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PubMed This is a summary of 13 peer-reviewed journal articles Updated
Ophthalmology

Beyond the Eyes: Systemic Features of Axenfeld-Rieger Syndrome

At a Glance

Axenfeld-Rieger syndrome affects more than the eyes: dental and facial differences and unusual skin around the belly button are common, while heart or hearing problems occur in some people. PITX2 and FOXC1 results help guide screening, but features vary widely.

While the most common concerns in Axenfeld-Rieger Syndrome (ARS) involve the eyes, the condition is “systemic,” meaning it can affect several other parts of the body [1]. Because ARS is caused by genes that help direct how an embryo develops, tissues like the teeth, facial bones, and even the heart can be involved [1][2].

It is important to remember that ARS is highly variable. Not every person will have every symptom; some may have significant dental issues but no heart concerns, while others may have only very subtle physical traits [3][1]. Genotype-phenotype correlations are tendencies with substantial overlap, rather than strict rules predicting your exact future.

Craniofacial Features

Many individuals with ARS have distinct facial characteristics. These are often subtle and may not be noticeable to anyone except a specialist, but they are helpful for making an accurate diagnosis. Common features include:

  • Prominent forehead: A forehead that appears slightly larger or more forward-leaning [4].
  • Broad nasal bridge: The top of the nose between the eyes may appear wider than average [5].
  • Hypertelorism: This is the medical term for eyes that are spaced further apart [4].
  • Midface hypoplasia: The middle part of the face (cheeks and nose area) may appear slightly flattened [5].
  • Thin upper lip: A common finding where the upper lip has less visible volume [4].

Dental Anomalies

Dental issues are among the most frequent systemic features of ARS, appearing in a majority of patients, especially those with certain genetic variants [1]. These are not just “bad teeth” but rather developmental differences in how the teeth formed.

  • Hypodontia and Oligodontia: These terms mean that some teeth are missing because they never developed. Hypodontia is missing fewer than six teeth, while oligodontia is missing six or more [1][6].
  • Microdontia: Teeth that are unusually small and may be shaped like cones or pegs [1].
  • Impact on the patient: These anomalies can affect chewing, speech development, and the alignment of the jaw. Early evaluation by a pediatric dentist or orthodontist is often recommended to plan for long-term care [7][8].

Umbilical (Belly Button) Changes

The way the skin forms around the belly button is a classic diagnostic sign of ARS.

  • Redundant periumbilical skin: This looks like extra or “bunched up” skin around the navel [1]. It is often mistaken for a simple umbilical hernia, but it is actually a specific developmental trait of the syndrome (though an umbilical hernia can also occur) [5].

Other Systemic Involvements

While less common than dental or facial features, ARS can affect other organ systems. Screening for these should be guided by your specific genetic variant and symptoms.

  • Heart (Cardiac) Anomalies: Some patients are born with structural heart issues, such as small holes between the chambers of the heart [9][10].
  • Hearing Impairment: Sensorineural hearing loss (hearing loss caused by issues in the inner ear) has been reported in some cases [1][11].
  • Uncommon or Deletion-Associated Findings: Features such as growth hormone deficiency, developmental delays, “floppy” muscle tone (hypotonia), severe feeding/swallowing issues, or skeletal differences like flat feet are not core features of isolated ARS. When present, they may point toward broader chromosomal deletions (such as 6p25 contiguous-gene syndromes) rather than standard ARS [12][1][13]. If a child experiences choking, feeding difficulties, or developmental concerns, these need independent pediatric assessment.

Genetic Tendencies

The specific gene involved—PITX2 or FOXC1—can provide a starting point for which symptoms a doctor might look for more closely, though there is a lot of overlap [6]. Your examination and genetics clinician will ultimately guide your care.

Feature PITX2 Variant Tendency FOXC1 Variant Tendency
Dental Anomalies Very common (missing/small teeth) [1] Less common; may see crowding [1]
Umbilical Skin Very characteristic [1] Rarely seen [1]
Heart Issues Less common [6] More frequently associated [1]
Hearing Loss Rarely reported [6] More frequently associated [1]

Red Flags and Urgent Concerns

While ARS is generally a lifelong, manageable condition, certain symptoms require prompt medical attention:

  • Sudden changes in vision: Any sudden cloudiness of the eye or eye pain (covered in detail on the Glaucoma page).
  • Cardiac symptoms: If a child experiences unexplained fainting, extreme fatigue during exercise, or a bluish tint to the lips (cyanosis) [9].

Common questions in this guide

What parts of the body besides the eyes can Axenfeld-Rieger syndrome affect?
Axenfeld-Rieger syndrome can affect tooth development, facial structure, and the skin around the belly button. Some people also have congenital heart differences or hearing loss, while broader developmental, feeding, muscle-tone, or skeletal findings are less typical and may suggest a larger chromosomal deletion.
What dental problems are common in Axenfeld-Rieger syndrome?
Missing teeth, called hypodontia or oligodontia, and unusually small teeth, called microdontia, are common dental findings. These differences can affect chewing, speech, and jaw alignment, so early evaluation by a pediatric dentist or orthodontist can help plan care.
Does a child with Axenfeld-Rieger syndrome need heart or hearing screening?
Screening should be individualized based on the child's genetic result, symptoms, and examination. A clinician may consider an echocardiogram or hearing test, especially when a FOXC1 variant or related concerns are present.
What do PITX2 and FOXC1 results tell us about Axenfeld-Rieger syndrome?
These results can suggest which features a clinician may watch more closely, but they do not predict exactly what one person will experience. PITX2 variants are more often linked with dental and umbilical findings, while FOXC1 variants are more often associated with heart or hearing problems.
Is unusual skin around the belly button the same as an umbilical hernia?
Not necessarily. Redundant skin around the navel is a characteristic developmental feature of Axenfeld-Rieger syndrome and can look like a hernia, although a true umbilical hernia can also occur.
What symptoms need prompt medical attention in Axenfeld-Rieger syndrome?
Sudden eye cloudiness or eye pain needs prompt eye evaluation. Fainting, extreme fatigue with exercise, or blue lips can signal a heart problem and should be assessed urgently.
Could feeding problems or developmental delays be part of Axenfeld-Rieger syndrome?
Severe feeding or swallowing problems, low muscle tone, and developmental delays are not typical core features of isolated Axenfeld-Rieger syndrome. They need an independent pediatric assessment and may occur with a broader chromosomal deletion or another condition.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Given the genetic results, should we prioritize specific screenings like a cardiac echocardiogram or a hearing test?
  2. 2.Are the dental anomalies we are seeing typical for this diagnosis, and when is the best time to start seeing a pediatric dentist or orthodontist?
  3. 3.Do the craniofacial or umbilical findings have any implications for my child's health beyond being visible physical traits?
  4. 4.Based on the genetic mutation identified (PITX2 or FOXC1), are there specific developmental or neurological red flags we should watch for?

Questions For You

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References

References (13)
  1. 1

    Axenfeld-Rieger syndrome: more than meets the eye.

    Reis LM, Maheshwari M, Capasso J, et al.

    Journal of medical genetics 2023; (60(4)):368-379 doi:10.1136/jmg-2022-108646.

    PMID: 35882526
  2. 2

    The 6p25 deletion syndrome: An update on a rare neurocristopathy.

    de Vos IJ, Stegmann AP, Webers CA, Stumpel CT

    Ophthalmic genetics 2017; (38(2)):101-107 doi:10.3109/13816810.2016.1164191.

    PMID: 27070436
  3. 3

    Case Report: Novel FOXC1 variant c.311T>G (p.Ile104Ser) in a Chinese family with Axenfeld-Rieger syndrome.

    Lin B, Li L, Li DK

    Frontiers in medicine 2026; (13()):1868263 doi:10.3389/fmed.2026.1868263.

    PMID: 42338940
  4. 4

    Gene-specific facial dysmorphism in Axenfeld-Rieger syndrome caused by FOXC1 and PITX2 variants.

    Souzeau E, Siggs OM, Pasutto F, et al.

    American journal of medical genetics. Part A 2021; (185(2)):434-439 doi:10.1002/ajmg.a.61982.

    PMID: 33231930
  5. 5

    [National protocol for the diagnosis and management of Axenfeld-Rieger syndrome: Summary for the primary care physician].

    Bremond-Gignac D, Daruich-Matet A, Robert MP, et al.

    Journal francais d'ophtalmologie 2026; (49(2)):104736 doi:10.1016/j.jfo.2025.104736.

    PMID: 41455383
  6. 6

    Genotype-phenotype association of PITX2 and FOXC1 in Axenfeld-Rieger syndrome.

    Zhou L, Wang X, An J, et al.

    Experimental eye research 2023; (226()):109307 doi:10.1016/j.exer.2022.109307.

    PMID: 36442680
  7. 7

    Expanding the Phenotypic Spectrum of FOXC1-Related Axenfeld-Rieger Syndrome Type 3: A Case Report.

    Mourad A, Ward H, Lorenz N, et al.

    Cureus 2025; (17(12)):e98380 doi:10.7759/cureus.98380.

    PMID: 41487851
  8. 8

    Axenfeld–Rieger syndrome: ophthalmological and dental diagnostic and therapeutic options

    Bausz M, Csidey M, Csákány B, et al.

    Orvosi hetilap 2021; (162(5)):192-199 doi:10.1556/650.2021.31924.

    PMID: 33517333
  9. 9

    Cardiac anomalies in Axenfeld-Rieger syndrome.

    Valikodath N, Johns JA, Godown J

    Cardiology in the young 2023; (33(7)):1229-1231 doi:10.1017/S1047951122003857.

    PMID: 36543336
  10. 10

    Case report: Congenital mitral and tricuspid valve insufficiency in a patient with Axenfeld-Rieger syndrome.

    Feng J, Wang Y, Cheng S, et al.

    Frontiers in cardiovascular medicine 2022; (9()):977432 doi:10.3389/fcvm.2022.977432.

    PMID: 36211572
  11. 11

    Sensorineural hearing loss and hypoplastic cochlea in Axenfeld-Rieger syndrome with FOXC1 mutation.

    Yamazaki H, Nakamura T, Hosono K, et al.

    Auris, nasus, larynx 2021; (48(6)):1204-1208 doi:10.1016/j.anl.2020.07.006.

    PMID: 32741584
  12. 12

    Efficacy of long-acting growth hormone in Axenfeld-Rieger syndrome with a novel 3.824 Mb 4q25 deletion: a Case Report and systematic literature review.

    Guan S, Wang J, Liu Z, et al.

    Frontiers in genetics 2026; (17()):1856235 doi:10.3389/fgene.2026.1856235.

    PMID: 42382124
  13. 13

    Neuroimaging Findings in Axenfeld-Rieger Syndrome: A Case Series.

    White S, Taranath A, Hanagandi P, et al.

    AJNR. American journal of neuroradiology 2023; (44(10)):1231-1235 doi:10.3174/ajnr.A7995.

    PMID: 37679021

This page explains systemic features and screening considerations in Axenfeld-Rieger syndrome for informational purposes only and does not constitute medical advice. Your ophthalmologist, genetic clinician, pediatrician, dentist, or other healthcare professional can advise you about your specific situation.

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