Clinical characteristics.

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 characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.

Diagnosis/testing.

The diagnosis of TRPS is established in a proband with one of the following:

• Typical clinical findings including facial features, ectodermal manifestations, and distal limb anomalies and radiographic findings of cone-shaped epiphyses
• Suggestive findings of TRPS I and identification of a heterozygous pathogenic variant in TRPS1
• Suggestive findings of TRPS II and a contiguous 8q23.3-q24.11 deletion that includes TRPS1, RAD21, and EXT1

Management.

Treatment of manifestations: Management is principally supportive. Ectodermal issues: advice about hair care and use of wigs; extraction of supernumerary teeth can be considered. Skeletal issues: in those with short stature with and without proven growth hormone deficiency, use of human growth hormone therapy has had variable results; the mainstay treatment of joint pain is use of analgesics (e.g., NSAIDs or other non-opiates); physiotherapy may aid mobility; occupational therapy can benefit fine motor skills/tasks; prosthetic hip implantation should be considered in those with severe hip dysplasia.

Surveillance: For TRPS I and TRPS II: routine monitoring of linear growth and psychomotor developmental in childhood. For TRPS II only: x-ray evaluation of osteochondromas when symptomatic and at the end of puberty (when normal growth of osteochondromas has ceased) to provide a baseline for comparison with any future enlargement

Genetic counseling.

TRPS is inherited in an autosomal dominant manner.

• TRPS I. Many individuals with TRPS I have an affected parent; the exact proportion of TRPS I caused by a de novo pathogenic variant is unknown. Each child of an individual with TRPS I has a 50% chance of inheriting the TRPS1 pathogenic variant.
• TRPS II. Most individuals with TRPS II have the disorder as the result of a de novo contiguous gene deletion of TRPS1, RAD21, and EXT1. Each child of an individual with TRPS II has a 50% chance of inheriting the contiguous gene deletion.
• TRPS I and TRPS II. Once the genetic alteration causative of TRPS 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 and radiographic findings.

Clinical

TRPS I and TRPS II

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

Figure 1.

Facial features of a male age 16 years. Note the broad nasal ridge and tip without broadening of the nasal bridge. The alae nasi are underdeveloped; the columella is wide and low hanging; the philtrum is smooth. Some medial flaring of the eyebrows.

Figure 2.

Hands of a woman age 21 years. Note metacarpal shortening and 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.
• Intellectual disability, if present, is typically mild to moderate.

Radiographic

TRPS I and TRPS II

• Cone-shaped epiphyses. Present in almost all individuals with TRPS; detectable at an early age (typically after age 2 years) when epiphyses are just forming, and most frequently occuring in the middle phalanges, although they may occur in any phalanx of the hands and feet (see Figure 3, Figure 4) [Vaccaro et al 2005]
• Hip deformities such as coxa vara, coxa plana, and coxa magna
• Secondary joint degeneration, characterized by joint space narrowing and subchondral sclerosis; involving hips more commonly than fingers but may be found in almost any joint [de Barros & Kakehasi 2016]

Figure 3.

Frontal radiograph of the hand of a male age four years. Note the coned epiphyses of the third to fifth proximal phalanges (circles), and more subtle, partially fused coned 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

TRPS II only

• Multiple osteochondromas. Exostoses arising from the metaphyses of long bones which 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 5)

Figure 5.

Exostosis of the humerus (arrow)

Establishing the Diagnosis

The diagnosis of TRPS is established in a proband with:

• Typical clinical findings including facial features, ectodermal manifestations, and distal limb anomalies, and radiographic findings of cone-shaped epiphyses; OR
• Suggestive findings of TRPS I and identification of a heterozygous pathogenic (or likely pathogenic) variant in TRPS1 (see Table 1); OR
• Suggestive findings of TRPS II and a contiguous 8q23.3q24.11 deletion that spans the TRPS1-EXT1 interval (see Table 1).

Molecular genetic testing is often not required to make the diagnosis, as the phenotype is often marked and distinct. When the clinical presentation is mild or atypical, molecular confirmation can be helpful. Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

If molecular genetic testing is indicated, the approaches vary by phenotype:

• TRPS I: single-gene testing. Sequence analysis of TRPS1 is performed first. If no pathogenic variant is detected, either chromosomal microarray analysis (CMA) or gene-targeted deletion/duplication analysis is indicated to determine if the clinical findings are caused by a mild presentation of TRPS II. If no pathogenic variant is identified, karyotype may be considered to detect an apparently balanced translocation or inversion involving 8q24.
• TRPS II: chromosomal microarray analysis (CMA) using either array comparative genomic hybridization or SNP arrays

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 characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.

The largest cohort of individuals with TRPS reported to date is the 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] demonstrate that the phenotype of TRPS I within a family can vary markedly. The variability is present in all findings: face morphology, ectodermal signs, growth, and clinical and radiographic findings.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are evident in TRPS I. Marked variability is observed within and among families with the same TRPS1 pathogenic variant [Giedion et al 1973, Lüdecke et al 2001, Maas et al 2015].

Four of the five missense pathogenic variants identified by Lüdecke et al [2001] altered the GATA DNA-binding zinc finger, and six of the seven unrelated individuals with these pathogenic variants had more marked short stature in what appeared to be a distinguishable phenotype, which was designated TRPS III. However, this term is no longer in use as this phenotype is now considered to be within the spectrum of TRPS I [Lüdecke et al 2001, Maas et al 2015].

Penetrance

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

Nomenclature

Individuals with sparse hair, unusual facial features (predominantly in the shape of the nose), and anomalies of the distal limbs were first described by the Dutch physician Van der Werff ten Bosch [1959].

Giedion suggested the name tricho-rhino-phalangeal syndrome because of the triad of most prominent features [Giedion 1966].

Affected individuals who also had developmental delay and multiple oesteochondromas were described almost simultaneously by Langer [1969] and Gorlin et al [1969].

Hall et al [1974] suggested subdivision of TRPS into TRPS I for individuals with normal development and absent osteochondromas, and TRPS II or Langer-Giedion syndrome for those with intellectual disability and multiple osteochondromas.

TRPS III, a term coined by Niikawa & Kamei [1986] to describe what appeared to be a TRPS phenotype characterized by marked short stature, is no longer in use as this finding is now considered to be within the phenotypic spectrum of TRPS I.

Prevalence

Unbiased population-based estimates of the prevalence of TRPS are not available. TRPS may frequently remain undiagnosed. Nonetheless, the condition is probably rare, with a prevalence of 0.2-1 per 100,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease and support needs of an individual diagnosed with trichorhinophalangeal syndrome (TRPS), the following should be evaluated.

For TRPS I and TRPS II

• Measurement of height
• Developmental assessment, at younger age for both TRPS I and TRPS II as the distinction may clinically not yet be possible. At an older age, only for TRPS II
• X-rays of hands, feet, pelvis, and hip, if symptomatic
• If evidence of osteopenia on x-ray, further investigation of bone mineral density and metabolism may be warranted
• Dental examination for supernumerary teeth
• Cardiac evaluation (once)
• Consultation with a clinical geneticist and/or genetic counselor

For TRPS II only

• Review of osteochondromas by an orthopedic specialist for evidence of functional limitation
• Evaluation of vison and hearing as is recommended in all persons with intellectual disability of any cause

Treatment of Manifestations

Management of TRPS is principally supportive.

Surveillance

For TRPS I and TRPS II

• Monitor linear growth in childhood
• Routine developmental assessments in childhood

For TRPS II only. X-ray evaluation of osteochondromas when symptomatic and at the end of puberty (when normal growth of osteochondromas has ceased) to provide a baseline for comparison with any future enlargement

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.

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 deletion of the contiguous genes TRPS1, RAD21, and EXT1 on chromosome 8.

Risk to Family Members – TRPS I

Parents of a proband

• Many individuals diagnosed with TRPS I have an affected parent. Although the 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 each affected individual (see Clinical Description).
• Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the TRPS1 pathogenic variant occurred de novo, the exact proportion of TRPS I caused by a de novo pathogenic variant is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant (i.e., neither parent is known to be affected) include molecular genetic testing for the pathogenic variant identified in the proband, complete physical examination, and radiologic studies of hands and feet.
• If the TRPS1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or parental mosaicism. Somatic and germline mosaicism in an unaffected parent has been reported [Corsini et al 2014]. A reliable estimate of the frequency is not available; based on the authors’ experience, the frequency is low (<2%).
• The family history of some individuals with TRPS I may appear to be negative because of failure to recognize the disorder clinically in family members or early death of the parent before clinical findings are recognized. 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 genetic status of the proband’s parents:

• If a parent of the proband is affected, the risk to the sibs is 50%. The phenotype within a family can vary markedly [Giedion et al 1973, Lüdecke et al 2001, Maas et al 2015].
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the TRPS1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is greater than 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 is affected, the parent's family members may be at risk.

Risk to Family Members – TRPS II

Parents of a proband

• Most individuals diagnosed with TRPS II have the disorder as the result of a de novo contiguous gene deletion of TRPS1, RAD21, and EXT1. Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the deletion occurred de novo, the exact proportion of TRPS II caused by a de novo deletion is unknown.
• 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 is usually possible in each affected individual (see Clinical Description).
• Evaluation of the parents by genomic testing that will detect the deletion present in the proband is recommended.
• If the deletion found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo deletion in the proband or germline mosaicism in a parent. Although no instances of parental germline mosaicism have been reported, it remains a theoretic possibility.
• 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.
• Note: If the parent is the individual in whom the deletion first occurred, the parent may have somatic mosaicism for the deletion and may be mildly/minimally affected. To date only one instance of somatic mosaicism has been reported in an individual with a molecularly confirmed diagnosis [Shanske et al 2008].

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, the risk to the sibs is 50%. The phenotype within a family can vary but only to a limited extent.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the deletion found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism. To date this has not been reported.

Offspring of a proband. Each child of an individual with TRPS II has a 50% chance of inheriting the contiguous gene deletion of TRPS1, RAD21, and EXT1.

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

Related Genetic Counseling Issues

Prediction of phenotype. Because of intrafamilial clinical variability, it is not possible to predict the severity of the phenotype in family members who have inherited a TRPS1 pathogenic variant or deletion that includes TRPS1 (except that all individuals with a deletion that includes EXT1 as well will develop multiple exostoses, i.e., TRPS type II).

Considerations in families with an apparent de novo genetic alteration. When neither parent of a proband with an autosomal dominant condition has the genetic alteration identified in the proband or clinical evidence of the disorder, the genetic alteration is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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).

Prenatal Testing and Preimplantation Genetic Testing

Once the genetic alteration causative of TRPS 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, 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, discussion of these issues may be helpful.

Molecular Pathogenesis

TRPS1, RAD21, and EXT1 are located on chromosome 8q23.3-8q24.11 (within ~2.8 Mb). Single-nucleotide variants (missense, nonsense, small deletions) in TRPS1 cause trichorhinophalangeal syndrome type I (TRPS I), while larger deletions that include TRPS1, RAD21, and EXT1 cause TRPS II. Most of the phenotypic features of TRPS II are explained by deletion of TRPS1 and EXT1. However, the larger the deletion and the more genes that are deleted outside the interval TRPS1 – EXT1, the more likely that additional features (e.g., disturbance of cognitive functions) will be present [Lüdecke et al 1999]. Haploinsufficiency of RAD21, located between TRPS1 and EXT1, may contribute to more severe features, especially disturbed cognitive functioning. Characteristics of isolated RAD21 deletions are not identified in the physical appearance of individuals with TRPS II and, thus, are likely very limited.

Revision History

• 20 April 2017 (bp) Review posted live
• 20 September 2016 (rh) Original submission

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