Cleft lip and palate-craniofacial dysmorphism-congenital heart defect-hearing loss syndrome is a very rare genetic condition that changes how a baby’s face, mouth, heart, eyes, hands, feet, and ears develop before birth. Children usually have a cleft lip and/or cleft palate, special facial features, a heart defect present from birth, and hearing loss, but their intelligence is usually normal. In this syndrome, the craniofacial dysmorphism means that the bones and soft tissues of the head and face grow in a slightly different shape. Common findings include a high or prominent forehead (frontal bossing), eyes that look wider apart than usual (hypertelorism), a broad flat nasal bridge, cupped or thick-rimmed ears, and a small lower jaw (micrognathia).
Cleft lip and palate–craniofacial dysmorphism–congenital heart defect–hearing loss syndrome is a very rare genetic condition. Children are born with several problems together: a cleft lip and/or cleft palate, unusual facial features, a heart defect present from birth, and partial or full hearing loss. This is called a “multiple congenital anomalies” syndrome.
In many reported families, the cause is a change (mutation) in a gene called HYAL2. This gene helps break down a substance called hyaluronan in connective tissue. When HYAL2 does not work well, facial bones, the upper lip and palate, the heart, and the inner ear may not form in the usual way while the baby is growing in the womb.
Babies can also have different types of congenital heart disease, such as narrowing of major vessels, valve problems, or complex heart defects. These heart problems may cause fast breathing, trouble feeding, poor weight gain, or a heart murmur.
Hearing loss is common and is often conductive, meaning sound cannot travel well through the outer or middle ear, although some children have sensorineural (inner-ear) or mixed hearing loss. This can affect speech and language if it is not found and treated early.
Other features can include a sunken chest (pectus excavatum), differences in the fingers and toes, and eye problems such as short-sightedness (myopia), cataract, or bulging of the back of the eye (staphyloma).
This syndrome is now known to be caused by harmful changes in a gene called HYAL2, which gives instructions for making an enzyme called hyaluronidase-2 that helps break down hyaluronic acid in tissues. When the gene does not work well, normal development of the face, heart, and ears is disturbed.
Because it is so rare, fewer than one in a million people are thought to have this condition worldwide, and most information comes from small numbers of families studied by clinical geneticists.
Other names
Doctors and genetic databases use several other names for this syndrome. All of them point to the same basic pattern of problems.
Some commonly used other names are:
Cleft lip and palate-craniofacial dysmorphism-congenital heart defect-deafness syndrome – this highlights that the hearing problem can be severe enough to cause deafness.
Cleft lip and palate, craniofacial dysmorphism, congenital heart defect, hearing loss syndrome – a shorter way to list the main organs involved.
Hyaluronidase-2 (HYAL2) deficiency – this name focuses on the underlying enzyme problem caused by variants in the HYAL2 gene.
HYAL2-related syndromic cleft lip and palate – this name is often used in research papers that compare different families with HYAL2 variants.
Types
There is only one official syndrome, but doctors sometimes describe different “types” or clinical patterns based on which features are most obvious. These are descriptive groups, not strict separate diseases.
Type 1: Unilateral cleft lip and/or palate pattern
In this pattern, the cleft lip and palate affect mainly one side of the lip and/or the roof of the mouth. The face looks uneven, and hearing loss and heart problems may be milder, but craniofacial features and eye changes are still present.Type 2: Bilateral cleft lip and palate pattern
Here, both sides of the lip and palate are split. Feeding and speech can be more difficult, and surgery often needs several stages. Heart defects, chest shape changes, and hearing loss may be more noticeable.Type 3: Heart-dominant pattern
In some children, the heart defect is very complex and requires early surgery or intensive care, while the cleft and hearing loss are present but less severe. Doctors may first notice the syndrome because of the heart problem.Type 4: Hearing-dominant pattern
A few children have very strong hearing problems (sometimes needing cochlear implants) with clear craniofacial features and a cleft, but only mild heart changes. Audiology teams may be the first to suspect a genetic syndrome.Type 5: Mild craniofacial pattern with subtle internal problems
In other cases, the facial differences and cleft are obvious, but the heart defect is small and the child’s energy and growth are fairly good. Hearing loss may be mild or may appear only after repeated ear infections.Type 6: Severe multi-system pattern
Some families show a very broad combination of problems, with major clefts, serious heart disease, chest and limb abnormalities, marked eye disease, and significant hearing loss. These children need very close, long-term care from many specialists.
Causes
Biallelic HYAL2 loss-of-function variants
The main cause is having two harmful changes (variants) in both copies of the HYAL2 gene, one inherited from each parent. These variants reduce or destroy the function of hyaluronidase-2, leading to abnormal breakdown of hyaluronic acid and disturbing normal tissue formation in the embryo.Autosomal recessive inheritance
The pattern of inheritance is usually autosomal recessive, which means parents who each carry one altered copy of HYAL2 are typically healthy but have a one-in-four chance in each pregnancy to have an affected child with two altered copies.Compound heterozygous HYAL2 variants
Some children have two different harmful variants in HYAL2 (one on each chromosome). This “compound heterozygous” state can still stop the enzyme from working properly and produces the same syndrome features.Founder variants in specific populations
In a few communities, such as some Amish families, one particular HYAL2 variant has been passed down through many generations, so related parents may both carry the same change and have affected children.Missense variants in HYAL2
Missense variants change one amino acid in the hyaluronidase-2 protein. Some of these changes destabilize the enzyme or alter its shape so much that it can no longer break down hyaluronic acid correctly.Nonsense or frameshift variants in HYAL2
Nonsense and frameshift variants can create a shortened, non-functional protein or stop HYAL2 production entirely. This type of variant is often more damaging and is strongly linked with the full clinical syndrome.Reduced HYAL2 protein levels in tissues
Laboratory studies show that many disease-causing variants greatly reduce the amount of HYAL2 protein present in cells. This leads to accumulation of long hyaluronic acid chains and changes how cells in the heart, face, and ear grow and move during development.Abnormal hyaluronic acid turnover during development
Hyaluronic acid helps shape the extracellular matrix, which supports cells as organs form. When hyaluronidase-2 is missing or weak, hyaluronic acid is not broken down at the correct rate, disrupting the sculpting of structures like the palate, nose, and heart chambers in the embryo.Disrupted craniofacial morphogenesis
Animal models with HYAL2 knocked out show abnormal skull and midface development, including submucosal cleft palate and other craniofacial anomalies. This supports the idea that HYAL2 is crucial for shaping the lip and palate.Abnormal heart valve and vessel formation
Studies in humans and mice with HYAL2 deficiency have found complex heart defects, such as extra membranes in the left atrium (cor triatriatum sinister), valve atresia, and abnormal great vessels, showing that improper hyaluronan handling can disturb heart tube remodeling.Defective development of the middle ear and ossicles
Conductive hearing loss in affected children suggests that HYAL2 dysfunction may alter the formation or mobility of the middle ear bones and surrounding tissues, making sound transmission less efficient.Skeletal growth disturbance
Features such as pectus excavatum and digital anomalies indicate that cartilage and bone formation in the chest wall and limbs are also sensitive to hyaluronan balance, which is altered in HYAL2 deficiency.Ocular tissue vulnerability
Myopia, cataract, and staphyloma show that the eye’s connective tissues and lens are also affected. Changes in hyaluronic acid turnover in the eye may weaken certain layers and alter eye shape, increasing risk of retinal problems.Parental carrier status (unaffected carriers)
Parents who carry one altered HYAL2 gene usually have no symptoms. However, their carrier status is a crucial “cause” at the family level, because two carriers together can have affected children if the child inherits both altered copies.Consanguinity (parents who are related)
In some reported families, the parents are related by blood (for example, cousins). This increases the chance that both parents carry the same rare HYAL2 variant, raising the risk of having a child with the autosomal recessive syndrome.De novo HYAL2 variants in a child
Although many cases are inherited, a HYAL2 variant can sometimes arise for the first time in a child (de novo) when neither parent carries it in their blood, which still leads to HYAL2 deficiency if two variants are present or if a single variant affects both copies.Genetic background and modifier genes
Some children in the same family have more severe disease than others, suggesting that other genes which control face, heart, or ear development may modify how strongly HYAL2 deficiency shows itself.Environmental influences on severity (not primary cause)
Maternal health problems (such as poorly controlled diabetes), smoking, alcohol use, certain medicines, and low folate in pregnancy can make congenital anomalies more severe, even though they do not cause HYAL2 mutations themselves.Epigenetic and developmental timing effects
The exact timing of when HYAL2-related pathways fail during early embryonic development may influence which organs are most affected, leading to variation in heart, facial, ear, and eye findings between individuals.Random developmental variation (variable expressivity)
Even with the same HYAL2 variants, children can have different combinations and severities of features, a phenomenon called variable expressivity. This random variation in development is an important reason why the syndrome can look slightly different from one person to another.
Symptoms
Cleft lip
A cleft lip is a gap or split in the upper lip that is present at birth. In this syndrome, the cleft may be on one side or both sides, and it can make feeding more difficult and change the shape of the nose and mouth.Cleft palate
A cleft palate is a split in the roof of the mouth, so that the mouth and nose are connected. This can cause milk or food to leak into the nose, lead to nasal-sounding speech, and increase the risk of ear infections.Frontal bossing (prominent forehead)
Many children have a forehead that looks high or strongly curved forward. This facial feature is part of the craniofacial dysmorphism and helps doctors recognize a possible genetic syndrome.Hypertelorism (wide-spaced eyes)
The eyes may appear wider apart than usual. This is due to differences in skull and midface growth and is often seen together with the broad flat nasal bridge described in this syndrome.Broad, flat nasal bridge
The top part of the nose between the eyes can look wide and flat. This adds to the unique facial appearance and reflects changes in bone and cartilage formation in the midface.Cupped ears or thickened helices
The outer ears may be shaped differently, with the rims of the ears (helices) looking thick, rolled, or cupped. These ear changes often go along with the conductive hearing loss found in this condition.Micrognathia (small lower jaw)
Some children have a smaller than usual lower jaw. This can contribute to feeding difficulties, crowding of teeth, and breathing problems in infancy because the tongue and airway have less space.Congenital heart defects
Heart problems present from birth can include complex malformations of the heart chambers, valves, and major blood vessels. The exact type can vary, but they may cause tiredness, fast breathing, poor feeding, or failure to thrive.Pectus excavatum (sunken chest)
Some children have a chest wall that curves inward, giving a “funnel chest” appearance. This can be mainly cosmetic or, in more severe cases, can affect lung and heart function, especially when combined with a heart defect.Abnormalities of hands and feet
Differences in the fingers and toes, such as unusual shape or mild webbing (syndactyly), may be seen. These features show that skeletal development in the limbs is also influenced by HYAL2 deficiency.Myopia (short-sightedness)
Many affected individuals develop short-sightedness, sometimes quite severe. This means they can see things up close but not far away, and it may require strong glasses and regular eye checks.Cataract and staphyloma
Some patients develop clouding of the eye’s lens (cataract) or bulging of the eye wall at the back of the eye (staphyloma), which can reduce vision and increase the risk of retinal detachment if not monitored.Conductive or sensorineural hearing loss
Hearing loss can be mild to severe and may affect one or both ears. Conductive loss is due to middle ear problems, whereas sensorineural loss involves the inner ear or nerve; both types have been reported in HYAL2 deficiency.Feeding difficulties and poor weight gain in infancy
Because of the cleft lip/palate, small jaw, and heart defects, babies may struggle to suck effectively, tire easily when feeding, and gain weight slowly unless they receive special feeding support.Normal or near-normal intellectual development
Unlike many other multiple anomaly syndromes, most children with this condition have normal or near-normal intelligence, although their learning can still be affected by hearing loss, hospital stays, and communication challenges.
Diagnostic tests
Physical examination tests
Comprehensive newborn and child physical examination
The first and most important step is a full body check-up by a pediatrician or clinical geneticist. The doctor looks at growth, facial shape, hands and feet, chest, heart sounds, breathing, and overall tone to spot the combination of cleft, craniofacial differences, and possible heart problems that suggest this syndrome.Detailed craniofacial examination
A careful head and face exam measures head size, forehead shape, eye spacing, nose structure, jaw size, and ear shape. This helps distinguish HYAL2-related craniofacial dysmorphism from other cleft-related syndromes and guides referrals to cleft and craniofacial teams.Cardiovascular examination with auscultation
The doctor listens to the heart with a stethoscope to detect murmurs, extra sounds, or irregular rhythm, and checks pulses, respiratory rate, and oxygen levels. Abnormal findings raise suspicion of congenital heart disease, which is a key part of this syndrome.Otolaryngology (ENT) and ear examination
An ENT specialist examines the outer ear, ear canal, and eardrum using an otoscope, looking for fluid, structural differences, or chronic infections. This physical exam links ear shape changes to hearing concerns and helps plan further audiology testing.
Manual and bedside functional tests
Feeding and suck-swallow assessment
Nurses and speech-language therapists watch the baby feed, checking how well the lips seal, how the tongue moves, and how the infant breathes during feeds. This hands-on test guides the choice of special bottles, nipples, or feeding positions for cleft-affected babies.Speech and language evaluation
As the child grows, speech-language therapists assess sounds, word use, and sentence formation. For a child with cleft palate and hearing loss, this manual, interaction-based test shows how well they can communicate and whether therapy or devices are needed.Developmental milestone assessment
Clinicians use simple checklists and play-based tests to see how the child is doing in motor skills, social skills, and problem-solving. These bedside assessments help confirm that cognition is usually normal and pick up any delay that might need early intervention.Cardiorespiratory observation during feeding and activity
Nurses and doctors observe the baby’s breathing rate, heart rate, and color during feeding and gentle activity. If the baby becomes sweaty, breathless, or blue, this suggests significant heart disease and drives urgent heart imaging and treatment.
Laboratory and pathological tests
Targeted HYAL2 gene sequencing
A key test is DNA sequencing of the HYAL2 gene from a blood sample. This looks for disease-causing variants in both copies of the gene. Finding biallelic HYAL2 variants confirms the diagnosis and allows family carrier testing and genetic counseling.Broader gene panel or exome sequencing for syndromic clefting
If targeted HYAL2 testing is not available or is negative, doctors may use multi-gene panels or whole-exome sequencing that check many genes linked to clefts, heart disease, and hearing loss. HYAL2 is included in several panels for syndromic orofacial clefting.Chromosomal microarray analysis
This test scans the chromosomes for small deleted or duplicated segments (copy-number changes). It helps rule out other syndromes with cleft palate and heart disease, and can sometimes detect larger changes that include HYAL2 or related pathways.Basic blood tests (complete blood count and biochemistry)
Standard blood tests check for anemia, infection, and organ function. While these tests do not diagnose the syndrome directly, they help judge how sick the child is, whether the heart defect is stressing the body, and whether it is safe to plan surgery.Metabolic and endocrine screening in selected cases
If there are additional concerns about growth, energy, or other organ problems, doctors may test thyroid function, blood sugar, or other metabolic markers. These tests mostly rule out other conditions that could look similar or complicate care.
Electrodiagnostic tests
Electrocardiogram (ECG)
An ECG uses skin electrodes to record the electrical activity of the heart. It can show rhythm problems, chamber enlargement, or conduction delays related to some congenital heart defects, and is often done along with an echocardiogram.Brainstem auditory evoked response (BAER/ABR)
BAER or ABR testing measures how the brainstem responds to clicks or tones played through earphones. It does not depend on the child’s active cooperation, so it is very useful in infants to confirm the level and type of hearing loss caused by this syndrome.Otoacoustic emissions (OAE)
OAE testing places a tiny probe in the ear canal to measure sound waves produced by the inner ear. Abnormal results show that the cochlea is not working normally, supporting the diagnosis of sensorineural or mixed hearing loss when combined with other tests.Electroencephalogram (EEG) in selected cases
Although seizures are not a defining feature, if a child has spells of unresponsiveness or unusual movements, an EEG can check brain electrical activity. This mainly helps rule out other neurodevelopmental syndromes that might mimic aspects of the condition.
Imaging tests
Transthoracic echocardiogram (heart ultrasound)
Echocardiography uses sound waves to create moving pictures of the heart. It shows the chambers, valves, and major vessels in detail, and is the main test to describe the exact congenital heart defect pattern seen in this syndrome and guide surgery.Craniofacial CT scan or 3D imaging
In some cases, surgeons request CT scans or 3D imaging of the skull and face to plan cleft repair and jaw or midface surgery. These images highlight bone differences due to HYAL2-related craniofacial dysmorphism and help plan safe, accurate surgery.Ophthalmologic imaging (retinal photography or ocular ultrasound)
Eye specialists may photograph the retina or use ultrasound to look for staphyloma, retinal thinning, or detachment, especially in patients with high myopia or cataract. These images help protect vision by guiding the timing of eye surgery or laser treatment.Temporal bone CT or MRI for ear structures
When hearing loss is severe or asymmetric, imaging of the temporal bones can show whether the middle and inner ear structures are formed normally. This helps decide if surgery, bone-anchored hearing aids, or cochlear implants are suitable.Prenatal ultrasound and fetal echocardiography (during pregnancy)
In future pregnancies, high-resolution ultrasound and fetal echocardiography can sometimes detect cleft lip, craniofacial differences, and major heart defects before birth. This allows early counseling and planning of delivery in a center with the right specialists.
Non-pharmacological treatments
1. Special feeding support and positioning
Babies with cleft lip and palate often cannot create normal suction, so feeding is hard. Nurses and feeding specialists teach parents how to hold the baby more upright, pace the feeds, and watch for choking or milk in the nose. This reduces tiredness, improves weight gain, and lowers the risk of lung infection from milk going into the airway.
2. Cleft-specific feeding bottles and nipples
Special bottles with soft squeezable chambers and specially cut nipples let milk flow with gentle compression instead of strong suction. Parents can rhythmically squeeze the bottle to match the baby’s swallowing. This non-drug method can turn very poor feeding into safe, efficient feeding and may delay or even avoid the need for tube feeding in some infants.
3. Lactation counselling and breast-milk support
Lactation consultants help mothers express breast milk and, where possible, breast-feed using assistive devices. Even if direct breastfeeding is difficult, breast milk can be given by bottle or feeding tube. Breast milk supports immunity, gut health, and growth, which is very important in babies with heart defects and surgeries ahead.
4. Early speech and language therapy
Cleft palate and hearing loss can make speech unclear. Speech-language therapists begin work very early, sometimes before surgery, to guide parents on sound play, early words, and good communication habits. Later, they help with articulation, resonance (nasal speech), and language skills so the child can be understood at school and in daily life.
5. Hearing aids and audiologic rehabilitation
When there is hearing loss, audiologists fit hearing aids or bone-anchored devices. They regularly test hearing and adjust the devices as the child grows. Training in listening skills helps the brain make the best use of sound. Good hearing is essential to speech, language, and learning, so this is a key non-drug treatment.
6. Family genetic counselling
Genetic counsellors explain how the HYAL2-related syndrome is inherited, the chance of it happening again in the family, and options for prenatal or pre-implantation genetic testing. They also help families cope with guilt, anxiety, and difficult decisions in future pregnancies with clear, evidence-based information and emotional support.
7. Early intervention and developmental therapy
Even if intelligence is often normal, children can have mild delays due to hearing loss, long hospital stays, or frequent surgeries. Early-intervention programs provide physical, occupational, and play therapy. These services stimulate motor skills, language, and social development, aiming to keep the child as close as possible to age-based milestones.
8. Psychosocial and mental health support
Visible facial differences, scars, and hearing problems may lead to low self-esteem or bullying. Psychologists and social workers can provide counselling for the child and family. They teach coping skills, help manage stress around surgeries, and support healthy body image and social confidence during school years.
9. Educational support and classroom accommodations
Children with hearing loss or frequent hospital visits may struggle in school. Teachers can offer front-row seating, use of FM systems (microphones), written notes, and flexible deadlines. A special education plan can ensure the child hears the teacher well, keeps up with lessons, and has time to recover from surgeries without falling behind.
10. Cardiac rehabilitation and safe physical activity planning
Pediatric cardiologists and physiotherapists assess the child’s heart function and guide safe levels of exercise. They may design light activity programs that build endurance without overloading the heart. This non-drug approach supports heart health, reduces fatigue, and promotes overall fitness and confidence in movement.
11. Airway and sleep-position management
Some babies with craniofacial dysmorphism and micrognathia (small chin) have breathing problems, especially when lying flat. Positioning strategies, such as side-lying or semi-upright sleeping as advised by doctors, and monitoring for snoring or pauses in breathing, help reduce the risk of obstructive sleep apnoea and low oxygen levels at night.
12. Regular dental and orthodontic care
Cleft lip and palate often affect tooth position and enamel quality. Dentists and orthodontists monitor dental growth, guide tooth eruption, and plan braces or other devices to correct bite and jaw alignment. Good oral hygiene support and fluoride treatments help prevent cavities and gum disease, which are common in syndromic cleft conditions.
13. Nutritional counselling and growth monitoring
Dietitians track weight, length/height, and head growth. They adjust calorie intake, texture, and feeding schedules to support healthy growth before and after surgeries. This may include higher-calorie milk, extra feeding sessions, or temporary use of feeding tubes, always individualised to the child’s needs and medical status.
14. Parent training and support groups
Parents learn medical terms, home-care skills, and how to advocate for their child in schools and hospitals. Support groups connect families who are facing similar issues with cleft, heart defects, and hearing loss. Sharing experiences reduces isolation and provides practical tips that cannot be found in textbooks.
15. Infection prevention routines
Because children with heart defects can have higher risk from certain infections, families are taught good hand-washing, dental hygiene, timely vaccines, and when to seek care for fevers or breathing problems. These simple, daily habits are a powerful non-drug treatment to avoid serious complications like pneumonia or infective endocarditis.
16. Assistive communication tools
If speech is severely affected, the child may use sign language, picture boards, or communication apps, especially in early years. These tools let the child express needs and feelings, reducing frustration and supporting language development while speech is still forming or while hearing is being optimised.
17. Social skills training
Some children with complex medical conditions become shy or anxious around peers. Structured social skills groups teach turn-taking, conversation skills, and how to answer questions about scars or devices in a calm way. This reduces bullying impact and helps the child build friendships and confidence in social settings.
18. Transition planning for adolescence and adulthood
As the child grows, the care team helps them move from pediatric to adult services. Education about self-care, medication understanding, safe exercise, pregnancy risks (for future adults), and mental health is provided in simple language. The goal is independent, confident self-management of this lifelong condition.
19. Vocational guidance and career counselling
Teens and young adults may worry that scars, hearing devices, or heart limits will block job options. Vocational counsellors explain rights at work, reasonable accommodations, and suitable careers. This non-drug support helps young people set realistic but hopeful education and employment goals.
20. Spiritual and cultural support
Some families draw strength from religious or cultural communities. Hospital chaplains or community leaders may support families during long hospital stays or difficult decisions about surgery. Respecting these values and including them in care plans can reduce stress and improve coping with a rare, serious condition.
Drug treatments
⚠️ Very important: The drugs below are examples used for problems commonly seen in this syndrome (heart defects, infections, pain, etc.). Exact medicine, dose, timing, and combinations must always be chosen by a pediatric specialist who knows the child’s full history.
1. Diuretics such as furosemide
Furosemide is a “water tablet” that helps remove extra fluid from the body. In children with heart failure from congenital heart disease, it reduces lung congestion and swelling. It is a loop diuretic. Doses are carefully adjusted by weight, and side effects can include dehydration, low blood pressure, and changes in blood salts and kidney function.
2. ACE inhibitors (for example, enalapril)
ACE inhibitor drugs relax blood vessels and reduce the workload on the heart. In children with certain heart defects or heart muscle weakness, they can improve pumping efficiency. They are given by mouth at specialist-determined doses, with monitoring for low blood pressure, kidney effects, and high blood potassium.
3. Beta-blockers (for example, propranolol or carvedilol)
Beta-blockers slow the heart rate and reduce oxygen demand. They may be used in some forms of congenital heart disease or arrhythmia. They are usually given two or more times a day. Side effects can include tiredness, low heart rate, low blood pressure, and, rarely, breathing problems in susceptible children.
4. Digoxin
Digoxin is a cardiac glycoside used in some infants with heart failure or arrhythmias. It increases the strength of heart contractions and can help control certain abnormal rhythms. Because it has a narrow safety range, doctors carefully adjust the dose by weight and monitor blood levels and signs of toxicity such as vomiting or rhythm changes.
5. Low-dose aspirin (antiplatelet use)
Some children with repaired heart defects, shunts, or other risk factors may receive low-dose aspirin to reduce the chance of blood clots. It works by reducing platelet “stickiness.” Doctors balance benefits with risks such as stomach irritation or bleeding, and they avoid it in certain viral illnesses because of Reye’s syndrome risk.
6. Other anticoagulants (for example, warfarin or heparins)
In more complex heart repairs or artificial valves, stronger blood thinners may be needed. Warfarin and heparins reduce clotting but raise bleeding risk. Children on these drugs need frequent blood tests and careful monitoring of bruising, nosebleeds, or other bleeding signs under specialist care.
7. Palivizumab (RSV prophylaxis)
Palivizumab is a monoclonal antibody given by monthly injection during RSV season to high-risk infants, including some with congenital heart disease. It does not treat RSV but lowers the chance of severe RSV lung infection and hospitalisation. Main side effects are injection-site reactions and rare allergic responses.
8. Routine vaccines and catch-up immunisations
Standard childhood vaccines (such as those against measles, polio, pneumococcus, and influenza) are drug products used to train the immune system to prevent infection. Following the national schedule is especially important for children with heart disease, surgery history, or syndromic conditions. Side effects are usually mild, such as fever or soreness at the injection site.
9. Antibiotics for infections and endocarditis prevention
Children with heart defects and cleft palate can be prone to ear infections, chest infections, or, rarely, infection of the heart lining (endocarditis). Antibiotics like amoxicillin or others are chosen based on infection type and guidelines. Overuse can cause resistance or gut upset, so they are used only when truly needed.
10. Peri-operative antibiotics
Around the time of cleft, craniofacial, or cardiac surgery, short courses of antibiotics are often used to reduce the risk of wound or bloodstream infections. The choice of drug depends on the hospital protocol and likely germs. Doctors limit the duration to reduce side effects and drug resistance.
11. Analgesics such as paracetamol (acetaminophen)
Pain control after surgery is essential for breathing, feeding, and healing. Paracetamol is often the first-line pain reliever in children because it has few side effects when used at correct doses. Overdose can harm the liver, so parents must follow the doctor’s instructions exactly and avoid double-dosing with combination products.
12. Opioid analgesics (for example, morphine in hospital)
After major heart or craniofacial surgery, stronger pain relief may be needed for a short time. Opioids like morphine are carefully dosed and monitored in hospital to keep the child comfortable while minimising side effects such as constipation, nausea, drowsiness, or slowed breathing. They are usually tapered and stopped as soon as possible.
13. Acid-suppressing drugs (proton pump inhibitors or H2-blockers)
Some babies with cleft palate and heart disease have reflux, which can worsen feeding problems and risk of aspiration. Acid-suppressing medicines reduce stomach acid and can ease discomfort. Long-term use requires medical review because of possible effects on nutrient absorption and gut microbiome.
14. Iron supplements for anaemia
Repeated surgeries, poor intake, or chronic illness can lead to iron-deficiency anaemia. Liquid or tablet iron supplements help rebuild haemoglobin so the blood can carry oxygen better. Side effects can include dark stools, stomach upset, or constipation. Doctors confirm anaemia by blood tests before starting treatment.
15. Vitamin D and calcium supplements
Limited sunlight, feeding issues, or special diets may reduce vitamin D and calcium intake, which are important for bone and tooth health. Supplements are given in age-appropriate doses and monitored by blood tests. They support growth and healing, especially when children are less active due to heart problems.
16. Diuretics other than furosemide (for example, spironolactone)
Sometimes a second diuretic is added to control fluid in difficult heart failure. Spironolactone helps the body remove salt and water while keeping potassium. Doctors closely monitor blood tests because it can cause high potassium and changes in hormone-related effects such as breast tenderness.
17. Inotropic support (for example, milrinone in hospital)
After heart surgery or in severe heart failure, drugs that increase heart pumping strength and relax blood vessels may be given by drip in intensive care. They are short-term supports to stabilise the child until the heart recovers or further surgery is done. Continuous monitoring is essential due to rhythm and blood-pressure risks.
18. Diuretic combinations for complex cases
Some children need carefully designed combinations of diuretics and other heart medicines. This is highly individual and managed only by pediatric cardiology teams. Regular weight checks, blood tests, and kidney monitoring are necessary to balance benefits and side effects and to adjust therapy as the child grows.
19. Sedatives and anaesthetic agents for procedures
Children with this syndrome often need repeated imaging, hearing tests, and surgeries. Anesthesiologists select sedative and anaesthetic drugs based on heart status and airway anatomy. These drugs work by temporarily blocking awareness and pain, and they are used under strict monitoring to keep breathing and circulation safe.
20. Emergency drugs for arrhythmias or acute heart problems
If abnormal heart rhythms occur, emergency drugs may be needed in hospital. These medicines act on the electrical system of the heart to restore a safe rhythm. Doses and choices depend on the exact rhythm problem and guidelines, and treatment always occurs under continuous heart monitoring.
Dietary molecular supplements
⚠️ Supplements do not cure this syndrome. They may support general health but can interact with medicines. Always check with the child’s cardiologist and pediatrician.
1. Omega-3 fatty acids (fish-oil based)
Omega-3 fats from fish oil can support heart and blood vessel health and may help reduce inflammation. Typical children’s doses are weight-based, guided by a doctor or dietitian. They work by being incorporated into cell membranes and altering inflammatory pathways. Possible side effects include fishy aftertaste and, at higher doses, mild effect on bleeding time.
2. Vitamin D
Vitamin D helps the body absorb calcium and supports bones, teeth, and immune function. Many children with chronic illness or low sunlight exposure have low levels. Supplement dose depends on age and blood results. Vitamin D acts through nuclear receptors that control calcium-handling genes. Excessive doses can cause high calcium and kidney problems.
3. Calcium
Calcium is vital for bone growth, tooth development, and heart and muscle contraction. If dietary intake is low or if vitamin D is low, supplements may be used. They provide ionised calcium that enters bone and cell signalling pathways. Too much calcium can cause constipation, kidney stones, or interference with absorption of other minerals.
4. Iron
Iron supports haemoglobin production in red blood cells. In children with frequent surgeries or poor feeding, iron deficiency is common. Supplementation replaces lost iron and improves oxygen delivery. It works by providing the core metal for haemoglobin and enzymes. Over-supplementation can be toxic, so dosing is strictly based on blood tests.
5. Folate (folic acid)
Folate is needed for DNA synthesis and red blood cell production. Adequate folate is also important for future pregnancies in the family, because low folate is linked to some birth defects. Supplements act as cofactors in one-carbon metabolism. Too much folic acid can mask B12 deficiency, so professional advice is important.
6. Vitamin B12
Vitamin B12, together with folate, supports blood cell production and nerve health. Deficiency can cause anaemia and nerve symptoms. In children with restricted diets, B12 supplements may be needed. They work by supporting DNA synthesis and myelin formation. Over-supplementation is usually well tolerated but still should be monitored.
7. Zinc
Zinc is important for growth, wound healing, and immune function. Poor intake or chronic illness can reduce zinc levels. Supplements help many enzyme systems and support skin and mucosal healing after cleft or cardiac surgery. Too much zinc can cause nausea and interfere with copper absorption.
8. Probiotics
Probiotics are “good bacteria” given as drops, powders, or capsules. They may help balance the gut microbiome, especially in children who have had many antibiotics or hospital stays. They work by competing with harmful bacteria and supporting gut barrier and immune signalling. Product choice and dose should be discussed with the care team.
9. High-calorie oral nutritional supplements
When weight gain is poor, high-calorie milk or drink formulas provide extra protein, fat, and micronutrients in small volumes. They are designed to be energy-dense so the child can grow even with limited intake. They act simply by increasing net energy and nutrient availability for tissue growth and healing.
10. Multivitamin/mineral preparations
A carefully chosen multivitamin can fill small nutrient gaps in children with restricted or selective diets. These products combine vitamins and minerals in doses close to daily requirements. They support many metabolic pathways but should not replace a varied diet. Excess or overlapping products can cause overdose of fat-soluble vitamins.
Immunity-booster, regenerative, and stem-cell–related drugs
⚠️ Many “regenerative” or stem-cell therapies advertised online are unproven or unsafe. Only treatments within clinical trials or recognised guidelines should be considered.
1. Routine childhood vaccines (immune priming)
The safest and most effective “immune boosters” are standard vaccines. They train the immune system to recognise specific germs so future infections are milder or prevented. For children with heart defects or frequent hospital stays, vaccines like influenza and pneumococcal are especially important and act through long-lasting memory immune cells.
2. Palivizumab for RSV prevention
As noted above, palivizumab is a monoclonal antibody given to high-risk infants with congenital heart disease. It acts like ready-made immune protection against RSV until the infant’s immune system is stronger. It is not a general “booster” but a targeted preventive drug used only in specific seasons and risk groups.
3. Intravenous immunoglobulin (IVIG)
IVIG is a purified antibody product from many donors. In selected immune problems or after certain infections, it can support the immune system by providing broad antibodies. It is given by infusion in hospital and monitored for reactions like fever, headache, or rare kidney issues. It is not routine in this syndrome but may be used in specific complications.
4. Granulocyte-colony stimulating factor (G-CSF) in special cases
If a child develops severe low white-blood-cell counts (for example, after intensive treatments or infections), G-CSF may be used to stimulate the bone marrow to make more neutrophils. It acts on marrow stem cells to speed maturation. It is given only under specialist supervision because it can cause bone pain and other side effects.
5. Experimental gene or enzyme-replacement therapies (research setting)
Because this syndrome is linked to HYAL2 deficiency, researchers are interested in ways to restore normal enzyme activity, such as gene therapy or enzyme replacement. At present, these approaches are experimental and only available in clinical trials, where doses, safety, and long-term effects are carefully studied.
6. Hematopoietic stem-cell transplantation (HSCT) in rare, severe scenarios
Stem-cell transplantation replaces the bone marrow with donor cells. It is not standard for this syndrome, but in rare individuals with overlapping serious bone-marrow problems, HSCT might be considered. It works by giving donor stem cells that rebuild blood and immune systems. Risks include infections, graft-versus-host disease, and organ damage, so it is used only when benefits clearly outweigh risks.
Surgeries (5 main procedures and why they are done)
1. Cleft lip repair (cheiloplasty)
This surgery closes the split in the upper lip, usually within the first few months of life. Surgeons realign the muscle and skin to create a more normal lip shape and function. The goals are better feeding, improved facial appearance, and support for normal speech and dental development later in life.
2. Cleft palate repair (palatoplasty)
Palatoplasty closes the opening in the roof of the mouth, often between 9 and 18 months of age. The surgeon reconstructs muscles of the soft palate so it can close properly during speech and swallowing. This reduces nasal speech, helps food and drink stay out of the nose, and lowers the risk of recurrent ear infections.
3. Craniofacial reconstructive surgery
Because this syndrome includes craniofacial dysmorphism, some children need surgery on the jaw, cheekbones, or forehead. These procedures aim to improve airway, bite alignment, eye protection, and facial balance. They are often staged over several years and planned with 3D imaging and a multidisciplinary craniofacial team.
4. Cardiac surgery or catheter-based interventions
Many children have congenital heart defects such as holes between chambers or abnormal valves. Cardiac surgeons or interventional cardiologists repair or palliate these defects to improve blood flow and oxygen delivery. Successful heart surgery can greatly improve growth, energy, and long-term survival but carries risks that are carefully discussed with families.
5. Ear surgery, grommet insertion, or cochlear implantation
For chronic middle-ear fluid and infections, small tubes (grommets) may be placed in the eardrum to improve hearing. In more severe sensorineural hearing loss, cochlear implants may be considered. These devices directly stimulate the hearing nerve, helping the child develop listening and spoken language skills.
Prevention strategies
Pre-pregnancy folate and general maternal health care – Adequate folic acid and good control of maternal illnesses may reduce risks of some birth defects, though they cannot fully prevent this genetic syndrome.
Genetic counselling for families with a known HYAL2 mutation – Offers information on recurrence risk and options like prenatal or pre-implantation genetic testing.
Avoidance of harmful drugs, alcohol, and tobacco in pregnancy – Reduces additional risk to the baby’s growth and organ development.
Early and regular antenatal care – Allows detection of congenital anomalies by ultrasound and planning of delivery in a specialised centre.
Timely newborn screening and hearing tests – Ensures early hearing support and intervention, which is critical for language development.
Complete routine vaccination – Prevents serious infections that would be especially dangerous in children with heart disease.
Good dental and oral hygiene – Lowers the risk of dental infections and possibly endocarditis in susceptible heart conditions.
Healthy weight and nutrition – Helps the child face surgeries and recover better, reducing complications linked to malnutrition.
Avoiding second-hand smoke exposure – Protects the lungs and reduces respiratory infections that stress the heart.
Regular follow-up with the multidisciplinary team – Prevents small problems from becoming big ones and allows timely adjustments in treatment plans.
When to see doctors urgently
Parents or caregivers should seek urgent medical care if the child has trouble breathing, fast breathing, blue or grey lips or tongue, poor feeding with very few wet nappies, repeated vomiting, high fever, seizures, sudden worsening of swelling, or if they seem unusually sleepy or hard to wake. These signs can mean serious heart, lung, or infection problems.
Regular, non-urgent visits are also important for scheduled heart checks, hearing tests, dental visits, growth monitoring, and review with the cleft/craniofacial team. Even if the child seems well, these planned visits help keep development on track and detect silent complications early.
What to eat and what to avoid
Eat energy-dense foods – For children with poor weight gain, small but high-calorie feeds, as guided by a dietitian, help growth.
Use safe textures – Soft, smooth textures reduce choking risk in children with palate problems.
Include protein in each meal – Eggs, dairy, legumes, fish, or meat support healing and muscle growth.
Offer fruits and vegetables daily – Provide vitamins, minerals, and fibre for immunity and gut health.
Ensure enough fluids – Adequate water or milk prevents dehydration, especially when on diuretics.
Limit very salty processed foods – Excess salt can worsen fluid retention in children with heart disease.
Avoid sugary drinks and excessive sweets – Protects teeth and helps maintain a healthy weight.
Avoid alcohol (for older teens and adults) – Alcohol can strain the heart and interact with medicines.
Be careful with “natural” supplements without medical advice – Some herbs can affect the heart or interact with drugs.
Follow any special feeding or fluid instructions from the cardiologist or surgeon – Individual needs may differ after operations or with certain heart defects.
Frequently asked questions
1. Is this syndrome caused by something parents did wrong?
No. This syndrome is genetic and linked to changes in the HYAL2 gene. Parents do not cause the mutation by anything they did or did not do during pregnancy. Genetic counselling can explain inheritance patterns and recurrence risk in simple terms.
2. Can cleft lip and palate be completely fixed?
Cleft lip and palate can be surgically repaired, and many children eat and speak well after staged surgeries and speech therapy. However, some may still have mild differences in facial appearance, nasal speech, or dental alignment that need ongoing follow-up.
3. Will my child’s heart problem go away after surgery?
Heart surgery often greatly improves blood flow and symptoms, but some children still need medicines or later procedures. Lifelong cardiology follow-up is usually recommended, because repaired hearts can still have rhythm or valve issues later in life.
4. Does this syndrome always cause learning problems?
Most reports describe normal or near-normal intelligence, but hearing loss, long hospital stays, and speech issues can affect school performance. Early hearing support, speech therapy, and educational accommodations give the child the best chance to reach their full potential.
5. Can my child go to a regular school?
Many children with this syndrome attend regular schools, especially with early support and reasonable accommodations, such as seating near the teacher, FM systems, and extra time for homework after surgeries. Decisions are individual and based on the child’s needs and strengths.
6. Will future pregnancies have the same problem?
Recurrence risk depends on the exact gene change and inheritance pattern. Genetic testing and counselling are important to give accurate numbers. Some families may choose prenatal or pre-implantation genetic testing in future pregnancies.
7. How long will my child live?
Life expectancy depends mainly on the type and severity of the heart defect and how well it can be treated. With modern cardiac care, many children with complex heart disease survive into adulthood, but they often need lifelong follow-up and healthy lifestyle habits.
8. Is there a cure for the genetic cause?
At present, there is no cure for the underlying HYAL2 gene change. Treatment focuses on repairing structural problems, supporting development, and preventing complications. Research into gene and enzyme therapies is ongoing but still experimental.
9. Can alternative medicine cure this condition?
No alternative therapy has been proven to cure this syndrome or fix clefts or heart defects. Some complementary methods (like relaxation or gentle massage) may help with stress, but all herbal or “natural” treatments must be checked with the care team for safety.
10. Will my child need many operations?
Often yes. Children may need several surgeries for the lip, palate, jaw, heart, and ears as they grow. The team tries to spread out procedures to allow recovery and normal development between operations while still fixing important problems at the safest times.
11. Can my child play sports?
Many children can join light to moderate physical activities, depending on their heart status. The cardiologist will advise which sports are safe and which should be avoided. Activity is encouraged when possible because it supports heart health, mood, and social life.
12. How can I protect my child from infections?
Good hand-washing, keeping up with vaccines, avoiding smoking exposure, and seeking early care for fevers or breathing problems are key. In some high-risk infants, special RSV prophylaxis like palivizumab may be used during certain seasons.
13. Will facial scars be very noticeable?
Modern cleft and craniofacial surgery techniques aim to place scars along natural lines and minimise visibility. Over time, scars usually fade. Later procedures, scar care, and sometimes laser treatments can further improve cosmetic results.
14. Can hearing loss get worse over time?
Some types of hearing loss are stable, while others may progress. Regular hearing tests are vital to track changes and adjust hearing aids or consider cochlear implants if hearing declines. Prompt treatment of ear infections also helps protect hearing.
15. Where can families find support and information?
Rare-disease organisations, cleft and craniofacial teams, cardiac support groups, and hearing-loss associations provide reliable information, peer support, and advocacy. Many families find it helpful to connect with others who understand daily life with a rare, multi-system condition.,
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 28, 2025.
