Geleophysic dysplasia
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Geleophysic dysplasia is an inherited multisystem disorder characterised by short stature with short hands and feet, progressive joint contractures, thickened skin and progressive cardiac valvular disease.
Geleophysic dysplasia (GD) is a progressive multisystem disorder resembling a lysosomal storage disorder, with involvement of the skeletal, cardiac, respiratory and airway, ophthalmologic, hepatic and cutaneous systems. The majority of characteristic clinical findings are present within the first year of life. About 40% of affected individuals present with a birth length below the 5th percentile, and a skeletal disorder is usually suspected in the first months of life because of short stature and short hands and feet, with a final height between three and six standard deviations below the mean and relative macrocephaly. Progressive joint limitation and skin thickening lead to toe walking, contractures of the large joints, and limitation of wrist and hand movement. Postnatal cardiac valve thickening can include pulmonary stenosis, mitral insufficiency, mitral stenosis or aortic stenosis, and cardiac disease is progressive in approximately half of affected individuals, with 40% of children with valvular thickening undergoing valve replacement. Multilevel airway obstruction (laryngeal stenosis, tracheal stenosis, tracheomalacia, laryngomalacia, bronchomalacia) is identified in about 30% of individuals and is often progressive. Approximately one third of affected children died before age five years from combined cardiac, airway and pulmonary manifestations; the oldest reported living affected individual is aged 62 years.
Due to insufficient data, no reliable statement on prevalence can currently be made. Approximately 100 affected individuals have been reported in the literature to date.
Geleophysic dysplasia is caused by germline pathogenic variants in ADAMTSL2 (9q34.2; ~50% of affected individuals), FBN1 (15q21.1; ~50% of affected individuals) and, rarely, LTBP3 (11q13.1; <1% of affected individuals). At the molecular level, the disorder results from dysregulation of transforming growth factor beta (TGFβ) signalling within the extracellular microfibrillar network: ADAMTSL2 interacts with fibrillin-1 and modulates TGFβ bioavailability, LTBP3 encodes latent TGFβ-binding protein 3 which is incorporated into the extracellular matrix, and FBN1 missense variants cluster in exons 41-42 (TB5 domain) and disrupt microfibrillar architecture. Patient fibroblasts show elevated TGFβ in culture medium compared with controls, indicating enhanced TGFβ signalling.
Geleophysic dysplasia caused by biallelic pathogenic variants in ADAMTSL2 is inherited in an autosomal recessive manner; the rare forms associated with heterozygous FBN1 or LTBP3 pathogenic variants are inherited in an autosomal dominant manner. For the autosomal recessive form, the
recurrence risk for siblings of an affected proband is 25%; for the autosomal dominant forms, the recurrence risk for offspring of an affected individual is 50%. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.
The diagnosis of geleophysic dysplasia is established by molecular genetic testing. Suggestive radiographic findings include delayed bone age, broad proximal phalanges, cone-shaped phalangeal epiphyses, shortened long tubular bones and small capital femoral epiphyses; echocardiography is used to identify progressive cardiac valvular disease.
Main differential diagnoses include:
- Acromicric dysplasia: same acromelic short stature, short hands and feet, progressive joint limitation and thickened skin, but without the progressive cardiac valvulopathy; inherited in an autosomal dominant manner; FBN1, LTBP3.
- : short stature, joint stiffness, but distinguished by ectopia lentis, microspherophakia and secondary glaucoma; inherited in autosomal dominant or autosomal recessive manner; ADAMTS10, ADAMTS17, FBN1, LTBP2.
- Myhre syndrome: intrauterine growth restriction, short stature, short hands and feet, progressive joint limitation and thickened skin overlap with geleophysic dysplasia, but distinguished by characteristic facial features with prognathism, calvarial thickening, variable cognitive impairment and mixed conductive/sensorineural deafness; inherited in an autosomal dominant manner; SMAD4.
- Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for informed counselling of the affected individual and family.
- Identification of the causative variant enables specific and individualised surveillance of cardiac valvular disease, airway involvement and skeletal progression, and is the prerequisite for targeted medical care planned by the treating physicians in consultation with the affected individual.
- Once the familial pathogenic variant is known, predictive and carrier testing of at-risk relatives becomes technically possible and can be offered within genetic counselling.
- Marzin P, Cormier-Daire V. Geleophysic dysplasia.2009 Sep 22 [Updated 2024 Mar 28]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301776.
- Marzin P, Thierry B, Dancasius A, Cavau A, Michot C, Rondeau S, et al. Geleophysic and acromicric dysplasias: natural history, genotype-phenotype correlations, and management guidelines from 38 cases. Genet Med. 2021;23(2):331-40. doi:10.1038/s41436-020-00994-x. PMID:.
- Camarena V, Williams MM, Morales AA, Zafeer MF, Kilic OV, Kamiar A, et al. ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia. JCI Insight. 2024;9(5). doi:10.1172/jci.insight.174417. PMID:; PMCID: PMC10972594.
- Arnaud P, Mougin Z, Boileau C, Le Goff C. Cooperative mechanism of ADAMTS/ADAMTSL and fibrillin-1 in the Marfan syndrome and acromelic dysplasias. Front Genet. 2021;12:734718. doi:10.3389/fgene.2021.734718. PMID:; PMCID: PMC8667168.
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