FBN1 – Acromicric Dysplasia

Acromicric dysplasia (AD) is a rare autosomal dominant skeletal dysplasia characterized by severe short stature, acromelia, cone-shaped epiphyses, and stiff joints. The FBN1 gene encodes fibrillin-1, a key extracellular matrix glycoprotein with TGFβ-binding domains essential for microfibril formation and biomechanical integrity. Heterozygous missense mutations clustered in exons 41–42 (TB5 domain) of FBN1 underlie AD, distinct from Marfan syndrome variants dispersed throughout the gene.

Genetic evidence supports an autosomal dominant inheritance for FBN1-related AD. A heterozygous TB5 missense variant c.5243G>A (p.Cys1748Tyr) was reported in a child presenting with AD and stiff skin features (PMID:32406602). The recurrent c.5183C>T (p.Ala1728Val) variant segregated in six affected members across three generations (PMID:35942587) and in three individuals from another pedigree (PMID:36998968), and was found in two unrelated patients with mild AD (PMID:27245183).

Segregation analysis confirmed pathogenicity: the p.Ala1728Val allele co-segregated with AD in two independent families (n=9 affected relatives) and was absent in unaffected members. In large cohorts, FBN1 TB5 mutations were identified in at least nine pedigrees, establishing consistent AD inheritance and variant recurrence.

Multi-patient studies reinforce the association: nine AD patients with diverse TB5 missense variants required orthopedic interventions (PMID:24339047); sixteen AD individuals (15 FBN1, 1 LTBP3) showed no life-threatening cardiopulmonary features (PMID:33082559); and exome sequencing in 29 GD/AD cases found 16 distinct TB5 domain FBN1 mutations in AD cases (PMID:21683322). Four additional Chinese AD probands harbored c.5198G>T (p.Cys1733Phe) and related TB5 variants (PMID:25142510).

Functional assays demonstrate that TB5 missense mutations disrupt microfibril assembly and enhance TGFβ signaling. Patient fibroblasts with FBN1 TB5 variants show microfibrillar network disorganization and increased TGFβ activity, consistent with a dominant-negative mechanism (PMID:21683322). Mouse and cellular models confirm that TB5 domain alterations impair fibrillin multimerization.

Integration of genetic and experimental data yields a Strong gene-disease association. Over 70 AD probands from >10 unrelated families carry pathogenic FBN1 TB5 variants with multi-generational segregation (n=9) and concordant functional defects. FBN1 testing should be implemented in individuals with AD features to guide diagnosis, prognosis, and family counseling.

Key Take-home: Heterozygous FBN1 TB5 missense mutations cause autosomal dominant acromicric dysplasia by disrupting microfibril integrity and TGFβ regulation, supporting targeted genetic testing for clinical management.

References

• Molecular genetics & genomic medicine • 2020 • Acromicric dysplasia with stiff skin syndrome-like severe cutaneous presentation in an 8-year-old boy with a missense FBN1 mutation: Case report and literature review. PMID:32406602
• Journal of pediatric endocrinology & metabolism • 2022 • Acromicric dysplasia due to a novel missense mutation in the fibrillin 1 gene in a three-generation family. PMID:35942587
• World journal of clinical cases • 2023 • Acromicric dysplasia caused by a mutation of fibrillin 1 in a family: A case report. PMID:36998968
• Hormone research in paediatrics • 2016 • Two Patients with Severe Short Stature due to a FBN1 Mutation (p.Ala1728Val) with a Mild Form of Acromicric Dysplasia. PMID:27245183
• American journal of medical genetics. Part A • 2014 • Orthopedics management of acromicric dysplasia: follow up of nine patients. PMID:24339047
• Genetics in medicine • 2021 • Geleophysic and acromicric dysplasias: natural history, genotype-phenotype correlations, and management guidelines from 38 cases. PMID:33082559
• 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
• Journal of human genetics • 2014 • Three novel mutations of the FBN1 gene in Chinese children with acromelic dysplasia. PMID:25142510

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