Trichorhinophalangeal Syndrome Type I

Disease Overview

Summary

Trichorhinophalangeal syndrome type I (TRPS1) is a very rare genetic disorder that affects many organs of the body.

TRPS1 is characterized by thin, sparse scalp hair, unusual facial features with a distinctive nose shape abnormalities of the fingers and/or toes with abnormal nails and multiple abnormalities of the “growing ends” (epiphyses) of the bones (skeletal dysplasia), especially in the hands and feet.

Characteristic facial features may include a rounded (bulbous) “pear-shaped” nose, thick and broad eyebrows near the middle, an abnormally small jaw (micrognathia), a long area between the nose and upper lip, a thin upper lip, dental anomalies and/or unusually large (prominent) ears. In most people, the fingers and/or toes may be abnormally short (brachydactyly) and curved. In addition, affected individuals may have short stature. The range and severity of symptoms may vary from person to person.

TRP1 is caused by changes (variants) in the TRPS1 gene. Inheritance is autosomal dominant.

There is no cure for TRPS1 but symptoms can be managed with supportive care.

Introduction

The term trichorhinophalangeal syndrome type 3 (TRPS3) was used to describe individuals with severe short stature and brachydactyly (short fingers and toes). However, this term is no longer in use. What was previously referred to as TRPS3 is now considered to be part of the broader spectrum of TRPS1.

In 2023, the classification of genetic skeletal disorders was updated. These updates help to clarify the classification of these related conditions and provide a more accurate understanding of the genetic basis behind them. According to the new guidelines:

• TRPS caused by a pathogenic variant in the TRPS1 gene is now referred to as trichorhinophalangeal dysplasia (syndrome) types 1/3. This covers what was previously known as TRPS1 and TRPS3.
• TRPS caused by a larger deletion in chromosome 8 (specifically affecting the region 8q23.3-q24.11, which includes the TRPS1 and EXT1 genes is referred to as Langer-Giedion syndrome (TRPS2). 

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Synonyms

• TRPS1
• TRP syndrome
• trichorhinophalangeal dysplasia type I
• TRPS I
• trichorhinophalangeal dysplasia types 1/3

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Signs & Symptoms

TRPS1 is a condition that affects several parts of the body, particularly the bones, joints, face, skin, hair, teeth, sweat glands and nails. The name of the condition provides clues about the areas commonly impacted:

• Tricho- refers to the hair
• Rhino- refers to the nose
• Phalangeal refers to the fingers and toes

TRPS1 can vary greatly in how it affects different people, even among members of the same family. The severity of symptoms can differ widely from one individual to another and may include:

• Bone and joint problems: People with TRPS1 often have various bone and joint problems including:
  • Abnormal cone-shape of the bones in the fingers or toes, particularly at the ends
  • Fingernails and toenails are usually thin and may look unusual or abnormally formed
  • Short feet
  • Hip dysplasia, a condition where the hip joints are not aligned properly, often developing in early adulthood but sometimes occurring in infancy or childhood
  • Very flexible (hypermobile) joints in children, but as they age, these joints may wear down, leading to pain and making movement more difficult
• Distinctive facial features, including:

• • Thick eyebrows
  • Broad nose with a rounded tip
  • Large, protruding ears
  • A long, smooth area between the nose and upper lip (philtrum)
  • A thin upper lip
  • Small teeth, which can either be fewer in number (oligodontia) or, in some people, more than usual (supernumerary)

• Sparse scalp hair, especially noticeable in males who may experience significant hair loss, becoming almost or completely bald soon after puberty
• Loose skin in younger people that tends to tighten as they grow older
• Excessive sweat (hyperhidrosis)
• Growth delays, both before and after birth, which means they might be smaller or shorter than expected for their age.

As time passes, certain features of TRPS1 may become more noticeable:

• Growth delay may continue, making it more apparent that a child is smaller or shorter than their peers.
• Hair loss might increase, and dental overcrowding (teeth that are too close together) may become more obvious, making facial features stand out more.
• Brachydactyly (short fingers) becomes more visible over time. In childhood, the fingers may start to bend or deviate due to abnormal bone growth at the ends of the fingers, and this can continue into adulthood.

X-rays typically reveal joint dysplasia (abnormal joint development), reduced space in the joints and areas of hard or dense bone (sclerotic bone). Problems with mobility in the lower limbs, especially in the hips, often develop as a person ages. In some people, these hip problems are so severe that a hip replacement may be necessary in early adulthood.

A more severe form of TRPS1, previously referred to as TRPS3, describes individuals who have more pronounced facial features, shorter stature and more noticeable brachydactyly.

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Causes

TRPS1 is caused by changes (pathogenic variants) in the TRPS1 gene. This gene is located in the long arm (q) of chromosome 8 (8q23.3).

The TRPS1 gene provides instructions for making a protein that is found within the cell nucleus where it interacts with specific regions of DNA to turn off (repress) the activity of certain genes. Research suggests that the TRPS1 protein plays a role in regulating genes that control the growth of bone and other skeletal tissues.

TRPS1 gene variants lead to the production of an altered TRPS1 protein. The altered protein has a reduced ability to control the activity of genes that regulate the growth of bone and other tissues, leading to abnormal bones in the fingers and toes, joint abnormalities, distinctive facial features, and other signs and symptoms of TRPS1.

Less frequently, certain chromosomal anomalies such as inversions and balanced translocation within chromosome 8 disrupting the function of TRPS1 have been reported. Inversions are when a segment of chromosome 8 flips around, changing the order of the genes. This can disrupt the normal function of the TRPS1 gene. A balanced translocation occurs when parts of chromosome 8 swap places with parts of another chromosome. Even though no genetic material is lost or gained, the rearrangement can interfere with the function of the TRPS1 gene.

The variants that cause the disease are considerably different in type and location, with no clear correlation among the specific variant and the specific clinical symptoms.

TRPS1 is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

The exact prevalence is unknown. Around 250 cases have been published in the world literature. The disease is infrequently described as mildly affected people may go unnoticed.

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Disorders with Similar Symptoms

When diagnosing TRPS1, it’s important to consider other disorders that have similar symptoms, particularly those with ectodermal manifestations (involving the skin, hair, and nails) and abnormalities in the limbs or nose.

• Trichorhinophalangeal syndrome type II (TRPS2): Also known as Langer-Giedion syndrome, this extremely rare inherited disorder shares many symptoms and physical features with TRPS I. It is caused by the loss of the TRPS1gene and its neighboring genes. Differently from TRPS1, the symptoms of TRPS2 also include multiple benign (noncancerous) bone tumors called osteochondromas and intellectual disability. These additional features are associated with the loss of genes near TRPS1.
• Oculodentodigital dysplasia: This condition features similar facial and limb anomalies, including ectodermal manifestations and an unusual nose shape.
• Cartilage-Hair hypoplasia: This disorder also involves ectodermal abnormalities and distinctive limb features.
• Ellis-Van Creveld syndrome: Another condition with ectodermal manifestations and limb anomalies, including a distinctive nose shape.

In addition, the following condition may sometimes be associated with TRPS1 as a secondary characteristic:

• Legg-Calve-Perthes disease: This rare disorder involves the degeneration of the thigh bones, typically presenting in children aged six to 12. Initial symptoms may include mild hip pain and difficulty moving the affected leg, which can worsen over time. The condition often resolves spontaneously, but in some people, the affected thigh bone may become shorter, leading to a limp and potentially contributing to short stature.

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Diagnosis

Doctors can suspect TRPS1 if a person shows the typical facial features, hair and nail issues, joint problems and bone abnormalities like cone-shaped growth areas at the ends of the bones (epiphyses). A diagnosis is confirmed through genetic testing that identifies a specific change (pathogenic variant) in the TRPS1 gene.

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Standard Therapies

Treatment

Treatment for TRPS1 focuses on managing the symptoms specific to each affected person. Since TRPS1 can affect various parts of the body differently from person to person, the treatment plan is tailored to address the symptoms that a person is experiencing.

• For bone and joint issues: Pain relief is often provided through medications like NSAIDs (non-steroidal anti-inflammatory drugs). Physiotherapy can help manage pain and improve mobility, especially in the hips and fingers. In severe cases, particularly with hip dysplasia, surgery such as hip replacement may be necessary. Regular exercise is encouraged, and mobility aids at school or work may be needed.
  • Exposure to sunlight, a diet rich in calcium and vitamin D and supplements can help maintain bone health.
  • Some may benefit from medications like bisphosphonates if they have low bone density (osteopenia).
• For hair and skin: Practical advice on hair care is important. Some individuals may choose to wear wigs due to hair loss. Skin care may involve treatments to manage sweating (hyperhidrosis) and other skin conditions as they arise.
• For growth and development: If short stature is a concern, growth hormone therapy may be considered for those with a growth hormone deficiency. Occupational therapy can help improve fine motor skills, especially in children with joint hypermobility or stiffness.
• For dental issues: Dental overcrowding or the presence of extra teeth may require orthodontic treatment or extraction of extra teeth.
• For emotional and psychological support: Counseling or support groups can be beneficial, especially for those dealing with visible symptoms like hair loss or facial differences which can affect self-esteem.

Children with TRPS1 should have their growth and joint health checked regularly.  Doctors may check bone density if there are concerns about weak bones. High-impact or contact sports may be risky for those with mobility issues. Life expectancy is usually normal.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

 

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References

TEXTBOOKS

Hicks J. Trichorhinophalangeal Syndrome Type I. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:730.

JOURNAL ARTICLES

Seitz CS, et al. Trichorhinophalangeal syndrome type I: clinical and molecular characterization of 3 members of a family and 1 sporadic case. Arch Dermatol. 2001;137:1437-42.

Boni R, et al. Trichorhinophalangeal syndrome. Dermatology. 1995;190:152-5.

Dunbar JJ, et al. Hip pathology in the trichorhinophalangeal syndrome. J Pediatr Orthop. 1995;15:381-5.

Carrington PR, et al. Trichorhinophalangeal syndrome, type 1. J Am Acad Dermatol. 1994;31:331-6.

Braga D, et al. A case of trichorhinophalangeal syndrome, type I. Cutis. 1994;53:92-4.

Minguella I, et al. Trichorhinophalangeal syndrome, type I, with avascular necrosis of the femoral head. Acta Paediatr. 1993;82:329-30.

Burgess RC. Trichorhinophalangeal syndrome. South Med J. 1991;84:1268-70.

Naritomi K, et al. Partial trisomy of distal 8q derived from mother with mosaic 8q23.3—-24.13 deletion, and relatively mild expression of trichorhinophalangeal syndrome I. Hum Genet. 1989;82:199-201.

Meyer HH, et al. Hand and foot deformities in a type I trichorhinophalangeal syndrome. Studies in 3 members of a family. Z Orthop. 1988;126:34-8.

INTERNET

Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University.TRPS1. Last Edit Date 04/01/2020. https://www.omim.org/entry/190350 Accessed Sept 10, 2024.

Trichorhinophalangeal syndrome type I. MedlinePlus. June 1, 2017. https://medlineplus.gov/genetics/condition/trichorhinophalangeal-syndrome-type-i/ Accessed Sept 10, 2024.

Trichorhinophalangeal syndrome type 1. Orphanet. March 2023. https://www.orpha.net/en/disease/detail/77258 Accessed Sept 10, 2024.

Tüysüz B, Güneş N, Alkaya DU. Trichorhinophalangeal Syndrome. 2017 Apr 20 [Updated 2024 Mar 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425926/ Accessed Sept 10, 2024.

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Patient Organizations

National Foundation for Ectodermal Dysplasias (NFED)

NORD Member

Email: [email protected]

Related Rare Diseases: Split Hand/Split Foot Malformation, Hallermann-Streiff Syndrome, Pachyonychia Congenita, ...

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Human Growth Foundation

Phone: 516-671-4041 Email: [email protected] Fax: 516-671-4055

Related Rare Diseases: Recessive Multiple Epiphyseal Dysplasia, Schimke Immuno-Osseous Dysplasia, Pseudoachondroplasia, ...

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Little People of America, Inc.

Phone: 714-368-3689 Email: [email protected] Fax: 714-368-3367

Related Rare Diseases: Asphyxiating Thoracic Dystrophy, Pycnodysostosis, Hallermann-Streiff Syndrome, ...

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NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Phone: 301-495-4484 Email: [email protected] Fax: 301-718-6366

Related Rare Diseases: Chanarin-Dorfman Syndrome, Congenital Myasthenic Syndromes, Arterial Tortuosity Syndrome, ...

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Trichorhinophalangeal Syndrome Association

Phone: 651-450-0788 Email: [email protected]

Related Rare Diseases: Trichorhinophalangeal Syndrome Type III, Trichorhinophalangeal Syndrome Type II, Trichorhinophalangeal Syndrome Type I ...

https://rarediseases.org/organizations/trichorhinophalangeal-syndrome-association/

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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