WMS were published, one spontaneous and the other with rhegmatogenous retinal detachment [64, 65].

Growth. Short stature was described in all patients in GeneReviews, with growth deceleration in the first years of life, and adult height ranges from 142 to 169 cm in men and from 130 to 157 cm in women [9]. In the 2024 molecular series, short stature was present in 73% of patients, between −2.2 and −5.5 standard deviations (SD), and was more marked with FBN1 TB5 variants [21]. In several families with ADAMTS17, short stature was the only systemic finding [3]. There are no data on the efficacy of growth hormone in WMS [9].

Musculoskeletal system. Findings include brachydactyly, short metacarpals, prominent metacarpophalangeal and interphalangeal joints, progressive stiffness of the fingers, wrists, shoulders, hips, knees and ankles and a pseudomuscular build [9]. Radiology shows shortened long tubular bones, delayed bone age and broad proximal phalanges [9]. Osteoporosis has been described in a 28-year-old man 130 cm tall [1].

Heart and vessels. Cardiac anomalies are frequent: patent ductus arteriosus, pulmonary stenosis, aortic stenosis (including fibromuscular subvalvular stenosis) and mitral prolapse [1, 9]. Kojuri and colleagues found a QTc interval greater than 0.46 s in 3 of 6 patients and mitral prolapse in 3 [1]. Thoracic aortic aneurysm and cervical artery dissection have been described in a three-generation family with FBN1-related WMS [9]. In the 2024 series, 10 of 61 patients had valvular disease [21]. The 2003 review recorded cardiac anomalies in 39% of recessive cases and 13% of dominant cases [59].

Skin, development and other features. The skin is tight, with thickened folds [9]. Intellectual disability was recorded in 11% to 17% of patients and is always mild [9]. The oldest documented patient was 86 years old, with severe glaucoma that had left him blind and normal intellect [1]. Cases of tracheal stenosis have been described in WMS; hepatomegaly, frequent in GD, is not part of the picture [22].

3.2. Geleophysic dysplasia

Data sources. About 100 patients have been published: 51 in two French cohorts (Allali 2011 and Marzin 2021) and the rest in case reports [10]. The Necker Hospital cohort from 2008 to 2018 included 22 patients with GD (12 ADAMTSL2, 8 FBN1, 2 LTBP3), with a mean age of 12.3 years, 8 of whom had died [26]. Table 3.1 summarises the frequencies from the 2024 GeneReviews, which incorporate that cohort.

Table 3.1. Frequency of manifestations of geleophysic dysplasia [10]

Prenatal period and growth. In the Necker cohort, 70% of patients with GD had prenatal ultrasound signs (polyhydramnios in 10, short long bones in 8, growth restriction in 6, at a mean of 31.5 weeks), but no diagnosis was made before birth [26]. Rosser and colleagues saw no limb shortening on ultrasound before 28 weeks [4]. About 40% to 45% have a birth length below the 5th centile [10, 26]. Final height is 3 to 6 SD below the mean, with normal head circumference and relative macrocephaly [10]; in the Necker cohort mean stature was −4.6 SD and the four adults measured 115 and 143 cm (men) and 130 and 137 cm (women) [26]. The Spranger atlas gives adult heights between 140 and 150 cm [29]. The PNDS, based on the same cohort, reports normal birth weight and length in 60% of patients with GD or ACMICD, with birth weight around the 30th centile and length around the 15th centile in GD, and growth retardation established in the first year of life in all; head circumference is always normal and bone age always delayed [22].

Face and skin. The face is round and full, with a short nose and anteverted nares, a broad nasal bridge, upslanting palpebral fissures, a long smooth philtrum, a thin upper lip and a wide mouth with upturned corners, and becomes coarser with age [10, 38]. The skin is thick and tight [10]. The voice may be high-pitched [29]. The PNDS adds hypertelorism and describes narrow palpebral fissures [22].

Musculoskeletal system. The hands and feet are very short from birth, and progressive joint limitation with skin thickening leads to toe walking, contractures of the large joints and limitation of the wrists and hands [10]. Radiology shows short, broad tubular bones in the hands and feet, broad proximal phalanges, cone-shaped epiphyses, small or dysplastic femoral epiphyses, markedly delayed bone age, ovoid vertebral bodies and, in some patients, a J-shaped sella turcica; proximally pointed metacarpals and “bullet-shaped” phalanges resemble dysostosis multiplex [29, 38]. Hip dysplasia, osteochondritis and carpal tunnel syndrome are frequent complications [10]; across the Necker cohort (GD and ACMICD), hip dysplasia affected 70%, osteochondritis 43% and carpal tunnel 35% [26]. Stiffness begins at the extremities, with progressive loss of finger mobility; toe walking follows, due to a short, infiltrated Achilles tendon, and then involvement of the elbows and shoulders; carpal tunnel syndrome appears mainly in adulthood [22]. Spinal alignment may show lumbar hyperlordosis or scoliosis, which the PNDS requires to be interpreted with the pelvic parameters (pelvic incidence and sacral slope), because lordosis may compensate for a hip flexion deformity [22]. Among the radiological signs, the PNDS also lists coxa vara or valga with hip dysplasia, a small femoral head, sometimes with a medial notch, and moderate platyspondyly [22].

Heart. Valvular thickening is postnatal and becomes evident in the first year of life [10]. In the Necker cohort, 15 of 22 patients (68%) had valvular disease: pulmonary stenosis in 8/15, mitral regurgitation in 5/15, mitral stenosis in 5/15 and aortic stenosis in 4/15, with multivalvular involvement in 23% [26]. Two profiles were distinguished: stable valvular disease, detected at a mean of 2.8 years (1 to 10 years), and rapidly progressive valvular disease, starting in the first year and responsible for early heart failure; of the nine patients with progressive disease, six underwent valve replacement (four in the first year of life), three were considered unfit for surgery and five died [26]. Atrioventricular septal defect occurred in 3 of 22 [26]. In older series, all survivors had cardiac involvement, sometimes mild [38]. Bicuspid aortic valve has been described in two siblings [4]. The PNDS ranks the lesions, in decreasing order of frequency, as mitral, pulmonary, aortic and tricuspid, an order taken from a Saudi family series and different from the distribution in the Necker cohort, in which pulmonary stenosis was the most frequent lesion; it also describes left intraventricular obstruction and ventricular diastolic dysfunction, and states that about 30% to 40% of children with valvular disease eventually undergo surgery [22, 26].

Lung and pulmonary hypertension. Chronic or acute pulmonary hypertension, multifactorial (mitral valve disease, interstitial disease and airway obstruction), occurred in 40% and may fluctuate, worsened by infection or surgery [10, 26]. All patients with progressive valvular disease had severe respiratory failure with chronic interstitial disease on CT, and total lung capacity was below 50% in the two in whom it was measured; there was also unexplained restrictive disease [26]. Asthma occurs in 30% to 40% [10].

Airway and ear. Multilevel airway obstruction (laryngeal or tracheal stenosis, laryngomalacia, tracheomalacia, bronchomalacia) was detected in 30%, mainly in the first year, often following a failed extubation, and tends to progress; in the Necker cohort it caused four deaths despite endoscopic treatment [10, 26]. The stenoses are active inflammatory lesions that any stimulus can aggravate [26]. Intermittent conductive hearing loss results from recurrent otitis and adenoid hypertrophy; obstructive sleep apnoea accompanies adenoid hypertrophy [10, 26]. The stenoses are initially inflammatory and granulomatous; the appearance of an evolving laryngotracheal lesion marks a turning point in the course of the disease and is a poor prognostic factor, and the course in adulthood remains poorly described [22]. Adenotonsillar hypertrophy is not specific, but has greater impact in these children because of their body type, and sleep apnoea should be sought early [22].

Eyes. Refractive errors (hypermetropia, myopia, astigmatism) affect about 40% of children [10]. Optic disc swelling without intracranial hypertension (pseudopapilloedema) has been described in asymptomatic patients; one patient in the Necker cohort had intracranial hypertension and needed a ventriculoperitoneal shunt at 10 years [26]. Glaucoma, corneal and lens thickening, vertical gaze palsy and microspherophakia in an adult have been reported occasionally [29, 38]. Reports from 2026 added optic disc drusen with ganglion cell dysfunction in a 3-year-old child with FBN1, and bilateral glaucoma with keratoconus-like corneal ectasia in a 29-year-old woman with ADAMTSL2 [66, 67]. The PNDS also mentions strabismus and Brown syndrome, considers pseudopapilloedema a rare complication of GD and ACMICD, and cites a 9-year-old child with GD and bilateral angle-closure glaucoma, treated with bilateral YAG laser iridotomy and, because of persistent ocular hypertension, with trabeculectomy with mitomycin C (0.2 mg/mL for 2 minutes), stable 3 years later [22].

Liver and other organs. Hepatomegaly occurs in about 40%, is not accompanied by liver disease and is partly related to right heart failure [10]. Cirrhosis with portal hypertension was reported in a 76-year-old man with FBN1-related GD, with no other cause identified; the authors could not establish a causal relationship [68]. Two patients had hypothyroidism [10]. Intellect is normal [10]. There is no disturbance of pubertal development; a mild language delay may accompany conductive deafness due to otitis media with effusion and recovers after the deafness is treated [22].

Natural prognosis. About one third of children die before 5 years of age, from a combination of cardiac, airway and pulmonary disease [10]. The oldest known living patient is 62 years old [10]. Spranger's first patient, re-evaluated at 48 years, had a high-pitched voice, thick skin, pectus excavatum, multiple contractures that obliged him to use a walking frame, severe and progressive restrictive lung disease, early cataracts and moderate to severe hearing loss; his childhood intelligence quotient of 74 had given way to almost normal cognitive function in adulthood [4, 39]. The French PNDS gives a similar figure, with death before 6 years in 30% of cases [22].

3.3. Acromicric dysplasia

ACMICD presents in early childhood with short stature, with normal birth length and a progressive fall across centiles [6, 11]. The face is round, with well-defined eyebrows, long eyelashes, narrow palpebral fissures, a short bulbous nose with anteverted nares, a long prominent philtrum, thick lips and a small mouth; the dysmorphism becomes less marked in the adult [6, 11]. The voice is hoarse and the build pseudomuscular [11]. The hands and feet are disproportionately short, with joint limitation mainly of the fingers [6]. Radiology shows the internal notch of the second metacarpal, the external notch of the fifth metacarpal and the internal notch of the femoral head, as well as delayed bone age and small, rounded femoral epiphyses in childhood [6, 11]. In the series of 22 patients by Faivre and colleagues, mean adult height was 130 cm [11]; the atlas gives 115 to 140 cm [6]; in the Necker cohort mean stature was −5.2 SD and the adults measured 119, 122 and 134 cm (women) and 140 cm (man) [26]. The metacarpal notches result from thickening of the tendons that insert there and can be seen from the first year; in a series of nine patients with FBN1 variants (5 to 64 years), the cone-shaped epiphyses and the notch of the 5th metacarpal became less marked with age, whereas the internal notch of the femoral head persisted into adulthood [22].

Life expectancy is good, but the disorder is not confined to the skeleton [26]. Otitis, tracheal and respiratory complications, adenoid hypertrophy, obstructive sleep apnoea and carpal tunnel syndrome, diagnosed at a mean age of 30 years, are frequent [6, 26]. In a series of 22 patients from 15 families, 4 had non-progressive heart disease (2 with bicuspid aortic valve and 2 with atrial septal defect) and 8 of 20 had myopia [10]. In the Necker cohort, 2 of 16 had non-progressive mitral thickening, detected at 6 and 40 years; there was unexplained restrictive lung disease, episodes of acute respiratory failure with pulmonary hypertension triggered by infection at 50 years and one death at 6 years from acute pulmonary oedema with pulmonary hypertension after rigid endoscopy [26]. In the Chinese series of TB5 variants, cardiopulmonary involvement (50%) was limited to patients with GD2 [58]. In the same cohort, 7 of the 16 patients with ACMICD had an asthma-like obstructive disorder and 7 of those who underwent lung function tests had a restrictive syndrome; there were two episodes of pulmonary hypertension, associated with pulmonary oedema and viral infection, and atrial or ventricular septal defects may be present [22].

3.4. ADAMTSL4-related eye disease

The disease manifests early: in the European series of 41 patients from 32 families, the median age at diagnosis was 1.3 years, and 0.5 years in those with ectopia lentis et pupillae, who made up one third [23]. In a British comparison of 16 patients with isolated ectopia lentis, the median age at diagnosis was 2 years with ADAMTSL4 and 35 years with FBN1 (p < 0.01) [32]. Dislocation may be present at birth; in mild forms it is recognised only in adulthood [7].

The lens is displaced in any direction through loss of zonular fibres without prior trauma, may be spherophakic or have a coloboma, and is accompanied by iridodonesis [7]. In the European series, subluxation was mainly inferior (about 33%) and the zonules were absent in most eyes [23]. When the pupil is displaced, the lens moves in the opposite direction [7]. Iris signs include enlarged iris processes with an abnormal angle, a deep anterior chamber, a thin, flat, cryptless iris with transillumination, peripupillary fibrosis with poor response to mydriatics and persistent pupillary membrane [7, 16].

Refractive errors dominate the picture. Hypermetropia (+5 to +15 dioptres) arises when the lens leaves the visual axis and the eye becomes functionally aphakic; myopia (−5 to more than −15 dioptres) results from axial growth, spherophakia or coloboma; astigmatism is often high [7]. The mean spherical equivalent in the European series was −10.27 dioptres, and the mean axial length in the British series was 27.54 mm with ADAMTSL4, versus 22.74 mm with FBN1 (p < 0.01) [23, 32]. Anisometropia and uncorrected errors lead to amblyopia, whose risk is greatest when the lens edge lies 0.3–2.3 mm from the centre of the pupil [7].

Cataract is early: in a Norwegian series, all affected individuals over 45 years had undergone surgery [7, 16]. IOP is raised in 20% to 25% of patients, and anterior subluxation can cause an acute rise; the median central corneal thickness of 589 μm (528–630) partly explains why few patients have glaucomatous optic nerve damage [7]. Retinal detachment is more frequent than in the general population, sometimes as a complication of lens surgery [7]. Lens displacement and cataract progress; pupillary displacement is stable [7]. Visual acuity ranges from light perception to 10/10, and some patients with markedly displaced pupils see normally [7].

The disease is usually isolated; some patients have had craniosynostosis, flat feet, pectus carinatum, scoliosis or joint laxity [7]. In the Norwegian series stature was normal, echocardiography (in two patients) and plasma homocysteine (in two) were normal and there were no Marfan or WMS features [16].

3.5. Rare forms of the class

The contiguous deletion of ADAMTS17 and CERS3 at 15q26.3 combines the manifestations of WMS (short stature, brachydactyly with stiffness, microspherophakia, ectopia lentis and mitral dysplasia) with a collodion membrane at birth and generalised ichthyosis, the latter attributed to partial loss of CERS3 [3, 61]. LTBP2-related WMS includes, in the original Iranian family, siblings with pulmonary and aortic stenoses, brachydactyly and stiffness without ocular findings, suggesting variable expressivity [12]. In LTBP3-related GD, a mother required an emergency tracheostomy after failed intubation for caesarean section, due to pre-existing subglottic stenosis [14].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

Prenatal period. Polyhydramnios, short long bones and third-trimester growth restriction occur in a large proportion of fetuses with GD, but are not specific and did not allow prenatal diagnosis in any case of the Necker cohort [26]. Limb shortening may not be visible before 28 weeks [4, 29]. A prenatal diagnosis of GD1 was published in 2026 in a family with recurrent increased nuchal translucency and hydrocephalus [69].

Newborn and infant. Small hands and feet at birth, a full face, finger stiffness, stridor, failed extubation, a heart murmur or heart failure in the first year, hepatomegaly and recurrent otitis should lead to consideration of GD [10, 26]. Congenital pupillary displacement, a flat iris with transillumination or a lens displaced at birth suggest ADAMTSL4-related disease [7]. The PNDS summarises the most common reason for suspicion in GD and ACMICD: growth retardation established in the first year of life, with preserved head circumference, short hands and feet and the dysmorphism characteristic of each entity; in the neonatal period, cardiorespiratory complications may be the first sign of GD [22].

Preschool and school age. In WMS, the presenting sign is often high, progressive myopia in a short child with short hands; in isolation, this myopia is easily misinterpreted, and some patients with ADAMTS17 have been diagnosed with isolated high myopia or primary angle-closure glaucoma [51, 55]. A child with short hands and feet, joint stiffness, stature below −3 SD and a hoarse voice, without valvular disease, suggests ACMICD [6, 11]. Ectopia lentis without trauma is always a sign of systemic disease until proven otherwise: slit-lamp examination is indispensable and Marfan syndrome and homocystinuria should always be considered [70, 71].

Adolescent and adult. Acute angle-closure glaucoma in a young person with high myopia and a shallow anterior chamber should suggest microspherophakia [9, 62]. Unexpected difficult intubation, the need for tracheostomy after surgery or early carpal tunnel syndrome in a short adult with short hands are late forms of presentation of the acromelic dysplasias [14, 26].

4.2. Warning and emergency signs

4.3. Newborn screening

None of these disorders is included in newborn screening [7, 9, 10]. In the presence of ectopia lentis, classic homocystinuria requires targeted investigation: with normal urinary amino acids and strong clinical suspicion, plasma amino acids are measured and a metabolic diseases consultation is requested, and pyridoxine-responsive forms present later [47, 72].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Suggestive findings and criteria

There are no consensus diagnostic criteria for any of the entities in this article [7, 9, 10]. The findings that GeneReviews considers suggestive are summarised in Table 5.1.

Table 5.1. Suggestive findings by entity

Table S1 of the Necker cohort used clinical and radiological criteria to separate GD from ACMICD: GD is distinguished by the “good-natured” face, toe walking, progressive valvular disease, airway stenosis and hepatomegaly, and ACMICD by the metacarpal and femoral notches, hoarse voice and good prognosis [26].

The revised Ghent nosology defines “ectopia lentis syndrome” as ectopia lentis with or without systemic features and with an FBN1 variant not associated with aortic dilatation, or without an FBN1 variant; in an index case without a family history, ectopia lentis with an FBN1 variant already associated with aortic root dilatation constitutes Marfan syndrome [47, 73]. In Loeys-Dietz syndrome there is no ectopia lentis, and the presence of ectopia lentis excludes the MASS and mitral valve prolapse phenotypes [47, 70].

5.2. Ophthalmological examination

The baseline examination when lens disease is suspected includes visual acuity and refraction, IOP (interpreted with pachymetry, because a thick cornea overestimates pressure), slit-lamp examination and dilated fundoscopy [7, 9]. In ADAMTSL4-related disease, orthoptic examination in the child, biometry (axial length), anterior segment optical coherence tomography and, in selected cases, ultrasound biomicroscopy, corneal topography with diameter and thickness and gonioscopy are added [7]. In microspherophakia, the lens equator is visible with the pupil maximally dilated, the anterior chamber is shallow and the axial length is normal or short, which distinguishes lenticular myopia from axial myopia [45, 55]. In WMS, diagnostic pupil dilatation should be weighed against the risk of pupillary block [9, 55].

5.3. Molecular tests

WMS. When a dominant form is suspected, FBN1 is sequenced and, if the result is negative, FBN1 deletion and duplication analysis is performed, because three of the nine probands with FBN1-related WMS had alterations of this type [9]. In practice, a multigene panel with ADAMTS10, ADAMTS17, FBN1 and LTBP2 is the highest-yield option; some commercial panels do not include these genes [9]. Exome or genome sequencing is preferable when the phenotype is non-specific [9]. Deep intronic ADAMTS17 variants may escape the exome and be identified by genome sequencing, with functional confirmation by minigene assay [57].

GD and ACMICD. If inheritance appears recessive or there is consanguinity, ADAMTSL2 is sequenced first, then FBN1 and finally LTBP3; alternatively, a panel with the three genes or the exome [10]. Sequencing detects about 99% of the known variants in the three genes, and FBN1 variants are concentrated in exons 41 and 42 [10]. When a patient appears homozygous, a deletion of one or more exons not detected by sequencing or uniparental isodisomy should be excluded [10]. The PNDS recommends molecular confirmation in all patients with clinical suspicion, at any age, because the gene and the variant type have prognostic value and define the mode of transmission, and referral to a reference or competence centre [22].

Isolated ectopia lentis. Sequencing of ADAMTSL4 detects all variants described to date; no large deletions have been reported, but dosage analysis may be considered when only one allele is found [7]. The recommended strategy for congenital ectopia lentis is a panel including FBN1, ADAMTSL4, ADAMTS10, ADAMTS17, LTBP2, CBS, SUOX, ASPH, CPAMD8 and PAX6: in a cohort of 497 Chinese probands with congenital ectopia lentis, the diagnostic yield was 93.36%, with FBN1 in 82.93% and other genes in 10.44% [24]. The proportion due to ADAMTSL4 varies with the population, from 0% in Chinese series to 50% in European series of non-syndromic ectopia lentis [7].

5.4. Test limitations and report content

The proportions in Table 5.2 describe what each method detects among already known variants; they do not correspond to clinical sensitivity, which depends on the pre-test probability and panel composition. A negative result does not exclude the diagnosis: exon sequencing misses FBN1 deletions and duplications, deep intronic variants, as yet unknown genes (a 70-year-old man and a 36-year-old woman with typical WMS had no variants in ADAMTS10, ADAMTS17 or FBN1) and low-level parental mosaicism [1, 3, 9, 57]. Variants of uncertain significance neither confirm nor exclude the diagnosis; in recessive disorders, a pathogenic variant with a variant of uncertain significance does not either [7, 9]. The report should state the gene, the transcript with version (for ADAMTSL4, MANE NM_019032.6), the HGVS c. and p. nomenclature, zygosity, the class according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria and, in recessive disorders, confirmation of phase by parental testing [7, 53, 55].

Table 5.2. Molecular tests by gene [7, 9, 10]

The 2024 counts come from the series by Marzin and colleagues [3, 21].

5.5. Non-genetic investigations

There is no biochemical biomarker for these disorders. GD mimics a lysosomal storage disease, but lysosomal enzyme and urinary glycosaminoglycan studies do not establish the diagnosis, and urinary mucopolysaccharide excretion is normal [4, 51]. Total plasma homocysteine and amino acids should be measured in any undiagnosed ectopia lentis, to exclude homocystinuria; its cardinal findings are markedly raised plasma homocystine, total homocysteine and methionine, urinary homocystine and reduced cystathionine β-synthase activity [9, 47]. Sulphite oxidase deficiency, isolated or due to molybdenum cofactor deficiency, can be screened for with a urine sulphite strip [74]. Hand radiographs (bone age, metacarpal notches), echocardiography and electrocardiography complete the syndromic assessment [9, 10]. Liver, skin or tracheal biopsies are of no use for diagnosis: they show lysosomal vacuoles and, in the liver, heparan accumulation, and the valves show diffuse fibrosis with chordae encased in collagen; in ACMICD, electron microscopy of growth cartilage showed disorganisation, abnormal collagen distribution around the lacunae and glycogen accumulation [22]. Bone age is always delayed, but reading it with the usual atlases is not appropriate in brachydactyly, and maturation is assessed mainly by comparison with the previous examination [22].

5.6. Practical algorithm

1. Ectopia lentis or lenticular myopia without trauma: complete ophthalmological examination (slit lamp, biometry, pachymetry, gonioscopy) and measurement of total homocysteine [7, 47].
2. Systemic assessment: stature and proportions, hands (brachydactyly or arachnodactyly), joint mobility, echocardiography with aortic root measurement [9, 71].
3. Short stature with brachydactyly and stiffness: WMS; tall or normal stature with systemic Marfan features: FBN1/Marfan; no systemic involvement, young child, pupillary displacement or high myopia: ADAMTSL4 [9, 23, 32].
4. Ectopia lentis panel (including the WMS genes and CBS), with FBN1 dosage analysis; if negative, exome or genome [9, 24, 57].
5. Acromelic short stature without lens anomaly: ADAMTSL2, FBN1, LTBP3 and SMAD4 panel, with echocardiography and airway assessment from diagnosis [10, 26].

5.7. Prenatal and preimplantation diagnosis

Once the family variant or variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible for all entities [7, 9, 10]. Without a molecular diagnosis, ultrasound does not allow prenatal diagnosis of GD [4, 26].

5.8. Initial assessment in geleophysic dysplasia and acromicric dysplasia

The French PNDS defines a complete initial assessment as soon as the diagnosis is suspected, directed at the target organs, which serves as the starting point for follow-up; prognosis depends mainly on cardiopulmonary complications [22]. Table 5.3 summarises it.

Table 5.3. Initial assessment of GD and ACMICD according to the PNDS [22]

Routine sleep polygraphy at 2 years is more prescriptive than GeneReviews, which reserves polysomnography for when it is indicated [10, 22].

6. Differential Diagnosis

The differential diagnosis is organised along two axes: ectopia lentis (with or without short stature) and acromelic short stature with joint stiffness (with or without lens anomaly). Table 6.1 brings together the main entities.

Table 6.1. Differential diagnosis

6.1. Ectopia lentis: what separates the main causes

The first question in the presence of ectopia lentis is whether the patient is tall, short or of normal stature. Marfan syndrome and homocystinuria produce a tall, thin habitus, WMS produces short stature with brachydactyly, and ADAMTSL4-related disease does not alter stature [7, 9, 47]. The direction of dislocation is a guide but not decisive: in Marfan it is bilateral, symmetrical and mainly superior, but can occur in any direction; in homocystinuria and WMS it is usually inferior; in ADAMTSL4-related disease it is variable, with an inferior predominance in a recent series [9, 23, 31, 70, 75]. Age at onset also helps: in untreated homocystinuria dislocation rarely appears before 3 years, is generally present by 10 years and by 38 years only 3% of patients retain both lenses in place; in ADAMTSL4-related disease the median age at diagnosis is under 2 years; in FBN1-related isolated ectopia lentis it may appear in adulthood [23, 32, 47, 75]. Lenticular myopia with normal or short axial length and a shallow anterior chamber suggests microspherophakia (WMS or LTBP2), whereas myopia with increased axial length is typical of Marfan and ADAMTSL4-related disease [32, 55, 70]. In the Shanghai series, patients without an FBN1 variant had more severe ectopia, different corneal curvature and more ocular comorbidities and more often needed robust intraocular lens (IOL) fixation [24]. Displacement of the pupil in the opposite direction to the lens, a flat iris with transillumination and persistent pupillary membrane are characteristic of ectopia lentis et pupillae [7, 16]. Traumatic ectopia lentis is the most frequent cause of dislocation overall and is accepted only with a clear history [70]. Among inherited metabolic diseases, Saudubray's table of ophthalmological signs lists classic homocystinuria and sulphite oxidase deficiency as causes of ectopia lentis, alongside Marfan and Marchesani syndromes [78].

6.2. Acromelic short stature: separating the four dysplasias

GeneReviews summarises the overlap between WMS, GD, ACMICD and Myhre: all share short stature, brachydactyly, stiffness, delayed bone age, thick skin and, to different degrees, heart disease [9, 10]. The lens anomaly is the only feature that identifies WMS; GD is distinguished by hepatomegaly, progressive valvular disease, airway stenosis and the “good-natured” face; ACMICD by its favourable prognosis, the absence of progressive valvular disease and the metacarpal notches; and Myhre syndrome by the face with prognathism, thick calvaria, broad ribs, mixed deafness and cognitive impairment [6, 9, 10, 29, 77]. In the Oxford Desk Reference table of brachydactylies, GD is distinguished by valvular thickening, toe walking and developmental delay in some patients [79]. The distinction is not absolute: patients with clinical overlap between GD and WMS, an adult with GD and microspherophakia, and patients with GD and glaucoma have been reported [29, 38, 67]. Because the same gene (FBN1) causes WMS, GD and ACMICD, the classification of an individual patient rests on the combination of phenotype, gene and variant type [10, 26]. The French PNDS adds, for WMS, the possibility of tracheal stenosis and the absence of hepatomegaly and, for Myhre syndrome (characterised in 1981 and described in 1998 as LAPS syndrome, from laryngotracheal stenosis, arthropathy, prognathism and short stature), upper airway obstruction in about 13% of patients, multilevel and inflammatory, which tends to worsen, as well as arterial hypertension, pericarditis, precocious puberty and prenatal growth restriction; the recurrent variants affect residue Ile500 of the MH2 domain of SMAD4 [22].

7. Treatments and Risk Management Strategies

7.1. General principles and sources of recommendations

No entity in this article has a treatment directed at the disease mechanism, and management is supportive and organ-directed [7, 9, 10]. There are no specific scientific society guidelines for WMS or for ADAMTSL4-related ectopia lentis; the GeneReviews recommendations are based on the authors' opinion and case series, without controlled trials [7, 9, 51]. For GD and ACMICD, Marzin and colleagues published management recommendations in supplementary material in 2021, based on the Necker cohort, which the 2024 GeneReviews adopted in its surveillance table [10, 26]. Management is multidisciplinary, with clinical genetics, paediatrics, cardiology, respiratory medicine, an airway team, ENT, orthopaedics and ophthalmology [26]. In France, the 2021 National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé for GD and ACMICD, prepared by the reference centre for constitutional bone diseases from the same cohort and a literature search from 1960 to 2021, organises the initial assessment, symptomatic treatment and an age-based follow-up schedule; it does not cover WMS, which is referred to a separate protocol [22].

7.2. Ophthalmological management of Weill-Marchesani syndrome

Initial assessment. GeneReviews recommends a complete ophthalmological examination after diagnosis [9]. IOP measurement should be corrected for corneal thickness, and gonioscopy assesses angle closure and synechiae [9, 55].

Agents to avoid. Ophthalmic miotics and mydriatics should be avoided because they can induce pupillary block; medical treatment of glaucoma is difficult because of the paradoxical response to these drugs [9]. In the case described in section 10, the acute attack was triggered by inadvertent instillation of atropine [55]. Contact sports and activities with a risk of eye trauma should be discussed with the ophthalmologist [9].

Lens. Early detection and removal of an ectopic lens reduce the likelihood of pupillary block and glaucoma [9]. Lens extraction controls pressure and improves vision when performed before advanced glaucomatous damage; in advanced glaucoma, it is combined with filtering surgery [55]. Management of ocular complications cannot be generalised and is decided case by case [9]. In children with microspherophakia and glaucoma, primary IOL implantation carries a risk of malignant glaucoma, and some surgeons defer the IOL in the first eye operated on [55]. In a classification of 99 eyes with microspherophakia, a shallow anterior chamber and the presence of glaucoma predicted worse visual and pressure outcomes after surgery, and the authors recommended early surgery in high-risk patients with a narrowing anterior chamber [80].

Glaucoma. Peripheral iridectomy prevents or relieves pupillary block [9]. Lens extraction and/or trabeculectomy may be necessary in advanced chronic angle-closure glaucoma [9]. In the microspherophakia series by Senthil and colleagues, only 9 of 51 eyes responded to medication and 2 of 16 to laser iridotomy [62]. Table 7.1 summarises the available intervention studies.

Table 7.1. Surgical intervention studies in microspherophakia and genetic ectopia lentis

These studies are small, uncontrolled, single-centre series with heterogeneous populations (isolated and syndromic microspherophakia, Marfan); the results are not comparable with each other and do not establish a reference technique [24, 45, 46, 82]. The lack of pressure control without medication after lensectomy in more than half of the eyes and the need for additional surgery show that lens extraction alone does not resolve established glaucoma [46]. In the Shanghai cohort, patients without an FBN1 variant more often needed robust IOL fixation techniques, suggesting that the genotype can guide surgical planning [24].

7.3. Ophthalmological management of ADAMTSL4-related disease

In the child, the main aim is to prevent amblyopia by early correction of refractive errors, supplemented by occlusion when correction is not enough [7]. Surgery is indicated in the presence of cataract, risk of complications of the dislocated lens (endothelial contact, pupillary block), lack of improvement with occlusion, the lens edge in the middle of the pupil or insufficient optical correction, especially with high astigmatism [7]. It is rarely necessary in the young child; most patients operated on are adolescents or young adults, and acuity may improve even after 7 years of age [7]. The classic technique is lensectomy with anterior vitrectomy and correction of aphakia with contact lenses or a secondary IOL; capsule-preserving techniques have been introduced, such as the “bag-in-the-lens” IOL with capsular rings or loop suture and, if this fails, capsule removal with implantation of a three-piece IOL by the Yamane technique from 4–5 years [7]. The decision weighs the loss of accommodation and the risks of secondary glaucoma and retinal detachment; before 2 years, eye growth causes a myopic shift [7, 82]. Sphincterotomy (enlargement of the pupil by incision of the pupillary margin) benefits patients with small, markedly displaced pupils [7]. Raised IOP is usually controlled with topical antiglaucoma medication [7]. Retinal detachment is treated with vitrectomy and, if necessary, scleral buckling, and the fellow eye should be examined [7]. Boxing and martial arts should be avoided and contact sports practised with care [7].

7.4. Systemic management of Weill-Marchesani syndrome

The initial assessment includes growth, joint range by an orthopaedic surgeon or physiotherapist, echocardiography (ductus arteriosus, valvular stenoses, arterial narrowing) and electrocardiography (QT interval) [9]. Physiotherapy may maintain joint mobility, although the efficacy of passive exercises has not been studied [9]. Heart defects are treated according to cardiology practice; in FBN1-related forms, the description of thoracic aortic aneurysm and cervical dissection in one family justifies vascular assessment [9]. There are no data on growth hormone in WMS [9].

7.5. Management of geleophysic dysplasia and acromicric dysplasia

Heart. Valve replacement is indicated in severe stenosis or regurgitation; septal defects are treated according to cardiology and cardiac surgery practice [10]. In the Necker cohort, four of the six valve replacements for progressive disease were performed in the first year of life, and three patients were unfit for surgery [26]. In a 48-year-old adult with severe aortic regurgitation and left ventricular outflow tract obstruction, transcatheter aortic valve replacement resolved heart failure in the following year [4, 39]. Valvular disease detected after the first year tends to remain stable and is associated with a better prognosis [26]. The PNDS adds that about 30% to 40% of children with valvular disease eventually undergo surgery, that any indication for cardiac surgery is discussed at a multidisciplinary meeting, that the percutaneous technique is preferred when appropriate and, when not, valve replacement or repair, and that the type of prosthesis depends on age and general condition and is decided at a reference centre [22]. Infection prevention is a priority in patients with valvular disease, who should know the precautions to take before invasive procedures, such as endoscopies and dental treatment [22].

Airway and anaesthesia. Tracheostomy is performed when tracheal stenosis is severe, but should not be considered a definitive solution, because secondary stenoses may form below it [10, 26]. Inflammatory laryngeal and tracheal stenoses are active lesions that any stimulus aggravates; after the first stenosis, the airway remains at high risk [26]. Several patients needed tracheostomy after failed extubation, and a patient with LTBP3 needed an emergency tracheostomy during a caesarean section [14, 26]. Anaesthetists should be warned of the risk before any surgery, and an endotracheal tube smaller than predicted for age should be used [26]. A child with ACMICD died at 6 years of acute pulmonary oedema with pulmonary hypertension after rigid endoscopy [26]. In WMS, anaesthesia is equally difficult because of joint stiffness, dental malalignment and maxillary hypoplasia [9]. The PNDS recommends that treatment of laryngotracheal stenoses be as minimally invasive as possible and that intubation and above all tracheostomy, which rapidly aggravate the local inflammatory and granulomatous reaction, be avoided whenever possible; options include local corticosteroids, in particular by aerosol, non-invasive mask ventilation and gentle balloon laryngotracheal dilatation [22]. In the tracheostomised patient with granulations, besides local corticosteroids and dilatation, changing the material, diameter or length of the cannula may be useful [22]. To limit the risk of stenosis, intubations should have restricted indications, be performed with small-diameter tubes and last as short a time as possible, and an ENT consultation is mandatory before any planned intubation [22]. In a rabbit model of tracheal stenosis, a TGFβ antagonist only partly reduced fibrosis and did not prevent luminal narrowing; there are no studies in patients with acromelic dysplasias [22].

Lung. Restrictive disease, obstructive sleep apnoea and asthma are treated by respiratory medicine, with polysomnography when indicated [10]. In the Necker cohort, asthma was controlled in most cases with corticosteroids and β2 agonists and with chest physiotherapy, and one patient needed continuous positive airway pressure [26]. Pulmonary hypertension may fluctuate and worsen with infections or surgery [26]. In a boy with FBN1-related GD and severe pulmonary hypertension, treprostinil lowered pulmonary arterial pressure, but mitral stenosis progressed and, after mitral valvuloplasty with atrial septostomy, it was not possible to wean extracorporeal membrane oxygenation; this is an isolated report, with no dose published in the abstract, which does not support a recommendation [83]. According to the PNDS, recurrent bronchopulmonary infections should be documented whenever possible and treated with appropriate antibiotic therapy, obstructive ventilatory disorder is treated with corticosteroids and β2 agonists and severe obstructive apnoea justifies continuous positive pressure [22]. In pulmonary hypertension with severe exertional dyspnoea or right heart failure, especially if associated with airway stenosis, physical exertion and situations that worsen hypoxia (for example, staying at altitude) become contraindicated; diuretics with a salt-free diet and oxygen therapy reduce the signs of right ventricular overload when there is no identified aggravating factor [22]. Exercise limitation is difficult to quantify, because of the overlap of orthopaedic and respiratory limitations [22]. The PNDS gives no doses; Table 7.2 brings together the label doses of the drugs commonly used in these indications, applied by extrapolation.

Table 7.2. Symptomatic drugs mentioned in the PNDS: label doses, by extrapolation from analogous indications

The budesonide label does not include laryngotracheal stenosis, and the asthma dose is the only regulatory reference for the corticosteroid aerosol proposed in the PNDS; oxygen therapy is adjusted to oximetry, with no target defined in the PNDS. Outside the label ages (nebulised budesonide after 8 years, pressurised salbutamol before 4 years), these doses do not apply directly.

Ear, nose and throat. Hearing loss and recurrent otitis are treated conventionally, with adenoidectomy and ventilation tubes; regular audiometry prevents language delay secondary to conductive deafness [10, 26]. The PNDS indicates grommets in recurrent acute otitis media and chronic otitis media with effusion, and adenoidectomy or tonsillectomy in adenotonsillar hypertrophy with obstructive sleep apnoea; speech and language therapy assessment and rehabilitation may be needed when conductive deafness delays language, a delay that recovers after grommet insertion [22].

Orthopaedics. Continuous physiotherapy aims to maintain joint range and avoid surgery [10, 26]. Hip dysplasia, osteochondritis and carpal tunnel syndrome are treated by orthopaedics; in the Necker cohort there were two hip osteotomies and six carpal tunnel operations [10, 26]. Clinical and radiographic follow-up of the hip every 2 to 3 years allows joint-preserving treatments [26]. The PNDS provides for annual orthopaedic or rheumatological surveillance in the child and every 2 to 3 years in the adult, with pain assessment at each visit and referral to a pain clinic when the usual measures are insufficient [22]. Osteonecrosis of the upper femoral epiphysis has been observed in children in dysplastic hips, with limping, pain and stiffness similar to those of primary osteochondritis of the hip; early screening and treatment aim to avoid progressive deformity of the femoral head (coxa magna and plana) and severe hip dysplasia [22]. Treatment follows that of primary osteochondritis: offloading by plaster immobilisation in younger children, sometimes preceded by traction; as epiphyseal revascularisation is slow, a pelvic osteotomy is often needed to recentre the femoral head and, if the deformities are significant, a Chiari-type acetabuloplasty, with the aim of improving hip function and postponing arthroplasty until adulthood [22]. In carpal tunnel syndrome, sometimes severe, treatment begins with a resting splint with or without injection, and surgery is reserved for failure or motor deficit, to avoid irreversible damage; in a series of nine patients with ACMICD, three needed carpal tunnel surgery and two hip surgery [22].

Rehabilitation, psychological support and therapeutic education. Physical and rehabilitation medicine coordinates rehabilitation care, sets realistic goals with the patient and family and assesses progress [22]. Early and regular physiotherapy limits contractures and improves functional capacity, with adapted exercise and endurance training; assessment covers joint ranges, muscle contractures, global mobility and pain [22]. Occupational therapy identifies difficulties in daily activities and proposes adaptations for short stature and hand use (orthoses, technical aids, home adaptation, with a home visit if necessary), and adapted physical activity tailors exercise to motor abilities, respecting joint limitations and pain [22]. Psychological support is offered from the time the diagnosis is disclosed and during phases of deterioration, serious complications or repeated infections, and distress associated with short stature should be sought [22]. Therapeutic education teaches the patient and family to recognise the signs of deterioration requiring urgent consultation, such as increasing dyspnoea in previously stable valvular disease [22].

Eyes and liver. Refractive errors and corneal thickening are treated in ophthalmology; optic disc swelling requires exclusion of intracranial hypertension [10, 26]. Liver size is assessed clinically and by ultrasound [10]. The PNDS requires refractive errors to be quantified and corrected, any appearance of optic disc swelling to be referred to a reference centre and glaucoma to be sought in the presence of abnormal optic disc cupping [22]. In two patients with pseudopapilloedema, acetazolamide was of little benefit [22].

7.6. Growth hormone: available data

There is no approved indication for recombinant human growth hormone (rhGH) in these dysplasias, and its use is off-label. The only published series is retrospective and Chinese, with patients with GD2 or ACMICD due to FBN1 TB5 variants [58]. The PNDS considers growth hormone treatment non-standardised and its efficacy difficult to assess; in the presence of a fall-off in the growth curve, it recommends measuring IGF-1 and a growth hormone stimulation test and, in treated patients, endocrinological follow-up every 3 to 6 months (at least twice a year) [22].

Table 7.3. Growth-promoting therapy in acromicric dysplasia and geleophysic dysplasia type 2 (off-label use) [58]

The series is small and has heterogeneous doses, ages at start, durations and adherence (poor adherence in three patients), without a control group; one patient treated at puberty reached 127.5 cm (−6.13 SD) [58]. These data do not allow rhGH to be recommended, and any use should be discussed as experimental use. Stanozolol is an anabolic steroid whose paediatric use is described here only as study data.

7.7. Regulatory status

The absence of registered clinical trials was verified on ClinicalTrials.gov [87]. The remaining statements on approvals are based on the absence of any reference to targeted drugs in the reference sources consulted [7, 9, 10].

7.8. Developments in the last 12 months and research

The proposal that TGFβ inhibitors could halt valvular and airway disease, put forward in 2021, was not supported by the results with losartan in the animal model [26, 48]. Betamethasone remains at the preclinical stage and there are no human data to support its use with disease-modifying intent [25].

7.9. Pregnancy, perioperative care and transition

In GD, pregnancy is complicated by a small pelvis, heart disease and tracheal stenosis; preconception assessment and follow-up at a high-risk perinatal centre are recommended [10]. Intubation for caesarean section may reveal an unknown subglottic stenosis [14]. In all entities, surgery requires anaesthetic airway planning [9, 26]. Transition to adult medicine should maintain cardiac, respiratory, orthopaedic (carpal tunnel) and ophthalmological follow-up, because late complications such as valvular disease, airway obstruction and acute respiratory failure arise in ACMICD [26]. The PNDS requires any surgery to be discussed at a reference or competence centre and, at any age, a preoperative assessment with cardiology (echocardiography and electrocardiography), respiratory medicine and ENT consultations [22]. At the anaesthetic consultation the airway is assessed, with the help of respiratory medicine and ENT, because of the foreseeable difficulties with mask ventilation, intubation and extubation: oropharyngeal examination with a tongue depressor and awake nasal, pharyngeal and supraglottic laryngeal fibreoptic endoscopy; if a laryngotracheal lesion is suspected, cervicothoracic CT with estimation of calibre is performed and laryngotracheal endoscopy under general anaesthesia may be performed before surgery [22]. For general anaesthesia a laryngeal mask is preferred when possible and, if intubation is necessary, a tube smaller than predicted for age and weight [22]. Among the aims of follow-up, the PNDS explicitly includes preparation for the move to adult medicine [22].

7.10. Recommendations and divergences between sources

The sources agree on annual ophthalmological surveillance in WMS, avoidance of miotics and mydriatics and multidisciplinary management of GD [9, 10]. They diverge on two points. The first is the timing of lens surgery in microspherophakia: GeneReviews recommends early removal of the ectopic lens, and recent series support early surgery in eyes with a narrowing anterior chamber, but other series show pressure control without medication in only about one third of operated eyes, which does not allow a threshold to be set [9, 46, 80]. The second is the significance of TGFβ in GD: the authors of the 2021 guideline saw it as a therapeutic target, and the 2026 preclinical data do not confirm this [26, 48]. In ADAMTSL4-related ectopia lentis, GeneReviews reserves surgery for precise indications and favours optical correction in the child, whereas recent paediatric series describe scleral-fixated IOL implantation from 5 years with good visual results and a long-term risk of IOL subluxation [7, 82].

The 2021 French PNDS and the 2024 GeneReviews are based on the same cohort and agree on most of the GD and ACMICD follow-up schedule, but diverge on several points [10, 22]. Polysomnography is routine at 2 years in the PNDS and reserved for when it is indicated in GeneReviews; chest CT is performed at 6 years in both, and the PNDS allows it to be repeated if there are symptoms; carpal tunnel electromyography is performed every 2 years from 11 years in GeneReviews and only if there are symptoms in the PNDS; adult orthopaedic follow-up is every 2 years in GeneReviews, every 2 to 3 years in the PNDS text and every 5 years without new symptoms in the schedule of the same PNDS; and the adult genetics clinic visit is every 2 to 3 years in the PNDS table and every 2 years in its text [10, 22]. On mortality, GeneReviews states that about one third of children with GD die before 5 years and the PNDS reports 30% of deaths before 6 years [10, 22]. The order of frequency of valvular lesions in the PNDS (mitral, pulmonary, aortic, tricuspid) comes from a family series and does not match that of the Necker cohort, in which pulmonary stenosis predominated [22, 26]. On growth hormone, the PNDS considers treatment non-standardised, but proposes investigating growth hormone secretion when there is a fall-off in the growth curve [22]. Table 11.1 follows, on each point, the most frequent interval and indicates the alternative.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

Determining the gene is what establishes the recurrence risk, because the recessive and dominant forms of WMS cannot be distinguished clinically [9, 51]. The same applies to GD, in which the ADAMTSL2 form is recessive and the FBN1 and LTBP3 forms are dominant and almost always de novo [10].

In ACMICD in the Necker cohort, 5 of 15 FBN1 variants were de novo, 5 inherited from an affected parent and 5 of unknown origin [26]. In the series of 22 patients by Faivre and colleagues, 16 cases appeared sporadic and there was vertical transmission in 3 families [11]. A parent with somatic and germline mosaicism for an FBN1 variant may have mild or minimal manifestations, and leucocyte DNA testing may not detect it [9]. The PNDS stresses that, when the dominant variant arose de novo in the proband, the proband's siblings do not have, for their offspring, a risk higher than that of the general population, and that, in ADAMTSL2 forms, the risk for the offspring of the proband and siblings is low because heterozygotes are rare, except in a consanguineous union, in which the family variant can be tested for in the partner [22].

8.2. Cascade testing and assessment of relatives

In relatives at risk of WMS, testing for the family variant or, failing that, an ophthalmological examination for microspherophakia and assessment by a clinical geneticist identify early those who need ophthalmological and cardiological surveillance [9]. In ADAMTSL4-related disease, siblings should have a complete ophthalmological examination (acuity, IOP, slit lamp, ophthalmoscopy) to prevent amblyopia, and molecular testing is more informative than examination given intrafamilial variability [7]. Carrier testing in relatives is only possible once the family variants have been identified [7, 9, 10]. In populations with a known founder variant (western Europeans, Maori, Bukharian Jews), testing for the founder variant is a reasonable first step [7].

8.3. Prenatal and preimplantation diagnosis

Once the family variants have been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible; attitudes towards these tests vary between professionals and families, and the discussion should take place before pregnancy [7, 9, 10]. The anomaly scan is not reliable for the diagnosis of GD without molecular information [4, 26].

8.4. Consanguinity, counselling of minors and DNA banking

Recessive forms are concentrated in consanguineous families and in populations with founder variants; in the Necker cohort, four families with homozygous ADAMTSL2-related GD were consanguineous [1, 26]. Counselling on the risk to offspring and reproductive options should be offered to young adults who are affected, carriers or at risk of being carriers [9, 10]. Clarifying the genetic status of at-risk children has a direct benefit in these disorders, because it allows ophthalmological and cardiological surveillance to start early and amblyopia to be prevented [7, 9]. DNA banking should be considered in probands without a molecular diagnosis [9, 10].

8.5. Disclosure of the diagnosis and information for the family

The French PNDS recommends that the diagnosis of GD or ACMICD be communicated at a dedicated consultation, by the specialist who suspected it or by the physician who requested the confirmatory molecular test [22]. The information covers the nature of the disease and the mode of transmission, the symptoms and warning signs requiring prompt consultation, the treatments, possible complications, the follow-up plan and social support measures (school or occupational medicine), and may include pregnancy [22]. The treating physicians receive a letter with the points discussed, a second consultation a few weeks later takes up outstanding questions and psychological support is recommended; the reference centre offers, when possible, multidisciplinary follow-up in a day hospital, which concentrates the investigations [22].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

None of the entities has population prevalence studies. The estimate of 1/100,000 for WMS, repeated by GeneReviews and Orphanet (class 1–9/100,000), is an expert estimate and is flagged by Orphanet as not validated [9, 17]. For GD, GeneReviews counted about 100 published patients in 2024 and Orphanet records the prevalence class below 1/1,000,000 [10, 19]. Orphanet records 60 cases or families of ACMICD and 90 cases or families of isolated ectopia lentis (FBN1 and ADAMTSL4 forms together), both in the class below 1/1,000,000 [8, 20]. These values are counts of published cases or class estimates and should not be read as prevalences; ADAMTSL4-related eye disease, in particular, is certainly underdiagnosed as “idiopathic” ectopia lentis [7]. The French PNDS estimates the prevalence of GD and ACMICD at about 1/1,000,000, based on a 2009 review that counted 55 published cases worldwide; this is likewise an estimate and not a population study [22].

9.2. Geography and founder populations

The ADAMTSL4 c.767_786del deletion is the predominant variant in western Europe: it has been found in Norway, Germany, the United Kingdom and Sweden, was present in 23 of 32 families in a series from six European centres and has a common ancestor estimated at about 4000 years [7, 16, 23]. The Maori and Bukharian Jews have their own founder variants [7]. In the Amish community, a complete deletion of ADAMTS10 is a founder variant [9]. The recessive forms of WMS and GD have been described mainly in consanguineous families from the Middle East (Lebanon, Saudi Arabia, Iran, United Arab Emirates), the Maghreb (Morocco, Algeria, Tunisia), India and Pakistan, and the most recent molecular series come from France and China [1, 3, 4, 12, 21, 58]. The contiguous ADAMTS17–CERS3 deletion is a founder variant in a region of Tunisia [3]. In Brazil, a family with recurrence of GD was described in 1984, whose proband, an 11-year-old girl, had toe walking, bilateral talipes equinovarus, hepatomegaly and aortic stenosis, and a sister who died at 3 years of heart failure [4]. The sources consulted contain no data from Portugal.

9.3. Special populations

Young children with GD and pregnant women with GD are the highest-risk groups, because of the airway and heart disease [10, 26]. Older people with ACMICD or GD may have late complications (tracheomalacia at 63 years, acute respiratory failure at 50 years, cirrhosis at 76 years), which supports lifelong follow-up [26, 68]. Patients with WMS undergoing routine eye examinations in other settings (for example, dilated fundoscopy) are at risk of a pupillary block crisis if the disease is not known [9, 55].

9.4. European reference networks and patient organisations

The European Reference Network on Rare Bone Diseases (ERN BOND) covers the acromelic dysplasias, and the European Reference Network for Rare Eye Diseases (ERN-EYE) covers WMS and ectopia lentis [27, 28]. The French Reference Centre for Skeletal Dysplasias at the Necker-Enfants Malades Hospital, where the main WMS and GD cohorts were assembled, and the International Skeletal Dysplasia Registry of the University of California, Los Angeles are listed by GeneReviews as resources [10]. The organisations listed by GeneReviews include the MAGIC Foundation, the Children's Glaucoma Foundation and the Human Growth Foundation, as well as the National Eye Institute low vision programme and the eyeGENE registry for eye diseases [7, 9].

In France, follow-up is organised at the reference centre for constitutional bone diseases (MOC), coordinated by the Necker-Enfants Malades Hospital, with constituent centres at the Cochin and Lariboisière hospitals and, in 2021, 20 competence centres distributed across the country, integrated into the rare bone, calcium and cartilage diseases health network (OSCAR, www.filiere-oscar.fr) [22]. GD and ACMICD are not on the list of 30 long-term conditions (ALD), but coverage as an off-list ALD may be granted after review of the file, for a serious disease or for multiple conditions requiring continuous care for more than 6 months (Social Security Code, art. L. 322-3 and D. 322-1) [22]. The Maison Départementale des Personnes Handicapées (MDPH), created by law no. 2005-102, grants compensation for technical aids and home adaptation and recognition of disabled worker status, by decision of its rights and autonomy commission (CDAPH); the individualised reception plan (PAI, circular no. 2003-135) adapts schooling, from nursery to secondary school, with suitable furniture and writing materials and with the schedule of health interventions [22]. The social worker supports the family from diagnosis, and the PNDS recommends always offering contact with patient organisations, in particular the Association des Personnes de Petite Taille (APPT, https://appt.asso.fr/) [22].

10. Illustrative Clinical Case

Li and colleagues described in 2026 an 8-year-old Chinese girl, daughter of consanguineous parents, born prematurely at 31 weeks and 5 days weighing 2400 g [55]. She was brought to hospital with sudden visual loss, eye pain, nausea and vomiting of three days' duration. She measured 114.5 cm, below the 3rd centile of the Chinese charts (118.5 cm), and weighed 23.7 kg; she had a round face, a short broad neck, short sturdy limbs, short thick fingers and toes and thick skin, with normal intelligence and hearing and no cardiovascular disease. Hand radiography showed delayed carpal ossification centres.

Ophthalmological examination revealed visual acuity of counting fingers at 20 cm in the right eye and light perception with correct projection in the left eye, IOP above 30 mmHg in both eyes, mixed conjunctival hyperaemia, corneal oedema, a very shallow anterior chamber (about 1.5 corneal thicknesses centrally), posterior synechiae, an exudative membrane at the pupillary margin and fixed pupils of about 5 mm, with anterior lenticonus. Corneal thickness was 714 and 724 μm, axial length 21.91 and 21.37 mm, anterior chamber depth 1.70 and 1.80 mm and lens thickness 5.12 and 5.34 mm. Gonioscopy showed iridotrabecular contact over 151° (41.9%) in the right eye and 236° (65.6%) in the left, and optical coherence tomography showed atrophy of the inner retinal layers and thinning of the nerve fibre layer, more marked on the left. The authors attributed the acute glaucoma attack to inadvertent instillation of atropine on a predisposed anatomy, with a shallow anterior chamber and peripheral anterior synechiae.

Exome sequencing identified the variant NM_030957.4:c.1560_1575dup, p.(Ile526ValfsTer51), homozygous in exon 3 of ADAMTS10, confirmed by clonal sequencing as a true tandem duplication; the phenotypically normal parents were heterozygous [53, 55]. The variant was classified as pathogenic (criteria PVS1, PM3 and PM2) [55].

The left eye was operated on first, with lens extraction, anterior vitrectomy, goniosynechialysis and reformation of the anterior chamber, without an IOL, because of the risk of malignant glaucoma; four days later the right eye was operated on in the same way, with implantation of a +24.0 dioptre IOL. On the first day IOP was 14 and 16 mmHg; corrected acuity was 0.7 logMAR in the right eye and 1.0 logMAR in the left eye (aphakic, with +16.75 dioptres) and, at 3 weeks, IOP was 16 and 19 mmHg, with clear corneas and deep anterior chambers [55].

The case brings together the core features of recessive WMS: microspherophakia with lenticular myopia and short axial length, thick cornea, angle-closure glaucoma in the first decade, short stature with short hands and thick skin [9, 55]. It also shows the iatrogenic risk of mydriatics, which GeneReviews advises avoiding, and the diagnostic delay in a child whose short stature and short hands had not led to a targeted ophthalmological examination [9, 55]. Bilateral surgery within four days and the decision not to implant an IOL in the first eye reflect the team's choice in the face of bilateral acute glaucoma and do not constitute standardised management; the published follow-up is short (three weeks) [55]. The phenotype photographs and pedigree are in Figure 1 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12977423/figure/Fig1/) and the images of the anterior segment, biometry, gonioscopy and optical coherence tomography in Figure 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12977423/figure/Fig2/) of the original article [55].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

WMS. Visual prognosis depends on glaucoma: in the Indian microspherophakia series, about 20% of eyes were blind from glaucoma at presentation and 30% at the last follow-up, and visual loss in WMS is earlier and more severe than in other lens dislocation syndromes [9, 62]. Early detection and surgery of the displaced lens aim to prevent this course [9]. Life expectancy is not documented in cohort studies, but patients have been described at 70 and 86 years [1]. Heart disease (valvular disease in 10 of 61 patients in the 2024 series) and, in FBN1-related forms, the possibility of thoracic aneurysm justify cardiological follow-up [9, 21].

GD. About one third of children die before 5 years of age [10]. In the Necker cohort, 8 of 22 patients with GD died, and valvular disease and airway obstruction detected in the first year of life were the markers of poor prognosis [26]. Valvular disease appearing after the first year tends to be stable [26]. Patients with ADAMTSL2, with cysteine-involving FBN1 variants or with LTBP3 splice or stop-loss variants account for the severe outcomes, and estimated mortality is 29.6% in GD2 [26, 58]. Survivors reach adulthood (oldest living patient 62 years) with stature below −3 SD, progressive contractures, thick skin and intermittent pulmonary hypertension [10]. The PNDS reports 30% mortality before 6 years [22].

ACMICD. Life expectancy is good, with an estimated mortality of 4.0% in a review of TB5 variants, but there are late complications (non-progressive valvular disease, airway obstruction, restrictive disease, acute respiratory failure with pulmonary hypertension and carpal tunnel), and one child died after rigid endoscopy [26, 58]. In a series of 22 patients with ACMICD aged 4.5 to 53 years, the dysmorphism became less marked in adults, carpal tunnel was frequent in the older patients, there were few orthopaedic or cardiovascular complications and life expectancy did not appear reduced [22].

ADAMTSL4-related disease. The disease is confined to the eye; prognosis depends on the prevention of amblyopia, early cataract and retinal detachment, and final acuity ranges from light perception to normal vision [7].

11.2. Surveillance

Table 11.1. Surveillance by entity

Surveillance of GD and ACMICD follows the same schedule, because the cohort on which it is based included both entities and because ACMICD also has late cardiorespiratory complications [10, 26]. GeneReviews recommends annual hip radiographs until 18 years and then every 2 years, whereas the Necker cohort text suggests clinical and radiographic hip follow-up every 2 to 3 years; the table follows the most frequent schedule [10, 26]. Prolonged liver surveillance in adults with TB5 variants was suggested on the basis of a single case of cirrhosis and is not supported as a universal measure [68].

The PNDS assigns to the treating physician (paediatrician or general practitioner) routine clinical follow-up and growth monitoring, detection of complications (fall-off in the growth curve, worsening joint contractures, changes on cardiopulmonary auscultation, unusual dyspnoea, sleep apnoeas, upper respiratory tract infections) and of psychological difficulties, and support for adherence to follow-up, which should be maintained even in the absence of initial complications [22]. Neurological assessment includes brain magnetic resonance imaging as clinically indicated [22, 26].

12. Summary and Final Considerations

The acromelic dysplasias and ADAMTSL4-related ectopia lentis are disorders of the microfibril. Fibrillin-1, the LTBPs and the ADAMTS family proteins cooperate in the assembly of the microfibrils that suspend the lens and that organise the matrix of the growth cartilage, heart valves and airway [7, 9, 10]. The same fibrillin-1 that, when altered, causes the tall phenotype of Marfan causes, with variants in the TB5 domain, the short phenotype of GD and ACMICD, and with other variants the dominant form of WMS [30, 33, 41].

WMS is identified by the association of microspherophakia, lenticular myopia, ectopia lentis and angle-closure glaucoma with short stature, brachydactyly and joint stiffness; the ocular anomaly is mandatory for the diagnosis, and the recessive (ADAMTS10, ADAMTS17, LTBP2) and dominant (FBN1) forms can only be separated by genetic testing [9, 21]. The main risk is blindness from glaucoma, and the measures that reduce it are annual ophthalmological surveillance, avoidance of miotics and mydriatics and early surgery of the displaced lens [9, 62]. GD shares the acromelic skeleton, but its prognosis depends on valvular and airway disease, which kill about one third of children before 5 years; ADAMTSL2 variants, cysteine-involving FBN1 variants and certain LTBP3 variants identify the patients at highest risk [10, 26]. ACMICD has a good life expectancy, but is not solely a skeletal disorder and requires lifelong respiratory, cardiac and orthopaedic follow-up [26, 58]. ADAMTSL4-related eye disease is the recessive form of isolated ectopia lentis, presents earlier and with higher myopia than the FBN1 form, has no systemic involvement and, in Europe, is largely due to a single founder deletion [7, 23, 32].

The diagnosis of any ectopia lentis requires a complete ophthalmological examination, exclusion of homocystinuria and aortic assessment, and a genetic panel that includes the WMS genes and ADAMTSL4 has a high yield [24, 47]. There is no targeted treatment: management rests on ophthalmological surgery, valve surgery, specialised airway and anaesthetic management and physiotherapy [7, 9, 10]. Growth hormone showed no height gain in a small series, losartan had no effect in the animal model of GD and betamethasone improved survival in the same model, with no human data [25, 48, 58]. The main gaps are the lack of prevalence data, the absence of society guidelines for WMS and isolated ectopia lentis, the small number of patients with LTBP2 and LTBP3 and the absence of clinical trials [7, 9, 87]. In France, the 2021 PNDS organises the initial assessment and follow-up of GD and ACMICD by age, with sleep polygraphy at 2 years and chest CT and lung function tests at 6 years [22].

13. References

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