Clinical characteristics.

Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by a contiguous gene deletion of TRPS1, RAD21, and EXT1). Both TRPS types are characterized by distinctive facial features (large nose with broad nasal ridge and tip and underdeveloped alae; thick and broad medial eyebrows; long philtrum; thin vermilion of the upper lip; and large prominent ears); ectodermal features (fine, sparse, depigmented, and slow-growing hair and dystrophic nails); and skeletal findings (short stature, brachydactyly with ulnar or radial deviation of the fingers, short feet, and early, marked hip dysplasia). TRPS II is additionally characterized by multiple osteochondromas and an increased risk of mild-to-moderate intellectual disability.

Diagnosis/testing.

The clinical diagnosis of TRPS can be established in a proband with characteristic facial features, ectodermal and joint manifestations, and skeletal findings of cone-shaped epiphyses. The molecular diagnosis of TRPS I is established in an individual with suggestive findings and identification of a heterozygous pathogenic variant in TRPS1; the molecular diagnosis of TRPS II is established in an individual with suggestive findings and a contiguous 8q23.3-q24.11 deletion that includes TRPS1, RAD21, and EXT1.

Management.

Treatment of manifestations: Management of TRPS is principally supportive. Practical advice on hair care and use of wigs; consider extraction of supernumerary teeth; consider growth hormone (GH) therapy in those with short stature and GH deficiency; occupational therapy can benefit fine motor skills; analgesics (e.g., NSAIDs or other non-opiods) for joint pain; physiotherapy may relieve pain and aid mobility; encourage regular exercise; support with mobility at school and work as needed; consider prosthetic hip implantation in those with severe hip dysplasia; sunlight exposure, adequate dietary intake of calcium and vitamin D, and/or calcium and vitamin D supplementation; modify activities to prevent fractures; consider bisphosphonates in those with osteopenia; treatment of cardiac anomalies per cardiologist; peer support and psychological counseling if indicated. In those with TRPS II, consider resection of symptomatic osteochondromas; developmental and educational support.

Surveillance: Monitor linear growth and assess for joint manifestations at each visit throughout childhood; assess for frequent fractures at each visit; DXA scan as needed in those with suspected osteopenia. In those with TRPS II, radiographs of osteochondromas when symptomatic and at the end of puberty. In those with a clinical diagnosis of TRPS (of unknown molecular cause) and those with TRPS II, developmental assessment annually throughout childhood.

Agents/circumstances to avoid: High-impact or contact sports may pose a risk to those with impaired mobility.

Genetic counseling.

TRPS is inherited in an autosomal dominant manner. 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. Most individuals with TRPS II whose parents have undergone genetic testing have the disorder as the result of a de novo contiguous 8q23.3-q24.11 deletion. Each child of an individual with TRPS has a 50% chance of inheriting the TRPS-related genetic alteration. Once the TRPS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

TRPS should be suspected in individuals with the following clinical, radiographic, and family history findings.

Clinical Findings

TRPS I and TRPS II

• Characteristic facial features. Most distinctive (and possibly unique) is the large nose with broad nasal ridge and tip, underdeveloped alae, and (on occasion) a broad nasal septum. Other findings include thick and broad medial eyebrows, long philtrum, thin vermilion of the upper lip, and large prominent ears (see Figure 1A and 1B).
• Ectodermal features are fine, sparse, depigmented, and slow-growing hair, dystrophic nails, and small breasts (see Figure 1B).
• Skeletal findings include short stature, brachydactyly with ulnar or radial deviation of the fingers (see Figure 2), short feet, and early, marked hip dysplasia.

Figure 1.

Clinical features of TRPS I and TRPS II A. Facial features of a male age 16 years with TRPS I. Note the broad nasal ridge and nasal tip without a broad nasal bridge; underdeveloped alae nasi; wide and low-hanging columella; long philtrum; and medial flaring (more...)

Figure 2.

Hands of a woman age 21 years with TRPS Note metacarpal shortening, ulnar deviation of the third fingers, radial deviation of the fourth fingers, and short thumbs.

TRPS II only

• Multiple osteochondromas are typically first observed clinically on the scapulae and around the elbows and knees between ages one month and six years (see Figure 1C).
• Intellectual disability, if present, is typically mild to moderate.

Radiographic Findings

TRPS I and TRPS II

• Cone-shaped epiphyses are present in almost all individuals with TRPS; detectable at an early age (typically after age two years) when the epiphyses are just forming, and most frequently occurring in the middle phalanges, although they may occur in any phalanx of the hands and feet (see Figure 3 and Figure 4) [Vaccaro et al 2005].
• In individuals with hip dysplasia, Perthes-like lesions such as flat (coxa plana) or irregular femoral head, as well as narrowing of the joint space and subchondral sclerosis (See Figure 5.)
• Secondary joint degeneration, characterized by narrowing of the joint space and subchondral sclerosis; in addition to the hip, the fingers and very rarely other joints may also be affected [Maas et al 2015, de Barros & Kakehasi 2016, Güneş et al 2023].

Figure 3.

AP radiograph of the hand of a boy age four years with TRPS Note cone-shaped epiphyses of the second to fifth proximal phalanges (circles) and more subtle, partially fused cone-shaped epiphyses of the second to fourth middle phalanges (arrows).

Figure 4.

Residual angulated deformity of the proximal aspects of the second and fifth middle phalanges (arrows) related to fusion of prior cone-shaped epiphyses

Figure 5.

Flattened capital femoral epiphyses (coxa plana) and broad femoral neck in a boy with TRPS II (age six years)

TRPS II only

• Multiple osteochondromas. Exostoses arising from the metaphyses of long bones that may be sessile (flat) or pedunculated and directed away from the joint; most common around the elbows and knees, but other joints can be involved; commonly observed on the scapulae (See Figure 6.)

Figure 6.

Exostosis of the radius (arrow)

Establishing the Diagnosis

Clinical diagnosis. The clinical diagnosis of TRPS can be established in a proband with typical clinical findings including characteristic facial features, ectodermal manifestations, and skeletal findings including cone-shaped epiphyses.

Molecular diagnosis. The diagnosis of TRPS is established in a proband with suggestive findings who has one of the following on molecular genetic testing (see Table 1):

• TRPS I. A heterozygous pathogenic (or likely pathogenic) variant in TRPS1
• TRPS II. A heterozygous deletion of 8q23.3-q24.11 that spans the TRPS1-EXT1 interval

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous TRPS1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include single-gene testing or chromosomal microarray analysis (CMA) depending on the phenotype.

TRPS I

• Single-gene testing. Sequence analysis of TRPS1 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• Karyotype may be considered to detect an apparently balanced translocation or inversion involving 8q24.

TRPS II

• Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TRPS1, RAD21, EXT1) that cannot be detected by sequence analysis.

Clinical Description

Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features, ectodermal features (fine, sparse, depigmented, and slow-growing hair, dystrophic nails, and small breasts), and skeletal findings (short stature, short feet, brachydactyly with ulnar or radial deviation of the fingers, and early, marked hip dysplasia). TRPS II is additionally characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages one month and six years) and an increased risk of mild-to-moderate intellectual disability (see Table 2).

The largest cohort of individuals with TRPS reported to date includes 103 affected individuals from a large European collaborative study [Maas et al 2015]. This study and other studies [Giedion et al 1973, Lüdecke et al 2001, Güneş et al 2023] demonstrate that the phenotype of TRPS I within a family can vary markedly, and variability can be seen in all clinical and radiographic features.

Genotype-Phenotype Correlations

There is no clear genotype-phenotype correlation in TRPS I. However, missense variants have been reported to be associated with a more severe phenotype such as significant brachydactyly and severe short stature [Lüdecke et al 2001, Maas et al 2015, Wang et al 2020, Güneş et al 2023, Öztürk et al 2023]. Phenotypic variability is also observed within and between families with the same TRPS1 pathogenic variant [Giedion et al 1973, Lüdecke et al 2001, Maas et al 2015].

The size of the minimal critical region responsible for the phenotypic features of TRPS II has been reported to be around 3 Mb [Favilla et al 2022, Güneş et al 2023]. In TRPS II, no correlation was found between the size of the deleted segment and the severity of intellectual disability [Favilla et al 2022].

Penetrance

No instances of reduced penetrance have been reported; thus, penetrance is believed to be 100% [Lüdecke et al 2001].

Nomenclature

It has been suggested that individuals with severe short stature and brachydactyly may have a distinguishable phenotype called TRPS III [Lüdecke et al 2001]. However, this term is no longer in use as this phenotype is now considered to be within the spectrum of TRPS I [Maas et al 2015].

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], TRPS caused by a heterozygous pathogenic variant in TRPS1 is referred to as trichorhinophalangeal dysplasia types 1/3. TRPS caused by a contiguous 8q23.3-q24.11 deletion spanning the TRPS1-EXT1 interval is referred to as Langer-Giedion syndrome (trichorhinophalangeal dysplasia type 2).

Prevalence

There are no population-based estimates of the prevalence of TRPS. To date, 350 affected individuals have been reported [Orphanet Report Series 2023]. However, since most individuals with TRPS I do not have intellectual disability or short stature, the prevalence of TRPS I may be higher than assumed because some individuals remain undiagnosed.

Evaluations Following Initial Diagnosis

To establish the extent of disease and support needs of an individual diagnosed with trichorhinophalangeal syndrome (TRPS), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management of TRPS is principally supportive (see Table 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

High-impact or contact sports may pose a risk to those with impaired mobility.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. To date, there are no therapies under investigation.

Mode of Inheritance

Trichorhinophalangeal syndrome (TRPS) is inherited in an autosomal dominant manner.

• TRPS I is caused by a heterozygous pathogenic variant in TRPS1.
• TRPS II is caused by a contiguous 8q23.3-q24.11 deletion that spans the TRPS1-EXT1 interval.

Risk to Family Members – TRPS I

Parents of a proband

• Many individuals diagnosed with TRPS I have an affected parent. Although the TRPS I phenotype can vary markedly within a family [Giedion et al 1973, Lüdecke et al 2001, Maas et al 2015], a clinical diagnosis is usually possible in affected individuals (see Clinical Description).
• Approximately one third of individuals diagnosed with TRPS I have the disorder as the result of a de novo pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of parents of a proband include complete physical examination, radiologic studies of hands and feet, and molecular genetic testing to evaluate the genetic status of the parents and inform recurrence risk assessment.
  Note: If the proband has a structural variant involving TRPS1 (e.g., a chromosome 8 inversion), chromosome analysis of the parents is recommended.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Corsini et al 2014]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with TRPS I may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing have been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The phenotype of TRPS I can vary markedly among affected family members, and variability can be seen in all clinical and radiographic features [Lüdecke et al 2001, Maas et al 2015, Güneş et al 2023, Öztürk et al 2023].
• If a parent has a structural chromosome rearrangement involving the 8q23.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If the TRPS1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Somatic and germline mosaicism in an unaffected parent has been reported [Corsini et al 2014].
• If the parents have not been tested for the TRPS1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low but still increased over that of that of the general population because of the possibility of parental germline mosaicism [Corsini et al 2014].

Offspring of a proband. Each child of an individual with TRPS I has a 50% chance of inheriting the TRPS1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TRPS1 pathogenic variant, the parent's family members may be at risk.

Risk to Family Members – TRPS II

Parents of a proband

• To date, most individuals diagnosed with TRPS II whose parents have undergone genetic testing have the disorder as the result of a de novo contiguous 8q23.3-q24.11 deletion.
• Some individuals diagnosed with TRPS II have an affected parent. The phenotype within a family can vary but only to a limited extent; however, a clinical diagnosis of TRPS II is usually possible in affected individuals (see Clinical Description).
• Evaluation of the parents by genomic testing that will detect the deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. Testing for a balanced chromosome rearrangement in the parents is also recommended.
• If the deletion identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo deletion.
  • The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with TRPS II may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or genomic testing have been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

• If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%. The TRPS II phenotype within a family can vary but only to a limited extent.
• If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If neither parent is found to have the deletion identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. To date this has not been reported.
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with TRPS II has a 50% chance of inheriting the 8q23.3-q24.11 deletion.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an TRPS-related genetic alteration or chromosome rearrangement, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with TRPS.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022b].

Prenatal Testing and Preimplantation Genetic Testing

Once the TRPS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing (PGT) are possible. Note: While prenatal testing and PGT can be used to detect a familial genetic alteration associated with TRPS, the severity of the TRPS I or TRPS II phenotype cannot be predicted on the basis of test results.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, a discussion of these issues may be helpful.

Molecular Pathogenesis

TRPS1 encodes the zinc finger transcription factor Trps1 (TRPS1), which represses GATA-regulated genes and binds to a dynein light chain protein. TRPS1 consists of nine zinc finger domains, seven classic and two Ikaros-like zinc finger domains, as well as a cysteine-rich and a GATA-like zinc finger region. Binding of the encoded protein to the dynein light chain protein impairs binding to GATA consensus sequences and represses its transcriptional activity. In addition, TRPS1 can also activate the transcription of target genes by binding to promoters [Yang et al 2022]. TRPS1 plays a role in various cellular processes such as bone mineralization, chondrocyte differentiation, and hair follicle development by mediating various signaling pathways such as osteocalcin, PTHrP, and Sox9/STAT3/Wnt/β-catenin.

TRPS1, RAD21, and EXT1 are located on chromosomes 8q23.3-q24.11 (within ~2.8 Mb). While loss-of-function variants in TRPS1 lead to TRPS I, the contiguous gene deletion of TRPS1, RAD21, and EXT1 causes TRPS II.

To date, 166 different TRPS1 pathogenic variants associated with TRPS have been reported in the Human Gene Mutation Database (HGMD). Of these pathogenic variants, 94 (56.6%) are truncating variants (including nonsense [21.7%], frameshift [32.5%], and splice variants [2.4%]), 31 (18.7%) are missense variants, 30 (18.1%) are gross deletions, two are gross insertions, and nine are complex rearrangements. With the exception of four missense variants, all missense variants are located in exons 6 and 7. Missense variants in TRPS1 are associated with more severe phenotypes, including pronounced short stature and brachydactyly [Lüdecke et al 2001, Maas et al 2015, Wang et al 2020, Güneş et al 2023, Öztürk et al 2023].

Most phenotypic features of TRPS II are explained by the deletion of TRPS1 and EXT1. The minimal critical region responsible for TRPS II spans approximately 3.2 Mb encompassing the TRPS1-EXT1 interval [Favilla et al 2022]. However, the larger the deletion and the greater the number of genes deleted outside the minimal critical region, the more likely additional features (e.g., cognitive dysfunction, epilepsy) will occur [Chen et al 2013, Maas et al 2015]. Haploinsufficiency of RAD21, which lies between TRPS1 and EXT1, may contribute to more severe manifestations, particularly cognitive impairment. The features of isolated RAD21 deletions have not been identified in individuals with TRPS II and are therefore likely to be very limited.

Mechanism of disease causation. Loss of function (haploinsufficiency)

Note: Missense variants are predicted to exhibit a dominant-negative effect as a part of a multimeric protein complex, unlike the haploinsufficiency (loss of function) associated with truncating variants [Lüdecke et al 2001].

Author History

Dilek Uludağ Alkaya, MD, PhD (2024-present)
Hennie Bikker, PhD; University of Amsterdam (2017-2024)
Nilay Güneş, MD (2024-present)
Raoul CM Hennekam, PhD, MD; University of Amsterdam (2017-2024)
Saskia Maas, MD; University of Amsterdam (2017-2024)
Adam Shaw, BM, MD; Guy's & Saint Thomas' Hospitals (2017-2024)
Beyhan Tüysüz, MD, PhD (2024-present)

Revision History

• 21 March 2024 (sw) Comprehensive update posted live
• 20 April 2017 (bp) Review posted live
• 20 September 2016 (rh) Original submission

Literature Cited

• Brenner P, Hinkel GK, Krause-Bergmann A. Surgical therapy of cone-shaped epiphyses of the proximal interphalangeal joints in tricho-rhino-phalangeal syndrome type I: a survey among three successive generations of a single family. Zentralbl Chir. 2004;129:460-9. [PubMed: 15616909]
• Chen CP, Lin SP, Liu YP, Chern SR, Wu PS, Su JW, Chen YT, Lee CC, Wang W. An interstitial deletion of 8q23.3-q24.22 associated with Langer-Giedion syndrome, Cornelia de Lange syndrome and epilepsy. Gene. 2013;529:176-80. [PubMed: 23933416]
• Chen LH, Ning CC, Chao SC. Mutations in TRPS1 gene in trichorhinophalangeal syndrome type I üin Asian patients. Br J Dermatol. 2010;163:416-9. [PubMed: 20394624]
• Choi M, Han A, Eichenfield LF. Successful topical minoxidil treatment for hair density and length in trichorhinophalangeal syndrome type 1. Pediatr Dermatol. 2024;41:366-8. [PubMed: 38193387]
• Choi MS, Park MJ, Park M, Nam CH, Hong SP, Kim MH, Park BC. Treatment of hair loss in the trichorhinophalangeal syndrome. Ann Dermatol. 2018;30:382-3. [PMC free article: PMC5929967] [PubMed: 29853764]
• Corsini C, Gencik M, Willems M, Decker E, Sanchez E, Puechberty J, Schneider A, Girard M, Edery P, Bretonnes P, Cottalorda J, Lefort G, Jeandel C, Sarda P, Genevieve D. Somatic mosaicism in trichorhinophalangeal syndrome: a lesson for genetic counseling. Eur J Hum Genet. 2014;22:136-9. [PMC free article: PMC3865400] [PubMed: 23572024]
• Crippa M, Bestetti I, Perotti M, Castronovo C, Tabano S, Picinelli C, Grassi G, Larizza L, Pincelli AI, Finelli P. New case of trichorinophalangeal syndrome-like phenotype with a de novo t(2;8)(p16.1;q23.3) translocation which does not disrupt the TRPS1 gene. BMC Med Genet. 2014;15:52. [PMC free article: PMC4081657] [PubMed: 24886451]
• David D, Marques B, Ferreira C, Araújo C, Vieira L, Soares G, Dias C, Pinto M. Co-segregation of trichorhinophalangeal syndrome with a t(8;13)(q23.3;q21.31) familial translocation that appears to increase TRPS1 gene expression. Hum Genet. 2013;132:1287-99. [PubMed: 23835950]
• de Barros GM, Kakehasi AM. Skeletal abnormalities of tricho-rhino-phalangeal syndrome type I. Rev Bras Reumatol Engl Ed. 2016;56:86-9. [PubMed: 27267340]
• Favilla BP, Burssed B, Yamashiro Coelho EM, Perez ABA, de Faria Soares MF, Meloni VA, Bellucco FT, Melaragno MI. Minimal critical region and genes for a typical presentation of Langer-Giedion syndrome. Cytogenet Genome Res. 2022;162:46-54. [PubMed: 35290978]
• Giedion A, Burdea M, Fruchter Z, Meloni T, Trosc V. Autosomal-dominant transmission of the tricho-rhino-phalangeal syndrome. Report of 4 unrelated families, review of 60 cases. Helv Paediatr Acta. 1973;28:249-59. [PubMed: 4723882]
• Grace F, Ashby E. Late presentation of tricho-rhino-phalangeal syndrome (TRPS1 affected) associated hip pathology. J Med Cases. 2023;14:244-50. [PMC free article: PMC10409537] [PubMed: 37560551]
• Güneş N, Usluer E, Yüksel Ülker A, Uludağ Alkaya D, Çifçi Sunamak E, Celep Eyüpoğlu F, Uyguner ZO, Tüysüz B. The clinical and molecular spectrum of trichorhinophalangeal syndrome types I and II in a Turkish cohort involving 22 patients. Turk Arch Pediatr. 2023;58:98-104. [PMC free article: PMC9885788] [PubMed: 36598218]
• Hennekam RC. Hereditary multiple exostoses. J Med Genet. 1991;28:262-6. [PMC free article: PMC1016830] [PubMed: 1856833]
• Huang D, Zhao J, Xia FL, Zou CC. Recombinant human growth hormone therapy for childhood trichorhinophalangeal syndrome type I: a case report. Children (Basel). 2022a;9:1447. [PMC free article: PMC9600025] [PubMed: 36291383]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022b;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Izumi K, Takagi M, Parikh AS, Hahn A, Miskovsky SN, Nishimura G, Torii C, Kosaki K, Hasegawa T, Neilson D. Late manifestations of tricho-rhino-phalangeal syndrome in a patient: expanded skeletal phenotype in adulthood. Am J Med Genet. 2010;152A:2115-9. [PubMed: 20635356]
• Jeon J, Kim JH, Oh CH. Trichorhinophalangeal syndrome type I--clinical, microscopic, and molecular features. Indian J Dermatol Venereol Leprol. 2014;80:54-7. [PubMed: 24448126]
• Lei M, Liang D, Yang Y, Mitsuhashi S, Katoh K, Miyake N, Frith MC, Wu L, Matsumoto N. Long-read DNA sequencing fully characterized chromothripsis in a patient with Langer-Giedion syndrome and Cornelia de Lange syndrome-4. J Hum Genet. 2020;65:667-74. [PMC free article: PMC7324355] [PubMed: 32296131]
• Levy-Shraga Y, Modan-Moses D, Wientroub S, Ovadia D, Zeitlin L. The effect of growth hormone treatment in a child with tricho-rhino-phalangeal syndrome: a case report and review of the literature. Eur J Med Genet. 2020;63:103830. [PubMed: 31884116]
• Lüdecke HJ, Schaper J, Meinecke P, Momeni P, Gross S, von Holtum D, Hirche H, Abramowicz MJ, Albrecht B, Apacik C, Christen HJ, Claussen U, Devriendt K, Fastnacht E, Forderer A, Friedrich U, Goodship TH, Greiwe M, Hamm H, Hennekam RC, Hinkel GK, Hoeltzenbein M, Kayserili H, Majewski F, Mathieu M, McLeod R, Midro AT, Moog U, Nagai T, Niikawa N, Orstavik KH, Plöchl E, Seitz C, Schmidtke J, Tranebjaerg L, Tsukahara M, Wittwer B, Zabel B, Gillessen-Kaesbach G, Horsthemke B. Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III. Am J Hum Genet. 2001;68:81–91. [PMC free article: PMC1234936] [PubMed: 11112658]
• Maas SM, Shaw AC, Bikker H, Lüdecke HJ, van der Tuin K, Badura-Stronka M, Belligni E, Biamino E, Bonati MT, Carvalho DR, Cobben J, de Man SA, Den Hollander NS, Di Donato N, Garavelli L, Grønborg S, Herkert JC, Hoogeboom AJ, Jamsheer A, Latos-Bielenska A, Maat-Kievit A, Magnani C, Marcelis C, Mathijssen IB, Nielsen M, Otten E, Ousager LB, Pilch J, Plomp A, Poke G, Poluha A, Posmyk R, Rieubland C, Silengo M, Simon M, Steichen E, Stumpel C, Szakszon K, Polonkai E, van den Ende J, van der Steen A, van Essen T, van Haeringen A, van Hagen JM, Verheij JB, Mannens MM, Hennekam RC. Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome. Eur J Med Genet. 2015;58:279-92. [PubMed: 25792522]
• Macchiaiolo M, Mennini M, Digilio MC, Buonuomo PS, Lepri FR, Gnazzo M, Grandin A, Angioni A, Bartuli A. Thricho-rhino-phalangeal syndrome and severe osteoporosis: a rare association or a feature? An effective therapeutic approach with biphosphonates. Am J Med Genet A. 2014;164A:760-3. [PubMed: 24357341]
• Marques JS, Maia C, Almeida R, Isidoro L, Dias C. Should patients with trichorhinophalangeal syndrome be tested for growth hormone deficiency? Pediatr Endocrinol Rev. 2015;13:465-7. [PubMed: 26540763]
• Öztürk N, Karamık G, Mutlu H, Bayer ÖY, Mıhçı E, Çetin GO, Nur B.Expanding the clinical and molecular features of trichorhino- phalangeal syndrome with a novel variant. Turk J Pediatr. 2023;65:81-95. [PubMed: 36866988]
• Orphanet Report Series: Rare Diseases Collection. Prevalence and incidence of rare diseases: bibliographic data. Number 1, November 2023. Available online (pdf). Accessed 2-28-24.
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Shao C, Tian J, Shi DH, Yu CX, Xu C, Wang LC, Gao L, Zhao JJ. A novel mutation in TPRS1 gene caused tricho-rhino-phalangeal syndrome in a Chinese patient with severe osteoporosis. Chin Med J (Engl). 2011;124:1583–5. [PubMed: 21740822]
• Shin BS, Kwak JH, Choi H, Na CH, Kim MS. Generalized hypertrichosis after 5% minoxidil solution in trichorhinophalangeal syndrome: a case report and review of the literatures. Indian J Dermatol. 2023;68:112-4. [PMC free article: PMC10162767] [PubMed: 37151249]
• Solc R, Klugerova M, Vcelak J, Baxova A, Kuklik M, Vseticka J, Beharka R, Hirschfeldova K. Mutation analysis of TRPS1 gene including core promoter, 5'UTR, and 3'UTR regulatory sequences with insight into their organization. Clin Chim Acta. 2017;464:30-6. [PubMed: 27826100]
• Stagi S, Bindi G, Galluzzi F, Lapi E, Salti R, Chiarelli F. Partial growth hormone deficiency and changed bone quality and mass in type I trichorhinophalangeal syndrome. Am J Med Genet A. 2008;146A:1598-604. [PubMed: 18478599]
• Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, Cohn DH, Cormier-Daire V, Girisha KM, Hall C, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191:1164-209. [PMC free article: PMC10081954] [PubMed: 36779427]
• Vaccaro M, Guarneri C, Blandino A. Trichorhinophalangeal syndrome. J Am Acad Dermatol. 2005;53:858-60. [PubMed: 16243138]
• Wang C, Xu Y, Qing Y, Yao R, Li N, Wang X, Yu T, Wang J. TRPS1 mutation detection in Chinese patients with Tricho-rhino-phalangeal syndrome and identification of four novel mutations. Mol Genet Genomic Med. 2020;8:e1417. [PMC free article: PMC7549555] [PubMed: 33073934]
• Yang L, Gong X, Wang J, Fan Q, Yuan J, Yang X, Sun X, Li Y, Wang Y. Functional mechanisms of TRPS1 in disease progression and its potential role in personalized medicine. Pathol Res Pract. 2022;237:154022. [PubMed: 35863130]