Geleophysic Dysplasia

Disease Overview

Summary

Geleophysic dysplasia is a rare genetic condition that affects growth and multiple organs and systems of the body. Signs and symptoms are typically noticeable in the first year of life and may include short stature, stiff joints, heart problems and a distinctive face (described as a “happy face”).^1,2

This condition is caused by changes (variants) in one of three genes and can be inherited in different ways depending on which gene is involved.

There is no cure, so treatment focuses on managing symptoms and preventing complications. About one-third of affected children die before age five, but some individuals live into adulthood.¹

Introduction

The term “geleophysic” comes from the Greek words for happy (“gelios”) and nature (“physis”) which describe the “happy” facial appearance seen in most affected people.²

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Synonyms

• geleophysic dwarfism
• geleophysic dwarfism syndrome

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Subdivisions

• geleophysic dysplasia 1
• geleophysic dysplasia 2
• geleophysic dysplasia 3

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Signs & Symptoms

Geleophysic dysplasia is a rare genetic condition that affects many parts of the body, especially the skeleton, heart, lungs and joints. Most signs and symptoms appear within the first year of life.

Common features may include:^1,2,3,4

• Bone and growth issues
  • Short stature often noticeable within the first few months of life (about 40% of babies are born smaller than average)
  • Short arms, hands, legs and feet
  • Stiff joints that get worse and can lead to difficulty walking, bending elbows and wrists, and even toe walking
  • Other bone-related issues that can include:
    • hip problems
    • inflammation in growing bones (osteochondritis)
    • compression of nerves in the wrist (carpal tunnel syndrome)
• Skin that can become tight and thick, further limiting movement
• Distinctive facial features often described as a “happy” or “smiling” appearance including:
  • Round face with full cheeks
  • Small nose with upturned nostrils
  • Broad nasal bridge
  • Thin upper lip
  • Upturned corners of the mouth
  • Flat area between the nose and mouth (philtrum)
• Heart problems that usually appear in the first year and may get worse over time:
  • Heart valve problems especially of the mitral, aortic and pulmonary valves
  • Holes in the wall between the heart’s chambers (atrioventricular septal defect)
• Lung and breathing problems that can worsen over time and may include:
  • High blood pressure in the lungs (pulmonary hypertension) which may result from a combination of heart problems, stiff lungs, or blocked airways
  • Asthma (seen in 30–40% of affected people) that can be mild or severe
  • Lungs that can’t fully expand (restrictive lung disease) sometimes related to heart problems
  • Narrowing or weakness in different parts of the airway, such as the voice box (larynx), windpipe (trachea) and smaller airways (bronchi)
• Hearing loss (in about 40% of people) often due to repeated ear infections or enlarged adenoids (tissue in the back of the nose that can block airways and affect hearing)
  Vision problems such as:
  • Nearsightedness (myopia) a common eye condition where distant objects appear blurry
  • Farsightedness (hyperopia) a condition where distant objects appear clearer than nearby objects
  • Astigmatism, a common eye condition where the eye’s cornea or lens is irregularly shaped, causing light to focus unevenly on the retina resulting in blurry vision at all distances
  • Swelling at the back of the eye (papilledema) which is not caused by pressure in the brain
  • High pressure inside the eye (glaucoma), a condition that damages the eye (optic) nerve
• Enlarged liver (hepatomegaly) not due to liver disease but often related to heart problems, particularly those involving the right side of the heart (40% of cases)
• Low levels of thyroid hormone (hypothyroidism), though this is not common

Adults continue to have issues with short stature, limited joint movement, thick skin and occasional lung problems such as pulmonary hypertension.

Geleophysic dysplasia can be classified into 3 subtypes according to the gene involved.¹

• Geleophysic dysplasia 1 caused by ADAMTSL2 gene variants
• Geleophysic dysplasia 2 caused by FBN1 gene variants
• Geleophysic dysplasia 3 caused by LTBP3 gene variants

People with all three types of geleophysic dysplasia have similar features, such as short stature, joint stiffness and distinctive facial features.^1,5,6

The clinical features of type 1 and type 2 geleophysic dysplasia are indistinguishable. To date, people described with type 3 geleophysic dysplasia have not had heart valve involvement but do have more severe lung issues. The absence of heart valve thickening and more severe lung disease may be a distinctive feature for type 3 geleophysic dysplasia but this has not been confirmed because of the very small number of people described with this condition.¹

Lab tests on skin, liver, windpipe (trachea) and heart tissue have shown abnormal storage inside cells that may look like lysosomes (tiny compartments in cells that break down waste). Some people have tested positive with a special stain, suggesting a possible glycoprotein or storage disorder. These are rare conditions where certain substances like sugars attached to proteins build up in cells because the body can’t break them down properly.¹

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Causes

Geleophysic dysplasia is caused by changes (variants) in one of three genes:^1,2

• ADAMTSL2
• FBN1
• LTBP3

These genes help make proteins that are important for the structure of tissues throughout the body. They also control a substance called TGF-beta which helps regulate how cells grow and develop.^1,3

Inheritance

Geleophysic dysplasia can be inherited in two different ways:^1,2

• When caused by variants in the ADAMTSL2 gene, it follows an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.¹
• When caused by FBN1 or LTBP3 gene variants, it follows 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. Most people with FBN1 or LTBP3 variants have de novo variants, meaning they were not inherited from a parent.¹

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Affected populations

Geleophysic dysplasia is a rare genetic disorder and about 100 cases have been reported in the medical literature as of 2024.¹  It affects males and females equally.

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Disorders with Similar Symptoms

Geleophysic dysplasia is considered a type of skeletal dysplasia. In 2023, the Nosology Committee of the International Skeletal Dysplasia Society (ISDS) updated the classification of skeletal dysplasias, dividing them into 41 groups including 771 clinical conditions. Geleophysic dysplasia belongs to the acromelic dysplasia group which also includes three rare disorders with many signs and symptoms that overlap with geleophysic dysplasia:^1,4,7

• Weill-Marchesani syndrome
• Acromicric dysplasia
• Myhre syndrome

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Diagnosis

Doctors may suspect geleophysic dysplasia based on signs and symptoms. They can establish the diagnosis in a person who has the characteristic signs and symptoms and features seen on X-rays. Diagnosis can be confirmed by genetic testing identifying variants in the ADAMTSL2, FBN1 or LTBP3 genes.¹

 A heart ultrasound (echocardiogram) can show the heart valve problems.

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Standard Therapies

There is no cure for geleophysic dysplasia. Treatment focuses on managing symptoms and may include:^1,

• Physical therapy to maintain joint movement
• Orthopedic treatment for hip problems and other bone issues
• Heart valve replacement surgery if needed
• Breathing tube (tracheostomy) for severe airway narrowing
• Treatment for lung problems and sleep apnea
• Hearing aids and treatment for ear infections
• Vision correction

Growth hormone therapy is generally not effective in geleophysic dysplasia.⁸

Management requires a team of specialists including geneticists, cardiologists (heart specialists), orthopedists (bone specialists), pulmonologists (lung specialists), ENT (ear, nose and throat doctors) and ophthalmologists (eye specialists) that should work together as a team to care for people with geleophysic dysplasia. Regular check-ups are needed to monitor for complications.

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://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:

Tollfree: (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, contact:
http://www.centerwatch.com/

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

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References

1. Marzin P, Cormier-Daire V. Geleophysic Dysplasia. 2009 Sep 22 [Updated 2024 Mar 28]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11168/ Accessed April 28, 2025.
2. Geleophysic dysplasia. MedlinePlus. December 1, 2009. https://medlineplus.gov/genetics/condition/geleophysic-dysplasia/ Accessed April 28, 2025.
3. Geleophysic dysplasia. Orphanet. Updated June 2012. https://www.orpha.net/en/disease/detail/2623 Accessed April 28, 2025.
4. Online Mendelian Inheritance in Man (OMIM). Geleophysic Dysplasia 1; GPHYSD1. Johns Hopkins University. Updated 5/7/2024. https://www.omim.org/entry/231050 Accessed April 28, 2025.
5. Online Mendelian Inheritance (OMIM). Phenotypic Series. Geleophysic dysplasia. 2025. https://omim.org/clinicalSynopsis/table?mimNumber=231050,617809,614185&from=PS231050 Accessed April 28, 2025.
6. Liang J, Han Y, Tao H, et al. Expanded phenotypes and pathogenesis of geleophysic dysplasia 3 resulted from a de novo LTBP3 mutation: A case report. Medicine (Baltimore). 2024;103(51):e41000. doi:10.1097/MD.0000000000041000
7. Unger S, Ferreira CR, Mortier GR, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164-1209. doi:10.1002/ajmg.a.63132
8. Globa E, Zelinska N, Dauber A. The Clinical Cases of Geleophysic Dysplasia: One Gene, Different Phenotypes. Case Rep Endocrinol. 2018;2018:8212417. Published 2018 Jul 3. doi:10.1155/2018/8212417

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Programs & Resources

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