Hyaluronidase 2 deficiency is a very rare genetic disease. It happens when both copies of a gene called HYAL2 do not work properly. This gene makes an enzyme (a kind of protein) that helps break down a sugar called hyaluronan. Hyaluronan is an important “gel-like” part of the tissues in the face, heart, eyes, ears, bones, and many other organs. When HYAL2 does not work, hyaluronan can build up in the wrong way. This can disturb how the baby’s face, heart, ears, eyes, and skeleton form during pregnancy.
Hyaluronidase 2 deficiency (HYAL2 deficiency) is a very rare genetic condition. It happens when both copies of the HYAL2 gene do not work properly, so the body does not make enough of the enzyme hyaluronidase-2. This enzyme helps break down a natural sugar called hyaluronan, which is part of the “gel” that surrounds cells in many tissues. When HYAL2 does not work, hyaluronan builds up and can disturb normal development of the heart, face, eyes, ears, chest, and bones. Most children have congenital heart defects, cleft lip or palate, high short-sightedness (myopia), hearing loss, and chest or finger changes, but their intelligence is usually normal. [GeneReviews and other medical reports describe fewer than 20 patients so far, so knowledge is still growing.][
Doctors know this condition as a “syndromic” disease. This means it affects many body systems at the same time. The main features are cleft lip and/or cleft palate, unusual face shape (craniofacial dysmorphism), congenital (from birth) heart defects, hearing loss (usually because sound cannot pass well through the middle ear), eye problems like strong short-sightedness, and some bone and chest wall changes. Most people who have been reported have normal thinking and learning ability, but they may need many operations and medical visits.
Other names
Doctors and databases use several other names for hyaluronidase 2 deficiency. One common name is “cleft lip and palate-craniofacial dysmorphism-congenital heart defect-hearing loss syndrome.” This name lists the four main groups of problems: cleft lip and palate, unusual facial shape, heart defects, and hearing loss.
Other names that can be used include: “cleft lip and palate, craniofacial dysmorphism, congenital heart defect, deafness syndrome” and simply “HYAL2 deficiency” or “Hyal2 deficiency.” In some scientific papers it is also described as “HYAL2-related syndromic cleft lip and palate” or “Muggenthaler-Chowdhury-Chioza syndrome,” named after the first group of researchers who clearly linked HYAL2 mutations to this pattern of birth defects.
Types
There is only one basic genetic cause (mutations in the HYAL2 gene), but the condition can look different from person to person. Doctors sometimes talk about different clinical forms or “types” based on how severe the signs are.
Classic (full) HYAL2 deficiency form
In the classic form, children have the full pattern: cleft lip and/or palate, very typical facial features, serious heart defects, hearing loss, and often eye problems like strong short-sightedness. This is the picture first described in detail in affected families.Partial or attenuated form
Some people have mutations in HYAL2 but do not show all the classic signs. For example, they may have facial changes and heart defects but no cleft lip or palate, or they may have eye and hearing problems with milder heart changes. This “partial” form still comes from HYAL2 deficiency but looks less obvious.Mild form with limited features
A few reported people have mainly eye problems (severe myopia), mild facial differences, or subtle heart findings, and only genetic testing revealed HYAL2 mutations. In these mild forms, the child may look almost typical at first, so the diagnosis can be delayed until someone carefully connects the different features and orders genetic tests.
Causes
All causes below describe different ways the same basic problem happens or becomes worse: loss of normal HYAL2 function and abnormal handling of hyaluronan during development.
Biallelic pathogenic HYAL2 variants
The main cause is having harmful changes (variants) in both copies of the HYAL2 gene, one from each parent. Because the condition is autosomal recessive, a child usually becomes affected only when both parents are healthy carriers and each passes on one changed gene copy.Nonsense mutations in HYAL2
A nonsense mutation is a change in the DNA code that tells the cell to stop making the protein too early. When this happens in HYAL2, the enzyme becomes very short and non-functional. This “loss-of-function” directly leads to reduced or absent hyaluronidase 2 activity.Missense mutations that damage the protein structure
Some HYAL2 variants change just one amino acid in the protein (missense changes), but this can still be very harmful. Studies show that many missense mutations disturb protein folding, make the enzyme unstable, or prevent it from reaching the cell surface, where it normally acts.Splice-site mutations affecting RNA processing
Splice-site variants occur at the borders between exons and introns of the gene. They can cause the cell to cut and join the RNA message incorrectly. This can delete important parts of HYAL2 or insert extra pieces, so the final enzyme does not work.Frameshift mutations
Some variants add or delete a small number of bases in the gene. This shifts the reading frame, usually creating a wrong and early stop signal. The result is another type of non-functional HYAL2 protein and strong enzyme deficiency.Larger deletions in the HYAL2 region
In some families, copy number changes such as small deletions around or within the HYAL2 gene have been suspected. When a large part of the gene is missing, the cell cannot make a normal enzyme at all, which again causes hyaluronidase 2 deficiency.Autosomal recessive inheritance in carrier parents
When both parents are carriers of a HYAL2 pathogenic variant, each pregnancy has a 25% chance that the child will inherit both changed copies and be affected. This genetic pattern explains why the syndrome appears in siblings and why parents are usually healthy.Consanguinity (parents related by blood)
In some reported families, parents are related (such as cousins). This raises the chance that both carry the same rare HYAL2 variant, so their children have a higher risk of inheriting two faulty copies and developing the syndrome.Possible founder effects in certain populations
When the same HYAL2 variant is seen in several related families from a limited area, doctors suspect a “founder” mutation, meaning the change came from a common ancestor. This can make HYAL2 deficiency slightly more frequent in that group.Failure to break down high-molecular-weight hyaluronan
HYAL2 normally helps to chop long chains of hyaluronan into smaller pieces on the cell surface. Without HYAL2, very large hyaluronan molecules build up in the spaces around cells. Animal studies show this build-up in heart and lung tissues and link it to malformations and organ dysfunction.Disrupted heart valve and chamber development
During early pregnancy, hyaluronan helps shape the cushions and valves in the growing heart. When HYAL2 is missing, the balance of hyaluronan is abnormal. This can lead to extra tissue or wrong tissue shapes and causes heart defects such as cor triatriatum or other complex malformations.Abnormal fusion of the palatal shelves (cleft palate)
To form the roof of the mouth, two palatal shelves must grow and fuse. Hyaluronan is part of the supporting matrix for this process. HYAL2 deficiency changes this matrix and may prevent complete fusion, which leads to cleft palate and sometimes cleft lip.Craniofacial mesenchyme overgrowth or mis-shaping
The bones and soft tissues of the face come from special cells called cranial neural crest cells. These cells move and grow inside a hyaluronan-rich environment. When HYAL2 cannot control hyaluronan size and amount, the facial tissues may overgrow or bend in the wrong ways, causing broad nasal bridges, frontal bossing, and other facial changes.Abnormal development of the middle ear and ossicles
Conductive hearing loss in HYAL2 deficiency suggests that the sound-carrying structures of the middle ear (ossicles, eardrum, and surrounding spaces) do not form normally. Hyaluronan is important in these small structures, so its abnormal breakdown may lead to stiff or malformed parts that do not pass sound well.Fragile or elongated eye tissues causing high myopia
In many affected people, the eyeball grows too long, causing strong short-sightedness (myopia). This suggests that the outer layers of the eye, which also contain hyaluronan and related matrix, are weakened or stretched when HYAL2 is missing, leading to more severe refractive errors.Weakness in the retina increasing risk of detachment
The retina is held in place partly by its surrounding gel and tissue matrix. If hyaluronan balance is abnormal, the retina may be more likely to pull away (detach), especially in very myopic eyes. This is why HYAL2 deficiency is linked not only to myopia but also to a higher risk of retinal detachment.Abnormal chest wall and bone matrix
Skeletal findings such as pectus excavatum (sunken chest) and finger or toe anomalies suggest that bone and cartilage also depend on proper HYAL2 function. When the hyaluronan in these tissues is not controlled, the shape of ribs, sternum, and digits can become abnormal.Other modifying genes affecting the hyaluronan pathway
Not all people with the same HYAL2 variant look the same. This suggests that other genes in the hyaluronan or extracellular matrix pathway may change the severity of the disease. These “modifier” genes do not cause HYAL2 deficiency alone but can influence how serious the signs are.Environmental factors that modify expression (but do not cause it alone)
Current data show that the main cause is genetic, but pregnancy factors such as maternal health, nutrition, or exposures might slightly change how the genetic defect shows itself. However, by themselves, these factors do not create HYAL2 deficiency without the gene variants.Reduced HYAL2 at the cell surface due to protein instability
Laboratory work has shown that many disease-causing HYAL2 variants make the protein unstable. The misfolded enzyme is broken down inside the cell before it can reach the cell membrane. This reduces cell-surface HYAL2 and leads to a functional “deficiency,” even if some protein is still produced.
Symptoms
Cleft lip (often unilateral or bilateral)
Many babies are born with a split in the upper lip. This split may be on one side (unilateral) or on both sides (bilateral). It is usually visible at birth. Cleft lip causes cosmetic concerns and can make feeding more difficult, so early surgical planning is important.Cleft palate (opening in the roof of the mouth)
The roof of the mouth may also have an opening that connects the mouth with the nose. This cleft palate can cause milk to come out through the nose, nasal-sounding speech later in life, and frequent ear infections. It almost always needs surgery and speech therapy as the child grows.Craniofacial dysmorphism (unusual facial shape)
Children often have a characteristic facial appearance. Features can include frontal bossing (prominent forehead), wide-set eyes, a broad and flat nasal bridge, and a small chin. These signs help genetic specialists recognize the syndrome and differentiate it from other causes of cleft lip and palate.Broad, flat nasal bridge and nasal changes
The bridge of the nose often looks wide and flat. The nostrils and the lower part of the nose may be formed in an unusual way. This is part of the craniofacial pattern linked to abnormal hyaluronan handling in facial bones and soft tissues.Micrognathia (small lower jaw)
Many affected babies have a small lower jaw, which can make the chin look very small or set back. This may cause crowding of the tongue and can contribute to feeding difficulties or breathing problems, especially when lying on the back.Cupped or thickened ears
The ears may be low-set or shaped in a special way, with thick outer rims (helices) or a cupped form. These ear changes are part of the facial pattern and, together with cleft lip/palate and heart defects, support the clinical suspicion of HYAL2 deficiency.Congenital heart disease
Many children have heart defects present from birth. These can include rare problems like cor triatriatum (extra chamber or membrane in the atrium) as well as more common complex defects. These heart lesions can cause fast breathing, poor feeding, poor weight gain, or blue-tinged skin if blood oxygen is low.Cyanosis or breathing problems due to heart defects
When heart defects limit blood flow to the lungs or body, the child may have bluish lips or fingers (cyanosis) and may tire or breathe quickly with feeding or crying. In HYAL2 deficiency, these symptoms reflect the underlying structural heart problems rather than lung disease alone.Hearing loss (usually conductive)
Hearing loss is common and often conductive, meaning sound does not move well through the outer or middle ear. This may result from abnormal ear structures, fluid in the middle ear, or both. Undetected hearing loss can delay speech and language, so early hearing tests and support (like hearing aids) are very important.Recurrent ear infections
Because of cleft palate and Eustachian tube dysfunction, children may have frequent middle ear infections (otitis media). This can worsen conductive hearing loss and cause ear pain, fevers, and irritability. Ear tubes (grommets) may be needed to drain fluid and prevent repeated infections.Severe myopia (strong short-sightedness)
Many affected people have high degrees of myopia, sometimes very severe. This means distant objects look very blurry, and thick glasses or special lenses are needed. Severe myopia in young children with cleft lip/palate and heart disease should alert doctors to a possible HYAL2-related syndrome.Risk of retinal detachment and other eye problems
Because the eye is longer and tissues may be more fragile, the retina can tear or detach. Retinal detachment is an emergency and can cause permanent vision loss if not treated quickly. People with HYAL2 deficiency need regular eye exams and urgent care if they notice flashes, floaters, or sudden vision changes.Chest wall and skeletal abnormalities (like pectus excavatum)
Some individuals have a sunken chest (pectus excavatum) or other skeletal differences such as unusual finger or toe shapes. These may not cause serious symptoms but can affect appearance and, in severe cases, breathing or heart function.Growth and feeding difficulties, especially in infancy
Cleft palate, heart defects, and breathing issues can make feeding slow and tiring. Babies may not gain weight as expected and may need special feeding techniques or tube feeding. Over time, with treatment, many improve, but early nutrition support is important.Usually normal intellect with possible delays from medical burden
Reported cases suggest that basic intelligence is often normal. However, long hospital stays, hearing loss, and repeated surgeries can lead to delays in speech or school progress. With proper hearing support, therapies, and medical care, many children can reach good developmental outcomes.
Diagnostic tests
Doctors use many tests together to diagnose hyaluronidase 2 deficiency. These tests help describe the physical features, check the heart, ears, and eyes, and confirm the gene changes.
Physical exam
Comprehensive newborn and pediatric physical examination
The first and most important step is a full head-to-toe examination by a pediatrician or geneticist. The doctor looks for cleft lip or palate, facial differences, heart murmurs, chest shape, limb anomalies, and general growth. This exam raises early suspicion that a multisystem genetic syndrome such as HYAL2 deficiency may be present.Detailed craniofacial assessment
A specialist carefully measures the head and face, checks the distance between the eyes, the shape of the forehead, nose, ears, and jaw, and documents the pattern of facial features. The typical combination of cleft lip/palate, broad nasal bridge, small chin, and special ear shape supports the diagnosis and helps distinguish it from other cleft syndromes.Cardiovascular physical examination
The doctor listens to the heart with a stethoscope to detect murmurs, extra sounds, or abnormal rhythms. They also check pulses, blood pressure, breathing rate, and signs of heart failure such as liver enlargement or swelling. Abnormal findings point to congenital heart disease, which is a core part of HYAL2 deficiency.Musculoskeletal examination
The chest wall, spine, arms, and legs are examined for pectus excavatum, scoliosis, joint problems, and digital anomalies. These skeletal clues, together with facial and heart findings, support the idea of a single genetic cause affecting connective tissue, such as HYAL2 deficiency.
Manual / bedside tests
Feeding and suck-swallow assessment in infancy
Nurses or speech-language therapists watch how an infant with cleft palate sucks, swallows, and breathes during feeds. Problems such as milk leakage from the nose, choking, or tiring quickly suggest significant cleft-related dysfunction and sometimes heart compromise. This practical assessment guides feeding support and highlights the need for multi-disciplinary care.Developmental milestone assessment
Over time, doctors and therapists check if the child is sitting, walking, talking, and playing at expected ages. Simple tests in the clinic (like asking a child to stack blocks, point to pictures, or name objects) help detect delays. In HYAL2 deficiency, development may be normal or slightly delayed, and this assessment helps plan early support.Clinical hearing checks (whisper test and tuning fork tests)
In older children and adults, the clinician can do simple bedside hearing tests. The whisper test checks how well the person hears quiet speech. Tuning fork tests (Rinne and Weber) help decide if hearing loss is conductive (middle ear) or sensorineural (inner ear). In HYAL2 deficiency, these tests often suggest a conductive pattern.Basic visual acuity and eye movement screening
Simple eye charts or age-adapted picture tests can detect myopia and other vision issues. The examiner also checks eye alignment and movements. If strong short-sightedness or other problems are found, a full eye exam is arranged. Severe myopia together with cleft and heart disease supports suspicion of HYAL2 deficiency.
Lab and pathological tests
Targeted HYAL2 gene sequencing
The key confirmatory test is DNA sequencing of the HYAL2 gene from a blood sample. This test looks for disease-causing variants in the coding regions and nearby splice sites. Finding two harmful variants in HYAL2 in a person with the typical clinical features establishes the diagnosis.Syndromic cleft lip/palate multigene panel
When the exact syndrome is not clear, laboratories can use a panel that tests many genes linked to cleft lip/palate and craniofacial syndromes at once. HYAL2 is included in some modern panels. This approach can quickly pick up HYAL2 deficiency among other possible genetic causes.Whole-exome or whole-genome sequencing
If targeted tests are negative but suspicion remains high, doctors may order exome or genome sequencing. These broad tests read most or all genes in the genome and can detect rare or novel HYAL2 variants, as well as other genes if the diagnosis is uncertain.Sanger sequencing for family studies and carrier testing
Once a HYAL2 variant is found, Sanger sequencing can check parents and other relatives for the same change. This confirms the autosomal recessive pattern, identifies carriers, and supports genetic counseling for future pregnancies.Copy-number analysis (microarray or MLPA)
Chromosomal microarray or MLPA (Multiplex Ligation-dependent Probe Amplification) can detect small deletions or duplications affecting HYAL2. These tests are useful when sequencing does not show clear variants but the syndrome is strongly suspected.Hyaluronan (HA) measurement or tissue staining (research-level)
In research settings, doctors may measure hyaluronan levels in blood or analyze tissue samples using special stains. Increased hyaluronan in certain tissues has been shown in hyaluronidase-deficient animal models and helps confirm that the pathway is disturbed, although this is not yet a routine clinical test.
Electrodiagnostic tests
Electrocardiogram (ECG)
An ECG records the electrical activity of the heart. It can show signs of heart strain, chamber enlargement, or rhythm problems related to congenital heart defects. In HYAL2 deficiency, ECG is part of the full heart work-up and helps plan treatment and follow-up.Auditory brainstem response (ABR)
ABR testing is used in babies and young children who cannot reliably respond to hearing tests. Small electrodes on the head measure the brain’s response to sounds. In HYAL2 deficiency, ABR helps confirm and grade hearing loss and guides early use of hearing aids or other interventions.Otoacoustic emissions (OAE) screening
OAE testing measures tiny sounds made by the inner ear in response to clicks or tones. It is often used for newborn hearing screening. Abnormal or absent OAEs in a baby with cleft lip/palate and heart anomalies suggest a need for full hearing evaluation and raise concern for syndromes such as HYAL2 deficiency.
Imaging tests
Echocardiography (heart ultrasound)
Echocardiography uses sound waves to create moving pictures of the heart. It is essential for identifying structural defects such as cor triatriatum, valve problems, or other complex malformations seen in HYAL2 deficiency. This test guides decisions about surgery, medications, and long-term follow-up.Craniofacial CT or MRI
CT or MRI scans of the head and face can show the detailed structure of bones, palate, jaw, and skull base. These images are useful for surgical planning of cleft repair and for understanding the full extent of craniofacial anomalies linked to HYAL2 deficiency.Temporal bone CT or MRI for ear structures
Imaging of the temporal bones (the skull parts around the ears) can show whether the tiny hearing bones (ossicles), middle ear spaces, or inner ear structures are malformed or abnormal. These findings help explain conductive hearing loss and guide ear surgeries or other treatments in people with HYAL2 deficiency.
Non-Pharmacological Treatments
Important: These are general options. What is right for one child may not be right for another. Always follow the plan made by your doctors.
Multidisciplinary care coordination
A care coordinator (often a pediatrician, geneticist, or nurse) brings together heart, eye, ear, surgical, rehab, and social care. The purpose is to avoid gaps, repeated tests, and conflicting advice. The main mechanism is regular team meetings and shared medical records so all specialists understand the child’s full picture and adjust treatment early when new problems appear. [This model is recommended in rare multisystem genetic disorders.][Early intervention and developmental therapy
Many children with serious heart or facial problems may have feeding difficulties, delayed motor skills, or speech issues, even if intelligence is normal. Early intervention programs offer physical therapy, occupational therapy, and play-based learning. The goal is to help the child reach milestones as close to on time as possible. The mechanism is simple: frequent guided practice strengthens weak muscles and builds skills in small steps.Physiotherapy and cardiac-safe exercise
Gentle, supervised movement helps improve stamina, muscle strength, and breathing, especially if heart defects have caused tiredness or poor fitness. Therapists design low-intensity activities that do not stress the heart, such as walking, play-based games, or swimming if allowed. This works by gradually training the heart, lungs, and muscles, improving oxygen use and reducing shortness of breath in daily life.Speech and language therapy
Children with cleft palate, hearing loss, or frequent ear infections can have trouble with clear speech. Speech therapists work on sound production, understanding language, and safe swallowing. Regular practice teaches the brain and mouth muscles new patterns, so language becomes clearer and the child can communicate better at home and school. [Speech therapy is standard care in cleft palate and hearing disorders.][Special education and classroom support
Intelligence is usually normal, but repeated hospital stays, hearing loss, or vision problems can affect school performance. Tailored support (seating near the teacher, printed notes, visual aids, and assistive listening devices) helps the child keep up with lessons. The mechanism is to remove barriers (like poor hearing or reading difficulty) so the brain can focus on learning, not on “fighting” the environment.Audiologic rehabilitation and hearing devices training
For conductive hearing loss, hearing aids, bone-anchored devices, or other aids may be used. Audiologic rehabilitation teaches the child and family how to use and care for the device and how to listen in noisy places. This improves speech understanding and social interaction by increasing the loudness and clarity of sounds reaching the inner ear. [Hearing loss is a core feature of HYAL2 deficiency and usually needs this support.][Low-vision services and visual aids
Severe myopia and risk of retinal problems mean many children need strong glasses and monitoring. Low-vision services can add large-print books, high-contrast materials, and good lighting. The mechanism is to maximize the remaining vision and reduce eye strain so that the child can learn and move safely, even if vision cannot be fully corrected. [Severe myopia and retinal detachment risk are reported in HYAL2 deficiency.][Nutritional counseling and feeding support
Cleft palate, heart failure, or frequent illness can reduce appetite or make feeding tiring. A dietitian teaches the family how to give enough calories, protein, and fluids in small, frequent meals. In some cases, special feeding techniques or thickened fluids are used. This works by matching food texture and timing to the child’s abilities so growth and wound healing are supported.Psychological counseling and family support
Living with a rare disease is stressful for the child and family. Counseling gives a safe space to talk about worry, sadness, or frustration. Therapists teach coping skills, such as relaxation, problem-solving, and communication strategies in the family. This helps reduce anxiety and depression and can improve treatment adherence.Genetic counseling
HYAL2 deficiency is usually inherited in an autosomal recessive pattern, meaning both parents carry one non-working copy of the gene. Genetic counseling explains recurrence risk in future pregnancies and options such as prenatal diagnosis. Its mechanism is education and shared decision-making, helping families plan with full information. [Inheritance patterns are described in HYAL2 deficiency reports.][Respiratory physiotherapy
If heart disease or chest wall deformity causes shallow breathing or frequent chest infections, respiratory physiotherapists teach breathing exercises, airway clearance techniques, and postural drainage. These techniques loosen mucus, improve ventilation, and reduce infection risk.Postural and orthopedic support
Chest wall issues like pectus excavatum and finger anomalies can affect posture and hand use. Bracing, customized chairs, and adapted tools help the child sit and move with less pain and better function. The mechanism is mechanical: good alignment reduces strain on muscles and joints, making activity easier. [Skeletal findings including pectus excavatum are part of the HYAL2 phenotype.][Regular cardiology monitoring and lifestyle advice
Even after surgery, children may have residual heart problems or risk of heart failure. Regular heart check-ups, safe activity guidelines, and advice on managing infections and fever reduce strain on the heart. This preventive approach aims to catch problems early before they cause severe symptoms. [Reports highlight congenital heart defects and risk of heart failure in HYAL2 deficiency.][Cleft lip and palate team follow-up
After surgery, children need regular reviews by a combined team (surgeon, dentist, orthodontist, speech therapist). They check healing, teeth growth, and speech development. Ongoing care makes sure the child can eat, speak, and smile as normally as possible.Dental and orthodontic care
Cleft palate, jaw shape, and long-term medication may affect dental health and tooth alignment. Early, regular dental care, fluoride use, and orthodontic planning protect teeth and improve chewing and appearance. This supports good nutrition and self-confidence.Social work and community resource support
Social workers help families access financial aid, disability services, school support, and transport. The mechanism is practical: by reducing money and access stress, families can focus more on caring for the child and attending appointments.Home safety adaptations
Vision problems, hearing loss, or unsteady balance can increase accident risk at home. Simple measures like good lighting, handrails, non-slip mats, and visual or vibrating alarms make the home safer. This reduces falls and injuries, especially after surgery or during illness.Peer and patient-support groups
Even though HYAL2 deficiency is ultra-rare, families can connect through rare-disease networks. Sharing experiences can reduce feelings of isolation and provide practical tips on coping with hospital visits, school, and daily care. The mechanism is emotional and social support from people in similar situations.Vaccination according to guidelines
Routine vaccines and any extra vaccines recommended by specialists (for heart disease or immunosuppression, if present) help prevent infections that could stress the heart or lungs. This preventive approach supports long-term stability.Advance care planning in severe cases
If heart defects remain serious, families may discuss future care goals with the medical team. Advance care planning is not about “giving up”; it is about understanding possible future scenarios and choosing treatments that fit family values. This can reduce crisis decisions and anxiety.
Drug Treatments
Very important: No drug is currently approved specifically to cure or reverse HYAL2 deficiency. Medications are used to treat related problems such as heart failure, arrhythmias, pain, or infections. Dose and timing must always be decided by a doctor, using official prescribing information such as FDA labels.[
Below are examples of drug types commonly used for the complications seen in HYAL2 deficiency, especially heart disease. Doses are general adult ranges from FDA-approved labels; children need different doses, so this is not a guide for self-treatment.
Enalapril (ACE inhibitor)
Class: ACE inhibitor. Purpose: treat heart failure and high blood pressure related to congenital heart disease. Mechanism: relaxes blood vessels by blocking angiotensin-converting enzyme, reducing workload on the heart. Typical adult dose ranges from 2.5–40 mg per day in divided doses, as directed on the label. Common side effects include cough, low blood pressure, and high potassium. [ACE inhibitors are standard in heart failure management.][Losartan (Angiotensin receptor blocker – ARB)
Used when ACE inhibitors are not tolerated. It blocks angiotensin II receptors, relaxing blood vessels and reducing blood pressure and heart strain. Adult doses often start at 25–50 mg once daily and can be adjusted. Side effects may include dizziness, high potassium, or kidney function changes.Carvedilol (Beta-blocker)
Class: beta-blocker. Purpose: improve survival and symptoms in chronic heart failure. It slows heart rate and reduces the force of contraction, giving the heart more time to fill and pump more effectively over time. Doses are started very low and slowly increased. Side effects include tiredness, low heart rate, and low blood pressure. [Beta-blockers are key therapies in pediatric and adult heart failure care.][Metoprolol succinate (Long-acting beta-blocker)
Another beta-blocker option. Once-daily dosing in adults (for example 25–200 mg) is common in heart failure. It blocks adrenaline on the heart, reducing strain. Side effects are similar to carvedilol: slow heart rate, low blood pressure, and fatigue.Furosemide (Loop diuretic)
Class: diuretic (“water tablet”). Purpose: relieve fluid overload, swelling, and breathlessness when the heart cannot pump effectively. It makes the kidneys pass more salt and water. Adult doses vary widely (e.g., 20–80 mg) depending on symptoms. Side effects include low potassium, dehydration, and low blood pressure. [Diuretics are central in managing congestive heart failure edema.][Spironolactone (Mineralocorticoid receptor antagonist)
This drug blocks aldosterone and helps the body get rid of salt and water while keeping potassium. It improves survival in some heart failure patients. Doses may be 25–50 mg daily in adults. Side effects include high potassium and breast tenderness or enlargement in some people.Dapagliflozin or empagliflozin (SGLT2 inhibitors)
Originally developed for diabetes, these drugs are now also used for chronic heart failure, even in some people without diabetes. They make the kidneys pass extra glucose and water, reducing blood volume and heart strain. Adult doses are usually once daily (e.g., 10 mg). Side effects can include genital infections and dehydration.Low-dose aspirin
In selected patients with congenital heart disease or after surgery, low-dose aspirin is used to reduce clot risk. It works by making platelets less sticky. Typical low-dose adult regimens are 75–100 mg daily, but children’s dosing is different and must be specialist-guided. Side effects include stomach irritation and bleeding risk.Anticoagulants (e.g., warfarin or newer agents when appropriate)
If there is a strong risk of blood clots (for example, certain heart defects or arrhythmias), anticoagulants may be used. They inhibit the clotting cascade. Doses are adjusted by monitoring blood tests (for warfarin) or using fixed doses in newer agents. Side effects mainly relate to bleeding. [Chronic thrombotic microangiopathy has been seen in HYAL2-deficient mice, underscoring clot concerns.][Loop or thiazide diuretics combination
Sometimes doctors combine furosemide with a thiazide diuretic (like hydrochlorothiazide) in resistant fluid overload. The mechanism is blocking sodium reabsorption at different points in the kidney to remove more fluid. This must be done carefully to avoid electrolyte problems.Digoxin (in selected heart rhythm/heart failure cases)
Digoxin helps some hearts pump more strongly and slows heart rate in certain arrhythmias. It works by inhibiting the sodium-potassium pump in heart cells. Dosing is weight-based and very carefully monitored because overdose is dangerous. Side effects include nausea, vision changes, and abnormal heart rhythms.Inhaled bronchodilators (if reactive airway symptoms)
If chest problems or infections cause wheeze, inhaled beta-agonists such as salbutamol may be used. They relax airway muscles and open the breathing tubes. Side effects can include tremor and rapid heart rate.Antibiotics for infections
Children with heart disease may be more vulnerable to severe infections. Antibiotics are chosen by the doctor based on suspected bacteria and infection site. They kill or slow bacterial growth, helping the immune system clear infection. Overuse should be avoided to prevent resistance.Analgesics (paracetamol/acetaminophen)
For postoperative pain or chronic discomfort, simple painkillers are often used. Paracetamol reduces pain and fever by acting in the brain. Dose must be calculated by weight and total daily maximum must not be exceeded to protect the liver.Proton-pump inhibitors (PPIs) after surgery or with certain drugs
Medicines such as omeprazole reduce stomach acid and help prevent ulcers when a child is on aspirin, anticoagulants, or steroids. They block the proton pump in stomach cells. Side effects can include headache and, with long-term use, altered mineral absorption.Iron supplements (if iron-deficiency anemia)
If blood tests show low iron due to poor intake or surgery blood loss, iron therapy may be used. Iron is needed for hemoglobin, which carries oxygen. Oral preparations are usually given once or twice daily, with side effects like stomach upset and constipation.Vitamin D and calcium (if deficient and safe for heart)
If bone health is affected by limited activity or nutrition, doctors may prescribe vitamin D and calcium. They help build and maintain strong bones. Doses depend on blood levels and age. Over-supplementation can harm kidneys and the heart, so monitoring is essential.Topical or local anesthetics plus hyaluronidase for procedures
Hyaluronidase (such as Hylenex recombinant) is an FDA-approved adjuvant used to spread local anesthetic and fluids under the skin. It is not a cure for HYAL2 deficiency but may be used during some procedures to improve drug dispersion. It works by temporarily breaking down hyaluronan in connective tissue. Side effects can include local swelling or allergic reactions. [FDA labels describe its indication as a tissue permeability modifier.][Corticosteroids (short courses when clinically necessary)
In certain situations, such as severe postoperative inflammation or autoimmune problems, short courses of steroids like prednisolone may be used. They reduce inflammation by altering gene expression in immune cells. Long-term use has serious side effects (weight gain, infection risk, bone thinning), so doctors try to keep dose and duration as low as possible.Emergency medicines for heart rhythm or heart failure crises
In intensive care, drugs such as inotropes (for example, milrinone) or vasopressors may be used in dangerous heart situations. They change how strongly the heart beats and how blood vessels constrict. These medicines are highly specialized and only used in hospital under close monitoring.
Dietary Molecular Supplements
Evidence for supplements specifically in HYAL2 deficiency is very limited. These are general ideas used in heart and connective-tissue support. Always ask a doctor before starting any supplement, especially in children or with heart disease.
Omega-3 fatty acids (fish oil)
Omega-3 fats (EPA and DHA) may help reduce inflammation and support heart health. They slightly lower triglycerides and may improve blood vessel function. Typical adult doses in studies range around 1 g/day, but dosing in children must be individualized. Possible side effects include fishy aftertaste and mild bleeding tendency at high doses.Coenzyme Q10 (CoQ10)
CoQ10 is involved in energy production in mitochondria, especially in heart muscle cells. Supplementation may support energy metabolism in some heart conditions, although data are mixed. Adult doses in studies range from 30–200 mg/day. Side effects are usually mild, such as stomach upset.L-carnitine
L-carnitine helps move fatty acids into mitochondria for energy use. In some inherited heart or muscle diseases it has been used to support heart function. Doses in children are weight-based and must be prescribed. Too much can cause diarrhea and fishy body odor.Vitamin D
Vitamin D helps maintain bone health and immune function. Children with chronic illness may spend less time in sunlight and be deficient. Corrective doses belong to the doctor, who checks blood levels. Side effects of excessive doses include nausea, weakness, and high calcium.Calcium (if needed)
Calcium is vital for bones and muscle contraction, including the heart. If diet is poor or steroids are used, doctors may suggest supplements. Over-supplementation can raise blood calcium and strain kidneys and the heart, so it must be monitored.Magnesium
Magnesium helps keep heart rhythm stable and supports muscle and nerve function. Mild deficiency can worsen arrhythmias. Supplements can be given orally in controlled doses. Too much magnesium can cause diarrhea or, in severe overdose, low blood pressure and slow breathing.B-complex vitamins
B vitamins (like B1, B6, B12, folate) support energy metabolism and red blood cell production. Poor intake or chronic illness can lower levels. Balanced supplements may help correct mild deficiencies and improve overall energy. Excessive intake can cause side effects, especially with B6 (nerve issues) or niacin (flushing).Antioxidant vitamins (C and E in moderate amounts)
Antioxidants help neutralize free radicals that can damage cells. In heart disease research, results are mixed, so mega doses are not recommended. Small doses within recommended daily allowances can be part of a balanced diet. High doses may interfere with some medicines and should be supervised.Probiotics
Probiotic supplements may support gut health, especially if the child has taken many antibiotics. A healthier gut may improve nutrient absorption and immune balance. They are generally safe in healthy people but may not be suitable in some immune-compromised states.Zinc
Zinc is important for wound healing and immune function. After surgeries like cleft repair or cardiac surgery, adequate zinc intake supports recovery. Supplements should match age-appropriate recommended doses to avoid nausea or interference with copper absorption.
Regenerative, Immunity-Boosting and Stem-Cell-Related Drugs
Right now, there are no specific regenerative or stem-cell drugs approved to treat HYAL2 deficiency itself. The items below describe broader research or related therapies that might be discussed in complex cases. They are usually experimental or only used for other conditions.[
Standard childhood vaccines (immune “boosting” the safe way)
The best proven way to strengthen immunity is to keep vaccinations up to date. Vaccines train the immune system to recognize and fight specific infections. This reduces the chance that infections will worsen heart or lung problems. They are given in age-based schedules with well-known safety profiles.Palivizumab or similar monoclonal antibodies in high-risk infants (where indicated)
In some infants with serious congenital heart disease, monoclonal antibodies against RSV are used seasonally to prevent severe lung infection. They do not “fix” HYAL2 deficiency but can reduce hospitalization risk. They work by giving ready-made antibodies that neutralize the virus.Growth factors for red blood cells (e.g., erythropoiesis-stimulating agents in selected anemia)
If chronic illness or kidney problems cause anemia that does not respond to iron, doctors may consider agents that stimulate red blood cell production. They bind to bone marrow receptors and signal the body to make more red cells. Their use must be carefully weighed because of clotting risks.Experimental cardiac regenerative therapies
In the future, stem-cell-based therapies aimed at repairing damaged heart tissue might be studied in people with congenital heart defects or heart failure. They try to replace or support damaged heart muscle cells. At present, these are mostly in research trials and not standard care for HYAL2 deficiency.Gene-therapy research concepts
Because HYAL2 deficiency is caused by mutations in a single gene, scientists may consider gene-replacement or gene-editing approaches in the long term. The idea is to deliver a working copy of HYAL2 to key tissues. As of now, there are no approved gene-therapy products for HYAL2 deficiency; any such work would be highly experimental.Hematopoietic stem-cell transplantation (HSCT) – theoretical discussion only
In some lysosomal storage disorders, HSCT is used to provide enzyme from donor cells. However, current literature does not support HSCT as standard treatment for HYAL2 deficiency, partly because the main problems are structural heart and craniofacial defects already formed in fetal life. Any consideration of HSCT would require specialist center review and is not routine care.
Surgical and Procedural Treatments
Congenital heart defect repair
Many children with HYAL2 deficiency have complex heart malformations. Cardiac surgeons may repair holes between heart chambers, faulty valves, or abnormal blood vessel connections. The goal is to improve blood flow and reduce heart failure symptoms. The procedure is done under general anesthesia with heart-lung bypass and requires intensive care afterwards. [Heart defects and heart failure are central features in HYAL2 deficiency.][Cleft lip and palate repair
Cleft lip and/or palate surgery is usually done in early childhood. Surgeons reconnect the muscles and tissues of the lip and palate to restore the ability to feed, speak, and grow the midface correctly. Multiple surgeries may be needed as the child grows.Eye surgeries (for retinal detachment or severe myopia complications)
High myopia increases the risk of retinal detachment. If part of the retina peels away, urgent surgery such as scleral buckle or vitrectomy may be required to reattach it. The purpose is to preserve as much vision as possible. These operations are delicate and require long-term eye follow-up. [Ophthalmic problems, including myopia and retinal detachment risk, are well described.][Chest wall surgery (for severe pectus excavatum)
If the sternum is sunken deeply and compresses the heart or lungs, operations like the Nuss procedure may be considered. Surgeons place a curved bar under the sternum to lift it forward. This can improve breathing, exercise tolerance, and appearance, but is usually reserved for severe cases.Ear surgery and hearing implants
Children with conductive hearing loss may benefit from tympanostomy tubes, reconstructive ear surgery, or bone-anchored hearing systems. These procedures aim to improve transmission of sound to the inner ear, supporting speech and learning. The exact choice depends on the type and severity of hearing loss.
Prevention and Risk Reduction
Genetic counseling before future pregnancies – helps parents understand recurrence risk and options such as carrier testing or prenatal diagnosis.
Early diagnosis in siblings – if another pregnancy occurs, early testing allows newborns to be monitored from birth, so heart and feeding problems can be treated promptly.
Strict follow-up with cardiology and ophthalmology – regular checks catch problems early (for example, worsening valve disease or early retinal changes).
Prompt treatment of infections – infections can stress the heart and lungs, so fevers, cough, or breathing difficulty should be checked quickly.
Adherence to medication and appointment plans – keeping to the agreed plan reduces risk of heart failure flare-ups or sudden events.
Healthy lifestyle (age-appropriate activity, no smoking exposure) – avoiding tobacco smoke and encouraging gentle activity helps protect the heart and lungs.
Safe surgery planning in specialized centers – children with complex heart disease benefit from surgery in experienced centers, reducing complications.
Eye-safety and avoiding eye trauma – with fragile retinas, protecting the eyes from impact (sports goggles, careful play) reduces retinal detachment risk.
Good dental hygiene – reduces the chance of infections that could, in some heart conditions, contribute to endocarditis.
Clear emergency plans – families are taught when to go to hospital and which symptoms are urgent, reducing delays in serious situations.
When to See a Doctor
You should seek urgent medical care (emergency room or immediate contact) if the child or adult with HYAL2 deficiency shows:
Sudden difficulty breathing, fast breathing, or blue lips or fingers
Chest pain, fainting, or a sudden drop in activity and alertness
Sudden vision loss, flashing lights, or “curtain” over part of the vision (possible retinal detachment)
New or rapidly worsening swelling of legs, belly, or face
High fever, especially with fast breathing or poor feeding
You should arrange a prompt routine appointment if there is:
Gradual worsening tiredness, poor weight gain, or reduced appetite
Changes in hearing (needing higher TV volume, not responding to sounds)
Worsening short-sightedness or frequent headaches from eye strain
Any new heart murmur or change noticed by a local doctor
Concerns about school progress, behavior, or mood
Regular planned visits with cardiology, ENT, ophthalmology, cleft team, and genetics are important even when the child looks “well,” because some problems progress quietly. [GeneReviews emphasizes ongoing monitoring to manage complications in HYAL2 deficiency.][
Diet: What to Eat and What to Avoid
Eat plenty of fruits and vegetables – they provide vitamins, minerals, and antioxidants that support overall health and healing after surgeries.
Choose whole grains – brown rice, whole-wheat bread, and oats support energy and healthy weight, especially important when illness has reduced appetite.
Include lean proteins – fish, lean meat, eggs, beans, and lentils help build and repair heart, muscle, and surgical wounds.
Use healthy fats – small amounts of olive oil, nuts (if safe), and seeds supply essential fatty acids, including some omega-3s, for heart and brain health.
Limit added salt – too much salt can worsen fluid retention and blood pressure in heart disease. Avoid heavily salted snacks, instant noodles, and processed meats unless a doctor says otherwise.
Avoid sugary drinks and excess sweets – they add calories without nutrients and can contribute to weight problems and poor dental health.
Limit trans fats and deep-fried foods – they are harmful to blood vessels and heart health. Choose baking, steaming, or grilling instead.
Keep good hydration – unless a cardiologist has given a specific fluid limit, regular water intake supports circulation and kidney function.
Avoid self-prescribed herbal mixtures – some herbs can interact with heart drugs or cause bleeding. Always check with the medical team before trying any herbal product.
Work with a dietitian – especially after heart or cleft surgery, a dietitian can design meal plans that meet energy needs in small, easy-to-eat portions.
Frequently Asked Questions ( FAQs)
Is hyaluronidase 2 deficiency the same as hyaluronidase 1 deficiency or mucopolysaccharidosis?
No. HYAL2 deficiency is a different, very rare condition. It mainly causes heart, face, eye, ear, and chest problems, with usually normal intelligence. HYAL1 deficiency causes a more classic mucopolysaccharidosis-like storage disorder. [These conditions are classified separately in rare-disease resources.][Can extra hyaluronidase injections cure HYAL2 deficiency?
No. Hyaluronidase injections, like Hylenex, are used as helpers during other injections to spread fluids and drugs under the skin. They do not correct the genetic lack of HYAL2 in development and are not a cure for the condition. [FDA labels list only adjuvant indications for hyaluronidase.][Will my child’s intelligence be affected?
Based on reported cases so far, most individuals with HYAL2 deficiency have normal intellect, although some may have learning difficulties due to hearing or vision problems, many surgeries, or time away from school. Supportive education can help them reach their potential. [Case summaries report typical intellect but multisystem physical issues.][Is HYAL2 deficiency always life-threatening?
The severity can vary. Some children have serious heart defects or heart failure that are life-threatening without surgery. Others have milder heart changes and live longer with careful monitoring. Early diagnosis and treatment improve outcomes.Can HYAL2 deficiency be found before birth?
If the exact HYAL2 mutations are known in the family, prenatal genetic testing or preimplantation genetic testing may be possible. Detailed fetal heart and anatomy scans can also sometimes detect major structural problems. These options require specialist genetic counseling.Is there a special “HYAL2 diet”?
No specific diet can fix the gene defect, but a heart-healthy, balanced diet supports surgeries, growth, and heart function. Low-salt, nutrient-rich foods and avoiding excess sugar and unhealthy fats are generally advised, adjusted to the child’s needs.Can children with HYAL2 deficiency play sports?
Some physical activity is usually helpful, but limits depend on the heart condition. The cardiologist should specify what is safe (for example, light walking may be fine, while competitive high-intensity sports may not).Will my other children have the same condition?
If both parents are carriers, each pregnancy has a 25% chance of an affected child, 50% chance of a carrier, and 25% chance of a non-carrier. Genetic testing can clarify risk for each family.Are there research studies or clinical trials?
Because HYAL2 deficiency is ultra-rare, research is limited, but new case reports and reviews continue to appear. Families can ask genetic specialists or rare-disease networks about registries or observational studies, which help improve future care. [Recent literature adds new HYAL2 mutation cases and clinical descriptions.][Does HYAL2 deficiency affect life expectancy?
Data are limited, but severe, uncorrected heart defects and heart failure can shorten life. With modern surgery and careful monitoring, some individuals may live longer than earlier cases. Each person’s outlook depends on their specific heart and organ problems.Can HYAL2 deficiency cause blood problems?
In mouse models, HYAL2 deficiency causes chronic thrombotic microangiopathy with hemolytic anemia, meaning small-vessel clots and blood cell damage. In humans, this link is less clear but is being studied. Doctors may monitor blood tests in some patients. [Animal studies highlight this hematologic mechanism.][Can HYAL2 deficiency be missed or misdiagnosed?
Yes. Because it is so rare and the signs (heart defects, cleft palate, myopia, hearing loss) overlap with other syndromes, diagnosis often needs advanced genetic testing, such as exome sequencing.Is pregnancy possible for adults with HYAL2 deficiency?
There are almost no data yet, but any pregnancy in someone with congenital heart disease needs high-risk obstetric and cardiology care. Genetic counseling is essential beforehand to discuss recurrence risk and maternal health.Should we avoid all vaccines or procedures because of the heart condition?
No. Most vaccines and many procedures are especially important because they prevent complications. However, timing and type should be guided by the heart and genetics teams, and any anesthesia should be planned in a center with congenital heart expertise.What is the most important thing families can do?
Stay linked with a specialist team, keep regular appointments, share any new symptoms early, and ask questions when something is unclear. With good coordination, families and clinicians can work together to give the child the best possible quality of life despite this rare 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.
