FBN1 – Geleophysic Dysplasia

Geleophysic dysplasia (GD) is a rare, autosomal dominant acromelic dysplasia characterized by severe short stature, joint limitation, skin thickening, and distinctive facial features including a short nose and full cheeks. Cardiac valvular disease and respiratory compromise contribute to high morbidity and mortality. While ADAMTSL2 mutations underlie recessive GD, heterozygous mutations in the TB5 domain of fibrillin-1 (FBN1) have been implicated in dominant GD. This summary reviews clinical, genetic, and functional data supporting the FBN1–GD association.

Multiple unrelated probands with heterozygous FBN1 TB5 domain variants present with classical GD features. A single Japanese child with a de novo TB5 mutation was described (1 proband) (PMID:23124041). A separate report detailed a patient with GD and refractory pulmonary hypertension harboring a TB5 mutation (1 proband) (PMID:40740820). Targeted sequencing in Chinese children identified four probands with TB5 missense variants, including the recurrent c.5198G>A (p.Cys1733Tyr) in GD (PMID:25142510). Exome studies across GD and acromicric dysplasia cases found 16 heterozygous TB5 mutations in 29 patients, with at least two variants (p.Cys1733Tyr, p.Asn1730Ile) exclusively in GD cases (PMID:21683322).

Inheritance is autosomal dominant. To date, no formal segregation studies enumerate additional affected relatives, though several kindreds exhibit cosegregation. Across studies, at least 10 unrelated GD probands carry heterozygous TB5 missense variants, demonstrating a recurrent mutational hotspot in exons 41–42 of FBN1. The variant spectrum includes cysteine substitutions disrupting disulfide bonds and non-cysteine changes within the TB5 motif, consistent with a mutational mechanism targeting this domain.

Functional assays demonstrate that TB5 mutations disrupt microfibrillar architecture and enhance TGF-β signaling in patient fibroblasts, mirroring GD pathology (PMID:21683322). Direct interaction between FBN1 TB5 and ADAMTSL2 is perturbed by these variants, supporting a dominant-negative effect on microfibril assembly and extracellular matrix integrity. Concordant findings in multiple cell models reinforce a pathogenic mechanism of dominant-negative impairment rather than haploinsufficiency.

No studies formally dispute the FBN1–GD link, and no conflicting phenotypic assignments have been reported for TB5 domain variants outside of GD, acromicric dysplasia, or Weill-Marchesani syndrome. Comprehensive case series have consistently replicated the association, with no refuting data.

Integration of genetic and experimental evidence yields a robust gene–disease relationship. Heterozygous TB5 domain variants in FBN1 result in dominant GD with a characteristic multisystem phenotype. Genetic testing focusing on exons 41–42 of FBN1 enables molecular diagnosis, informs prognosis given risk of cardiac and respiratory complications, and guides early intervention. Key Take-home: Heterozygous TB5 mutations in FBN1 cause autosomal dominant Geleophysic dysplasia and should be included in diagnostic gene panels for acromelic dysplasias.

References

• Gene • 2013 • A Japanese child with geleophysic dysplasia caused by a novel mutation of FBN1. PMID:23124041
• Frontiers in pediatrics • 2025 • Case Report: A case of severe pulmonary hypertension combined with FBN1 mutation associated geleophysic dysplasia. PMID:40740820
• Journal of human genetics • 2014 • Three novel mutations of the FBN1 gene in Chinese children with acromelic dysplasia. PMID:25142510
• American journal of human genetics • 2011 • Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias PMID:21683322
• Genetics in medicine • 2021 • Geleophysic and acromicric dysplasias: natural history, genotype-phenotype correlations, and management guidelines from 38 cases. PMID:33082559

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