Trichorhinophalangeal Syndrome Type I

Mendelian MONDO:0008596 Pathograph 25 Show in embeddings browser Skeletal Dysplasia Malformation Syndrome

Trichorhinophalangeal syndrome type I is an autosomal dominant skeletal and ectodermal dysplasia caused by heterozygous pathogenic variants in TRPS1, which encodes an atypical GATA-type zinc-finger transcription factor that mainly represses its targets. MONDO includes the more severe type III form, caused by missense variants in the GATA DNA-binding zinc finger, in this term. Patients have fine, sparse, slow-growing scalp hair, eyebrows that are thick medially and thin laterally, a bulbous nose with underdeveloped alae, a long philtrum, a thin upper lip and protruding ears, together with brachydactyly with cone-shaped epiphyses of the phalanges, short metacarpals, short stature, hip dysplasia and, as the main lifelong morbidity, joint problems progressing to premature osteoarthritis. Osteopenia is common and dystrophic nails and supernumerary teeth occur. In mouse models, loss of TRPS1 repression of Runx2 and of the Ihh/PTHrP loop uncouples chondrocyte differentiation from perichondrial mineralisation in the growth plate, and disrupted Wnt-inhibitor and Sox9 regulation in the hair follicle explains the sparse hair. Intelligence is normal and life expectancy is not reduced. Management is supportive. The contiguous-gene TRPS type II (Langer-Giedion syndrome), which also deletes EXT1 and RAD21, is curated as a subtype of Hereditary_Multiple_Osteochondromas.

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1
Inheritance
8
Pathophys.
16
Phenotypes
25
Pathograph
6
Medical Actions
2
Subtypes
2
Models
1
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous TRPS1 variants, inherited or de novo, with complete penetrance and marked variable expressivity even within families.
Autosomal dominant inheritance
Show evidence (5 references)
PMID:10615131 SUPPORT Human Clinical
"Tricho-rhino-phalangeal syndrome type I (TRPS I, MIM 190350) is a malformation syndrome characterized by craniofacial and skeletal abnormalities and is inherited in an autosomal dominant manner."
States dominant inheritance in the gene-discovery paper.
PMID:11112658 SUPPORT Human Clinical
"We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations."
Complete penetrance in a 44-patient mutation study.
PMID:28426188 SUPPORT Human Clinical
"TRPS is inherited in an autosomal dominant manner."
GeneReviews states the mode of inheritance.
+ 2 more references
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Subtypes

2
Classic TRPS I (truncating or deletion alleles)
The usual form, caused by nonsense, frameshift or whole-gene deletion alleles that act by haploinsufficiency.
Show evidence (1 reference)
PMID:10615131 SUPPORT Human Clinical
"Our findings suggest that haploinsufficiency for this putative transcription factor causes TRPS I."
Haploinsufficiency as the mechanism of classic TRPS I.
TRPS III (GATA zinc-finger missense alleles)
The severe end of the spectrum, with severe brachydactyly from short metacarpals and severe short stature, mostly caused by missense variants in the GATA DNA-binding zinc finger (exons 6 and 7).
Show evidence (2 references)
PMID:11112658 SUPPORT Human Clinical
"Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene."
TRPS III is the severe, missense-driven end of one spectrum.
PMID:42361898 SUPPORT Human Clinical
"Missense variants in exon 6 were consistently associated with severe brachydactyly, whereas the overall stature showed no clear correlation with genotype."
Genotype-phenotype correlation in a Korean cohort.
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Pathophysiology

8
Heterozygous TRPS1 Variants
Nonsense, frameshift, splice and whole-gene deletion alleles reduce TRPS1 dosage; missense alleles in the GATA zinc finger impair DNA binding and repression and give more severe disease.
TRPS1 hgnc:12340 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRPS1 (hgnc:12340). hgnc:12340 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of TRPS1 GATA-Dependent Transcriptional Repression
Show evidence (3 references)
PMID:10615131 SUPPORT Human Clinical
"We identified six different nonsense mutations in ten unrelated patients."
Truncating variants in the first patient series.
PMID:11950061 SUPPORT Human Clinical
"Seven of the nine mutations result in a premature stop codon, leading to a truncated, nonfunctional TRPS1 protein. The final two mutations are missense mutations in the GATA DNA binding zinc finger, which is believed to be important for the protein's normal function."
The two allele classes.
PMID:25792522 SUPPORT Human Clinical
"Missense mutations are located exclusively in exon 6 and 7 of TRPS1."
Location of missense alleles in a 103-patient cohort.
Loss of TRPS1 GATA-Dependent Transcriptional Repression
TRPS1 binds GATA sequences through its single GATA zinc finger and represses transcription through an Ikaros-like C-terminal domain. Its targets include Runx2, the PTHrP gene, Sox9 and Wnt-pathway genes; in the hair follicle it can also activate targets.
DNA-binding transcription repressor activity GO:0001227 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA-binding transcription repressor activity, annotated with DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227). GO:0001227 is a molecular function from the Gene Ontology.
Downstream
Uncoupled Chondrocyte Differentiation and Perichondrial Mineralisation
Disrupted Hair Follicle Morphogenesis
Craniofacial and Axial Skeletal Dysplasia
Disordered Tooth Development and Dentin Mineralisation
Show evidence (2 references)
PMID:11285235 SUPPORT In Vitro
"TRPS1 is a nuclear protein that binds GATA sequences but fails to transactivate a GATA-dependent reporter. Instead, TRPS1 potently and specifically represses transcriptional activation mediated by other GATA factors."
TRPS1 is a GATA-binding repressor.
PMID:36990068 SUPPORT In Vitro
"In vitro functional studies showed that the TRPS1 variant did not affect the cellular localization and the expression of TRPS1, but the transcriptional repression effect of the TRPS1 on the RUNX2 and STAT3 was disturbed."
A patient variant impairs repression of RUNX2 and STAT3.
Disordered Tooth Development and Dentin Mineralisation
TRPS1 regulates dentin mineralisation in odontoblasts. Patients have supernumerary and impacted teeth, and one patient with a missense variant had large pulp spaces suggesting impaired dentin mineralisation, together with microdontia and a missing premolar.
odontoblast CL:0000060 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves odontoblast (CL:0000060). CL:0000060 is a cell type from the Cell Ontology.
dentinogenesis GO:0097187 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal dentinogenesis (GO:0097187). GO:0097187 is a biological process from the Gene Ontology.
Downstream
Supernumerary teeth
Show evidence (2 references)
PMID:32442662 SUPPORT Human Clinical
"Having large dental pulp spaces suggests that impaired dentin mineralization was the result of the TRPS1 pathogenic variant."
Impaired dentin mineralisation in a patient with a TRPS1 variant.
PMID:32442662 SUPPORT Human Clinical
"TRPS1 has an important function in regulating bone and dentin mineralization."
The authors' conclusion about TRPS1 in dentin.
Uncoupled Chondrocyte Differentiation and Perichondrial Mineralisation
In Trps1 mutant growth plates, chondrocyte differentiation is delayed while the perichondrium mineralises early, with increased Runx2 and Ihh signalling and expanded PTHrP expression that enlarges the proliferative zone. Halving Runx2 dosage rescues the growth-plate phenotype. This dysregulated endochondral ossification is the proposed basis of the cone-shaped epiphyses, short phalanges and metacarpals, short stature and hip malformation.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
chondrocyte differentiation GO:0002062 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chondrocyte differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology. endochondral ossification GO:0001958 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology.
Animal models
Trps1 GATA-domain deletion mouse Mouse recapitulates The growth-plate defect behind the human skeletal phenotype.
Downstream
Cone-shaped epiphyses
Brachydactyly
Short metacarpals
Short stature
Abnormal Hip Joint Development
Show evidence (3 references)
PMID:18424451 SUPPORT Model Organism
"Analyses of growth plates demonstrated delayed chondrocyte differentiation and accelerated mineralization of perichondrium in Trps1 mutant mice."
The core growth-plate defect.
PMID:18424451 SUPPORT Model Organism
"Importantly, generation of Trps1(DeltaGT/+);Runx2(+/-) double heterozygous mice rescued the opposite growth plate phenotypes of single mutants, demonstrating the genetic interaction between Trps1 and Runx2 transcription factors."
Genetic rescue confirms that derepressed Runx2 drives the defect.
PMID:18456591 SUPPORT Model Organism
"Furthermore, promoter analysis combined with the chromatin immunoprecipitation (ChIP) assay demonstrated that direct binding of Trps1 to the PTHrP promoter suppressed the transcription of PTHrP."
A second direct growth-plate target.
Abnormal Hip Joint Development
Abnormal epiphyseal development of the hip, including Perthes-like changes, coxa magna and acetabular dysplasia, appears early in life.
Animal models
Trps1 intronic regulatory-element deletion mouse Mouse recapitulates Acetabular dysplasia and patellar dislocation.
Downstream
Hip dysplasia
Premature Joint Degeneration
Show evidence (2 references)
PMID:28426188 SUPPORT Human Clinical
"skeletal findings (short stature, brachydactyly with ulnar or radial deviation of the fingers, short feet, and early, marked hip dysplasia)"
GeneReviews describes early, marked hip dysplasia.
PMID:38899779 SUPPORT Model Organism
"This strain displayed delayed secondary ossification center formation in the long bones and misshaped hip joint development that resulted in acetabular dysplasia."
A hypomorphic Trps1 mouse develops acetabular dysplasia.
Premature Joint Degeneration
Joint problems, with pain and altered mobility progressing to premature osteoarthritis, are the main lifelong morbidity.
Downstream
Premature osteoarthritis
Show evidence (1 reference)
PMID:25792522 SUPPORT Human Clinical
"Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age."
Joint disease as the main morbidity.
Craniofacial and Axial Skeletal Dysplasia
Mice heterozygous for deletion of the TRPS1 GATA domain show facial anomalies resembling the human syndrome and develop kyphoscoliosis and cortical and trabecular bone deficits, suggesting a generalised bone dysplasia beyond the hands and hips.
Downstream
Bulbous nose
Underdeveloped nasal alae
Long philtrum
Thin upper lip vermilion
Protruding ears
Osteopenia
Show evidence (2 references)
PMID:12446778 SUPPORT Model Organism
"Here we report that heterozygous mice with deletions of the TRPS1 GATA domain (TRPS1(+/Deltagt)) display facial anomalies that overlap with findings for TRPS, whereas TRPS1(Deltagt/Deltagt) mice additionally reveal a complete absence of vibrissae."
Facial anomalies in heterozygous mutant mice.
PMID:12446778 SUPPORT Model Organism
"These findings directly implicate the GATA type zinc finger of TRPS1 in regulation of bone and hair development and suggest that skeletal abnormalities emphasized in descriptions of TRPS are only the extreme manifestations of a generalized bone dysplasia."
Generalised bone dysplasia in the mouse model.
Disrupted Hair Follicle Morphogenesis
Trps1 regulates a network of secreted Wnt inhibitors and transcription factors in the developing follicle and represses Sox9 in the follicle epithelium; loss reduces follicle number and causes vibrissa follicle degeneration in mice, the counterpart of sparse, fine, slow-growing hair in patients.
hair follicle development GO:0001942 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased hair follicle development (GO:0001942). GO:0001942 is a biological process from the Gene Ontology.
Animal models
Trps1 GATA-domain deletion mouse Mouse recapitulates Fewer pelage follicles and absent vibrissae.
Downstream
Sparse scalp hair
Sparse lateral eyebrows
Show evidence (2 references)
PMID:22115758 SUPPORT Model Organism
"Mice in which the GATA domain of Trps1 has been deleted (Trps1(Δgt/Δgt)) have a reduced number of pelage follicles and lack vibrissae follicles postnatally."
Follicle loss in the GATA-deletion mouse.
PMID:22115758 SUPPORT Model Organism
"Our findings identify Trps1 as a novel regulator of the Wnt signaling pathway and of early hair follicle progenitors in the developing vibrissa follicle."
Trps1 regulates Wnt signalling in follicle progenitors.
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Pathograph

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Pathograph: causal mechanism network for Trichorhinophalangeal Syndrome Type I Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

16
Ear 1
Protruding ears HP:0000411 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protruding ear (HP:0000411). HP:0000411 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10615131 SUPPORT Human Clinical
"TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears."
Protruding ears.
Head and Neck 7
Sparse scalp hair VERY_FREQUENT HP:0002209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse scalp hair (HP:0002209). HP:0002209 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28426188 SUPPORT Human Clinical
"ectodermal features (fine, sparse, depigmented, and slow-growing hair and dystrophic nails)"
GeneReviews lists the hair phenotype.
PMID:25792522 SUPPORT Human Clinical
"Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella."
Sparse hair as a defining feature in 103 patients.
Sparse lateral eyebrows HP:0005338 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse lateral eyebrow (HP:0005338). HP:0005338 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38574886 SUPPORT Human Clinical
"Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion."
Lateral eyebrow thinning in a Danish series.
Bulbous nose VERY_FREQUENT HP:0000414 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bulbous nose (HP:0000414). HP:0000414 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10615131 SUPPORT Human Clinical
"TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears."
The core facial description.
Underdeveloped nasal alae HP:0000430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Underdeveloped nasal alae (HP:0000430). HP:0000430 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792522 SUPPORT Human Clinical
"Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella."
Underdeveloped alae as a defining facial feature.
Long philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10615131 SUPPORT Human Clinical
"TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears."
Long flat philtrum.
Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10615131 SUPPORT Human Clinical
"TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears."
Thin upper vermilion.
Supernumerary teeth Supernumerary tooth HP:0011069 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supernumerary tooth (HP:0011069). HP:0011069 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32442662 SUPPORT Human Clinical
"Oral examination showed supernumerary teeth, large dental pulp spaces, dental pulp stones, microdontia of the maxillary permanent lateral incisors, absence of the mandibular left second premolar and short root of the maxillary right second premolar, and hypoplastic mandibular condyles with long..."
Supernumerary teeth in a patient with a TRPS1 missense variant.
PMID:37147064 SUPPORT Human Clinical
"Radiographic images showed a total of 45 teeth: two deciduous, 32 permanent, and 11 supernumerary teeth."
Eleven supernumerary teeth in a TRPS I patient.
Integument 1
Nail dystrophy HP:0008404 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nail dystrophy (HP:0008404). HP:0008404 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792522 SUPPORT Human Clinical
"Nails of fingers and toes are typically thin and dystrophic."
Thin, dystrophic nails.
Limbs 3
Cone-shaped epiphyses VERY_FREQUENT Cone-shaped epiphyses of the phalanges of the hand HP:0010230 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cone-shaped epiphyses of the phalanges of the hand (HP:0010230). HP:0010230 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792522 SUPPORT Human Clinical
"The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses."
Cone-shaped epiphyses as the radiological hallmark.
Brachydactyly VERY_FREQUENT HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792522 SUPPORT Human Clinical
"In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened."
Short hands and feet in 103 patients.
Short metacarpals HP:0010049 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short metacarpal (HP:0010049). HP:0010049 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38574886 SUPPORT Human Clinical
"Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs."
Shortened metacarpals on radiographs.
Musculoskeletal 3
Hip dysplasia HP:0001385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip dysplasia (HP:0001385). HP:0001385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28426188 SUPPORT Human Clinical
"skeletal findings (short stature, brachydactyly with ulnar or radial deviation of the fingers, short feet, and early, marked hip dysplasia)"
GeneReviews lists early, marked hip dysplasia.
Premature osteoarthritis HP:0003088 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature osteoarthritis (HP:0003088). HP:0003088 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38574886 SUPPORT Human Clinical
"The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established."
Universal joint complaints.
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792522 SUPPORT Human Clinical
"Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally."
Osteopenia is common.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25792522 SUPPORT Human Clinical
"Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally."
Reduced linear growth before and after birth.
PMID:42361898 SUPPORT Human Clinical
"Short stature (standard deviation score [SDS] of height < -2) was observed in 21% of patients."
Frequency of short stature in a Korean cohort.
💊

Medical Actions

6
Growth hormone therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: somatropin NCIT:C837 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses somatropin (NCIT:C837). NCIT:C837 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Recombinant growth hormone can improve growth velocity in patients with documented growth hormone deficiency; response without deficiency is poor.
Show evidence (4 references)
PMID:22964620 SUPPORT Human Clinical
"Over 10 years of GH therapy, the mean growth velocity was 5.7 ± 0.9 cm/year."
Sustained response in a growth hormone-deficient patient.
PMID:22964620 REFUTE Human Clinical
"However, the patient 2 did not show apparent GH deficiency by GH stimulation test, had a poor response with rhGH therapy and GH therapy was discontinued after 6 months."
Poor response without growth hormone deficiency.
PMID:28426188 SUPPORT Human Clinical
"consider growth hormone (GH) therapy in those with short stature and GH deficiency"
GeneReviews recommends GH only with documented deficiency.
+ 1 more reference
Bisphosphonates for severe osteoporosis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: neridronate CHEBI:135145 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses neridronate, annotated with neridronic acid (CHEBI:135145). CHEBI:135145 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Off-label intravenous neridronate stopped fractures and raised lumbar bone density in one child with severe osteoporosis.
Show evidence (2 references)
PMID:24357341 SUPPORT Human Clinical
"The treatment was, in this patient, effective both in terms of clinical (absence of new fractures) and mineralomethric (+45% BMD ath the lumbar level)."
Single-case response to neridronate.
PMID:28426188 SUPPORT Human Clinical
"consider bisphosphonates in those with osteopenia"
GeneReviews recommendation.
Hip replacement
Action: hip replacement for severe hip dysplasiaNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hip replacement for severe hip dysplasia, annotated with Hip Replacement (NCIT:C157876). NCIT:C157876 is a clinical intervention from the NCI Thesaurus. Ontology label: Hip Replacement NCIT:C157876
Platform: Surgery
Prosthetic hip implantation for severe hip dysplasia.
Show evidence (1 reference)
PMID:28426188 SUPPORT Human Clinical
"consider prosthetic hip implantation in those with severe hip dysplasia"
GeneReviews management recommendation.
Physiotherapy and analgesia for joint pain
Action: physiotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physiotherapy, annotated with Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Physiotherapy, regular exercise and non-opioid analgesics for joint pain and mobility.
Show evidence (1 reference)
PMID:28426188 SUPPORT Human Clinical
"analgesics (e.g., NSAIDs or other non-opiods) for joint pain; physiotherapy may relieve pain and aid mobility; encourage regular exercise"
GeneReviews joint-pain management.
Extraction of supernumerary teeth
Action: extraction of supernumerary teethNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is extraction of supernumerary teeth, annotated with Extraction of Tooth (NCIT:C51770). NCIT:C51770 is a clinical intervention from the NCI Thesaurus. Ontology label: Extraction of Tooth NCIT:C51770
Platform: Surgery
Extraction of impacted and supernumerary teeth, sometimes under general anaesthesia, after full clinical and radiographic oral examination.
Show evidence (2 references)
PMID:28426188 SUPPORT Human Clinical
"Practical advice on hair care and use of wigs; consider extraction of supernumerary teeth"
GeneReviews recommends considering extraction.
PMID:37147064 SUPPORT Human Clinical
"Four impacted third molars, supernumerary teeth, retained deciduous teeth, and impacted maxillary premolars were removed under general anaesthesia."
Extraction under general anaesthesia in one patient.
Topical minoxidil
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: minoxidil CHEBI:6942 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses minoxidil (CHEBI:6942). CHEBI:6942 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Used for sparse hair with variable response in a Korean cohort.
Show evidence (1 reference)
PMID:42361898 SUPPORT Human Clinical
"Responses to rhGH and minoxidil treatments were variable."
Variable response to minoxidil and growth hormone.
🔬

Diagnosis

1
Clinical and radiographic diagnosis with TRPS1 testing
Characteristic facial and ectodermal features with cone-shaped epiphyses on hand radiographs establish the clinical diagnosis, confirmed by a heterozygous TRPS1 variant; deletion testing distinguishes TRPS II.
Show evidence (1 reference)
PMID:28426188 SUPPORT Human Clinical
"The molecular diagnosis of TRPS I is established in an individual with suggestive findings and identification of a heterozygous pathogenic variant in TRPS1"
GeneReviews diagnostic criteria.
📊

Prevalence

1
Denmark (single-centre series)
Point Prevalence 0.5 per 100,000 (0.3–0.8) 1–9 per 1,000,000
Minimum point prevalence of 0.5 per 100,000 (95% CI 0.3-0.8) estimated from 15 patients seen at one Danish university hospital; likely an underestimate because mild cases go undiagnosed.
Show evidence (1 reference)
PMID:38574886 SUPPORT Human Clinical
"We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3-0.8 per 100,000) persons."
Source of the normalized rate and its interval.
🐁

Animal Models

2
Trps1 GATA-domain deletion mouse
Heterozygotes show facial anomalies, kyphoscoliosis and bone deficits; homozygotes lack vibrissae and die of neonatal respiratory failure. Growth plates show delayed chondrocyte differentiation with accelerated perichondrial mineralisation, rescued by Runx2 heterozygosity.
Species
Mouse
Genotype
Trps1 delta-GT (deletion of the GATA zinc finger), heterozygous and homozygous
Publication
PMID:18424451
Pathograph links
Uncoupled Chondrocyte Differentiation and Perichondrial Mineralisation recapitulates fidelity: moderate The growth-plate defect behind the human skeletal phenotype.
Limitations: Most growth-plate analyses use mutants more severe than the human heterozygous state.
Show evidence (1 reference)
PMID:18424451 SUPPORT Model Organism
"These abnormalities were accompanied by increased Runx2 and Ihh expression and increased Indian hedgehog signaling."
Molecular readout of the growth-plate defect.
Disrupted Hair Follicle Morphogenesis recapitulates fidelity: moderate Fewer pelage follicles and absent vibrissae.
Limitations: Vibrissae have no human counterpart; the pelage reduction is in homozygotes.
Show evidence (1 reference)
PMID:22115758 SUPPORT Model Organism
"Mice in which the GATA domain of Trps1 has been deleted (Trps1(Δgt/Δgt)) have a reduced number of pelage follicles and lack vibrissae follicles postnatally."
Follicle phenotype in the mutant.
Trps1 intronic regulatory-element deletion mouse
A viable hypomorph that reproduces postnatal growth retardation and hip dysplasia, avoiding the early lethality of knockouts.
Species
Mouse
Genotype
Trps1 delta-int/delta-int (hypomorph)
Publication
PMID:38899779
Pathograph links
Abnormal Hip Joint Development recapitulates fidelity: moderate Acetabular dysplasia and patellar dislocation.
Show evidence (1 reference)
PMID:38899779 SUPPORT Model Organism
"Our novel Trps1 hypomorphic strain recapitulates many postnatal pathologies observed in human TRPS patients, thus positioning this strain as a useful animal model to study postnatal TRPS pathogenesis."
The model reproduces postnatal TRPS pathology.
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name: Trichorhinophalangeal Syndrome Type I
creation_date: '2026-10-12T18:40:00Z'
category: Mendelian
parents:
- Skeletal Dysplasia
- Malformation Syndrome
disease_term:
  preferred_term: trichorhinophalangeal syndrome type I
  term:
    id: MONDO:0008596
    label: trichorhinophalangeal syndrome type I
synonyms:
- TRPS I
- tricho-rhino-phalangeal syndrome type I
- trichorhinophalangeal syndrome type III
- TRPS III
- Sugio-Kajii syndrome
description: >-
  Trichorhinophalangeal syndrome type I is an autosomal dominant skeletal and
  ectodermal dysplasia caused by heterozygous pathogenic variants in TRPS1,
  which encodes an atypical GATA-type zinc-finger transcription factor that
  mainly represses its targets. MONDO includes the more severe type III form,
  caused by missense variants in the GATA DNA-binding zinc finger, in this
  term. Patients have fine, sparse, slow-growing scalp hair, eyebrows that are
  thick medially and thin laterally, a bulbous nose with underdeveloped alae,
  a long philtrum, a thin upper lip and protruding ears, together with
  brachydactyly with cone-shaped epiphyses of the phalanges, short metacarpals,
  short stature, hip dysplasia and, as the main lifelong morbidity, joint
  problems progressing to premature osteoarthritis. Osteopenia is common and
  dystrophic nails and supernumerary teeth occur. In mouse models, loss of
  TRPS1 repression of Runx2 and of the Ihh/PTHrP loop uncouples chondrocyte
  differentiation from perichondrial mineralisation in the growth plate, and
  disrupted Wnt-inhibitor and Sox9 regulation in the hair follicle explains
  the sparse hair. Intelligence is normal and life expectancy is not reduced.
  Management is supportive. The contiguous-gene TRPS type II (Langer-Giedion
  syndrome), which also deletes EXT1 and RAD21, is curated as a subtype of
  Hereditary_Multiple_Osteochondromas.
prevalence:
- population: Denmark (single-centre series)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.5
  rate_low: 0.3
  rate_high: 0.8
  notes: >-
    Minimum point prevalence of 0.5 per 100,000 (95% CI 0.3-0.8) estimated
    from 15 patients seen at one Danish university hospital; likely an
    underestimate because mild cases go undiagnosed.
  evidence:
  - reference: PMID:38574886
    reference_title: "Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3-0.8 per 100,000) persons."
    explanation: >-
      Source of the normalized rate and its interval.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous TRPS1 variants, inherited or de novo, with complete
    penetrance and marked variable expressivity even within families.
  evidence:
  - reference: PMID:10615131
    reference_title: "Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tricho-rhino-phalangeal syndrome type I (TRPS I, MIM 190350) is a malformation syndrome characterized by craniofacial and skeletal abnormalities and is inherited in an autosomal dominant manner."
    explanation: >-
      States dominant inheritance in the gene-discovery paper.
  - reference: PMID:11112658
    reference_title: "Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations."
    explanation: >-
      Complete penetrance in a 44-patient mutation study.
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRPS is inherited in an autosomal dominant manner."
    explanation: >-
      GeneReviews states the mode of inheritance.
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many individuals with TRPS I have an affected parent; about one third of affected individuals have the disorder as the result of a de novo pathogenic variant."
    explanation: >-
      GeneReviews supports both inherited and de novo occurrence.
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with TRPS has a 50% chance of inheriting the TRPS-related genetic alteration."
    explanation: >-
      GeneReviews recurrence risk for offspring.
has_subtypes:
- name: TRPS I
  display_name: Classic TRPS I (truncating or deletion alleles)
  description: >-
    The usual form, caused by nonsense, frameshift or whole-gene deletion
    alleles that act by haploinsufficiency.
  evidence:
  - reference: PMID:10615131
    reference_title: "Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that haploinsufficiency for this putative transcription factor causes TRPS I."
    explanation: >-
      Haploinsufficiency as the mechanism of classic TRPS I.
- name: TRPS III
  display_name: TRPS III (GATA zinc-finger missense alleles)
  description: >-
    The severe end of the spectrum, with severe brachydactyly from short
    metacarpals and severe short stature, mostly caused by missense variants
    in the GATA DNA-binding zinc finger (exons 6 and 7).
  evidence:
  - reference: PMID:11112658
    reference_title: "Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene."
    explanation: >-
      TRPS III is the severe, missense-driven end of one spectrum.
  - reference: PMID:42361898
    reference_title: "Clinical and genetic spectrum of trichorhinophalangeal syndrome type I/III in 20 children of Korean origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense variants in exon 6 were consistently associated with severe brachydactyly, whereas the overall stature showed no clear correlation with genotype."
    explanation: >-
      Genotype-phenotype correlation in a Korean cohort.
pathophysiology:
- name: Heterozygous TRPS1 Variants
  biological_scale: MOLECULAR
  description: >-
    Nonsense, frameshift, splice and whole-gene deletion alleles reduce TRPS1
    dosage; missense alleles in the GATA zinc finger impair DNA binding and
    repression and give more severe disease.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: TRPS1
    term:
      id: hgnc:12340
      label: TRPS1
  evidence:
  - reference: PMID:10615131
    reference_title: "Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six different nonsense mutations in ten unrelated patients."
    explanation: >-
      Truncating variants in the first patient series.
  - reference: PMID:11950061
    reference_title: "Analysis of novel and recurrent mutations responsible for the tricho-rhino-phalangeal syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven of the nine mutations result in a premature stop codon, leading to a truncated, nonfunctional TRPS1 protein. The final two mutations are missense mutations in the GATA DNA binding zinc finger, which is believed to be important for the protein's normal function."
    explanation: >-
      The two allele classes.
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense mutations are located exclusively in exon 6 and 7 of TRPS1."
    explanation: >-
      Location of missense alleles in a 103-patient cohort.
  downstream:
  - target: Loss of TRPS1 GATA-Dependent Transcriptional Repression
    causal_link_type: DIRECT
- name: Loss of TRPS1 GATA-Dependent Transcriptional Repression
  biological_scale: MOLECULAR
  description: >-
    TRPS1 binds GATA sequences through its single GATA zinc finger and
    represses transcription through an Ikaros-like C-terminal domain. Its
    targets include Runx2, the PTHrP gene, Sox9 and Wnt-pathway genes; in the
    hair follicle it can also activate targets.
  molecular_functions:
  - preferred_term: DNA-binding transcription repressor activity
    modifier: DECREASED
    term:
      id: GO:0001227
      label: DNA-binding transcription repressor activity, RNA polymerase II-specific
  evidence:
  - reference: PMID:11285235
    reference_title: "Transcriptional repression and developmental functions of the atypical vertebrate GATA protein TRPS1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TRPS1 is a nuclear protein that binds GATA sequences but fails to transactivate a GATA-dependent reporter. Instead, TRPS1 potently and specifically represses transcriptional activation mediated by other GATA factors."
    explanation: >-
      TRPS1 is a GATA-binding repressor.
  - reference: PMID:36990068
    reference_title: "Molecular Genetic Analysis and Growth Hormone Treatment in a Three-Generation Chinese Family with Tricho-Rhino-Phalangeal Syndrome I."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro functional studies showed that the TRPS1 variant did not affect the cellular localization and the expression of TRPS1, but the transcriptional repression effect of the TRPS1 on the RUNX2 and STAT3 was disturbed."
    explanation: >-
      A patient variant impairs repression of RUNX2 and STAT3.
  downstream:
  - target: Uncoupled Chondrocyte Differentiation and Perichondrial Mineralisation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18424451
      reference_title: "Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We demonstrated that Trps1 physically interacts with Runx2 and represses Runx2-mediated trans-activation."
      explanation: >-
        Mechanistic link from TRPS1 repression to its growth-plate target.
  - target: Disrupted Hair Follicle Morphogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23133399
      reference_title: "Trps1 and its target gene Sox9 regulate epithelial proliferation in the developing hair follicle and are associated with hypertrichosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that Trps1 directly represses expression of the hair follicle stem cell regulator Sox9 to control proliferation of the follicle epithelium."
      explanation: >-
        Direct follicle target of TRPS1.
  - target: Craniofacial and Axial Skeletal Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Disordered Tooth Development and Dentin Mineralisation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22508542
      reference_title: "Transcriptional repression of the Dspp gene leads to dentinogenesis imperfecta phenotype in Col1a1-Trps1 transgenic mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "On the molecular level, we demonstrated that sustained high levels of Trps1 in odontoblasts lead to dramatic decrease of Dspp expression as a result of direct inhibition of the Dspp promoter by Trps1."
      explanation: >-
        TRPS1 directly represses the dentin gene Dspp in odontoblasts; shown
        by overexpression, so the link to loss-of-function disease is
        inferential.
- name: Disordered Tooth Development and Dentin Mineralisation
  biological_scale: TISSUE
  description: >-
    TRPS1 regulates dentin mineralisation in odontoblasts. Patients have
    supernumerary and impacted teeth, and one patient with a missense variant
    had large pulp spaces suggesting impaired dentin mineralisation, together
    with microdontia and a missing premolar.
  cell_types:
  - preferred_term: odontoblast
    term:
      id: CL:0000060
      label: odontoblast
  biological_processes:
  - preferred_term: dentinogenesis
    modifier: ABNORMAL
    term:
      id: GO:0097187
      label: dentinogenesis
  evidence:
  - reference: PMID:32442662
    reference_title: "Impaired dentin mineralization, supernumerary teeth, hypoplastic mandibular condyles with long condylar necks, and a TRPS1 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Having large dental pulp spaces suggests that impaired dentin mineralization was the result of the TRPS1 pathogenic variant."
    explanation: >-
      Impaired dentin mineralisation in a patient with a TRPS1 variant.
  - reference: PMID:32442662
    reference_title: "Impaired dentin mineralization, supernumerary teeth, hypoplastic mandibular condyles with long condylar necks, and a TRPS1 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRPS1 has an important function in regulating bone and dentin mineralization."
    explanation: >-
      The authors' conclusion about TRPS1 in dentin.
  downstream:
  - target: Supernumerary teeth
- name: Uncoupled Chondrocyte Differentiation and Perichondrial Mineralisation
  biological_scale: TISSUE
  description: >-
    In Trps1 mutant growth plates, chondrocyte differentiation is delayed
    while the perichondrium mineralises early, with increased Runx2 and Ihh
    signalling and expanded PTHrP expression that enlarges the proliferative
    zone. Halving Runx2 dosage rescues the growth-plate phenotype. This
    dysregulated endochondral ossification is the proposed basis of the
    cone-shaped epiphyses, short phalanges and metacarpals, short stature and
    hip malformation.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: chondrocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  - preferred_term: endochondral ossification
    modifier: ABNORMAL
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:18424451
    reference_title: "Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analyses of growth plates demonstrated delayed chondrocyte differentiation and accelerated mineralization of perichondrium in Trps1 mutant mice."
    explanation: >-
      The core growth-plate defect.
  - reference: PMID:18424451
    reference_title: "Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Importantly, generation of Trps1(DeltaGT/+);Runx2(+/-) double heterozygous mice rescued the opposite growth plate phenotypes of single mutants, demonstrating the genetic interaction between Trps1 and Runx2 transcription factors."
    explanation: >-
      Genetic rescue confirms that derepressed Runx2 drives the defect.
  - reference: PMID:18456591
    reference_title: "Trps1 deficiency enlarges the proliferative zone of growth plate cartilage by upregulation of Pthrp."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, promoter analysis combined with the chromatin immunoprecipitation (ChIP) assay demonstrated that direct binding of Trps1 to the PTHrP promoter suppressed the transcription of PTHrP."
    explanation: >-
      A second direct growth-plate target.
  downstream:
  - target: Cone-shaped epiphyses
  - target: Brachydactyly
  - target: Short metacarpals
  - target: Short stature
  - target: Abnormal Hip Joint Development
- name: Abnormal Hip Joint Development
  biological_scale: TISSUE
  description: >-
    Abnormal epiphyseal development of the hip, including Perthes-like
    changes, coxa magna and acetabular dysplasia, appears early in life.
  evidence:
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal findings (short stature, brachydactyly with ulnar or radial deviation of the fingers, short feet, and early, marked hip dysplasia)"
    explanation: >-
      GeneReviews describes early, marked hip dysplasia.
  - reference: PMID:38899779
    reference_title: "Deletion of Trps1 regulatory elements recapitulates postnatal hip joint abnormalities and growth retardation of Trichorhinophalangeal syndrome in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This strain displayed delayed secondary ossification center formation in the long bones and misshaped hip joint development that resulted in acetabular dysplasia."
    explanation: >-
      A hypomorphic Trps1 mouse develops acetabular dysplasia.
  downstream:
  - target: Hip dysplasia
  - target: Premature Joint Degeneration
- name: Premature Joint Degeneration
  biological_scale: TISSUE
  description: >-
    Joint problems, with pain and altered mobility progressing to premature
    osteoarthritis, are the main lifelong morbidity.
  evidence:
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age."
    explanation: >-
      Joint disease as the main morbidity.
  downstream:
  - target: Premature osteoarthritis
- name: Craniofacial and Axial Skeletal Dysplasia
  biological_scale: TISSUE
  description: >-
    Mice heterozygous for deletion of the TRPS1 GATA domain show facial
    anomalies resembling the human syndrome and develop kyphoscoliosis and
    cortical and trabecular bone deficits, suggesting a generalised bone
    dysplasia beyond the hands and hips.
  evidence:
  - reference: PMID:12446778
    reference_title: "Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhino-phalangeal syndromes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we report that heterozygous mice with deletions of the TRPS1 GATA domain (TRPS1(+/Deltagt)) display facial anomalies that overlap with findings for TRPS, whereas TRPS1(Deltagt/Deltagt) mice additionally reveal a complete absence of vibrissae."
    explanation: >-
      Facial anomalies in heterozygous mutant mice.
  - reference: PMID:12446778
    reference_title: "Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhino-phalangeal syndromes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings directly implicate the GATA type zinc finger of TRPS1 in regulation of bone and hair development and suggest that skeletal abnormalities emphasized in descriptions of TRPS are only the extreme manifestations of a generalized bone dysplasia."
    explanation: >-
      Generalised bone dysplasia in the mouse model.
  downstream:
  - target: Bulbous nose
  - target: Underdeveloped nasal alae
  - target: Long philtrum
  - target: Thin upper lip vermilion
  - target: Protruding ears
  - target: Osteopenia
- name: Disrupted Hair Follicle Morphogenesis
  biological_scale: TISSUE
  description: >-
    Trps1 regulates a network of secreted Wnt inhibitors and transcription
    factors in the developing follicle and represses Sox9 in the follicle
    epithelium; loss reduces follicle number and causes vibrissa follicle
    degeneration in mice, the counterpart of sparse, fine, slow-growing hair
    in patients.
  biological_processes:
  - preferred_term: hair follicle development
    modifier: DECREASED
    term:
      id: GO:0001942
      label: hair follicle development
  evidence:
  - reference: PMID:22115758
    reference_title: "Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice in which the GATA domain of Trps1 has been deleted (Trps1(Δgt/Δgt)) have a reduced number of pelage follicles and lack vibrissae follicles postnatally."
    explanation: >-
      Follicle loss in the GATA-deletion mouse.
  - reference: PMID:22115758
    reference_title: "Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings identify Trps1 as a novel regulator of the Wnt signaling pathway and of early hair follicle progenitors in the developing vibrissa follicle."
    explanation: >-
      Trps1 regulates Wnt signalling in follicle progenitors.
  downstream:
  - target: Sparse scalp hair
  - target: Sparse lateral eyebrows
phenotypes:
- name: Sparse scalp hair
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: >-
    Fine, sparse, slow-growing scalp hair, often with a high anterior
    hairline.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ectodermal features (fine, sparse, depigmented, and slow-growing hair and dystrophic nails)"
    explanation: >-
      GeneReviews lists the hair phenotype.
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella."
    explanation: >-
      Sparse hair as a defining feature in 103 patients.
- name: Sparse lateral eyebrows
  category: Craniofacial
  description: >-
    Eyebrows thick and broad medially and thin laterally.
  phenotype_term:
    preferred_term: Sparse lateral eyebrow
    term:
      id: HP:0005338
      label: Sparse lateral eyebrow
  evidence:
  - reference: PMID:38574886
    reference_title: "Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion."
    explanation: >-
      Lateral eyebrow thinning in a Danish series.
- name: Bulbous nose
  category: Craniofacial
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:10615131
    reference_title: "Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears."
    explanation: >-
      The core facial description.
- name: Underdeveloped nasal alae
  category: Craniofacial
  phenotype_term:
    preferred_term: Underdeveloped nasal alae
    term:
      id: HP:0000430
      label: Underdeveloped nasal alae
  evidence:
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella."
    explanation: >-
      Underdeveloped alae as a defining facial feature.
- name: Long philtrum
  category: Craniofacial
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:10615131
    reference_title: "Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears."
    explanation: >-
      Long flat philtrum.
- name: Thin upper lip vermilion
  category: Craniofacial
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:10615131
    reference_title: "Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears."
    explanation: >-
      Thin upper vermilion.
- name: Protruding ears
  category: Craniofacial
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: PMID:10615131
    reference_title: "Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears."
    explanation: >-
      Protruding ears.
- name: Cone-shaped epiphyses
  category: Skeletal
  frequency: VERY_FREQUENT
  description: >-
    Cone-shaped epiphyses of the phalanges are the radiological hallmark.
  phenotype_term:
    preferred_term: Cone-shaped epiphyses of the phalanges of the hand
    term:
      id: HP:0010230
      label: Cone-shaped epiphyses of the phalanges of the hand
  evidence:
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses."
    explanation: >-
      Cone-shaped epiphyses as the radiological hallmark.
- name: Brachydactyly
  category: Skeletal
  frequency: VERY_FREQUENT
  description: >-
    Short hands and feet with short, deviated fingers; severe in TRPS III.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened."
    explanation: >-
      Short hands and feet in 103 patients.
- name: Short metacarpals
  category: Skeletal
  phenotype_term:
    preferred_term: Short metacarpal
    term:
      id: HP:0010049
      label: Short metacarpal
  evidence:
  - reference: PMID:38574886
    reference_title: "Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs."
    explanation: >-
      Shortened metacarpals on radiographs.
- name: Short stature
  category: Growth
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally."
    explanation: >-
      Reduced linear growth before and after birth.
  - reference: PMID:42361898
    reference_title: "Clinical and genetic spectrum of trichorhinophalangeal syndrome type I/III in 20 children of Korean origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short stature (standard deviation score [SDS] of height < -2) was observed in 21% of patients."
    explanation: >-
      Frequency of short stature in a Korean cohort.
- name: Hip dysplasia
  category: Skeletal
  phenotype_term:
    preferred_term: Hip dysplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
  evidence:
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal findings (short stature, brachydactyly with ulnar or radial deviation of the fingers, short feet, and early, marked hip dysplasia)"
    explanation: >-
      GeneReviews lists early, marked hip dysplasia.
- name: Premature osteoarthritis
  category: Skeletal
  description: >-
    Joint complaints were reported by every patient in a Danish series, often
    before diagnosis.
  phenotype_term:
    preferred_term: Premature osteoarthritis
    term:
      id: HP:0003088
      label: Premature osteoarthritis
  evidence:
  - reference: PMID:38574886
    reference_title: "Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established."
    explanation: >-
      Universal joint complaints.
- name: Osteopenia
  category: Skeletal
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally."
    explanation: >-
      Osteopenia is common.
- name: Supernumerary teeth
  category: Dental
  description: >-
    Supernumerary and impacted teeth; one patient had 45 teeth including 11
    supernumerary.
  phenotype_term:
    preferred_term: Supernumerary tooth
    term:
      id: HP:0011069
      label: Supernumerary tooth
  evidence:
  - reference: PMID:32442662
    reference_title: "Impaired dentin mineralization, supernumerary teeth, hypoplastic mandibular condyles with long condylar necks, and a TRPS1 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral examination showed supernumerary teeth, large dental pulp spaces, dental pulp stones, microdontia of the maxillary permanent lateral incisors, absence of the mandibular left second premolar and short root of the maxillary right second premolar, and hypoplastic mandibular condyles with long condylar necks."
    explanation: >-
      Supernumerary teeth in a patient with a TRPS1 missense variant.
  - reference: PMID:37147064
    reference_title: "Trichorhinophalangeal syndrome type 1 (Giedion syndrome): A case report with literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic images showed a total of 45 teeth: two deciduous, 32 permanent, and 11 supernumerary teeth."
    explanation: >-
      Eleven supernumerary teeth in a TRPS I patient.
- name: Nail dystrophy
  category: Dermatologic
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:25792522
    reference_title: "Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nails of fingers and toes are typically thin and dystrophic."
    explanation: >-
      Thin, dystrophic nails.
diagnosis:
- name: Clinical and radiographic diagnosis with TRPS1 testing
  description: >-
    Characteristic facial and ectodermal features with cone-shaped epiphyses
    on hand radiographs establish the clinical diagnosis, confirmed by a
    heterozygous TRPS1 variant; deletion testing distinguishes TRPS II.
  evidence:
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis of TRPS I is established in an individual with suggestive findings and identification of a heterozygous pathogenic variant in TRPS1"
    explanation: >-
      GeneReviews diagnostic criteria.
treatments:
- name: Growth hormone therapy
  description: >-
    Recombinant growth hormone can improve growth velocity in patients with
    documented growth hormone deficiency; response without deficiency is
    poor.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  evidence:
  - reference: PMID:22964620
    reference_title: "Clinical, biochemical, and genetic analysis of two korean patients with trichorhinophalangeal syndrome type I and growth hormone deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 10 years of GH therapy, the mean growth velocity was 5.7 ± 0.9 cm/year."
    explanation: >-
      Sustained response in a growth hormone-deficient patient.
  - reference: PMID:22964620
    reference_title: "Clinical, biochemical, and genetic analysis of two korean patients with trichorhinophalangeal syndrome type I and growth hormone deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the patient 2 did not show apparent GH deficiency by GH stimulation test, had a poor response with rhGH therapy and GH therapy was discontinued after 6 months."
    explanation: >-
      Poor response without growth hormone deficiency.
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consider growth hormone (GH) therapy in those with short stature and GH deficiency"
    explanation: >-
      GeneReviews recommends GH only with documented deficiency.
  - reference: PMID:36990068
    reference_title: "Molecular Genetic Analysis and Growth Hormone Treatment in a Three-Generation Chinese Family with Tricho-Rhino-Phalangeal Syndrome I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband and his brother have been treated with growth hormone (GH) for 2 years until now, and we have observed the improvement of the linear growth in both."
    explanation: >-
      Improved linear growth in two brothers on GH.
- name: Bisphosphonates for severe osteoporosis
  description: >-
    Off-label intravenous neridronate stopped fractures and raised lumbar
    bone density in one child with severe osteoporosis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: neridronate
      term:
        id: CHEBI:135145
        label: neridronic acid
  evidence:
  - reference: PMID:24357341
    reference_title: "Thricho-rhino-phalangeal syndrome and severe osteoporosis: a rare association or a feature? An effective therapeutic approach with biphosphonates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment was, in this patient, effective both in terms of clinical (absence of new fractures) and mineralomethric (+45% BMD ath the lumbar level)."
    explanation: >-
      Single-case response to neridronate.
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consider bisphosphonates in those with osteopenia"
    explanation: >-
      GeneReviews recommendation.
- name: Hip replacement
  description: >-
    Prosthetic hip implantation for severe hip dysplasia.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: hip replacement for severe hip dysplasia
    term:
      id: NCIT:C157876
      label: Hip Replacement
  evidence:
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consider prosthetic hip implantation in those with severe hip dysplasia"
    explanation: >-
      GeneReviews management recommendation.
- name: Physiotherapy and analgesia for joint pain
  description: >-
    Physiotherapy, regular exercise and non-opioid analgesics for joint pain
    and mobility.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physiotherapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "analgesics (e.g., NSAIDs or other non-opiods) for joint pain; physiotherapy may relieve pain and aid mobility; encourage regular exercise"
    explanation: >-
      GeneReviews joint-pain management.
- name: Extraction of supernumerary teeth
  description: >-
    Extraction of impacted and supernumerary teeth, sometimes under general
    anaesthesia, after full clinical and radiographic oral examination.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: extraction of supernumerary teeth
    term:
      id: NCIT:C51770
      label: Extraction of Tooth
  evidence:
  - reference: PMID:28426188
    reference_title: "Trichorhinophalangeal Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Practical advice on hair care and use of wigs; consider extraction of supernumerary teeth"
    explanation: >-
      GeneReviews recommends considering extraction.
  - reference: PMID:37147064
    reference_title: "Trichorhinophalangeal syndrome type 1 (Giedion syndrome): A case report with literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four impacted third molars, supernumerary teeth, retained deciduous teeth, and impacted maxillary premolars were removed under general anaesthesia."
    explanation: >-
      Extraction under general anaesthesia in one patient.
- name: Topical minoxidil
  description: >-
    Used for sparse hair with variable response in a Korean cohort.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: minoxidil
      term:
        id: CHEBI:6942
        label: minoxidil
  evidence:
  - reference: PMID:42361898
    reference_title: "Clinical and genetic spectrum of trichorhinophalangeal syndrome type I/III in 20 children of Korean origin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Responses to rhGH and minoxidil treatments were variable."
    explanation: >-
      Variable response to minoxidil and growth hormone.
animal_models:
- name: Trps1 GATA-domain deletion mouse
  species: Mouse
  genotype: Trps1 delta-GT (deletion of the GATA zinc finger), heterozygous and homozygous
  publication: PMID:18424451
  description: >-
    Heterozygotes show facial anomalies, kyphoscoliosis and bone deficits;
    homozygotes lack vibrissae and die of neonatal respiratory failure.
    Growth plates show delayed chondrocyte differentiation with accelerated
    perichondrial mineralisation, rescued by Runx2 heterozygosity.
  modeled_mechanisms:
  - target: Uncoupled Chondrocyte Differentiation and Perichondrial Mineralisation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The growth-plate defect behind the human skeletal phenotype.
    limitations: >-
      Most growth-plate analyses use mutants more severe than the human
      heterozygous state.
    evidence:
    - reference: PMID:18424451
      reference_title: "Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These abnormalities were accompanied by increased Runx2 and Ihh expression and increased Indian hedgehog signaling."
      explanation: >-
        Molecular readout of the growth-plate defect.
  - target: Disrupted Hair Follicle Morphogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Fewer pelage follicles and absent vibrissae.
    limitations: >-
      Vibrissae have no human counterpart; the pelage reduction is in
      homozygotes.
    evidence:
    - reference: PMID:22115758
      reference_title: "Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice in which the GATA domain of Trps1 has been deleted (Trps1(Δgt/Δgt)) have a reduced number of pelage follicles and lack vibrissae follicles postnatally."
      explanation: >-
        Follicle phenotype in the mutant.
- name: Trps1 intronic regulatory-element deletion mouse
  species: Mouse
  genotype: Trps1 delta-int/delta-int (hypomorph)
  publication: PMID:38899779
  description: >-
    A viable hypomorph that reproduces postnatal growth retardation and hip
    dysplasia, avoiding the early lethality of knockouts.
  modeled_mechanisms:
  - target: Abnormal Hip Joint Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Acetabular dysplasia and patellar dislocation.
    evidence:
    - reference: PMID:38899779
      reference_title: "Deletion of Trps1 regulatory elements recapitulates postnatal hip joint abnormalities and growth retardation of Trichorhinophalangeal syndrome in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our novel Trps1 hypomorphic strain recapitulates many postnatal pathologies observed in human TRPS patients, thus positioning this strain as a useful animal model to study postnatal TRPS pathogenesis."
      explanation: >-
        The model reproduces postnatal TRPS pathology.
references:
- reference: PMID:28426188
  title: Trichorhinophalangeal Syndrome.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:28426188
Trichorhinophalangeal Syndrome.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Trichorhinophalangeal Syndrome Type I · 2026-10-12T19:40:49Z · View source

New entry for trichorhinophalangeal syndrome type I (MONDO:0008596), TRPS1, with TRPS I (truncating, haploinsufficiency) and TRPS III (GATA zinc-finger missense, severe brachydactyly) as subtypes, since MONDO folds type III into this term. TRPS II (Langer-Giedion) stays a subtype of Hereditary_Multiple_Osteochondromas. Pathograph: heterozygous TRPS1 variants -> loss of GATA-dependent transcriptional repression -> (a) uncoupled chondrocyte differentiation and perichondrial mineralisation via Runx2/Ihh/PTHrP -> hand, stature and hip phenotypes and joint degeneration; (b) disrupted hair follicle morphogenesis via Wnt inhibitors and Sox9 -> sparse hair; (c) craniofacial and axial dysplasia from the mouse GATA-deletion model -> facial features and osteopenia. 14 of 15 phenotypes connected; nail dystrophy has no mechanism node. GeneReviews chapter PMID:28426188 tagged and used as the phenotype baseline. One OpenScientist deep-research report: built-in validation completed (43/43 references resolved); preflight-dr PASS, RUNX2 mentions reflecting the TRPS1 target, and the report's OMIM 604386 is the gene record rather than the disease. Several NCIT treatment CURIEs in the report resolve to unrelated concepts and were not used. Validated with just validate-disorders and the offline CI gates.

OpenScientist ▸
Trichorhinophalangeal Syndrome Type I (TRPS I): A Comprehensive Disease-Characterization Report
openscientist-autonomous 39 citations 2026-10-12T19:08:50.831965

Trichorhinophalangeal Syndrome Type I (TRPS I): A Comprehensive Disease-Characterization Report

Disease: Trichorhinophalangeal Syndrome Type I MONDO ID: MONDO:0008596 · OMIM: 190350 · Orphanet: ORPHA:77258 · Category: Mendelian (autosomal dominant) Causal gene: TRPS1 (8q23.3) · HGNC: 12340 · OMIM: 604386

Summary

Trichorhinophalangeal syndrome type I (TRPS I) is a rare (~1 in 100,000; minimum point prevalence ~0.5/100,000) autosomal-dominant craniofacial–skeletal dysplasia caused by heterozygous loss-of-function/haploinsufficient variants in TRPS1, a gene on chromosome 8q23.3 encoding a GATA-type zinc-finger transcriptional repressor. The disorder is defined by a clinical triad reflected in its name: tricho (fine, sparse, slow-growing scalp hair and thin lateral eyebrows), rhino (a bulbous, pear-shaped nose with underdeveloped/hypoplastic alae nasi), and phalangeal (brachydactyly with pathognomonic cone-shaped epiphyses). Short stature, hip dysplasia, and progressive premature osteoarthrosis round out the phenotype. Intelligence and life expectancy are normal.

Mechanistically, TRPS1 is a master transcriptional regulator of endochondral ossification, hair-follicle morphogenesis, and odontogenesis. Reduced TRPS1 activity de-represses RUNX2, Indian hedgehog (Ihh), SOX9, STAT3, and PTHrP in growth-plate cartilage, uncoupling chondrocyte differentiation from perichondrial mineralization; it disrupts a Wnt-inhibitor/transcription-factor network required for hair-follicle development; and it dysregulates Dspp-dependent dentin mineralization. Most pathogenic variants are truncating (nonsense/frameshift) LOF alleles causing haploinsufficiency, whereas missense variants in the exon-6 GATA DNA-binding domain act in a dominant-negative fashion and produce the more severe, brachydactyly-predominant TRPS III end of the allelic spectrum. TRPS II (Langer–Giedion syndrome) is a contiguous-gene deletion removing TRPS1 plus EXT1 (± RAD21), adding multiple exostoses and sometimes intellectual disability.

There is no disease-modifying or curative therapy. Management is symptomatic and multidisciplinary: recombinant human growth hormone (rhGH) in the subset with documented GH deficiency, bisphosphonates for severe osteoporosis, orthopedic surgery for hip/joint disease, dental care for supernumerary/impacted teeth, and genetic counseling for the 50% transmission risk. TRPS1 biology extends well beyond the clinical triad—to kidney development/fibrosis (BMP7/TGF-β/Smad) and to oncology, where TRPS1 is now a highly sensitive, largely breast-specific immunohistochemistry marker.

Section 1 — Disease Information

Overview. TRPS I is a hereditary skeletal dysplasia with a characteristic clinical presentation, classified into types I, II, and III based on phenotype and genotype (PMID: 21844942). TRPS I—the most common subtype—is caused by heterozygous mutations in the single gene TRPS1; it exhibits distinctive craniofacial, ectodermal, and skeletal abnormalities with extremely variable expressivity, such that many mild cases remain undiagnosed (PMID: 30458885).

Key identifiers.

Resource Identifier
MONDO MONDO:0008596
OMIM 190350 (TRPS I)
Orphanet ORPHA:77258
MeSH Langer-Giedion Syndrome / Tricho-rhino-phalangeal syndrome
ICD-10 Q87.1 (congenital malformation syndromes predominantly associated with short stature)
Gene (HGNC) TRPS1, HGNC:12340, OMIM 604386, locus 8q23.3 (older literature: 8q24.1/8q24.12)

Synonyms / alternative names. Tricho-rhino-phalangeal syndrome type I; TRPS1; TRP syndrome type I; trichorhinophalangeal dysplasia syndrome (PMID: 3958163); "Giedion syndrome" is used for the broader TRPS spectrum (PMID: 37147064).

Information source. The knowledge base here is derived primarily from aggregated disease-level resources (OMIM, Orphanet) supplemented by individual-patient clinical reports and cohort studies (103-patient international cohort, PMID: 25792522; 20-child Korean cohort, PMID: 42361898; 15-patient single-center series, PMID: 38574886) and from mouse/in-vitro mechanistic studies. No local datasets or EHR data were used; this is a literature synthesis.

Section 2 — Etiology

Primary cause (genetic). TRPS I is monogenic and autosomal dominant, caused by heterozygous pathogenic variants in TRPS1. In an international cohort of 103 molecularly/cytogenetically confirmed patients, TRPS I was present in 85 individuals (22 missense, 62 "other" mutations) versus 14 with TRPS II (PMID: 25792522). The review by Saeki et al. states the disorder "occurs in 1 in 100,000 people globally and is caused by several types of mutations of the TRPS1 gene" (PMID: 40995872).

Genetic risk factors. The causal variant in TRPS1 is the sole established risk factor. No susceptibility loci or modifier genes outside TRPS1 have been established in humans, though RUNX2 is a genetic modifier of the growth-plate phenotype in mice (double-heterozygote rescue; PMID: 18424451).

Environmental risk factors. None known. TRPS I is a Mendelian disorder with no demonstrated environmental or infectious contribution. A substantial fraction of cases are de novo ("fresh") mutations (PMID: 10405449).

Protective factors. No genetic or environmental protective factors have been described. Not applicable for this Mendelian disorder.

Gene–environment interactions. None documented. Not applicable.

Section 3 — Phenotypes

The phenotype is variable and presents a wide clinical spectrum (PMID: 31343132). The defining features, per the 103-patient cohort (PMID: 25792522), are fine/sparse hair, thick medial eyebrows, broad/bulbous nasal ridge and tip, underdeveloped nasal alae, short hands/feet, cone-shaped epiphyses, and reduced linear growth.

Phenotype Type HPO term (suggested) Onset Frequency / severity
Sparse, fine, slow-growing scalp hair Ectodermal/physical HP:0002213 (sparse hair) Congenital/childhood Near-universal; variable; non-terminal hairs, low density (PMID: 40790426)
Thin lateral eyebrows / thick medial eyebrows Physical HP:0045025 (lateral eyebrow thinning) Childhood Common; diagnostic clue
Bulbous/pear-shaped nose, hypoplastic alae nasi Physical HP:0000414 (bulbous nose), HP:0000430 (underdeveloped nasal alae) Congenital Near-universal; characteristic
Brachydactyly, short metacarpals/phalanges Skeletal HP:0001156 (brachydactyly) Childhood (radiographic) Near-universal; severe with exon-6 missense (PMID: 42361898)
Cone-shaped epiphyses Skeletal/radiographic HP:0010579 (cone-shaped epiphysis) Childhood Pathognomonic radiographic sign
Short stature Growth HP:0004322 (short stature) Prenatal + postnatal Common; variable; GH deficiency in a subset
Hip dysplasia / Perthes-like changes Skeletal HP:0001385 (hip dysplasia) Childhood–adult Frequent; dominant morbidity (PMID: 3958163)
Progressive premature osteoarthrosis Skeletal HP:0002758 (osteoarthritis) Childhood → adult 100% in one cohort (PMID: 38574886); progressive
Osteopenia / low bone mass Skeletal/lab HP:0000938 (osteopenia) Childhood–adult Common (PMID: 25792522)
Dental anomalies (supernumerary/impacted teeth, microdontia) Physical HP:0011069 (supernumerary tooth), HP:0000699 (microdontia) Childhood Variable; up to 45 teeth reported (PMID: 37147064)
Protruding ears Physical HP:0000411 (protruding ear) Congenital Common

Age of onset. Most features are congenital or manifest in childhood; radiographic cone-shaped epiphyses appear in childhood; joint disease often precedes diagnosis and can present as late as adulthood (>40 years; PMID: 3958163).

Progression. Craniofacial and digital features are stable/structural; joint disease and osteoarthrosis are progressive.

Quality-of-life impact. The dominant QoL burden is lifelong joint disease—reported by all patients in one cohort, often before diagnosis (PMID: 38574886)—plus cosmetic concerns (hair, nose, stature) and dental complications. Formal EQ-5D/SF-36 data are not available for TRPS I (knowledge gap).

Section 4 — Genetic / Molecular Information

Causal gene. TRPS1 (8q23.3; OMIM 604386), encoding a GATA-type transcription factor with nine zinc-finger motifs that functions primarily as a transcriptional repressor (PMID: 21630221).

Pathogenic variants — spectrum and classification. Most variants are truncating loss-of-function. In the landmark mutation survey, "seven of the nine mutations result in a premature stop codon, leading to a truncated, nonfunctional TRPS1 protein. The final two mutations are missense mutations in the GATA DNA binding zinc finger" (PMID: 11950061). The Korean cohort reported truncating 65%, exon-6 missense 15%, exonic deletions 20% (PMID: 42361898).

Representative variants (all ACMG pathogenic/likely-pathogenic, germline, heterozygous):

Variant (cDNA / protein) Type Phenotype note PMID
c.2086C>T (p.Arg696Ter) Nonsense Classic TRPS I, familial 30458885
c.2854_2858del (p.Asn952ArgfsTer2) Frameshift TRPS I, 4-generation family 36093893
c.880_882delAAG In-frame del Disturbed RUNX2/STAT3 repression 36990068
c.2783A>G (p.Tyr928Cys) Missense (GATA domain) Severe brachydactyly + short stature 30914275
c.2762G>A (p.Arg921Gln) Missense Dental anomalies, impaired dentin mineralization 32442662
p.Ala932Ser (exon 6, GATA) Missense TRPS III 28468609
c.3809_3811delACTinsCATGTTGTG Indel (Ikaros-like ZnF) TRPS I + supernumerary teeth 27706911

Functional consequences. Truncating variants → haploinsufficiency (LOF). GATA-domain missense variants act as dominant-negatives, disturbing the protein's transcriptional repression of targets such as RUNX2 and STAT3 despite normal cellular localization and expression (PMID: 36990068).

Allele frequency. Pathogenic TRPS1 variants are private/rare and essentially absent from population databases (gnomAD); the disorder is fully penetrant and dominant.

Modifier genes. RUNX2 dosage modifies the skeletal phenotype in mouse models (double-heterozygote rescue; PMID: 18424451). No validated human modifiers.

Epigenetic information. No disease-specific DNA-methylation/histone signature has been defined for TRPS I (knowledge gap). Note that TRPS1 itself acts on chromatin as a transcriptional regulator.

Chromosomal abnormalities. Large deletions at 8q23–q24 cause the contiguous-gene TRPS II (Langer–Giedion), removing TRPS1, RAD21, and EXT1; a ~3.2-Mb critical region defines typical LGS (PMID: 35290978; PMID: 41683676). Intragenic deletions/microdeletions of TRPS1 alone cause TRPS I.

Section 5 — Environmental Information

Environmental factors. None established. TRPS I is purely genetic. Lifestyle factors. None. Not applicable. Infectious agents. None. Not applicable.

(Any environmental contribution would be limited to general modifiers of growth/bone health; no TRPS-specific data exist.)

Section 6 — Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Skeletal/chondrogenic branch: 1. A heterozygous TRPS1 variant (truncating LOF → haploinsufficiency, or exon-6 GATA-domain missense → dominant-negative) results in reduced functional TRPS1 transcriptional-repressor activity in cartilage. 2. Reduced TRPS1 leads to de-repression of its direct targets RUNX2, SOX9, STAT3, PTHrP and increased Indian hedgehog (Ihh) expression/signaling in the growth plate (PMID: 18424451; PMID: 24709795). 3. Loss of TRPS1–RUNX2 repression results in delayed chondrocyte differentiation but accelerated perichondrial mineralization—i.e., uncoupling of chondrocyte differentiation from perichondrial mineralization (PMID: 18424451). 4. Dysregulated chondrocyte condensation, proliferation, maturation, apoptosis, and phalangeal-joint formation (downstream of Gdf5 signaling; TRPS1 also directly interacts with activated Gli3) leads to abnormal endochondral ossification (PMID: 24709795). 5. Abnormal endochondral ossification results in the cone-shaped epiphyses, brachydactyly, short stature, hip dysplasia, and premature osteoarthrosis observed clinically.

Hair-follicle branch: 1. Reduced TRPS1 in dermal papilla / peri-hair-peg mesenchyme leads to downregulation of a network of secreted Wnt inhibitors and transcription factors and upregulation of extracellular-matrix proteins (PMID: 22115758). 2. (TRPS1 here acts as both repressor and direct transcriptional activator, binding target-gene promoters to activate them — PMID: 22115758.) 3. Disrupted Wnt-dependent follicle morphogenesis results in reduced/absent follicles → sparse, fine, slow-growing, non-terminal hair (PMID: 40790426).

Dental branch: 1. Dysregulated TRPS1 in odontoblasts alters direct repression of the Dspp promoter and expression of mineralization genes (Alpl, Phospho1) (PMID: 22508542; PMID: 25128529). 2. This leads to impaired dentin mineralization and, via APC/RUNX2/Wnt dysregulation, supernumerary/impacted teeth and dental anomalies (PMID: 32442662; PMID: 27706911).

(Steps 2–4 of the skeletal branch are directly demonstrated in mouse models and in-vitro assays; their quantitative applicability to human tissue is inferred.)

ASCII schematic

TRPS1 variant (LOF haploinsufficiency  OR  GATA-domain dominant-negative)
                 │  ↓ functional TRPS1 repressor activity
    ┌────────────┼───────────────────────────┬──────────────────────┐
    ▼            ▼                             ▼                      ▼
 CARTILAGE    de-repress RUNX2/Ihh/        HAIR FOLLICLE          ODONTOBLAST
 growth       SOX9/STAT3/PTHrP             ↓ Wnt inhibitors       dysreg. Dspp,
 plate        + Gli3 interaction           + TF network           Alpl, Phospho1
    │            │                             │                      │
    ▼            ▼                             ▼                      ▼
 uncoupled chondrocyte diff. vs          disrupted follicle      impaired dentin
 perichondrial mineralization            morphogenesis           mineralization;
    │                                         │                  supernumerary teeth
    ▼                                         ▼                      ▼
 cone-shaped epiphyses, brachydactyly,   sparse/fine/non-        dental anomalies
 short stature, hip dysplasia, OA        terminal hair

Molecular pathways and processes

  • Pathways: Indian hedgehog (Ihh) signaling; Wnt signaling (via secreted Wnt inhibitors); Gdf5/BMP signaling; TGF-β/Smad (chiefly in kidney). KEGG/Reactome: Hedgehog signaling, Wnt signaling pathway.
  • Cellular processes (GO): chondrocyte differentiation (GO:0002062), endochondral ossification (GO:0001958), regulation of transcription (GO:0006357), hair follicle morphogenesis (GO:0031069), apoptotic process (GO:0006915), biomineral tissue development (GO:0031214).
  • Protein dysfunction: truncation → nonfunctional protein (LOF); GATA-domain missense → impaired DNA binding and loss of repression (dominant-negative) (PMID: 11950061; PMID: 36990068).
  • Cell types (CL): chondrocyte (CL:0000138), odontoblast (CL:0000060), dermal papilla / perichondrial mesenchymal cells, osteoblast (CL:0000062).
  • Pleiotropy beyond the triad: In kidney, Trps1 acts downstream of Bmp7 in mesenchymal–epithelial transition; its loss activates TGF-β/Smad3, suppressing ureteric-bud branching (PMID: 23537899), and haploinsufficiency promotes renal fibrosis via increased Arkadia and reduced Smad7 (PMID: 20507941). Trps1 also promotes tubular repair after ischemia-reperfusion via Pde4d/AKT (PMID: 27466160).
  • Molecular profiling: Microarray of mutant mouse whisker pads identified downregulated Wnt inhibitors/transcription factors and upregulated ECM proteins (PMID: 22115758); ChIP-seq in kidney/cancer contexts confirms direct promoter binding.

Section 7 — Anatomical Structures Affected

Organ/system level. - Primary: skeleton (hands, feet, phalanges, hips, long bones), skin appendages (hair follicles), nose/craniofacial structures, teeth. - Body systems: musculoskeletal (dominant), integumentary (ectodermal), craniofacial. - Secondary/pleiotropic (chiefly from model organisms): kidney (development, fibrosis); oncologic relevance (breast and other GATA-factor-expressing tumors).

UBERON suggestions: phalanx (UBERON:0003221), epiphysis (UBERON:0006716), hip joint (UBERON:0001464), growth plate (UBERON:0006233), hair follicle (UBERON:0002073), nose (UBERON:0000004), tooth (UBERON:0001091), dentine (UBERON:0001751), kidney (UBERON:0002113).

Tissue/cell level. Cartilage (growth-plate chondrocytes, CL:0000138), perichondrium/mesenchyme, dermal papilla and peri-hair-peg mesenchymal cells, odontoblasts (CL:0000060), osteoblasts (CL:0000062).

Subcellular level (GO Cellular Component). Nucleus (GO:0005634) — TRPS1 is a nuclear transcription factor with sequence-specific DNA binding at target-gene promoters.

Localization / lateralization. Skeletal involvement is bilateral and generally symmetric (hands, feet, hips); hair and facial features are midline/bilateral.

Section 8 — Temporal Development

Onset. Largely congenital facial/ectodermal features; childhood radiographic skeletal signs; onset pattern is chronic/insidious. Diagnosis is often delayed—median age at diagnosis 15 years in one series (PMID: 38574886), with some patients first diagnosed after age 40 (PMID: 3958163).

Progression. Craniofacial/digital morphology is structurally stable. Joint disease is progressive — Perthes-like hip dysplasia and "severe and progressive degenerative arthritis" (PMID: 3958163); premature osteoarthrosis (PMID: 3621840). Growth retardation is prenatal and postnatal.

Disease course/duration. Chronic, lifelong; non-remitting. No spontaneous remission; interventions (rhGH, bisphosphonates, orthopedic surgery) modify specific complications.

Critical periods. The childhood/prepubertal window is key for growth intervention—GH therapy is most effective when initiated earlier and continued longer in prepubertal/early-pubertal stages (PMID: 36990068).

Section 9 — Inheritance and Population

Epidemiology. Prevalence ~1 in 100,000 globally (PMID: 40995872); minimum point prevalence 0.5/100,000 (95% CI 0.3–0.8) in a single-center series (PMID: 38574886). Incidence not formally established; many mild cases are undiagnosed.

Inheritance. Autosomal dominant. Both inherited and de novo ("fresh") mutations occur (PMID: 10405449). Transmission risk to offspring is 50%.

Penetrance / expressivity. High penetrance but markedly variable expressivity, even within families (PMID: 25792522; PMID: 30458885).

Genotype–phenotype correlation. Exon-6 GATA-domain missense variants → severe brachydactyly (consistent across cohorts; PMID: 42361898; PMID: 30914275), and define TRPS III. Stature shows no clear genotype correlation (PMID: 42361898). Facial features do not differ between TRPS I and II (PMID: 25792522).

Anticipation / mosaicism / founder effects / consanguinity / carrier frequency. No genetic anticipation (not a repeat-expansion disorder). Germline mosaicism not specifically characterized. No founder effects or consanguinity role (dominant, often de novo). Carrier frequency not applicable (dominant).

Demographics. Reported worldwide (European, Turkish, Korean, Chinese, Thai, Moroccan, Cypriot cohorts). Female predominance noted in some series (e.g., 73% female; PMID: 38574886), likely ascertainment-related rather than a true sex effect. No established sex-ratio bias expected in a dominant disorder.

Section 10 — Diagnostics

Clinical/radiographic. Diagnosis is based on characteristic facial features + sparse hair + brachydactyly with cone-shaped epiphyses on hand/foot X-rays (PMID: 21844942). Cone-shaped epiphyses are the hallmark radiographic sign (PMID: 42705688). Trichoscopy reveals non-terminal, thin, sparse hairs with low density and increased single-hair follicular units; a high occipital hairline is proposed as a diagnostic pearl (PMID: 40790426). DXA documents low bone mineral density/osteopenia. Endocrine work-up (GH stimulation tests) identifies the GH-deficient subset (PMID: 22964620). Full dental/radiographic examination is recommended to detect supernumerary/impacted teeth (PMID: 37147064).

Genetic testing. Molecular confirmation by TRPS1 sequencing (Sanger / next-generation / whole-exome) is the gold standard (PMID: 36990068; PMID: 42705688). Chromosomal microarray / molecular karyotyping detects 8q23–q24 contiguous-gene deletions distinguishing TRPS II (PMID: 36866988; PMID: 35290978). Skeletal-dysplasia NGS panels, CMA, and MLPA are all employed (PMID: 40626694). WES is valuable when the clinical picture is atypical or overlaps mimics.

Clinical criteria / differential diagnosis. Differentials include cleidocranial dysplasia (RUNX2; supernumerary teeth; PMID: 30095610), FBXO11-related IDDFBA syndrome (TRPS-like facies but with developmental delay; PMID: 38679370), juvenile idiopathic arthritis and other skeletal dysplasias presenting with non-inflammatory musculoskeletal complaints (PMID: 40626694), and TRPS II/III within the spectrum.

Screening. No population newborn screening (rare dominant disorder). Cascade testing of at-risk relatives and prenatal/preimplantation testing are feasible once the familial variant is known.

Section 11 — Outcome / Prognosis

Survival/mortality. Life expectancy is normal. TRPS I is not life-limiting; intelligence is normal in TRPS I (PMID: 10405449).

Morbidity. The dominant morbidity is joint disease—reported by all patients in one cohort, often before diagnosis (PMID: 38574886); "morbidity mostly concerns joint problems" in the 103-patient cohort (PMID: 25792522). Progressive premature osteoarthrosis and Perthes-like hip dysplasia may require hip replacement (PMID: 3958163; PMID: 3621840). Osteopenia/osteoporosis can cause fractures (PMID: 24357341).

Complications. Degenerative arthritis, hip deformity, fractures from low BMD, dental impaction/malocclusion, short stature. Occasional rare findings: renal cyst/stone (PMID: 3621840), cerebral hamartoma/long-bone cysts (rare; PMID: 36866988).

Prognostic factors. Exon-6 GATA-domain missense predicts more severe brachydactyly (PMID: 42361898; PMID: 30914275). GH-deficiency status predicts GH-therapy response (PMID: 22964620).

Section 12 — Treatment

There is no causal/curative treatment; management is symptomatic and supportive, requiring coordination among pediatrics, endocrinology, orthopedics, dermatology, rehabilitation, and dentistry (PMID: 21844942; PMID: 31343132).

Intervention Indication Evidence NCIT (suggested)
Recombinant human GH (rhGH) Short stature with documented GH deficiency Improved growth velocity & radiographic femoral epiphyses (PMID: 31884116); 5.7±0.9 cm/yr over 10 yr in GH-deficient patient, poor response if non-deficient (PMID: 22964620); improved linear growth over 2 yr in two patients (PMID: 36990068) Recombinant Human Growth Hormone (NCIT:C1898)
Bisphosphonates (IV neridronate) Severe osteoporosis / recurrent fractures Off-label 2 mg/kg q3mo stopped new fractures and raised lumbar BMD by +45% (PMID: 24357341) Bisphosphonate (NCIT:C1476)
Minoxidil (topical) Hair thinning Variable response (PMID: 42361898) Minoxidil (NCIT:C47641)
Orthopedic surgery Hip dysplasia, degenerative arthritis Valuable for many (PMID: 21844942) Orthopedic Surgery (NCIT:C15300)
Dental surgery / extraction Impacted & supernumerary teeth 4 third molars + 11 supernumerary teeth removed under GA (PMID: 37147064) Tooth Extraction (NCIT:C51818)
Cosmetic aids, rehabilitation (PT/OT) Hair, stature, joint function Supportive (PMID: 21844942) —
Genetic counseling 50% transmission risk Recommended for patient and family (PMID: 21844942) Genetic Counseling (NCIT:C15648)

Pharmacogenomics / advanced therapeutics. No gene therapy, cell therapy, RNA-based, targeted, or immunotherapy exists for TRPS I. Animal-model work proposes potential therapeutic targets in the dysregulated pathways (RUNX2/Ihh, Wnt, TGF-β/Smad) but none are clinically translated (PMID: 40995872). No TRPS-specific clinical trials (NCT) are established.

Treatment outcomes/strategy. rhGH benefit is conditional on GH deficiency (PMID: 22964620)—a genotype/phenotype-guided (personalized) approach. Earlier, longer GH therapy in prepubertal/early-pubertal stages associates with better height outcomes (PMID: 36990068).

Section 13 — Prevention

Primary prevention. None possible for a dominant genetic disorder other than reproductive options: genetic counseling, prenatal diagnosis, and preimplantation genetic testing once the familial TRPS1 variant is known.

Secondary prevention. Cascade genetic testing of at-risk relatives enables early diagnosis; early orthopedic, endocrine, and dental surveillance allows timely intervention (PMID: 30458885; PMID: 37147064).

Tertiary prevention. Prevent complications: DXA monitoring and bisphosphonates to prevent fractures (PMID: 24357341); orthopedic management to delay/manage degenerative arthritis; dental monitoring to prevent impaction complications.

Immunization / public-health / environmental interventions. Not applicable (non-infectious, non-environmental).

Counseling. Genetic counseling is central, emphasizing the 50% transmission risk and variable expressivity (PMID: 21844942).

Section 14 — Other Species / Natural Disease

Taxonomy / orthologs. TRPS1 is conserved; the principal experimental ortholog is mouse Trps1 (Mus musculus, NCBI Taxon:10090), with rat (Rattus norvegicus, Taxon:10116) used for kidney studies (PMID: 27466160).

Natural disease in other species / breeds. No naturally occurring TRPS-equivalent disease in companion animals or wildlife is documented in the reviewed literature (OMIA entry not identified; knowledge gap).

Comparative biology / evolutionary conservation. The TRPS1 regulatory functions in cartilage, hair follicle, kidney, and tooth are evolutionarily conserved, as mouse models recapitulate human skeletal, hair, and dental phenotypes (PMID: 40995872; PMID: 21630221).

Transmission / zoonosis. Not applicable (non-communicable genetic disorder).

Section 15 — Model Organisms

Rodent models are central to TRPS research—"several animal models have been established and studied intensively to address this rare disease" (PMID: 40995872).

Model Type Phenotype recapitulated PMID
Trps1^Δgt/Δgt (GATA-domain deletion) Knock-in/deletion Delayed chondrocyte differentiation, accelerated perichondrial mineralization, ↑Runx2/Ihh; reduced pelage follicles, absent vibrissae, ↓Wnt inhibitors 18424451; 22115758
Trps1-null Knockout Early postnatal lethality; expanded renal interstitium, impaired ureteric-bud branching (TGF-β/Smad3) 23537899
Trps1^+/− Haploinsufficient Renal tubulointerstitial fibrosis via ↑Arkadia / ↓Smad7 20507941
Trps1^Δint/Δint (regulatory-element deletion, hypomorph) Novel knock-in Postnatal growth retardation, delayed secondary ossification centers, acetabular/hip dysplasia, patellar dislocation 38899779
Col1a1-Trps1 transgenic (overexpression) Transgenic Dentinogenesis-imperfecta-like dentin via Dspp-promoter repression 22508542
Preodontoblast cell lines (Trps1-deficient / -overexpressing) In vitro Dual role in dentin mineralization (Alpl/Phospho1) 25128529; 30691926

Model value and limitations. The Trps1^Δint hypomorph is notable for recapitulating postnatal hip-joint pathology relevant to the dominant human morbidity (PMID: 38899779). A key limitation is that homozygous null mice are postnatally lethal, whereas human TRPS I is heterozygous and viable—so dosage-sensitive models (Δgt heterozygotes, hypomorphs) better mirror the human condition. Models have been used to dissect RUNX2/Ihh, Wnt, TGF-β/Smad, and Dspp mechanisms and to nominate therapeutic targets (PMID: 40995872). Resource: Mouse Genome Informatics (MGI) for Trps1 alleles.

Mechanistic Model / Interpretation

TRPS1 is best understood as a dosage-sensitive master transcriptional regulator of mesenchymal differentiation. The unifying theme across all three cardinal tissues (cartilage, hair, tooth)—and the pleiotropic kidney phenotype—is that TRPS1 sets the correct timing and level of differentiation programs, principally by repressing key drivers (RUNX2, SOX9, STAT3, PTHrP, Dspp) but also, context-dependently, activating others (Wnt inhibitors, FOXA1). When TRPS1 activity falls below a threshold—whether by haploinsufficiency (truncating variants) or dominant-negative poisoning of the GATA domain (exon-6 missense)—these programs become temporally and quantitatively uncoupled, producing structural malformation rather than cell death.

The genotype–phenotype gradient is mechanistically coherent: truncating LOF alleles remove one functional copy (milder, classic TRPS I), whereas GATA-domain missense alleles produce a mutant protein that actively interferes with DNA binding, yielding more severe brachydactyly and the TRPS III phenotype (PMID: 11950061; PMID: 28468609). TRPS II layers an EXT1-deletion exostoses phenotype onto the TRPS1 deficiency. This single axis—TRPS1 dosage/function—thus explains the entire TRPS I/III/II allelic and contiguous-gene spectrum.

Evidence Base

PMID Role Key contribution
25792522 Supports Disease Info, Genotype, Prognosis 103-patient cohort; mutation spectrum; morbidity = joints
40995872 Supports Epidemiology, Models Prevalence ~1/100,000; animal-model synthesis; therapeutic targets
18424451 Supports Mechanism Core skeletal mechanism: TRPS1–RUNX2 repression, ↑Ihh, uncoupling
42361898 Supports Genotype-Phenotype Exon-6 missense → severe brachydactyly; genotype classes
30914275 Supports Genotype-Phenotype GATA-domain missense → severe phenotype
31884116, 22964620 Support Treatment rhGH efficacy conditional on GH deficiency
22115758 Supports Mechanism (hair) TRPS1 activates Wnt-inhibitor network; dual repressor/activator
32442662, 22508542 Support Mechanism (dental) Dental phenotype; Dspp-promoter repression mechanism
38574886 Supports Epidemiology, Prognosis Prevalence 0.5/100,000; joint disease in 100%
20507941, 38647255 Support Pleiotropy Renal fibrosis (TGF-β/Smad); TRPS1 as breast-cancer IHC marker
24357341 Supports Treatment Bisphosphonate +45% BMD, no new fractures
11950061, 28468609 Support Variant Spectrum Truncating LOF predominance; TRPS I/II/III distinctions
24709795 Supports Mechanism Multi-target chondrogenic network (Sox9, Runx2, Stat3, Pthrp, Gli3)
38899779 Supports Models Hypomorphic mouse recapitulates postnatal hip pathology

Challenging/nuancing evidence: The cancer literature (PMID: 26969828, 40197498) shows TRPS1 can be context-dependently tumor-suppressive or oncogenic, underscoring that "loss of function" is tissue-specific and that TRPS1 acts as both repressor and activator—caution against over-simplified LOF narratives.

Limitations and Knowledge Gaps

  1. No systematic natural-history/QoL data — formal EQ-5D/SF-36/PROMIS outcomes for TRPS I are unavailable; cohorts are small and retrospective.
  2. Epidemiology uncertainty — prevalence estimates (~1/100,000; minimum 0.5/100,000) derive from small/single-center series; incidence unknown; underdiagnosis of mild cases is acknowledged.
  3. Mechanism mostly from mouse/in-vitro — the RUNX2/Ihh/Wnt/Dspp causal chain is well supported in models but less directly validated in human tissue; several steps are inferred.
  4. No disease-specific epigenetic signature has been defined.
  5. No OMIA/veterinary natural-disease counterpart identified; comparative biology rests on engineered rodent models.
  6. Human modifier genetics largely unexplored; RUNX2 is a mouse modifier only.
  7. Therapy evidence is anecdotal — rhGH and bisphosphonate data come from case reports/small series, not controlled trials; no targeted/molecular therapy exists.

Proposed Follow-up Experiments / Actions

  1. Prospective multicenter TRPS registry with standardized QoL instruments and longitudinal joint/skeletal outcomes to quantify natural history and GH/bisphosphonate efficacy.
  2. Patient-derived iPSC chondrocyte/organoid models carrying truncating vs. GATA-domain-missense variants to directly test the haploinsufficiency vs. dominant-negative dichotomy on RUNX2/Ihh/SOX9 targets in human cells.
  3. Genome-wide TRPS1 ChIP-seq/CUT&RUN + RNA-seq in human growth-plate chondrocytes and hair-follicle dermal papilla to map the direct target network and validate the dual repressor/activator model.
  4. Controlled or registry-based evaluation of bisphosphonates for TRPS-associated osteoporosis, given the striking single-case +45% BMD response.
  5. Screen the RUNX2/Ihh and Wnt-inhibitor axes for druggable nodes (e.g., Ihh-pathway modulation) using the Trps1^Δint hypomorphic mouse as a preclinical platform for hip-dysplasia/osteoarthrosis prevention.
  6. Define exon-6 missense dominant-negative mechanism biochemically (DNA-binding, co-repressor recruitment) to support variant classification and prognostic counseling.

Report compiled from 12 confirmed findings and 53 reviewed papers across 5 investigation iterations. Evidence types: human clinical cohorts/case reports, mouse/rat model-organism studies, and in-vitro functional assays, as annotated throughout.

Artifacts

Reference Validation

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References checked 43
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Quoted claims checked 4
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References weighed for topical relevance 43
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Term Validation

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Terms whose name was checked 16
Terms named correctly 7
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Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0008596 (2 mentions) - the report calls it "MONDO"; MONDO calls it trichorhinophalangeal syndrome type I
  • HP:0045025 (1 mention) - the report calls it "lateral eyebrow thinning"; HP calls it Narrow palpebral fissure
  • NCIT:C1898 (1 mention) - the report calls it "Recombinant Human Growth Hormone"; NCIT calls it Physical Carcinogens
  • NCIT:C1476 (1 mention) - the report calls it "Bisphosphonate"; NCIT calls it Denileukin Diftitox
  • NCIT:C47641 (1 mention) - the report calls it "Minoxidil"; NCIT calls it Orphenadrine Citrate
  • NCIT:C15300 (1 mention) - the report calls it "Orthopedic Surgery"; NCIT calls it Photodynamic Therapy
  • NCIT:C51818 (1 mention) - the report calls it "Tooth Extraction"; NCIT calls it Coordinating Investigator
  • NCIT:C15648 (1 mention) - the report calls it "Genetic Counseling"; NCIT calls it Continuous Infusion Procedure

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  • HP:0002213 (1 mention) - the report calls it "sparse hair"; HP calls it Fine hair

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Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Taxon.