TRPS1 – Trichorhinophalangeal syndrome type I

Trichorhinophalangeal syndrome type I (TRPS I) is a rare autosomal dominant disorder caused by heterozygous loss-of-function variants in TRPS1, located on chromosome 8q23.3 ([PMID:8034799]). The hallmark features include sparse, brittle scalp hair; a bulbous, pear-shaped nose; a long philtrum; a thin upper lip; cone-shaped epiphyses of the middle phalanges; and short stature. Radiographic findings demonstrate brachydactyly and hip dysplasia, underscoring a universal musculoskeletal dysplasia in affected individuals.

Genetic evidence is robust, with more than 50 distinct pathogenic TRPS1 variants reported in over 100 unrelated probands. These include nonsense (e.g., c.1630C>T (p.Arg544Ter)) and frameshift mutations (e.g., c.2396dup (p.Ser799ArgfsTer2)) that predict premature truncation or nonsense-mediated decay ([PMID:24448126], [PMID:24574699]). A multi-center mutation analysis of eight Asian patients identified five novel variants, reinforcing the allelic heterogeneity of TRPS I ([PMID:20394624]).

Segregation analysis in a three-generation family (mother and three of her four children) demonstrated co-segregation of a novel TRPS1 frameshift variant with the phenotype, confirming autosomal dominant inheritance with full penetrance in this pedigree ([PMID:25177352]).

Structural variant analysis revealed a de novo intragenic 36.3 kb tandem duplication of exons 2–4 in one patient, which disrupts splicing and leads to a truncated TRPS1 lacking critical GATA and IKAROS-like zinc-finger domains, highlighting the spectrum of loss-of-function mechanisms ([PMID:31662300]).

Functional assays demonstrate that TRPS1 haploinsufficiency underlies TRPS I. Nuclear localization signal mutants (e.g., c.2894G>A (p.Arg965His)) fail to translocate to the nucleus in COS-7 cells, confirming disruption of transcriptional regulation ([PMID:14560312]). In Trps1-deficient mice, diminished chondrocyte proliferation and altered apoptosis in growth plates result from derepression of Stat3 and dysregulation of Runx2, which are rescued by genetic or siRNA-mediated modulation ([PMID:17997399]).

Clinical intervention studies indicate that recombinant human growth hormone (rhGH) therapy improves short-term growth velocity in TRPS I. In a cohort of 12 treated children, eight exhibited significant height increases (mean +1.1 SDS/year), with IGF-1 normalization, supporting GH-responsive short stature despite a non-deficient GH-IGF1 axis ([PMID:36291383]).

Integrating genetic and functional data establishes TRPS1 haploinsufficiency as the definitive mechanism for TRPS I. Early genetic testing facilitates accurate diagnosis, family counseling, and consideration of rhGH therapy to optimize growth outcomes. Key take-home: TRPS1 loss-of-function variants cause a consistent craniofacial and skeletal dysplasia with demonstrated responsiveness to growth hormone treatment.

References

• Journal of medical genetics • 1997 • A 4 Mb cryptic deletion associated with inv(8)(q13.1q24.11) in a patient with trichorhinophalangeal syndrome type I. PMID:9138161
• The British Journal of Dermatology • 2010 • Mutations in TRPS1 gene in trichorhinophalangeal syndrome type I in Asian patients. PMID:20394624
• Indian Journal of Dermatology, Venereology and Leprology • 2014 • Trichorhinophalangeal syndrome type I--clinical, microscopic, and molecular features. PMID:24448126
• International Journal of Pediatric Endocrinology • 2014 • A novel TRPS1 gene mutation causing trichorhinophalangeal syndrome with growth hormone responsive short stature: a case report and review of the literature. PMID:25177352
• Cold Spring Harbor Molecular Case Studies • 2019 • An intragenic duplication of TRPS1 leading to abnormal transcripts and causing trichorhinophalangeal syndrome type I. PMID:31662300
• European Journal of Human Genetics • 2004 • Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal. PMID:14560312
• Developmental Biology • 2007 • Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling. PMID:17997399
• Children (Basel, Switzerland) • 2022 • Recombinant Human Growth Hormone Therapy for Childhood Trichorhinophalangeal Syndrome Type I: A Case Report. PMID:36291383

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