TRPS1 – Trichorhinophalangeal Syndrome

Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant skeletal dysplasia caused by heterozygous variants in the TRPS1 gene, characterized by sparse hair, craniofacial dysmorphism, and cone-shaped epiphyses. The disease spectrum spans three subtypes (TRPS I–III) with overlapping features of pear-shaped nose, thin upper lip vermilion, and brachydactyly ([PMID:23691375]).

Over 50 probands from at least 17 unrelated families harbor truncating, missense, and frameshift TRPS1 variants, including recurrent nonsense mutations c.2086C>T (p.Arg696Ter) and c.1198C>T (p.Gln400Ter) observed de novo in TRPS I ([PMID:23691375], [PMID:30458885]). Frameshift variants such as c.2854_2858del (p.Asn952ArgfsTer2) segregate across four generations in a Cypriot kindred ([PMID:36093893]), and exon-6 missense changes (e.g., c.2893C>T (p.Arg965Cys)) impair nuclear localization, defining a genotype-phenotype correlation ([PMID:14560312], [PMID:17854380]). Large deletions encompassing TRPS1–EXT1 underlie TRPS II ([PMID:26269715], [PMID:36598218]).

Segregation analyses document at least eight additional affected relatives carrying familial TRPS1 variants, confirming autosomal dominant inheritance with high penetrance in multiple pedigrees ([PMID:30458885], [PMID:36093893]). The variant spectrum includes 15 truncating, 7 missense, 3 frameshift, and multiple whole-gene deletions or microdeletions, indicating loss-of-function as the primary pathogenic mechanism.

Functional assays demonstrate that TRPS1 haploinsufficiency disrupts transcriptional repression of STAT3 and RUNX2, impairs chondrocyte proliferation and apoptosis, and accelerates perichondrial mineralization in mouse growth plates, recapitulating human skeletal defects ([PMID:17997399], [PMID:18424451]). Immunohistochemical studies reveal markedly reduced TRPS1 expression in patient hair follicles, with consequent upregulation of phospho-Stat3 signaling ([PMID:23451857]). Palatal fusion assays in Trps1-null mice show cleft palate due to failure of epithelial chondroitin sulfate proteoglycan and TGF-β3 expression, underscoring a developmental role in craniofacial skeletogenesis ([PMID:31130868]).

To date, no studies have refuted the TRPS1–TRPS association, and somatic TRPS1 alterations in other diseases (e.g., endometrial cancer) do not phenocopy TRPS syndrome. The concordance of extensive genetic, segregation, and functional data fulfills ClinGen criteria for a Definitive gene‐disease association.

Key Take-home: TRPS1 genetic testing is essential for diagnosis and management of trichorhinophalangeal syndrome due to its autosomal dominant inheritance, broad variant spectrum, and clear mechanistic insights.

References

• Case Rep Genet • 2013 • Trichorhinophalangeal Syndrome Type I: A Patient with Two Novel and Different Mutations in the TRPS1 Gene. PMID:23691375
• J Dermatol • 2013 • Trichorhinophalangeal syndrome with low expression of TRPS1 on epidermal and hair follicle epithelial cells. PMID:23451857
• Ital J Pediatr • 2018 • An early diagnosis of trichorhinophalangeal syndrome type 1: a case report and a review of literature. PMID:30458885
• Appl Immunohistochem Mol Morphol • 2022 • Characterization of a Novel Frameshift Mutation Within the TRPS1 Gene Causing Trichorhinophalangeal Syndrome Type 1 in a Kindred Cypriot Family. PMID:36093893
• Turk Arch Pediatr • 2023 • The Clinical and Molecular Spectrum of Trichorhinophalangeal Syndrome Types I and II in a Turkish Cohort Involving 22 Patients. PMID:36598218
• Eur J Hum Genet • 2004 • Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal. PMID:14560312
• Dev Biol • 2007 • Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling. PMID:17997399
• Hum Mol Genet • 2008 • Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome. PMID:18424451
• Front Physiol • 2019 • Trps1 Regulates Development of Craniofacial Skeleton and Is Required for the Initiation of Palatal Shelves Fusion. PMID:31130868

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