Cleft lip and palate–craniofacial dysmorphism–congenital heart defect–deafness (hearing loss) syndrome is a very rare genetic condition. It affects how the face, heart, and ears form before birth. Children usually have a cleft lip and/or cleft palate, unusual facial shape, a heart defect present from birth, and some degree of hearing loss.
Cleft lip and palate-craniofacial dysmorphism-congenital heart defect-deafness syndrome (also called hyaluronidase-2 deficiency) is a very rare genetic condition. Children are born with cleft lip and/or palate, unusual facial features, heart defects, and permanent hearing loss, but usually normal intelligence. [1] The main cause is harmful changes (mutations) in the HYAL2 gene. This gene normally helps break down hyaluronan, a substance in connective tissue. When HYAL2 does not work properly, tissues in the face, heart, and inner ear do not form normally during early pregnancy, leading to the typical combination of problems. [2]
This syndrome belongs to a group of “multiple congenital anomalies” conditions, which means several organs are affected at the same time. Most reported families show no intellectual disability, so thinking and learning can be close to normal, but some children may still need extra support because of hearing, speech, or medical complications.
Researchers have shown that the main cause is a harmful change in a gene called HYAL2. This gene makes an enzyme called hyaluronidase-2, which helps break down a sugar called hyaluronan in the body. When HYAL2 does not work well, hyaluronan builds up, and this disturbs normal development of the face, heart, ears, eyes, and skeleton.
Because this disease is so rare, doctors are still learning about its full spectrum. However, the core pattern of cleft lip/palate, special craniofacial features, congenital heart disease, and hearing loss is now well recognized in people who have two faulty copies of the HYAL2 gene.
Other names
Doctors and researchers use several names for this condition. These names all describe the same basic syndrome:
Cleft lip and palate–craniofacial dysmorphism–congenital heart defect–hearing loss syndrome
Cleft lip and palate–craniofacial dysmorphism–congenital heart defect–deafness syndrome
Cleft lip and palate, craniofacial dysmorphism, congenital heart defect, hearing loss syndrome
Hyaluronidase 2 deficiency
HYAL2 deficiency syndrome
These alternative names appear in rare-disease databases such as Orphanet, GARD, and MalaCards, and all are linked to disease code ORPHA508476 and the HYAL2 gene.
Types
Experts do not have strict official “types,” but clinical reports show patterns that can be grouped into practical subtypes.
Classic full syndrome pattern
In the classic pattern, a child has a cleft lip and/or cleft palate, very characteristic facial features, a structural heart defect, and permanent hearing loss. This combination is the most typical presentation described in families and case series of HYAL2 deficiency.Craniofacial–cardiac dominant pattern
Some children have very clear facial differences and a significant heart defect, but their hearing loss may be milder or appear later. The cleft lip or palate can still be present, but cardiology issues are more prominent in these cases.Craniofacial–hearing dominant pattern with mild heart disease
In other children, the most obvious problems are the cleft lip/palate, facial features, and hearing loss. The heart defect may be small (for example a small ventricular septal defect) or may even be found only on detailed imaging and cause few symptoms early in life.Mild or incomplete form
A few people may have only part of the syndrome, such as a cleft palate and distinctive facial features, but no major heart defect, or only subtle hearing loss. In these milder cases, careful genetic testing can still show changes in HYAL2, and the pattern is considered part of the same spectrum.
Causes
First, it is important to say clearly: the main direct cause of this syndrome is a genetic change in the HYAL2 gene. The 20 “causes” below describe the different parts of that genetic cause, biological mechanisms, and risk factors that influence how and when the syndrome appears.
Biallelic HYAL2 pathogenic variants
Most patients have harmful variants in both copies of their HYAL2 gene (one from each parent). When both copies carry damaging changes, the cell cannot make enough normal HYAL2 enzyme, which leads directly to the syndrome.Loss of HYAL2 enzyme activity
HYAL2 normally breaks down hyaluronan, a large sugar molecule in the extracellular matrix. Disease-causing variants reduce or almost abolish the enzyme’s activity, so hyaluronan is not cleared properly from tissues during development.Accumulation of hyaluronan in tissues
When HYAL2 does not work, hyaluronan accumulates around cells. In animal models, this build-up is seen in many organs and is linked to changes in heart structure, craniofacial bones, and other tissues, helping explain the malformations in affected children.Disrupted extracellular matrix in the developing face
The face forms from small cell groups that must move and fuse in precise ways. Abnormal hyaluronan levels disrupt the extracellular matrix scaffold around these cells, which can prevent complete fusion of the upper lip and palate, leading to cleft lip and/or cleft palate.Abnormal neural crest cell migration
Many craniofacial structures and parts of the heart arise from neural crest cells. Studies of HYAL2-deficient animals suggest that disturbed hyaluronan turnover may interfere with the migration and differentiation of these cells, contributing to distinctive facial features and heart defects.Defective heart cushion and valve formation
During early heart development, cushions of mesenchymal cells form the valves and septa. HYAL2 deficiency is linked to expansion of these mesenchymal cell populations and abnormal cushion remodeling, helping explain findings such as ventricular septal defects and unusual valve or atrial anatomy.Cardiac mesenchymal overgrowth and heart failure risk
In mouse models, HYAL2 deficiency causes marked overgrowth of mesenchymal cells in the heart, leading to thickened valves, atrial enlargement, and heart failure. These findings support the idea that similar mechanisms underlie congenital heart disease in human patients.Abnormal development of the ear and hearing pathway
HYAL2 is expressed in tissues that form parts of the ear. Many affected people have external ear anomalies, middle-ear problems, and hearing loss, suggesting that disturbed hyaluronan processing also alters the structure or function of the hearing system.Autosomal recessive inheritance
The syndrome usually follows an autosomal recessive pattern: both parents carry one faulty HYAL2 copy, but are healthy. A child who inherits both faulty copies (one from each parent) will usually develop the syndrome.Parental carrier status
Carrier parents have one normal and one mutated HYAL2 gene copy. When both parents are carriers, with each pregnancy there is a 25% chance the baby will inherit both mutated copies and be affected. Carrier testing in families can clarify this risk.Consanguinity (parents related by blood)
In several reported families, the parents are related (such as cousins). In such families, the chance that both parents carry the same rare HYAL2 variant is higher, increasing the likelihood of an affected child.Founder HYAL2 variants in specific populations
Some populations, such as certain Amish communities, share a single “founder” HYAL2 variant that has been passed down through many generations. This can lead to more cases of the syndrome within that group compared with the general population.Compound heterozygous HYAL2 variants
In other families, a child inherits two different disease-causing HYAL2 variants, one from each parent. Even though the variants are not identical, together they severely reduce HYAL2 function and cause the same clinical picture.Possible genetic heterogeneity in related phenotypes
Some people may show a similar combination of clefting, craniofacial differences, heart defects, and hearing loss due to changes in genes other than HYAL2, but with overlapping developmental pathways. In such cases, the phenotype can look like this syndrome, even when HYAL2 is normal.Modifier genes affecting severity
Even when HYAL2 is the main cause, other genes that control facial, cardiac, and ear development can modify how severe the features are. This may help explain why some people have life-threatening heart disease, while others have milder defects.Maternal smoking and toxic exposures in early pregnancy
In general, maternal smoking and certain toxins increase the risk of orofacial clefts and heart defects. While they do not cause HYAL2 variants, they may worsen the expression or severity of clefting and cardiac disease in genetically susceptible embryos.Maternal diabetes or obesity
Poorly controlled diabetes and obesity in pregnancy are known risk factors for congenital heart defects and clefts. In a baby with HYAL2 deficiency, these factors might add extra stress on development, possibly increasing the complexity of malformations.Teratogenic medicines in early pregnancy
Some drugs, such as isotretinoin and certain anti-seizure medicines, can cause craniofacial and heart defects. If a fetus also has HYAL2 deficiency, the combination of genetic and environmental insults could lead to more severe anomalies.Low folate and poor prenatal nutrition
Low folate intake is linked to a higher risk of clefts and other birth defects. Good folate status cannot prevent HYAL2 mutations, but may reduce additional malformation risk in the general population and possibly lessen the background risk in families with genetic susceptibility.Advanced paternal age and new gene changes
New (de novo) gene changes occur more often with older paternal age. Although most reported HYAL2 cases are inherited, de novo variants are possible, and advanced paternal age may slightly increase that chance.
Symptoms
Cleft lip
Many babies are born with a gap in the upper lip, which may be on one side or both sides. This cleft can affect feeding, appearance, and speech sounds later on, and usually requires surgical repair in the first months of life.Cleft palate
A cleft in the roof of the mouth can allow milk to leak into the nose and makes it hard to build pressure for clear speech. Palate repair surgery and special feeding techniques are often needed in infancy and early childhood.Broad, flattened nasal bridge
Many patients have a broad and flat bridge of the nose. This facial feature is very common in HYAL2 deficiency and helps specialists recognize the syndrome when combined with other signs.Hypertelorism (wide-spaced eyes)
The eyes may sit farther apart than average. This wide spacing contributes to the distinctive craniofacial appearance that geneticists describe in their clinical reports of the condition.Micrognathia (small lower jaw)
Some children have a small, receding lower jaw. This can narrow the airway, cause breathing and feeding difficulties, and may later need orthodontic or surgical correction.External ear abnormalities
The outer ears may be unusually shaped or positioned. These ear anomalies often go together with hearing loss and encourage early referral to ear, nose, and throat (ENT) and audiology specialists.Congenital heart defects
Many affected babies have structural heart problems, such as ventricular septal defects, tetralogy of Fallot, or rare defects like cor triatriatum. The exact type can vary, but heart disease is a key part of the syndrome.Signs of heart failure in infancy
When the heart defect is significant, babies may breathe fast, sweat with feeds, turn dusky or blue, or fail to gain weight. These signs show that the heart is struggling and need urgent evaluation by pediatric cardiology.Hearing loss (sensorineural and/or conductive)
Many children have reduced hearing. Some have inner-ear (sensorineural) loss, others mainly middle-ear (conductive) problems, and some have both. Without early screening and hearing aids or other support, speech and language can be delayed.Frequent ear infections and middle-ear fluid
Children with cleft palate are prone to fluid behind the eardrum and recurrent ear infections. In this syndrome, those issues can add to permanent hearing loss and may require ear tubes and close ENT follow-up.Myopia and other eye problems
Nearsightedness (myopia) is very common in HYAL2 deficiency, and some patients have additional eye abnormalities. Regular eye exams are important to preserve vision and support learning.Chest wall differences (such as pectus excavatum)
Some individuals have a sunken chest (pectus excavatum) or other chest wall changes. This feature is reported in several cases and may slightly affect breathing or exercise tolerance in combination with heart disease.Growth delay or failure to thrive
Feeding difficulty, heart strain, and frequent illnesses can lead to poor weight gain and slower growth in infancy and early childhood. With proper medical and nutritional support, many children can catch up over time.Speech and language delay or nasal-sounding speech
The cleft palate and hearing loss together often cause speech problems. Children may have a nasal voice and trouble making certain consonant sounds, and they benefit from early and ongoing speech-language therapy.Psychosocial and learning challenges
Even when intelligence is in the normal range, repeated surgeries, visible facial differences, hearing issues, and speech problems can affect school performance, confidence, and social life. Emotional and educational support are therefore important parts of care.
Diagnostic tests
Doctors use many tests to confirm the diagnosis, understand how the syndrome affects the child, and plan treatment. Below are 20 important tests, grouped into physical exam, manual/clinical tests, lab and pathological tests, electrodiagnostic tests, and imaging tests.
Physical exam–based tests
Comprehensive newborn and general physical exam
Soon after birth, a pediatrician examines the baby from head to toe. They look for cleft lip or palate, facial shape, heart murmurs, breathing pattern, and any other unusual features. This first exam often raises the initial suspicion of a syndromic condition.Detailed craniofacial and oral examination
A craniofacial team carefully inspects the face, mouth, jaw, and teeth (when they appear). They classify the cleft, note nasal bridge shape, jaw size, and other facial signs that match the known HYAL2-related pattern.Cardiovascular examination
The clinician listens to the heart for murmurs, feels pulses, and checks for signs of heart failure such as fast breathing, enlarged liver, or swelling. This bedside exam helps decide how urgent heart imaging and treatment need to be.Ear, nose, and throat (ENT) examination with otoscopy
The ENT specialist examines the ears, nose, and throat, looking at the eardrum with an otoscope and assessing nasal airflow and palate movement. This exam screens for structural ear problems and airway concerns related to the syndrome.
Manual / clinical functional tests
Feeding and swallowing assessment
A speech or feeding therapist watches the baby feed and may feel how the jaw and tongue move. They look for choking, nasal regurgitation, or poor suck, and then suggest special bottles, positioning, or textures to keep feeding safe and efficient.Growth and nutritional assessment using growth charts
Doctors measure weight, length/height, and head size regularly and plot them on growth charts. Slow growth can signal feeding problems or heart strain, and this manual chart review guides decisions about extra calories, tube feeds, or timing of surgery.Developmental and neurologic screening exams
Simple hands-on tests, such as checking muscle tone, reflexes, and age-appropriate milestones (sitting, walking, talking), help identify any developmental delays. While many children have normal cognition, early screening ensures timely therapies if delays are present.Behavioral hearing assessment (age-appropriate audiology)
Audiologists use play-based methods like visual-reinforcement or conditioned-play audiometry to see how a child responds to sounds. These manual, interactive tests help measure hearing levels and guide decisions about hearing aids or other devices.
Lab and pathological tests
HYAL2 gene sequencing
A blood or saliva sample is used for DNA testing focused on the HYAL2 gene. Finding two disease-causing HYAL2 variants confirms the genetic diagnosis and distinguishes this syndrome from other craniofacial-cardiac conditions.Multigene panel for cleft lip/palate and congenital heart disease
Sometimes doctors order a panel that tests many genes related to facial clefts and heart defects at once. This can detect HYAL2 variants and also check for other genes if the clinical picture is unclear.Chromosomal microarray or exome/genome sequencing
If a simple panel is negative or the phenotype is atypical, broader tests such as chromosomal microarray or whole exome/genome sequencing may be used. These tests can detect larger deletions, duplications, or rare variants affecting HYAL2 and related pathways.Complete blood count and basic chemistry panel
Before surgeries or anesthesia, clinicians often order routine blood tests. These include hemoglobin, white cell and platelet counts, and kidney and liver function tests, to be sure the child is safe for operations and healing.Coagulation profile and blood type testing
Because cleft and heart surgeries can involve blood loss, clotting tests (such as PT/INR) and blood typing and cross-matching are done. This helps prepare for transfusion if needed and reduces surgical risk.Serum hyaluronan measurement (mainly research)
In research settings, doctors sometimes measure hyaluronan levels in blood or tissues. Raised levels in HYAL2-deficient animals and some human studies support the idea that impaired hyaluronan breakdown is central to this syndrome’s biology, although this is not yet a standard clinical test.
Electrodiagnostic tests
Electrocardiogram (ECG)
An ECG uses small skin electrodes to record the heart’s electrical activity. In this syndrome, it helps detect rhythm problems or signs of heart enlargement that can go along with structural heart defects.Auditory brainstem response (ABR)
ABR testing uses small electrodes on the scalp and clicks in the ears while the child sleeps. It measures how sound signals travel along the hearing nerve to the brainstem and is very useful for estimating hearing thresholds in babies and young children.Otoacoustic emissions (OAE) testing
In OAE, a tiny probe in the ear canal records echoes from the inner ear’s outer hair cells. Absent or reduced OAEs suggest inner-ear damage and, together with ABR, define the type and degree of hearing loss.
Imaging tests
Transthoracic echocardiogram (heart ultrasound)
Echocardiography is the key imaging test for heart defects. It uses ultrasound waves on the chest to show the heart’s chambers, valves, and blood flow, and can identify the exact type of congenital heart disease present.Prenatal ultrasound and fetal echocardiogram (in at-risk pregnancies)
In pregnancies with a known family history, high-resolution ultrasound and fetal echocardiography can sometimes detect facial clefts and heart defects before birth. This allows planning delivery in a center with cleft, cardiac, and neonatal specialists.Craniofacial and temporal bone CT or MRI
CT or MRI scans of the skull and temporal bones give detailed views of the palate, jaw, facial bones, and inner ear. Surgeons and ENT doctors use these images to plan cleft repairs, orthodontic treatment, and, in some cases, ear surgery or cochlear implantation.
Non-pharmacological treatments
In this syndrome there is no single cure. Non-drug care focuses on feeding, breathing, heart support, hearing, speech, and family well-being. These supports work together with medicines and surgery. [5]
Early feeding support
Special feeding bottles, nipples, or cups help milk go safely around a cleft palate. A feeding therapist or nurse teaches parents how to position the baby and control flow to reduce choking and milk going into the nose or lungs. This support improves weight gain and lowers the risk of chest infections. [1]Nutritional counseling
A dietitian plans high-calorie, high-protein meals so the child can grow well even if eating is slow or tiring. They may suggest frequent small feeds and energy-dense foods like fortified milk or purees. Good nutrition supports wound healing after surgery and helps the heart and immune system work better. [2]Lactation support for breastfeeding
Some babies with clefts can still receive breast milk using special positions or devices. Lactation consultants show mothers how to express milk and use specialty feeders. Breast milk gives ideal nutrition and antibodies, which may lower infections in children with heart disease and ear problems. [3]Physiotherapy and cardiac rehabilitation exercises
Gentle, age-appropriate movement programs help babies and children with heart defects build strength without putting too much strain on the heart. Therapists teach safe positions, handling, and later simple play-based exercises so the child can reach motor milestones and stay active. [4]Speech and language therapy
Because cleft palate and hearing loss affect how sounds are made and heard, early speech therapy is very important. Therapists use games, pictures, and simple exercises to teach correct sound production and improve understanding, helping the child develop clear, confident communication. [5]Audiology care and hearing aids
Hearing tests are done early and often. If hearing loss is present, audiologists can fit hearing aids or bone-anchored devices. Better hearing makes language learning easier, supports school progress, and improves safety in daily life. [6]Educational support and early intervention programs
Even if intelligence is usually normal, children may have learning challenges because of hearing loss, hospital stays, or speech problems. Early intervention teachers, special educators, and classroom accommodations (like seating in front and captioning) help the child keep up in school. [7]Psychological counseling for child and family
Repeated surgeries, hospital stays, and visible facial differences can affect self-esteem and cause anxiety. Psychologists or counselors offer coping strategies, play therapy, and family sessions to help everyone manage stress, grief, or worry and build resilience. [8]Social work and care coordination
Social workers help families access financial support, transport, special education services, and local resources. They coordinate appointments between heart doctors, surgeons, audiologists, and therapists so care is organized and less overwhelming. [9]Genetic counseling
Because this syndrome is genetic, parents may want to understand recurrence risk for future pregnancies. Genetic counselors explain the HYAL2 mutation pattern in simple language, discuss carrier testing, and talk about options such as prenatal or pre-implantation genetic testing where available. [10]Regular dental and orthodontic care
Cleft lip/palate and craniofacial differences often affect tooth position and jaw growth. Early dental visits, fluoride care, and later braces or orthodontic devices improve chewing, appearance, and speech, and help protect teeth from decay. [11]Ear, nose, and throat (ENT) follow-up
ENT specialists monitor for fluid behind the eardrum, middle-ear infections, and airway problems. They may recommend ear tube insertion and close follow-up, which reduces repeated infections and improves hearing in children with cleft palate. [12]Respiratory physiotherapy
Some children with heart defects and feeding problems are prone to chest infections. Chest physiotherapists teach airway-clearing techniques, breathing exercises, and safe coughing methods to keep lungs clear and reduce hospital admissions. [13]Post-surgical wound and scar care
After cleft or heart surgery, nurses teach parents how to clean wounds, protect sutures, and apply approved creams or silicone sheets to help scars heal flat and soft. Good wound care lowers infection risk and improves long-term appearance. [14]Sleep and positioning support
Babies with craniofacial differences may have obstructive sleep apnea. Sleep studies, safe sleeping positions, and sometimes special pillows or mild oxygen support can reduce nighttime breathing pauses and improve overall daytime energy. [15]Assistive communication tools
For children with severe hearing loss or delayed speech, picture boards, sign language, or simple communication apps can be used alongside speech therapy so the child can express needs and reduce frustration. [16]Parental education programs
Teaching parents about heart failure warning signs, feeding strategies, infection prevention, and when to seek urgent help builds confidence. Clear written plans and emergency contact numbers reduce fear and improve day-to-day safety at home. [17]Support groups and peer networks
Meeting other families living with cleft, heart disease, or deafness helps parents feel less alone. They can share practical tips, emotional support, and information about services in their region or online. [18]Environmental noise control
For children using hearing aids, reducing background noise at home and school (turning off TV, using soft furnishings) makes it easier to hear speech and reduces listening fatigue during learning and social play. [19]Routine immunizations and infection prevention habits
Staying up to date with vaccines, hand-washing, avoiding smoke, and prompt treatment of infections is vital for children with heart disease and cleft-related airway risks. This lowers serious illness and hospital stay chances. [20]
Drug treatments
There is no drug that cures HYAL2 deficiency itself. Medicines treat problems such as heart failure, infections, pain, reflux, and RSV (respiratory) risk. All doses must be chosen by a pediatric specialist based on weight, age, and kidney or liver function. Never change doses without medical advice. [1]
Furosemide (Lasix)
Furosemide is a loop diuretic often used in children with congenital heart failure to remove extra fluid and reduce lung congestion. Typical pediatric dosing is weight-based and divided during the day, following FDA label guidance for edema in heart failure. It improves breathing and reduces swelling but can disturb salts (electrolytes) and cause dehydration or low blood pressure. [2]Spironolactone
Spironolactone is a potassium-sparing diuretic sometimes added when furosemide alone is not enough. It blocks aldosterone, helping the body lose salt and water while keeping potassium. It supports heart function but can cause high potassium and, rarely, hormone-related side effects like breast tenderness. [3]Enalapril (ACE inhibitor)
Enalapril lowers blood pressure and reduces the heart’s workload by blocking the renin-angiotensin-aldosterone system. It is approved for pediatric hypertension and used off-label in some children with heart failure under specialist care, with careful dosing and monitoring for low blood pressure, kidney effects, and high potassium. [4]Beta-blockers (for example, carvedilol)
Beta-blockers slow the heart rate and reduce the force of contraction so the heart works more efficiently. In selected children with congenital heart disease, cardiologists use low doses, slowly increased, to improve symptoms, always monitoring blood pressure and rhythm to avoid dizziness or extreme slowing of the heart. [5]Acetaminophen (paracetamol)
Acetaminophen is used for pain and fever relief after surgeries such as cleft repair or cardiac operations. The FDA label gives detailed weight-based dosing limits to prevent liver damage, and doctors calculate doses carefully. It reduces discomfort so children can eat, breathe deeply, and sleep better. [6]Ibuprofen
Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used in some children for pain and inflammation. Doctors are cautious in babies or those with kidney problems or complex heart lesions. When used short-term at weight-based doses, it can reduce post-surgical pain and swelling but may irritate the stomach or affect kidney function. [7]Omeprazole (Prilosec)
Omeprazole is a proton-pump inhibitor that reduces stomach acid. It is FDA-approved for conditions like GERD and erosive esophagitis and may be used if a child with cleft or heart disease has reflux, poor weight gain, or pain with feeds. Dosing is once daily, adjusted to weight, with side effects like diarrhea or headache. [8]Amoxicillin
Amoxicillin is a penicillin-class antibiotic widely used for ear, lung, and other infections. Children with cleft palate and heart defects may need it more often, following FDA-approved dosing schedules based on weight and infection type. Overuse must be avoided to prevent resistance and allergies such as rashes or, rarely, severe reactions. [9]Other antibiotics (for example, ceftriaxone, azithromycin)
When infections are severe or bacteria are resistant, doctors choose other antibiotics according to local guidelines, culture results, and FDA labeling. These medicines can be given by vein during hospital stays, with close monitoring for allergic reactions, diarrhea, and liver or kidney effects. [10]Palivizumab (Synagis)
Palivizumab is a monoclonal antibody given monthly during RSV season to high-risk infants, including many with significant congenital heart disease. It does not cure RSV but reduces the chance of serious lung infection and hospital stay. Dose is calculated by weight and given as an intramuscular injection. [11]Diuretic combinations
Sometimes physicians combine low doses of different diuretics (for example, furosemide plus thiazide) to control fluid overload in advanced heart failure, always checking electrolytes and kidney function. This careful balance can improve breathing and feeding when single drugs are not enough. [12]Inotropes (for acute heart failure in hospital)
In severe cases, short-term IV inotropes like milrinone or dobutamine are used in intensive care to strengthen heart contractions before or after surgery. These medicines are tightly controlled, with continuous monitoring of heart rhythm and blood pressure. They are not long-term home treatments. [13]Antiarrhythmic medicines
Some children with structural heart defects develop abnormal heart rhythms. Cardiologists may prescribe drugs such as propranolol or other antiarrhythmics to keep the rhythm steady, with ECG monitoring to avoid serious side effects. [14]Iron supplements (as a drug preparation)
When iron-deficiency anemia is present, doctors may prescribe medicinal iron drops or tablets. These improve red blood cell levels, oxygen delivery, and energy. Dosing is weight-based and can cause dark stools or stomach upset, so it is monitored and sometimes given with vitamin C. [15]Vitamin D and calcium preparations
Children with long hospital stays or limited sun exposure may receive vitamin D and calcium medicines to support bone health and growth, especially before and after major surgeries. Doses follow pediatric guidelines to avoid very high levels that could harm kidneys. [16]Antihypertensives (other than ACE inhibitors)
In some children, blood pressure remains high due to kidney or heart issues. Doctors may use calcium-channel blockers or other agents according to pediatric hypertension guidelines and FDA labeling, carefully adjusting doses and checking for dizziness or swelling. [17]Sedatives and anxiolytics (short-term)
Before big operations or invasive tests, short-acting sedatives or anti-anxiety medicines may be used under close supervision to reduce distress. Doses are strictly controlled by anesthesiologists to avoid breathing depression. [18]Post-operative anticoagulants (when indicated)
If a child receives certain heart surgeries or devices, doctors may prescribe low-dose anticoagulants or antiplatelet drugs to prevent clots. These drugs require careful monitoring of blood tests and bleeding risk. [19]Nasal saline and topical preparations
Simple saline sprays or drops (non-drug or low-risk products) are used to keep nasal passages moist, help clear secretions, and improve comfort in children with nasal deformities or mouth breathing. [20]Emergency medicines (epinephrine, bronchodilators) when needed
Children with heart or airway problems may rarely need emergency medicines for allergic reactions or severe wheezing. Parents are taught when to seek urgent care; these medicines are not routine daily drugs but part of hospital or emergency plans. [21]
Dietary molecular supplements
These supplements do not cure the gene problem, but they support growth, healing, and immune function when used under medical guidance. [1]
Folic acid
Folic acid is a B-vitamin needed for DNA production. In children, it supports growth and red blood cell formation. It is usually given in low daily doses under supervision. Folic acid is more important before and during early pregnancy for prevention of some birth defects, as part of prenatal care. [2]Iron (elemental iron)
Iron supplements correct iron-deficiency anemia, which can worsen fatigue and strain the heart. Pediatric doses are based on mg/kg of elemental iron per day. Iron helps make hemoglobin so blood can carry oxygen well, but too much can be toxic, so dosing must be precise. [3]Vitamin D
Vitamin D helps calcium absorb into bones and supports immune function. Drops or tablets are often used in children at risk of deficiency, especially if they spend long periods indoors. Correct levels help bone healing after surgery and reduce risk of rickets. [4]Calcium
Calcium works together with vitamin D to make bones and teeth strong. Supplementation may be needed if diet is poor or if medications affect bone health. It is usually split into several doses with meals to improve absorption and reduce stomach upset. [5]Omega-3 fatty acids (DHA/EPA)
Omega-3 fats from fish oil may support heart and brain health. In children, small doses in liquid or capsule form can be used if tolerated. They may have mild blood-thinning effects and can cause fishy aftertaste, so families should discuss them with their doctor first. [6]Zinc
Zinc plays a key role in wound healing, taste, and immune function. Short-term supplements may be given after major surgeries or when zinc deficiency is suspected from poor growth or recurrent infections. Over-supplementation can cause nausea and interfere with copper balance. [7]Vitamin C
Vitamin C is an antioxidant that supports collagen formation and wound healing. It can be given through food (fruits and vegetables) or as a small daily supplement if intake is low. Large doses may cause stomach upset or diarrhea, so typical doses stay modest. [8]Multivitamin syrup or drops
For children with picky eating, feeding problems, or many hospital stays, a broad pediatric multivitamin helps cover small gaps in vitamins and minerals. It cannot replace good food but gives a safety net for micronutrients important for healing and growth. [9]Probiotics
Probiotic supplements contain helpful bacteria that may support gut health, especially during or after antibiotic use. They can reduce some types of diarrhea and may support immunity, but strains and doses vary, so pediatric guidance is important. [10]High-calorie modular supplements (maltodextrin, fat emulsions)
Sometimes dietitians add special powders or liquids to milk or purees to increase calories without increasing volume. These “molecular” energy supplements help children gain weight when they tire easily with feeding. They must be carefully measured to avoid excess sugar or fat. [11]
Immune-supporting and regenerative approaches
Currently, there are no approved stem-cell or gene-therapy drugs specifically for this syndrome. The approaches below are supportive or experimental concepts that may be discussed in specialist centers. [1]
Routine childhood vaccines
Staying fully vaccinated against infections like measles, pertussis, and pneumococcus is one of the strongest “immune boosters.” Vaccines train the immune system to recognize germs and respond quickly, lowering risk of severe illness in children with heart disease or cleft-related airway problems. [2]Palivizumab (passive immunization)
As noted above, palivizumab is a monoclonal antibody used seasonally in some babies with serious heart disease to prevent severe RSV lung infection. It acts like a ready-made immune protein, giving temporary protection while the child’s own immune system is still maturing. [3]Intravenous immunoglobulin (IVIG) in selected cases
If a child has proven immune deficiency or specific antibody problems, doctors may use IVIG, a blood-derived product with pooled antibodies. It supports immunity for a short time but is expensive and reserved for clearly defined conditions after careful testing. [4]Nutritional immune support (vitamins A, C, D, zinc)
Correcting vitamin and mineral deficiencies, especially vitamins A, C, D and zinc, supports normal immune function and tissue repair. This is not a quick boost but a steady, long-term way to help the body respond to infections and heal wounds after surgeries. [5]Experimental gene therapy for HYAL2
In the future, gene therapy might be explored to replace or correct faulty HYAL2 in animal models or research settings. At present this remains experimental and is not available as a standard treatment, but families may hear about such research in rare-disease news. [6]Experimental stem-cell or tissue-engineering approaches
Tissue engineering and stem-cell-based methods are being studied in many congenital heart and craniofacial conditions, such as engineered heart valves or bone grafts. However, they are not routine care for this syndrome. Participation in any trial must go through strict ethical review and detailed informed consent. [7]
Surgeries
Cleft lip repair (cheiloplasty)
This surgery usually happens in the first months of life. The surgeon carefully brings together the split parts of the upper lip, muscles, and skin. It improves feeding, reduces drooling, and gives a more typical lip shape, which supports speech development and social confidence. [1]Cleft palate repair (palatoplasty)
Palatoplasty is done later in infancy or early childhood. The surgeon closes the opening in the palate and repositions muscles so the child can build pressure in the mouth to make clear speech. It also reduces food and liquid going into the nose and lowers ear infection risk. [2]Cardiac surgery for congenital heart defects
Depending on the exact defect (holes in the heart walls, valve problems, or abnormal connections), heart surgeons may close openings, repair valves, or reroute blood flow. The goal is to improve oxygen delivery, growth, and exercise tolerance, and to prevent heart failure and dangerous rhythms. [3]Ear tube insertion (myringotomy with ventilation tubes)
Repeated middle-ear fluid and infections are common in children with cleft palate. In this minor surgery, a tiny tube is placed in the eardrum to let fluid drain and air circulate. It helps improve hearing and reduces infections, supporting language and school performance. [4]Craniofacial reconstructive surgery
Later in childhood or adolescence, some children may have additional surgeries to reshape facial bones, correct jaw alignment, or improve nose and orbital structures. These operations can improve chewing, breathing, eye protection, and appearance, which may strengthen self-esteem and social participation. [5]
Preventions
Because this syndrome is genetic, it cannot always be fully prevented, but some steps can reduce risks or improve early detection and care. [1]
Preconception genetic counseling for at-risk families – Couples with a known HYAL2 mutation or previous affected child can discuss recurrence risks and testing options before pregnancy. [2]
Adequate folic acid before and during early pregnancy – Folic acid supports normal fetal development and is recommended for all women planning pregnancy, even though it may not fully prevent this specific syndrome. [3]
Avoiding smoking, alcohol, and harmful drugs in pregnancy – These exposures can add extra risks for growth and development problems in any fetus, including those with genetic syndromes. [4]
Managing maternal illnesses (diabetes, infections) – Good control of chronic diseases and prompt treatment of infections in pregnancy help protect fetal development. [5]
Early and regular antenatal care – Ultrasound and other prenatal tests may show structural anomalies such as clefts or heart defects so delivery can be planned at a specialist center. [6]
Family carrier testing where available – In some regions, relatives can be tested for HYAL2 variants, which may inform reproductive decisions and early monitoring of future pregnancies. [7]
Planned delivery in a hospital with neonatal and cardiac services – This ensures the baby gets immediate airway, feeding, and heart evaluation, lowering early complications. [8]
Strict infection prevention in infancy – Hand-washing, smoke-free homes, vaccines, and RSV prophylaxis for eligible infants reduce severe infections in babies with heart disease and cleft airway vulnerabilities. [9]
Early hearing screening – Universal newborn hearing screening and repeat tests in at-risk infants allow quick fitting of hearing aids and early language support. [10]
Close growth and development monitoring – Regular check-ups help detect feeding, growth, or developmental problems early so therapies can start quickly. [11]
When to see doctors
Parents should keep regular appointments with the child’s pediatrician, cardiologist, cleft team, and audiologist. Urgent medical help is needed if you notice any of the following: [1]
Fast or difficult breathing, grunting, flaring nostrils, or blue lips or tongue.
Poor feeding, sweating with feeds, or very slow weight gain.
High fever, chesty cough, or repeated vomiting.
New or worsening swelling of legs, face, or belly.
Fainting, unusual sleepiness, or seizures.
Sudden hearing change, ear discharge, or strong ear pain.
Red, swollen, or opening surgical wounds.
These signs may indicate heart failure, serious infection, or surgical problems and always need quick assessment by a doctor or emergency department. [2]
What to eat and what to avoid
Choose soft, smooth, high-calorie foods – Mashed potato, yogurt, blended meats, and pureed fruits slip past the cleft area more easily and reduce choking. Avoid very hard, crunchy foods until the cleft team says they are safe. [1]
Offer small, frequent meals – Children with heart disease tire easily. Smaller, more frequent feeds are less exhausting than large meals. Avoid forcing large volumes at once, which can cause vomiting or distress. [2]
Include good protein sources – Eggs, dairy, beans, lentils, and soft meats help build muscles and repair tissues after surgeries. Try to avoid diets heavy in only snacks or sugary drinks with low protein. [3]
Use healthy fats for extra energy – Vegetable oils, nut butters (when age-appropriate and safe), and full-fat dairy add calories in small volumes. Deep-fried or very salty fast foods should be limited to protect heart and overall health. [4]
Encourage fruits and vegetables – Soft or cooked fruits and vegetables give vitamins and fiber. Avoid very stringy or seedy items if they are hard to chew or get stuck in the cleft area. [5]
Limit sugary drinks and sweets – High sugar increases tooth decay risk, which is already higher in cleft and craniofacial conditions. Water and milk are better daily drinks; sweets should be occasional treats with good tooth-brushing. [6]
Watch salt intake – In children with heart failure, high-salt foods (chips, instant noodles, processed meats) can worsen fluid retention. Follow the cardiologist’s advice about salt levels in the child’s diet. [7]
Avoid alcohol and caffeine for older children/teens – These are not recommended; alcohol is unsafe, and high caffeine can affect heart rhythm and sleep, which are especially important in congenital heart disease. [8]
Ensure safe swallowing – If speech or feeding therapists see signs of aspiration, they may recommend thickened liquids or certain food textures. Avoid giving thin liquids or mixed textures that the child cannot handle safely. [9]
Follow allergy and intolerance plans – If the child has milk allergy or other food problems, work with an allergist and dietitian to choose alternatives so growth remains normal. Avoid guessing restrictive diets without professional help. [10]
Frequently asked questions (FAQs)
Is this syndrome always inherited from parents?
Often it is inherited in an autosomal recessive way: both parents carry one HYAL2 mutation but are healthy, and the child receives both changed copies. In some cases, the mutation may be new (de novo). Genetic testing and counseling explain the pattern for each family. [1]Will my child have learning problems?
Reports suggest that many children with this syndrome have normal intelligence, but hearing loss, frequent hospitalizations, and speech issues can affect school performance. Early hearing aids, speech therapy, and educational support greatly improve learning outcomes. [2]Can surgery completely fix the cleft lip and palate?
Surgery can greatly improve appearance and function but may not make the lip and palate perfectly “normal.” Some children need more than one operation, plus speech therapy and dental work, to reach their best speaking and eating abilities. [3]Will my child’s heart defect go away over time?
Small heart defects may close or improve as the child grows, but many structural problems need surgery or long-term follow-up. The cardiologist can explain the specific heart condition and long-term plan for your child. [4]Can hearing loss be cured?
Sensorineural hearing loss is usually permanent, but hearing aids, bone-anchored devices, or cochlear implants can provide strong improvement in hearing and communication. Early fitting and consistent use are key. [5]Is there any medicine that treats the gene problem itself?
At present there is no approved medicine that corrects the HYAL2 gene defect. Treatment focuses on managing clefts, heart disease, and deafness. Research into gene therapy and regenerative methods is ongoing but still experimental. [6]How often will my child need to see doctors?
In early childhood, visits are frequent: pediatrician, cardiologist, cleft surgeon, ENT, audiologist, and therapists. As the child grows and becomes more stable, visits can be spaced out, but regular follow-up remains important for life. [7]Can my child play sports?
Many children with repaired heart defects and well-controlled symptoms can do light to moderate activity, but limits depend on heart function and oxygen levels. Cardiologists and physiotherapists give personalized advice about safe sports and school physical education. [8]Will future pregnancies be affected?
The chance of having another affected child depends on the inheritance pattern and whether both parents carry the HYAL2 mutation. Genetic counseling, carrier testing, and possibly prenatal testing can help families plan. [9]Can we detect this syndrome before birth?
Sometimes cleft lip/palate and major heart defects can be seen on prenatal ultrasound or fetal echocardiography, but the full syndrome may not be clear. In families with a known HYAL2 mutation, specific genetic tests can be offered in some centers. [10]Is my child more likely to get infections?
Children with clefts, heart defects, and frequent hospital stays can get more respiratory and ear infections. Good hygiene, vaccines, RSV prophylaxis when indicated, and prompt treatment reduce risks. [11]Can school teachers understand this condition?
Teachers may not know this rare name, so a simple summary letter from the medical team describing hearing needs, speech issues, and heart limits is very helpful. Many schools are willing to make reasonable adjustments when they understand the child’s needs. [12]Will my child look very different as an adult?
Modern cleft and craniofacial surgery can greatly improve facial symmetry and function. Some scars or differences will usually remain, but most adults can have a natural appearance that allows them to work, study, and socialize normally. [13]Is normal life expectancy possible?
Because the syndrome is rare, long-term data are limited. Outcome depends mainly on the severity of heart defects and how early they are treated. With good cardiac, cleft, and hearing care, many children may reach adulthood with good quality of life. [14]Where can we find more information and support?
National rare-disease organizations, cleft lip and palate charities, congenital heart disease foundations, and deafness/hearing-loss groups all provide educational materials and support. Your local hospital’s genetics and cleft teams can direct you to trustworthy resources. [15]
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.
