FBN1 TB5 domain variants in acromelic dysplasia: multisystem manifestations, genotype-phenotype correlations, and partial responses to growth hormone therapy.

BACKGROUND: Acromelic dysplasias, including acromicric dysplasia (AD) and geleophysic dysplasia type 2 (GD2), are ultrarare disorders caused by FBN1 variants in the transforming growth factor-β-binding protein-like domain 5 (TB5). These conditions are characterized by severe short stature and variable multisystem involvement, but genotype-phenotype correlations and treatment responses remain incompletely defined. OBJECTIVE: To characterize the clinical spectrum, genotype-phenotype correlations, and growth outcomes in a Chinese cohort of patients with FBN1-related AD/GD2. METHODS: We conducted a retrospective analysis of 14 patients with AD or GD2 from eight unrelated families. Clinical, radiographic, and genetic data were collected. Genotype-phenotype correlations were further explored by integrating data from two previously published cohorts (n = 52). Growth outcomes were evaluated in patients receiving recombinant human growth hormone (rhGH) therapy. RESULTS: All patients exhibited severe short stature (mean height-SDS of -5.28 ± 1.13) with brachydactyly and delayed bone age. Multisystem involvement, including skeletal abnormalities, airway and otologic complications, skin thickening, joint limitation, hepatomegaly, and cardiopulmonary disease (50.0%, exclusively on GD2), was common. All the variants were heterozygous missense mutations clustered in the TB5 domain, including two novel de novo variants. Genotype-phenotype preliminary analysis revealed a greater mortality in patients with GD2 than in patients with AD (29.6%(15.9 -48.5%) vs. 4.0%(0.7-19.5%), P = 0.038). Variants with cysteine or aromatic residues substitutions were associated with increased mortality compared with that associated with other substitutions (overall P < 0.001). Eleven patients received growth-promoting therapy. Among the eight patients treated at our center, growth-promoting therapy maintained a growth velocity during the first two years (approximately 6 cm/year) but declined thereafter, with no significant improvement in height-SDS over a mean treatment duration of 3.6 years. CONCLUSION: FBN1-related AD/GD2 represent multisystem disorders rather than isolated skeletal dysplasias. Variants affecting cysteine or aromatic residues in the TB5 domain maybe associated with worse outcomes. Growth-promoting therapy may contribute to maintaince of growth velocity but catch-up growth was not clearly observed. These findings suggest that molecular stratification may be helpful for risk assessment and clinical decision-making, pending further validation.