Cleft Lip–Progressive Retinopathy Syndrome

Cleft lip–progressive retinopathy syndrome is a very rare birth condition. In this condition a baby is born with a cleft lip (a gap in the upper lip) and later develops a slowly worsening eye disease of the retina (the light-sensitive layer at the back of the eye). Doctors describe this eye problem as a progressive retinopathy, often with cone–rod dystrophy-type changes, which means the light-sensing cells of the retina slowly stop working over time.

Cleft lip-progressive retinopathy syndrome (also called Ausems-Wittebol Post-Hennekam syndrome or cleft lip-cone-rod dystrophy syndrome) is an extremely rare genetic condition where a baby is born with a cleft lip and later develops a slowly worsening disease of the retina that leads to visual impairment or blindness. It is reported as a malformation syndrome with autosomal-recessive inheritance and a prevalence lower than 1 in 1,000,000 people worldwide. Because only very few patients have been described, there are no disease-specific trials or standard protocols. Doctors usually borrow treatments from cleft lip care and inherited retinal dystrophy (IRD) care, focusing on surgery for the lip, regular eye monitoring, vision rehabilitation, and genetic counseling.

This syndrome has been reported only in a very small number of families around the world. Because it is so rare, most of the information comes from case reports and summaries in rare-disease databases, not from large studies. Many details are still unknown, such as the exact gene or genes involved. However, experts agree that the key features are a non-midline cleft lip and a progressive retinal disease that leads to visual impairment.

Other names

Doctors and databases use several other names for cleft lip–progressive retinopathy syndrome. All these names describe the same basic combination of cleft lip and retinal disease:

• Ausems-Wittebol Post-Hennekam syndrome

• Ausems Wittebol-Post Hennekam syndrome

• Cleft lip–retinopathy syndrome

• Cleft lip with progressive retinopathy

• Cleft lip–cone rod dystrophy syndrome

• Cleft lip–progressive retinopathy syndrome

These different names come from the doctors who first described the families and from the main eye problem (retinopathy or cone–rod dystrophy). The core idea is always the same: a cleft lip together with a slowly worsening disease of the retina.

Types

There is no official, strict type classification for this syndrome, because so few patients have been reported. However, for clinical understanding, doctors may think about “types” in a practical way, based on what they see in the lip and the eyes. These groupings help to describe patients and plan care, but they are not formal subtypes in international classifications.

• Type 1 – Unilateral cleft lip with progressive retinopathy
  In this situation the cleft lip affects only one side of the upper lip, and the retina slowly becomes damaged over years. The eye problem may start later in childhood, with slowly worsening vision.

• Type 2 – Bilateral cleft lip with progressive retinopathy
  Here both sides of the upper lip are involved. The child still develops a slowly progressive retinopathy. The facial difference is more obvious, and surgeries may be more complex, but the eye disease is similar.

• Type 3 – Cleft lip with mainly cone–rod dystrophy pattern
  In this pattern, eye tests show a cone–rod dystrophy type of damage, where cone cells (for central and colour vision) are affected early, and rod cells (night and peripheral vision) may be involved later. This gives a typical pattern on electroretinography (ERG) and optical coherence tomography (OCT).

• Type 4 – Cleft lip with milder retinal pigment changes and slower progression
  Some individuals might have a cleft lip and only mild pigment changes in the retina that progress more slowly, with relatively better vision for longer. Published cases are few, so the true range of severity is still not fully known.

These “types” mainly help to describe the variation doctors may see, rather than representing completely different diseases.

Causes

Because this condition is extremely rare, the exact cause is still uncertain. It is likely a genetic (inherited) condition, probably with autosomal recessive inheritance in at least some families, meaning both parents silently carry a changed gene. Environmental factors may influence general risk for cleft lip and retinal disease, but they have not been clearly proven for this specific syndrome.

1. Autosomal recessive inheritance
   Many rare malformation syndromes that combine facial clefts and eye disease follow an autosomal recessive pattern. This means a child gets one non-working copy of the gene from each parent. Both parents are usually healthy carriers with no symptoms. When two carriers have a baby, there is a 25% chance in each pregnancy for the child to be affected.

2. Shared family background (consanguinity)
   In some rare disorders, parents are related by blood (for example, cousins). This increases the chance that both parents carry the same rare gene change, so the chance of having a child with an autosomal recessive condition becomes higher. Consanguinity is not reported in every case, but it is a known general risk factor for autosomal recessive malformation syndromes.

3. Gene changes affecting early facial development
   The upper lip forms very early in pregnancy when facial buds grow and join together. A change in genes that guide this process can prevent proper fusion and cause a cleft lip. In this syndrome, the same or nearby developmental pathways may also be important for eye development.

4. Gene changes affecting retinal development
   The retina also forms early in the embryo from nerve tissue. If a gene important for retinal cell growth or maintenance is altered, the retina can slowly degenerate over time and cause progressive retinopathy or cone–rod dystrophy.

5. Disturbed craniofacial patterning pathways
   Multiple signalling pathways (such as SHH, BMP, FGF, and others) help pattern the growing face and skull. Even if the exact gene is unknown, a subtle disturbance in these networks could lead to a cleft lip together with other organ problems, including the retina. This is a general concept from craniofacial developmental biology rather than a proven pathway for this specific syndrome.

6. Disturbed photoreceptor survival pathways
   Progressive retinopathy often results from damage to rods and cones, the light-sensing cells. Many inherited retinal dystrophies arise from gene changes that affect the structure, energy supply, or signalling in these cells, leading to slow cell death and gradual loss of vision.

7. Small chromosomal deletions or duplications
   In some rare syndromes, a tiny piece of a chromosome can be missing or duplicated. This may remove or add extra copies of several genes at once. Such microdeletions or microduplications can cause combined malformations like facial cleft and retinal disease, even when the exact gene is not known. Chromosomal microarray can sometimes detect this.

8. New (de novo) mutations
   Sometimes a new gene change appears for the first time in the child and is not present in either parent. This is called a de novo mutation. If this mutation affects a key developmental gene, it can cause a syndrome with cleft lip and retinal problems even in a family with no history of similar disease.

9. Epigenetic changes
   Epigenetic changes are chemical “tags” on DNA that control how strongly genes are turned on or off. In theory, abnormal epigenetic marks during early development could disturb gene expression in facial and retinal tissues. At present this is a possible but unproven mechanism in this specific syndrome.

10. Maternal nutritional problems (general cleft risk)
    For cleft lip in general, low folate levels and poor overall nutrition in early pregnancy may increase risk. This has not been directly proven in cleft lip–progressive retinopathy syndrome, but it is an important general factor in facial clefts.

11. Maternal diabetes (general malformation risk)
    Poorly controlled diabetes in pregnancy can increase the risk of several birth defects, including facial clefts and some eye problems. Again, this is a general risk factor and not specific to this named syndrome, but it may contribute in some pregnancies.

12. Maternal exposure to certain medicines (general cleft risk)
    Some medicines taken in early pregnancy (for example, certain anti-seizure drugs) can increase the risk of facial clefts. These exposures have not been clearly reported in the very few known cases of this syndrome but are part of the background risk for cleft lip more broadly.

13. Maternal smoking or alcohol (general cleft risk)
    Smoking and heavy alcohol intake during pregnancy are known to raise the risk of cleft lip and palate in general populations. They are not proven specific causes of this particular syndrome but may contribute as general risk factors for facial formation problems.

14. Maternal infections in early pregnancy
    Some viral infections in the first trimester can disturb organ formation, including the eyes and face. Though not clearly documented for cleft lip–progressive retinopathy syndrome, such infections are recognised as general teratogens that can contribute to complex malformations.

15. Interaction of many genes (polygenic background)
    Even when a single main gene is responsible, many other genes may slightly raise or lower the risk of malformations. This broad genetic background may explain why some relatives have milder features such as isolated cleft lip or eye problems, while others develop the full syndrome.

16. Interaction of genes and environment
    Most birth defects are the result of interactions between genetic susceptibility and environmental exposures, not just one factor alone. For this syndrome, a sensitive genetic background may make the developing embryo more vulnerable to common environmental influences.

17. Family history of cleft lip
    Some families have multiple members with cleft lip or cleft palate. If such a family also carries a gene affecting retinal health, a child could inherit both tendencies, producing this rare association. Family history therefore can be an important clue.

18. Family history of inherited retinal disease
    Conditions like cone–rod dystrophy and retinitis pigmentosa commonly run in families. If a family also has a tendency to facial clefts, the chance that both traits occur together in one child is higher, which may appear as this syndrome.

19. Unknown or unrecognised genetic cause
    In many rare syndromes, even detailed genetic testing may not find the exact gene. This does not mean there is no cause. It simply means that medical science has not yet discovered it or that current tests are not sensitive enough. This is very likely in this extremely rare condition.

20. Chance combination and under-reporting
    Because both cleft lip and inherited retinal dystrophies exist in the population, a very small number of people may have both by chance, and they may not always be reported in medical literature. Whether all such cases share a single gene or represent a mixture of causes is still unclear.

Symptoms

The main symptoms of cleft lip–progressive retinopathy syndrome are visible at birth (cleft lip) and develop over time (eye and vision problems). Not everyone has every symptom, and severity can vary.

1. Visible cleft lip at birth
   The baby is born with a clear gap in the upper lip. In this syndrome the cleft is often non-midline, meaning it is off to one side rather than exactly in the middle. This is usually noticed immediately after birth and often needs surgical repair.

2. Feeding difficulties in the newborn
   The cleft lip can make it harder for the baby to seal the mouth properly around the breast or bottle. This may cause poor sucking, slow feeding, or milk leaking from the nose, especially if there is an associated small palate involvement.

3. Nasal regurgitation of milk
   Because the lip and sometimes the structures behind it do not close properly, milk can pass upward into the nose during feeding. This can cause coughing, choking, and discomfort during feeds.

4. Recurrent ear or respiratory infections
   Children with cleft lip (and especially those with cleft palate) may have more ear infections and fluid behind the eardrum. This is due to abnormal function of the Eustachian tube. Frequent infections can sometimes affect hearing.

5. Speech and articulation problems
   As the child grows, the altered shape of the upper lip and nose, and any subtle palate involvement, can make speech less clear. Early speech therapy and surgical repair can greatly improve this, but some children may still have nasal-sounding speech or mispronounced sounds.

6. Abnormal retinal pigmentation
   Eye examination often shows areas of abnormal pigment in the retina. This is a sign that the retinal cells and pigment layer are stressed or damaged. These changes may start in the periphery and move towards the centre over time.

7. Progressive retinopathy
   The key eye feature is a retinopathy that slowly gets worse, meaning the retina gradually loses function. Over years this can lead to increasing visual problems. Because the change is slow, parents may not notice it immediately.

8. Cone–rod dystrophy-type visual loss
   Many patients show a cone–rod dystrophy pattern. This means central and colour vision are affected early, while night and peripheral vision may become worse later. Symptoms include difficulty reading, recognising faces, or seeing details, especially in bright light.

9. Visual impairment (low vision)
   Over time, the child or adult may have reduced visual acuity (sharpness of sight). They may need strong glasses, magnifiers, or other low-vision aids and may have trouble with schoolwork or daily activities that need clear sight.

10. Night blindness (nyctalopia)
    As rod cells are affected, the person may find it very difficult to see in dim light or darkness. They may bump into things at night, move slowly in dark rooms, or be afraid of the dark because they cannot see well.

11. Loss of peripheral (side) vision
    Progressive retinal disease often starts in the mid-peripheral or peripheral retina. Over time, the field of vision can shrink like “tunnel vision”, making it hard to notice objects coming from the side or to navigate crowded spaces.

12. Photophobia (light sensitivity)
    Many people with cone or cone–rod dystrophy are very bothered by bright light. They may squint, close their eyes in sunshine, or prefer dim lighting indoors. Sunglasses, hats, or special filters can help but do not stop the disease.

13. Colour vision problems
    Because cone cells are responsible for colour vision, damage to these cells can make colours look washed out, dull, or hard to distinguish. Children may have trouble with colour-based tasks in school.

14. Nystagmus or strabismus (eye movement problems)
    Some people with significant retinal dysfunction develop nystagmus (involuntary rhythmic eye movements) or strabismus (eyes that are not aligned). This can further blur vision and may be noticed early in life.

15. Psychological and social impact
    The visible difference of a cleft lip (even after surgery) and the progressive loss of vision can cause emotional stress, low self-esteem, anxiety, or social isolation, especially in older children and teenagers. Psychological support and support groups can be very helpful.

Diagnostic tests

Because this is a rare syndrome, doctors usually do not have a single “one-step” test. Instead, they put together clues from physical examination, eye examination, imaging, electrical tests of the retina, and genetic or laboratory studies.

Physical exam–based tests

1. General newborn and child physical examination (Physical exam)
   The doctor checks the whole body, including head shape, face, mouth, limbs, skin, and heart, to see whether the cleft lip is isolated or part of a wider syndrome. They also check growth, muscle tone, and reflexes. This helps to rule out other syndromes with clefts and eye problems.

2. Detailed facial and oral examination (Physical exam)
   The specialist looks closely at the lip, nose, gum ridge, and palate to define the exact type and side of the cleft. They note whether it is unilateral or bilateral and whether the palate is also affected. This classification guides surgical planning and helps in comparing with previously reported cases.

3. Ophthalmic slit-lamp and fundus examination (Physical/clinical exam)
   An eye doctor uses a slit-lamp and special lenses to look at the front and back of the eye. They examine the retina for pigment changes, thinning, or other signs of retinopathy. This is a key step in confirming that the child has a progressive retinal problem, not just a simple refractive error.

4. Basic neurologic and developmental assessment (Physical exam)
   The doctor checks milestones (sitting, walking, talking) and simple neurologic signs. Although most reported patients do not have intellectual disability described, this examination helps identify any additional brain or nerve problems that might point to a broader syndrome.

5. Hearing assessment with otoscopic exam (Physical exam)
   Because cleft lip and possible palate involvement can be associated with ear problems, the doctor examines the eardrums and hearing. This ensures that any hearing loss is detected early and not wrongly blamed only on eye disease or attention issues.

Manual and clinical functional tests

6. Visual behaviour and fixation testing in infants (Manual/functional test)
   For very young babies, formal eye charts cannot be used. Instead, the doctor moves toys or lights and watches whether the baby tracks them and fixes gaze appropriately. Poor tracking or unusual responses can be an early sign of retinal dysfunction.

7. Standard visual acuity testing (Manual/functional test)
   In older children and adults, vision is measured with letter charts or symbol charts. This gives a number such as 6/18 or 20/80. Regular testing over time can show gradual worsening of vision, which supports the diagnosis of a progressive retinopathy or cone–rod dystrophy pattern.

8. Refraction test for glasses (Manual/functional test)
   The eye doctor checks whether glasses can improve the vision. Even if glasses help a bit, persistent reduction in best-corrected vision suggests that there is a deeper problem in the retina, not just a focusing error.

9. Visual field testing (Manual/functional test)
   Visual field tests measure how wide the person can see. In progressive retinal disease, especially cone–rod or rod–cone dystrophies, the visual field can slowly shrink. Computerised machines or manual perimetry can detect this and show its progression over time.

10. Colour vision testing (Manual/functional test)
    Simple colour plates or more advanced tests can reveal early problems with colour perception. Abnormal results support the presence of cone dysfunction, which fits with a cone–rod dystrophy type of retinopathy in this syndrome.

Laboratory and pathological-type tests

11. Routine blood tests (Lab test)
    Basic blood work (full blood count, metabolic panel, blood sugar, and others) helps rule out systemic diseases that could also cause retinal changes, such as uncontrolled diabetes or serious infections. In most reported cases these tests are normal, which supports a primary genetic cause.

12. Genetic counselling session (Lab/genetic pathway)
    Before complex genetic testing, families meet a genetic counsellor. The counsellor records a detailed family tree, explains possible inheritance patterns, and discusses the benefits and limits of tests. This step is essential for autosomal recessive and rare disease evaluation.

13. Chromosomal microarray analysis (Lab test)
    This test looks for small missing or extra pieces of chromosomes. It is used in many children with multiple birth defects. If a recurrent microdeletion or microduplication were found in this syndrome, it could point to a critical region for the disease, although such a region has not yet been clearly established.

14. Targeted inherited retinal disease gene panel (Lab test)
    Panels that screen many genes known to cause cone–rod dystrophy and other retinal dystrophies can be done. Even if a specific “cleft lip–retinopathy” gene has not been identified, finding a pathogenic variant in a known retinal gene may help explain the eye disease and guide prognosis and family counselling.

15. Whole-exome or whole-genome sequencing (Lab test)
    If standard panels are negative, broader tests that read most or all of the coding regions of the genome can be considered. These methods have discovered genes for many ultra-rare syndromes. For this syndrome, such testing may eventually reveal the exact genetic cause in individual families.

Electrodiagnostic tests

16. Full-field electroretinography (ERG) (Electrodiagnostic test)
    ERG measures the electrical responses of rods and cones when the eye is stimulated with light. In cone–rod dystrophy, cone responses are typically reduced or absent, sometimes with later rod involvement. An abnormal ERG strongly supports a diagnosis of progressive retinal dystrophy in this syndrome.

17. Pattern or multifocal ERG (Electrodiagnostic test)
    Pattern ERG and multifocal ERG focus more on central retinal function and macular cones. They can show early central dysfunction even when full-field ERG still seems relatively preserved. This can help detect disease earlier and monitor small changes over time.

18. Visual evoked potentials (VEP) (Electrodiagnostic test)
    VEP records the electrical response of the brain’s visual cortex to visual stimuli. In retinal dystrophy, the signal reaching the brain is often delayed or reduced. VEP is useful, especially in children who cannot cooperate well with other tests, to assess the overall integrity of the visual pathway.

Imaging tests

19. Optical coherence tomography (OCT) of the retina (Imaging test)
    OCT is a special scan that gives a cross-section picture of the retina, like an ultrasound but with light. In cone or cone–rod dystrophies, OCT often shows thinning and loss of normal layers in the outer retina. In this syndrome, OCT can document structural damage that matches the functional loss on ERG and visual tests.

20. Fundus photography, autofluorescence, and other retinal imaging (Imaging tests)
    High-resolution photographs and autofluorescence images show pigment changes, areas of retinal atrophy, and progression over time. These tools, sometimes combined with scanning laser ophthalmoscopy, help to map the retinopathy and monitor how fast it is spreading towards the centre of vision.

Non-pharmacological treatments

1. Multidisciplinary cleft and retina clinic care
   Children benefit most when a cleft team (plastic surgeon, ENT, speech therapist, dentist) works together with a retina team (pediatric ophthalmologist, retina specialist, low-vision team). The cleft team focuses on safe feeding, growth and lip repair, while the retina team follows visual development and performs regular eye exams. Early, coordinated care helps parents understand the condition and plan surgeries, school support and long-term follow-up.

2. Regular ophthalmologic monitoring
   Progressive retinopathy means that retinal damage can slowly get worse over years. Regular eye exams (visual acuity, visual fields, fundus imaging, OCT, ERG when possible) help doctors track progression, detect complications such as macular edema, cataract or glaucoma, and decide when treatment (for example anti-VEGF injections or low-vision aids) is needed. Frequent monitoring is standard in inherited retinal dystrophies and is adapted to each child’s age and cooperation.

3. Low-vision aids and vision rehabilitation
   As the retina becomes more damaged, many children develop reduced central or peripheral vision. Low-vision rehabilitation teaches them to use magnifiers, high-contrast reading materials, large-print books, screen enlargement, and audio tools. It also trains them to scan their environment safely. These strategies do not cure the retina, but they reduce disability in school and daily life and are recommended in all inherited retinal diseases.

4. Orientation and mobility training
   When visual fields shrink or night vision becomes poor, children may bump into objects, hesitate on stairs or be afraid of moving alone. Orientation and mobility specialists teach safe walking techniques, use of canes when needed, how to navigate streets and public transport, and how to adapt routes and lighting. Early training builds independence and confidence before severe vision loss appears.

5. Speech and language therapy
   Cleft lip (and sometimes associated palate anomalies) can affect how sounds are formed, especially if the palate or nasal passages are affected. Speech and language therapists work with the child on articulation, resonance and breath support. They also help after surgeries to correct compensatory speech habits. Good speech therapy improves communication, school participation and self-esteem.

6. Feeding support and nutritional counseling
   Infants with cleft lip may have difficulty forming a seal on the breast or bottle. Special nipples, feeding positions, and nutrition counseling help maintain growth until surgery. Dietitians can also guide parents on balanced nutrition that supports general health and eye health (adequate protein, vitamins and minerals, but avoiding dangerous megadoses such as too much vitamin A).

7. Psychological counseling for child and family
   A visible facial difference and progressive vision loss can cause anxiety, sadness, bullying and lowered self-confidence. Psychologists familiar with craniofacial and visual disorders help children process emotions, build coping skills, and support parents who may feel guilt or fear about the genetic diagnosis. Psychological support is considered a core component of care in inherited retinal dystrophies and cleft care.

8. Genetic counseling
   Because the syndrome appears to follow autosomal-recessive inheritance, parents and older patients should receive genetic counseling. The counselor explains recurrence risk, discusses options for future pregnancies, and may arrange genetic testing if an underlying retinal gene is discovered. Even when the exact gene is unknown, counseling helps families understand why the condition occurred and reduces feelings of blame.

9. Educational adaptations and inclusive schooling
   Teachers can adapt materials by using large print, high contrast, audio textbooks, and seating the child close to the board. Exams may allow extra time or oral formats. An individualized education plan (IEP) or similar document helps ensure the right support: classroom aides, orientation support inside school, and accessible digital tools. This keeps learning on track even if vision slowly declines.

10. Assistive technology and screen readers
    As the child grows, digital tools become essential. Screen readers, screen magnifiers, contrast-adjusting software, and smartphone accessibility features allow reading, writing, and internet use even with low vision. Training in these tools at a young age helps make the transition smoother if vision loss progresses in adolescence or adulthood.

11. Home and environment modifications
    Simple changes at home—good lighting, anti-slip flooring, high-contrast edges on stairs, removing trip hazards, and organized furniture—significantly reduce falls and accidents for people with reduced vision. Labeling items with large, high-contrast text or tactile markers also helps with independence in cooking, dressing and schoolwork.

12. Sun and UV protection
    Retinal cells already under stress from a dystrophy may be more vulnerable to light damage. Wearing UV-blocking sunglasses, broad-brimmed hats, and avoiding strong midday sun can reduce glare and photophobia. This not only improves comfort but may modestly reduce further retinal stress, as suggested for other inherited retinal diseases.

13. Regular dental and orthodontic care
    Cleft lip (with or without palate involvement) is often associated with dental malalignment and bite problems. Early dental visits and orthodontic assessment help plan tooth alignment, jaw growth, and later cosmetic improvements. Healthy teeth and jaws are important for speech, nutrition and self-image.

14. Hearing evaluation and ENT follow-up
    Craniofacial conditions can be associated with ear infections or hearing loss, which further complicate speech and learning. Early hearing screening, regular ENT follow-up, and use of hearing aids if needed ensure that the child is not dealing with both vision and hearing loss without support.

15. Parent education and training programs
    Parent workshops teach practical skills: feeding techniques, how to use low-vision devices, how to advocate in school, and how to recognize signs of eye deterioration (such as new clumsiness, complaints of dark spots, or night blindness). Educated parents can react quickly when problems appear.

16. Support groups and peer connections
    Even though this syndrome is ultra-rare, families can connect through cleft organizations and inherited retinal disease groups. Meeting others who live with similar challenges reduces isolation, provides practical tips, and offers emotional support for both parents and children.

17. Vocational guidance in adolescence
    As teenagers think about future jobs, counseling can help them choose careers compatible with their visual abilities. Vocational rehabilitation specialists can arrange internships, workplace adaptations and assistive technology to support employment. Planning early prevents sudden crises when vision worsens later.

18. Fall-prevention and physical activity programs
    Supervised exercise builds strength and balance, which helps when peripheral vision is reduced. Physiotherapists can design safe training programs, while also teaching strategies for safe street crossing, ball games or cycling with adaptations. The goal is to keep the child active, not over-protective, while respecting safety limits.

19. Early intervention programs in infancy
    In many countries, infants with major anomalies automatically qualify for early intervention: home visits from therapists, developmental stimulation, and parent training. These services support motor, cognitive, and social development despite medical challenges and frequent hospital visits.

20. Advance planning for eventual low vision or blindness
    Because the retinopathy is described as progressive, teams should gently prepare families for the possibility of severe visual loss. This includes learning Braille or tactile reading if appropriate, exploring audio-based learning, and psychological preparation for transitions (for example, from print to audio at school). Honest but hopeful discussions help families adapt over time.

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Drug treatments

Because cleft lip-progressive retinopathy syndrome is ultra-rare, no drugs are specifically tested or approved for it. In practice, doctors may use medicines that are approved for other retinal diseases (such as neovascular age-related macular degeneration, diabetic macular edema or other inherited retinal dystrophies) when similar complications occur. The doses below are from US FDA labels for those conditions; actual dosing and use must be individualized by a retina specialist.

1. Ranibizumab (LUCENTIS® and biosimilars such as BYOOVIZ®, CIMERLI®)
   Ranibizumab is an intravitreal anti-VEGF monoclonal antibody fragment used for wet age-related macular degeneration, retinal vein occlusion and diabetic macular edema. The standard adult dose is 0.5 mg (0.05 mL of 10 mg/mL solution) injected into the vitreous once a month, with a lower 0.3 mg dose for some diabetic indications. It blocks VEGF-A, reducing abnormal vessel growth and leakage. Side effects include eye pain, increased intraocular pressure, conjunctival hemorrhage, and rare serious events like endophthalmitis or retinal detachment.

2. Aflibercept (EYLEA® and EYLEA HD®; aflibercept-yszy, ENZEEVU®, OPUVIZ® biosimilars)
   Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and PlGF. For adult retinal diseases, a typical regimen is 2 mg (0.05 mL of 40 mg/mL) every 4 weeks for several doses, then every 8 weeks, while EYLEA HD 8 mg allows extended intervals. It is used when there is macular edema or choroidal neovascularization. Side effects are similar to other anti-VEGF agents, including intraocular inflammation and rare arterial thromboembolic events.

3. Ranibizumab implant (SUSVIMO®)
   SUSVIMO is a refillable port-delivery system implanted in the sclera to continuously release ranibizumab into the vitreous. For approved indications such as wet AMD, the recommended dose is 2 mg (0.02 mL of 100 mg/mL solution) with refills about every 24 weeks, providing long-term VEGF suppression. It may reduce injection burden but adds surgical risks such as conjunctival erosion or implant dislocation.

4. Topical prednisolone acetate 1% (e.g., OMNIPRED®, Pred Forte®)
   Prednisolone acetate 1% ophthalmic suspension is a corticosteroid eye drop used for inflammatory eye conditions. A common regimen in adults is one to two drops two to four times daily, adjusted by the physician. It reduces ocular inflammation by suppressing multiple inflammatory pathways. Long-term use can increase intraocular pressure, worsen glaucoma, and raise the risk of cataract and infection, so careful monitoring is essential, especially in children.

5. Dorzolamide/timolol combination (COSOPT®)
   COSOPT combines dorzolamide, a carbonic anhydrase inhibitor, with timolol, a beta-blocker, as an eye drop to lower intraocular pressure. The labeled dose is one drop in the affected eye(s) twice daily for glaucoma or ocular hypertension. It reduces aqueous humor production, helping protect the optic nerve. Side effects include local burning, bitter taste, and systemic beta-blocker risks such as bronchospasm or bradycardia, so it is contraindicated in asthma and certain heart conditions.

6. Dorzolamide ophthalmic solution (generic)
   Topical dorzolamide alone can also lower intraocular pressure by inhibiting carbonic anhydrase in the ciliary body. Guidance documents for generic dorzolamide describe a regimen of one drop in each affected eye three times daily for open-angle glaucoma or ocular hypertension. In children with retinal dystrophy and secondary glaucoma, such drops may be used under specialist care to protect remaining vision.

7. Systemic prednisolone (e.g., FLO-PRED®)
   Oral prednisolone suspension is approved for a wide range of inflammatory and autoimmune diseases. Typical doses vary widely (for example, 5–60 mg per day in divided doses in adults) depending on the indication. It works by broadly suppressing immune responses and inflammatory cytokines. It is not a routine treatment for inherited retinal dystrophy, but might be used short-term if there is superimposed inflammatory disease. Side effects include weight gain, hypertension, hyperglycemia, osteoporosis and adrenal suppression.

8. Analgesics and simple antipyretics (e.g., paracetamol/acetaminophen)
   Simple pain relievers are used after cleft surgery or eye procedures to keep the child comfortable. The dose is usually calculated by weight (for example, 10–15 mg/kg per dose every 4–6 hours in many pediatric guidelines, not exceeding the daily maximum). They block central prostaglandin production to reduce pain and fever and are generally safe when used correctly, but overdose can cause serious liver damage. (Use follows local pediatric guidelines; FDA labels vary by formulation.)

9. Antibiotic eye drops (for post-operative prophylaxis)
   After retinal or cleft-related eye surgery, topical antibiotic drops (for example fluoroquinolone formulations listed in FDA drug catalogs) may be prescribed to prevent infection. Dosing is usually one drop several times a day for about a week, depending on the product. They work by inhibiting bacterial replication in the tear film. Overuse can promote resistance or allergy, so they are used for short periods only.

10. Lubricant eye drops (artificial tears)
    Although usually regulated as medical devices rather than drugs, preservative-free lubricating drops are widely used to relieve dry eye, irritation and foreign-body sensation in patients with retinal diseases or after surgery. They provide a protective film over the cornea, improve comfort and may reduce microtrauma to the ocular surface. Side effects are minimal, but formulations with preservatives can irritate sensitive eyes.

11. Systemic iron or multivitamin preparations (for nutritional deficiencies)
    Some children with craniofacial anomalies have feeding difficulties that lead to anemia or micronutrient deficiencies. Iron and multivitamin supplements, at standard pediatric doses, help correct these deficiencies and support overall health, which indirectly benefits wound healing and neurological development. Excess iron or fat-soluble vitamins can be toxic, so supplementation is usually guided by blood tests.

12. Gene therapy for specific inherited retinal diseases (voretigene neparvovec-rzyl, LUXTURNA®)
    LUXTURNA is an FDA-approved gene therapy for biallelic RPE65-mutation–associated retinal dystrophy, delivered by subretinal injection in a specialized center. The dose is 1.5×10¹¹ vector genomes per eye in a single procedure. It introduces a functional RPE65 gene into retinal cells, improving retinal biochemistry and sometimes vision. It is not specific to cleft lip-progressive retinopathy syndrome, but illustrates how future gene therapies might be used if a causative gene is identified for this syndrome.

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Dietary molecular supplements

Because there is no proven supplement that stops this syndrome, dietary support focuses on overall health and eye-friendly nutrients, avoiding dangerous megadoses.

1. Omega-3 fatty acids (EPA/DHA) – Often provided as fish-oil capsules; many adult products use about 500–1000 mg EPA+DHA per day, adjusted by the doctor. Omega-3s are incorporated into retinal cell membranes and may support photoreceptor health and anti-inflammatory pathways. They can thin the blood slightly and may cause stomach upset or fishy aftertaste.

2. Lutein and zeaxanthin – These carotenoids accumulate in the macula as “macular pigment.” Typical supplements provide 10 mg lutein plus 2 mg zeaxanthin daily. They filter blue light and act as antioxidants in retinal tissue. Benefits are best proven in age-related macular degeneration, but similar logic is often applied in inherited retinal diseases. Excessive doses are uncommon but can rarely cause skin yellowing (benign carotenodermia).

3. Vitamin A within safe limits – Vitamin A is essential for the visual cycle, but both deficiency and overdose can harm the retina and liver. Any supplement must respect recommended dietary allowances for age; some IRD types even require restriction. Doctors sometimes prescribe vitamin A palmitate for selected dystrophies, but only after genetic confirmation and risk assessment. Self-medication with high-dose vitamin A is unsafe.

4. Vitamin D – Many children and adults have low vitamin D, which affects bone health and immune function. Typical supplementation might be 600–1000 IU/day in older children and adults, adjusted by blood levels. It supports general health and may modulate inflammation, but direct retinal benefits are not clearly proven.

5. Vitamin B-complex (B1, B2, B6, B12, folate) – B-vitamins are cofactors in energy metabolism and nerve function. Standard multivitamin doses help prevent deficiencies that could worsen fatigue, neuropathy or anemia. They do not specifically reverse retinal degeneration but support overall neurological function and energy production.

6. Vitamin C and vitamin E – As antioxidant vitamins, they neutralize reactive oxygen species generated in highly metabolic tissues like the retina. In some macular degeneration trials, combinations of vitamin C (500 mg) and vitamin E (400 IU) slowed progression, but evidence for inherited dystrophies is limited. High doses of vitamin E may increase bleeding risk in some patients and should be supervised.

7. Zinc – Zinc is crucial for retinal enzyme systems and immune function. Supplements often contain 10–25 mg elemental zinc daily. Very high doses can lead to copper deficiency, so balanced formulations and medical supervision are recommended.

8. Copper (in balanced multivitamins) – If zinc is supplemented, a small dose of copper is often included to prevent deficiency, which can cause anemia and neurological problems. Copper does not directly treat the retina but supports overall hematologic and nervous-system health.

9. Coenzyme Q10 (CoQ10) – CoQ10 participates in mitochondrial energy production. Some clinicians use 100–200 mg/day in patients with mitochondrial or neurodegenerative disorders to support cellular energy and reduce oxidative stress, although robust retinal data are lacking. Side effects are usually mild (stomach upset, insomnia in some people).

10. Alpha-lipoic acid – An antioxidant that regenerates other antioxidants such as glutathione and vitamins C and E. Doses of 100–300 mg/day are used in some neuropathy settings. For retinal disease, evidence is limited, so it should be considered experimental supportive care under medical supervision.

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Immune-support, regenerative and stem-cell–related drugs

For this syndrome, these approaches are mainly theoretical or experimental:

1. Voretigene neparvovec-rzyl (LUXTURNA® gene therapy) – As noted above, this is a first-in-class retinal gene therapy for RPE65-related disease. It demonstrates that durable vision improvement is possible when the causative gene is known and viable retinal cells remain. Future gene therapies might target the yet-unknown gene in cleft lip-progressive retinopathy syndrome.

2. Investigational retinal progenitor cell transplants – Clinical trials are testing injections of retinal progenitor or stem-cell–derived photoreceptors into eyes with inherited retinal dystrophies. The goal is to replace or support damaged cells. So far, these therapies are experimental and only available in trials, with unknown long-term safety and efficacy.

3. Systemic immunomodulators for overlapping inflammation – In rare patients with retinal dystrophy plus autoimmune uveitis or vasculitis, drugs like systemic corticosteroids or steroid-sparing immunosuppressants (for example, mycophenolate, methotrexate) may be used to calm inflammation and prevent additional damage. They do not fix the genetic dystrophy but may protect remaining tissue from inflammatory injury.

4. Vaccination programs (indirect immune “boosting”) – Keeping routine vaccinations up to date prevents severe infections that could endanger overall health, recovery from surgery, or eye health. This is not a specific drug for the syndrome, but an important immune-supportive strategy for any child with complex medical needs.

5. Nutritional and anemia correction as “immune support” – Correcting iron deficiency, vitamin D deficiency and other micronutrient deficiencies helps the immune system function properly. This makes the child more resilient during repeated surgeries and infections, indirectly protecting vision and healing.

6. Future CRISPR and gene-editing approaches (research stage) – Research into CRISPR-based editing for retinal diseases is underway. In future, if the gene for this syndrome is clearly identified and accessible, gene editing may offer a disease-modifying approach. At present, this remains experimental and is not available in routine care.

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Surgical treatments

1. Primary cleft lip repair (cheiloplasty)
   This is usually the first major intervention. In typical cleft lip care, surgery is performed between 3 and 6 months of age, when the baby is strong enough for anesthesia and before social interactions increase. The procedure closes the lip, aligns muscles and improves feeding and appearance. For this syndrome, standard cleft lip protocols are used, as the retinal disease does not change the lip surgery itself.

2. Secondary lip and nasal revision
   Some children need later revision to refine the scar, improve lip symmetry, or reshape the nose. These operations are usually done in childhood or adolescence, once facial growth has progressed. They aim to improve both function (speech, lip closure) and cosmetic appearance, supporting social confidence.

3. Palate repair (if a cleft palate is present)
   If the child also has a cleft palate, surgery often occurs between 6 and 12 months to close the roof of the mouth and support speech development. The goal is to create a functional palate that separates the mouth from the nose during speech and swallowing. This is standard cleft care and is not unique to the syndrome.

4. Retinal laser photocoagulation
   If the progressive retinopathy leads to areas of retinal ischemia and abnormal new vessels (neovascularization), retina specialists may use laser photocoagulation to destroy ischemic retina and reduce bleeding risk, similar to treatment in diabetic retinopathy or some inherited dystrophies. The aim is to preserve central vision and reduce complications such as vitreous hemorrhage.

5. Pars plana vitrectomy
   In advanced cases with retinal detachment, persistent vitreous hemorrhage or traction, a pars plana vitrectomy can be performed. Surgeons remove the vitreous gel, address retinal tears or membranes, and tamponade the retina with gas or oil. This is a complex procedure, and outcomes depend strongly on how advanced the underlying dystrophy is.

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Prevention

Because this is a genetic malformation syndrome, we cannot fully prevent it with lifestyle changes. However, we can try to prevent complications and reduce recurrence risk:

1. Genetic counseling for parents and affected adults before future pregnancies.

2. Offering genetic testing when possible to identify the causative gene and carrier status.

3. Early referral to a cleft and retina team as soon as the diagnosis is suspected.

4. Regular eye exams to detect treatable complications like cataract, glaucoma or macular edema.

5. Protection from eye trauma (safety glasses in sports, avoiding dangerous activities without supervision).

6. Avoidance of smoking exposure in the household, which can worsen general health and eye disease risk.

7. Good control of systemic diseases such as diabetes or hypertension later in life, as these can further damage retinal vessels.

8. Keeping vaccinations up to date to reduce serious infections around surgery or in general.

9. Ensuring good nutrition and avoidance of severe vitamin deficiencies or harmful megadoses.

10. Strong adherence to follow-up appointments, therapies and school adaptations to prevent secondary disability.

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When to see doctors urgently

Families should contact doctors immediately or seek urgent care if they notice:

• A baby with cleft lip who cannot feed, loses weight or has breathing difficulty.

• Sudden worsening of vision, new dark spots, flashes of light or a curtain-like shadow (possible retinal detachment).

• New eye redness, pain, or discharge after an injection or surgery (possible infection).

• Persistent severe headaches, vomiting or behavioral changes.

• Any sign that the child is bumping into objects more often, struggling in dim light, or refusing to walk in unfamiliar places.

Routine appointments with the cleft team and ophthalmologist are also very important, even when there is no obvious problem.

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What to eat and what to avoid

1. Eat: A balanced diet rich in fruits, vegetables, whole grains, and lean proteins to support growth and healing.

2. Eat: Green leafy vegetables (spinach, kale) and yellow/orange vegetables (carrots, pumpkin) for carotenoids, but in food form rather than huge vitamin A pills.

3. Eat: Oily fish (salmon, sardines) 1–2 times per week, or as advised, to provide natural omega-3 fatty acids.

4. Eat: Dairy or fortified alternatives, plus sunlight exposure according to local guidelines, to maintain good vitamin D and calcium levels.

5. Eat: Adequate iron-rich foods such as lentils, beans, meat or fortified cereals to prevent anemia.

6. Avoid: Very high-dose vitamin A or other megavitamin supplements unless specifically prescribed after genetic and medical evaluation.

7. Avoid: Sugary drinks and ultra-processed snacks, which can lead to obesity and later metabolic disease affecting the eyes.

8. Avoid: Smoking and second-hand smoke exposure, which harms blood vessels and general health.

9. Avoid: Excessive salt and saturated fat, to reduce later cardiovascular risk that might further damage retinal and brain blood vessels.

10. Avoid: Skipping meals or restrictive fad diets that might cause micronutrient deficiencies in a growing child.

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Frequently asked questions

1. Is cleft lip-progressive retinopathy syndrome the same as a simple cleft lip?
   No. A simple cleft lip affects only the lip and surrounding structures. This syndrome includes a cleft lip plus a specific progressive retinal disease that can lead to severe visual loss.

2. How common is this syndrome?
   It is classified as an ultra-rare disorder, with reported prevalence lower than 1 in 1,000,000, and only a small number of cases described worldwide.

3. How is it inherited?
   Available data suggest autosomal-recessive inheritance, meaning both parents are likely healthy carriers of one non-working copy of the responsible gene. A child who inherits both non-working copies develops the syndrome.

4. Can we know the exact gene?
   For this specific syndrome, the exact gene is not clearly established in public databases yet. Genetic testing panels for inherited retinal diseases may still be useful, and new discoveries may identify the causative gene in the future.

5. Will my child definitely go blind?
   The syndrome is described as having progressive retinopathy, but the speed and severity of vision loss can vary. Regular eye exams, low-vision rehabilitation and management of complications can help preserve useful vision and independence for as long as possible.

6. Is there a cure right now?
   There is no cure that reverses the underlying genetic defect at the moment. Treatment focuses on surgery for the cleft lip, managing retinal complications, and maximizing functional vision through rehabilitation and assistive technology.

7. Can gene therapy help?
   Gene therapy is approved for some other inherited retinal diseases (for example RPE65-related disease), proving that retinal gene therapy can work. However, a specific gene therapy for cleft lip-progressive retinopathy syndrome does not yet exist and would require identification of the responsible gene and dedicated trials.

8. Are the drugs you listed specific treatments for this syndrome?
   No. The anti-VEGF injections, steroids and pressure-lowering drops are approved for other retinal or eye diseases. In this syndrome, they may be used off-label to treat similar complications (like macular edema or glaucoma), always under specialist supervision.

9. What is the role of surgery in the eye problems?
   Surgery does not stop the genetic retinal degeneration but can treat structural issues such as retinal detachment or vitreous hemorrhage, giving the best chance to preserve remaining vision. Decisions depend on how advanced the disease is and the risks of anesthesia and surgery in each child.

10. Will my child be able to attend regular school?
    Many children with significant visual impairment attend mainstream schools with adaptations like large print, extra time, assistive technology and mobility training. Others may benefit from schools with strong visual-impairment support. Early planning with teachers and low-vision specialists is important.

11. Can anything be done during pregnancy to detect this condition?
    A cleft lip can sometimes be seen on prenatal ultrasound, but the retinal disease is usually not detectable before birth. If the causative gene is identified in a family, targeted prenatal or preimplantation genetic testing might be possible in future pregnancies after genetic counseling.

12. Does this syndrome affect the brain or other organs?
    Current descriptions mainly emphasize cleft lip and retinal disease. Because case numbers are so small, milder or less obvious features might be under-reported. Comprehensive pediatric assessment is recommended to look for any additional anomalies.

13. Is life expectancy normal?
    There is no clear evidence that this syndrome, by itself, shortens life expectancy. Most health challenges relate to visual disability, surgical needs for the cleft, and psychosocial impact. Good medical care and rehabilitation can support a long and productive life.

14. How often should eye checks be done?
    For progressive inherited retinal diseases, specialists usually recommend at least yearly exams, and more often in young children, after surgeries, or when symptoms change. The exact schedule is individualized.

15. What is the main message for families?
    Families should know that this condition is nobody’s fault, that multidisciplinary care can greatly improve quality of life, and that research into inherited retinal diseases is rapidly evolving. Early support, honest information, and strong rehabilitation help children grow into confident, independent adults despite visual challenges.

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: January 29, 2025.