Fontaine Progeroid Syndrome

Resumen

Summary
Fontaine progeroid syndrome is a very rare condition that affects many parts of the body. It can cause poor growth, changes in the shape of the bones and face, and skin that is thin, sagging, and appears older than normal (progeroid appearance). This aged appearance is most noticeable in babies and young children but tends to improve as they grow older. ¹

People with Fontaine progeroid syndrome may have specific features like a short, round head shape, large soft spots on the skull, and abnormalities in the tips of the fingers. Other problems may include heart issues, differences in urinary or reproductive organs, eye problems, or stomach and digestive system issues.¹

This condition is caused by changes (disease-causing variants) in the SLC25A24 gene. These gene variants occur randomly in most cases, meaning that in most people the condition is not inherited from parents.

There is no cure for Fontaine progeroid syndrome, but many of the symptoms can be treated or managed. ¹

Introduction

Fontaine progeroid syndrome was previously described under other names such as “Gorlin-Chaudhry-Moss syndrome”, “Fontaine-Farriaux syndrome” and “Petty syndrome”. Doctors now know that these conditions share the same underlying genetic cause and are all part of “SLC25A24 Fontaine progeroid syndrome” or Fontaine progeroid syndrome. ^1,2

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Sinónimos

• craniofacial dysostosis-genital, dental, cardiac anomalies syndrome
• craniofacial dysostosis, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies, patent ductus arteriosus, and normal intelligence
• FPS
• Gorlin Chaudhry Moss syndrome
• GCM syndrome
• Petty syndrome
• Petty-Laxova-Wiedemann syndrome
• progeroid syndrome congenital Petty type
• progeroid syndrome Petty type

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Signos y Síntomas

Fontaine progeroid syndrome is characterized by an abnormal skull shape, distinctive face and an appearance of premature aging that is sometime described as progeroid. The signs and symptoms of Fontaine progeroid syndrome may include: ^{1,2,3,4,5,6,7,8}

• Growth problems that can start before birth (intrauterine growth restriction) and continue after birth
• Feeding difficulties where babies struggle with feeding and may require extra nutritional support to ensure proper growth and weight gain
• Abnormal shape of the skull due to a premature fusion of certain skull bones (craniosynostosis), particularly along the coronal suture, the growth line stretching from ear to ear over the top of the head
  • The head may appear unusually wide and short with a pointed top due to the abnormal skull development (acrobrachycephaly)
• Slow hardening (ossification) of the skull bones, leaving a large, persistent anterior fontanelle (soft spot on the head) and that sometimes coexists with craniosynostosis, leading to uneven skull development
• Distinctive facial features that may include:
  • Middle part of the face appears flat or sunken due to underdevelopment of the facial bones (mid face hypoplasia)
  • Small eyes (microphthalmia)
  • Narrowed palpebral fissures where the openings of the eyes (eyelid slits) may be shorter or slanted
  • Flat nasal bridge where the bridge of the nose is often broad and low
  • Small, low-set ears
  • Thin, translucent skin on the face that results in an aged appearance
• Skin problems that make the affected people look older than their actual age which is described as “progeroid” (resembling premature aging)
  • Lipodystrophy, a marked loss of fatty tissue beneath the skin, especially in the face and limbs which leads to a thin, gaunt appearance
  • Thin, wrinkled and sagging skin where the skin may feel loose and appear excessively wrinkled, especially in infants (over time, the skin may improve but often remains thinner than normal)
• Hair abnormalities that may include:
  • Sparse scalp hair where babies often have thin or sparse hair on the scalp, paired with low hairlines at the front and back of the head
  • Coarse hair texture develops as children grow, with irregular patterns, such as multiple hair whorls (circular patterns in the hair’s growth)
  • Excessive hair growth (hypertrichosis), common on the face, back, arms and legs
• Abnormalities of the limbs, fingers, toes and nails
  • Shortness of the bones at the tips of the fingers and toes (distal phalanges) giving the fingers and toes a stubby appearance
  • Webbing (syndactyly) between the fingers or toes
  • Underdeveloped or missing nails where nails may be unusually small, poorly developed, or entirely absent
• Dental abnormalities such as:
  • Teeth may be smaller than average (microdontia)
  • Missing teeth
• Heart and vascular defects that are present at birth (congenital heart defects) including:
  • Holes between the heart’s chambers (e.g., atrial septal defect or ventricular septal defect)
  • Increased blood pressure in the arteries of the lungs may occur, leading to strain on the heart (pulmonary hypertension)
  • Enlargement of the aorta, the main artery that carries blood from the heart to the rest of the body (aortic dilation), increasing the risk of heart complications
• Umbilical hernias, which are bulges near the belly button and may result from weak or underdeveloped abdominal muscles
• Underdeveloped external genital folds (hypoplasia of the labia majora)
• Mild developmental delay that may include:
  • Mild delays in reaching motor milestones like sitting or walking
    • However, most children eventually catch up, and intelligence is typically within the normal range

• Vision problems that can include:
  • Farsightedness (hyperopia) which is common, making close-up vision blurry
  • Small eyes (microphthalmia) that may also contribute to visual impairments
• Hearing loss, which can vary in severity.

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Causas y Herencia

Fontaine progeroid syndrome is mainly caused by changes (disease-causing variants or pathogenic variants) in the SLC25A24 gene. This gene provides instructions for making a protein that helps transport important molecules, including ATP (the body’s main energy source), across the inner membrane of mitochondria. Mitochondria are like tiny power plants inside cells, responsible for producing energy and supporting essential cell functions, like building proteins and breaking down molecules for the body to use.^1,8

SLC25A24 gene variants change the structure of the protein, making it less effective at transporting molecules across the mitochondrial membrane. This leads to several problems:^1,6,8

• Mitochondria swell and grow larger than normal
• Mitochondria break apart into smaller pieces
• Energy production decreases, leaving cells with less fuel to function properly
• Cell death increases because of the lack of energy and damaged mitochondria

These energy problems and increased cell death are likely responsible for many of the signs and symptoms of Fontaine progeroid syndrome, like abnormal growth and connective tissue issues, though scientists are still working to understand the exact link between these changes and the specific symptoms people experience.

In some people with the syndrome, no variants in the SLC25A24 gene are found, suggesting that variants in other, still unknown genes may also cause the condition.

Fontaine progeroid syndrome 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. This means only one variant copy of the SLC25A24 gene is enough to cause the condition. 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.

In most cases of Fontaine progeroid syndrome, the variant is de novo, meaning it happens for the first time in the child and wasn’t inherited from the parents. When a variant is de novo, the chance of having another child with the same syndrome is generally very low.

However, there is a small chance (~1%) for the condition to be transmitted to a child if one of the parents has germline mosaicism, a rare situation where some of one parent’s reproductive cells carry the variant, even though the rest of their body cells do not. Because of this small possibility, genetic counseling and options like prenatal or pre-implantation genetic testing may be offered to families who are considering having more children.¹

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Frecuencia

Fontaine progeroid syndrome is extremely rare, with an estimated prevalence of less than 1 in 1,000,000.⁷As of 2024, only 13 individuals worldwide have been confirmed to have Fontaine progeroid syndrome through genetic testing.¹ 

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Enfermedades con síntomas similares

Symptoms of the following disorders may be similar to those of Fontaine progeroid syndrome. Comparisons may be useful for a differential diagnosis.^1,7

• De Barsy syndrome (subdivided in type A and type B). Type A is caused by variants in the ALDH18A1 gene with autosomal recessive inheritance. Similar features include poor growth after birth, wrinkled and sagging skin that looks prematurely aged, large soft spots on the head (fontanelles), down-slanted eyes, umbilical hernia and developmental delay. There are some differences with Fontaine progeroid syndrome such as brain malformations affecting the outer part of the brain (cortex) and the part of the brain known as cerebellum which controls the movement; prominent ears, cataracts, thumbs stuck in an inward position (adducted thumbs), unusual muscle tone and intellectual disability.

De Barsy syndrome B is caused by variants in the PYCR1 gene. Inheritance is autosomal recessive.                Similar features include poor growth after birth, large soft spots on the head, prominent forehead,                thin, wrinkled, sagging skin and sunken eyes with small eye openings. Intellectual disability is                        common.

• Cutis laxa autosomal dominant 3 (ADCL3), also caused by variants in the ALDH18A1 gene, but inherited in an autosomal dominant pattern. Similar features include growth problems, wrinkled and sagging skin, hernias and delayed closing of the fontanelles, but affected people with ADCL3 also have cataracts, abnormal twisting of cranial blood vessels (cranial vessel tortuosity) and intellectual disability.
• ATP6V0A2-related cutis laxa (ARCL2A), caused by variants in the ATP6V0A2 gene and with autosomal recessive inheritance. Similar features include growth delays, slow closure of fontanelles, thin, sagging skin, down-slanted eyes and hearing loss. Affected people also have abnormal brain development (neuronal migration anomalies) and specific findings on lab tests called TIEF and apoC-III screening (related to congenital disorders of glycosylation).
• Saul-Wilson syndrome, caused by variants in the COG4 Inheritance is autosomal dominant. Similar features include poor growth before and after birth, large soft spots on the head that close late, visible scalp veins, triangular face, short bones in the fingers and toes and developmental delay without intellectual disability. Affected people also have unique skeletal abnormalities, cloudy eye lens (cataracts) and retinal problems.
• EFEMP2-related cutis laxa, caused by variants in the EFEMP2 gene and has autosomal recessive inheritance. Similar features include thin, translucent skin, hernias, small or set-back lower jaw (micrognathia/retrognathia), misshapen ears, and problems with the aorta and lungs (aortic aneurysms and pulmonary hypertension). The differences include narrowing of the arteries (arterial stenosis), diaphragm abnormalities, lung issues like emphysema and long, slender fingers (arachnodactyly).
• Hutchinson-Gilford progeria syndrome is caused by variants in the LMNA gene and has autosomal dominant inheritance. Similar features include poor growth after birth, triangular face, loss of fat under the skin (subcutaneous fat loss) and changes in the nails. There are no growth problems before birth and there are other features such as hard, tight skin (sclerodermatous changes), partial or complete hair loss (alopecia) and bone changes in the fingertips (digital acro-osteolysis).
• Wiedemann-Rautenstrauch syndrome is caused by variants in the POLR3A gene and has autosomal recessive inheritance. Similar features include severe growth restriction before and after birth, large soft spots on the head (wide-open fontanelle), loss of body fat (generalized lipodystrophy), visible scalp veins and an aged appearance at birth. Affected people have other features such as teeth present at birth, no limb abnormalities, sparse hair on the scalp and intellectual disability.
• Mandibuloacral dysplasia with type B lipodystrophy is caused by variants in the ZMPSTE24 gene and inheritance is autosomal recessive. Similar features include poor growth after birth, slow closing of skull bones (cranial sutures), generalized fat loss (lipodystrophy) and visible blood vessels under the skin. The differences with Fontaine progeroid syndrome are bone loss in the fingers and toes (acro-osteolysis), misshaped collarbones (dysplastic clavicles), severe jaw underdevelopment (mandibular dysplasia) and sometimes kidney disease (focal sclerosing glomerulosclerosis).

Because many of these conditions share similar features like poor growth, sagging skin, and developmental delays, genetic testing is usually needed to confirm the diagnosis. If Fontaine progeroid syndrome is suspected, doctors may also order specific tests to rule out these other disorders and make sure the correct diagnosis is reached.

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Diagnóstico

Doctors suspect the diagnosis based on the signs and symptoms mentioned above, such as growth problems, skin problems, facial features, skull shape, hair patterns, hernia, finger and toe differences and abnormal genitalia.

Genetic testing identifying a variant in the SLC25A24 gene confirms the diagnosis ¹

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Tratamiento

Treatment

There is no cure for Fontaine progeroid syndrome but many of the symptoms can be treated or managed. Affected people may need to be treated by a team of multiple specialists including a craniofacial clinic (involving plastic surgery, neurosurgery and otolaryngology), cardiology, pulmonology, gastroenterology and clinical genetics.

While there are no official guidelines for treating this condition, doctors recommend personalized care based on a person’s symptoms and needs.

After a diagnosis is made, the following evaluations are suggested to evaluate all the problems that the affected person may have:¹

• A heart specialist (cardiologist) to check for high blood pressure in the lungs, enlarged blood vessels (aortic dilatation), or risks of tears (dissection)
• X-rays or CT scans to check for skull or bone issues, including delayed skull formation and abnormal bones in the spine or fingers
• An eye doctor (ophthalmologist) to evaluate vision, eyelids and other eye structures
• A feeding team or gastroenterologist to check for swallowing difficulties or poor weight gain and special feeding methods, such as feeding tubes, may be considered
• Regular dental checkups to help monitor for missing or small teeth and misalignment
• A hearing test to detect any hearing loss
• A urological evaluation in boys to check for undescended testicles (cryptorchidism) or other genital issues
• A brain MRI might be suggested for structural brain differences and regular assessments can track motor skills, speech and learning needs
• A genetic specialist who can help families understand the condition, risks for future pregnancies and available resources

Families may benefit from social work, parent support groups, or home nursing services.

Management and treatment are focused on relieving symptoms and improving quality of life.

Affected people need to be consulted and followed by several specialists who should work together as a team for the best management.

• A craniofacial team may help with skull surgery if needed. Protective helmets are sometimes recommended for babies with delayed skull formation.
• A cardiologist can evaluate the need for surgery when there are heart defects that need to be corrected.
• A pneumologist can manage specific lung issues with treatments like oxygen therapy, managing sleep problems, or addressing aspirations (inhalation of food or liquids).
• Ear tubes or hearing aids may be recommended for those with chronic ear infections or hearing loss.
• Surgery may be needed for an umbilical hernia that does not heal on its own.
• Early therapy, such as physical or speech therapy, can help children reach milestones. Schools can provide individualized education plans (IEPs) tailored to their needs.
• Therapists can help with feeding techniques or recommend, as commented before, the need to use feeding tubes if swallowing is unsafe.¹

Regular checkups are important to monitor health and catch any new issues early. Height, weight and head size should be measured at every visit. Echocardiograms are recommended at least every three years or more often if problems are found. Annual hearing and eye checkups are recommended. Progress in motor skills, learning and language should be assessed regularly.

It is recommended to avoid contact sports or any activities that may harm the skull or aorta (a major blood vessel) should be avoided. Heavy lifting or straining may increase the risk of complications, especially if the aorta is enlarged.

Aerobic exercise, such as walking or swimming, is encouraged if there are no restrictions from a doctor.

Families may benefit from connecting with parent support groups or online communities, as well as working with a social worker for additional help with caregiving or accessing resources.

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Investigaciones

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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Referencias

1. Velasco D, Olney AH, Starr L. SLC25A24 Fontaine Progeroid Syndrome. 2022 Jun 9. 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/NBK581082/ Accessed March 27, 2025.
2. Lally S, Walsh N, Kenny J, et al. Fontaine progeroid syndrome-A case report. Clin Case Rep. 2022;10(9):e6291. Published 2022 Sep 6. doi:10.1002/ccr3.6291
3. Rodríguez-García ME, Cotrina-Vinagre FJ, Cruz-Rojo J, et al. A rare male patient with Fontaine progeroid syndrome caused by p.R217H de novo mutation in SLC25A24. Am J Med Genet A. 2018;176(11):2479-2486. doi:10.1002/ajmg.a.40496
4. Legué J, François JHM, van Rijswijk CSP, van Brakel TJ. Is Gorlin-Chaudhry-Moss syndrome associated with aortopathy? Eur J Cardiothorac Surg. 2020;58(3):654-655. doi:10.1093/ejcts/ezaa108
5. Fontaine progeroid syndrome. OMIM. 6/4/2020. https://omim.org/entry/612289 Accessed March 27, 2025.
6. Writzl K, Maver A, Kovačič L, et al. De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise. Am J Hum Genet. 2017;101(5):844-855. doi:10.1016/j.ajhg.2017.09.017
7. Ryu J, Ko JM, Shin CH. A 9-year-old Korean girl with Fontaine progeroid syndrome: a case report with further phenotypical delineation and description of clinical course during long-term follow-up. BMC Med Genet. 2019;20(1):188. Published 2019 Nov 27. doi:10.1186/s12881-019-0921-9
8. Gorlin-Chaudhry-Moss syndrome. MedlinePlus. February, 2018. https://medlineplus.gov/genetics/condition/gorlin-chaudhry-moss-syndrome/ Accessed March 27, 2025.

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Enfermedades raras relacionadas: Hutchinson-Gilford Progeria Syndrome, Leukocyte Adhesion Deficiency Syndromes, De Barsy Syndrome, ...

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Enfermedades raras relacionadas: Hutchinson-Gilford Progeria Syndrome, Leukocyte Adhesion Deficiency Syndromes, De Barsy Syndrome, ...

Resource(s): Progeria Assistance Program

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