Cloverleaf skull–multiple congenital anomalies syndrome is a very rare condition that a baby is born with. In this syndrome, the bones of the skull close too early in many places. This makes the skull bulge out in three rounded parts, like a three-leaf clover. At the same time, the baby has problems in other parts of the body, such as the face, arms, legs, and inner organs. Doctors call these extra problems “multiple congenital anomalies.” In this syndrome, the skull shape problem is a severe type of craniosynostosis. Craniosynostosis means the seams (sutures) between skull bones close too early. In cloverleaf skull, several sutures, such as the sagittal, coronal, and lambdoid sutures, close before birth. Because the brain still wants to grow, it pushes the soft skull outward, creating the typical cloverleaf shape.
Cloverleaf skull (Kleeblattschädel)–multiple congenital anomalies syndrome is a very rare, severe birth condition where several skull seams (sutures) close too early before birth. This causes the skull to bulge in three directions like a cloverleaf, often with a very high, bossed forehead, bulging sides of the skull, and a flattened back. The abnormal bone growth blocks normal brain expansion and can lead to raised pressure in the head (intracranial hypertension), hydrocephalus (extra fluid in the brain), eye bulging, breathing problems, and developmental delay.
It is not a single disease but a pattern that can appear as part of several genetic syndromes, such as thanatophoric dysplasia type II, Pfeiffer syndrome type II, Crouzon syndrome, and other complex craniosynostosis syndromes. Many babies also have other congenital anomalies, including short limbs, chest narrowing, airway obstruction, and heart defects, so care must focus on the whole child, not just the skull shape.
Many babies with cloverleaf skull also develop hydrocephalus, which is extra fluid inside the brain spaces. This fluid raises pressure in the head and can harm the brain if not treated. Babies with this syndrome often have bulging eyes, a flat midface, and problems with breathing or feeding. The condition is usually part of serious genetic syndromes and is often life-threatening.
Other names
Cloverleaf skull–multiple congenital anomalies syndrome is part of the larger group called kleeblattschädel or cloverleaf skull. These are some other names or related terms that doctors may use:
-
Cloverleaf skull syndrome
-
Kleeblattschädel deformity
-
Holtermüller–Wiedemann syndrome (older name for cloverleaf skull)
-
Isolated cloverleaf skull syndrome
-
Cloverleaf skull–asphyxiating thoracic dysplasia syndrome (when the chest is also very narrow)
-
Cloverleaf skull associated with thanatophoric dysplasia or Pfeiffer syndrome
Types
Doctors sometimes group cases into simple “types” based on how the skull problem appears and what other problems are present:
-
Isolated type – the cloverleaf skull happens mostly alone, with fewer problems in other organs.
-
Syndromic craniofacial type – the cloverleaf skull occurs with a craniofacial syndrome, such as Crouzon or Pfeiffer syndrome, and the baby has face, hands, and feet changes.
-
Skeletal dysplasia type – the cloverleaf skull is part of a bone-growth disorder such as thanatophoric dysplasia. In this type the baby has short limbs and a very narrow chest, and many other organs can be affected.
These “types” are not strict official classes but help doctors think about patterns of problems that come together in each child.
Causes
-
Premature closure of many cranial sutures
The main direct cause is that several skull sutures (sagittal, coronal, lambdoid, sometimes metopic) close too early before birth. Because the skull cannot expand normally, the brain pushes outward wherever it can, making three rounded bulges that look like a cloverleaf. -
Hydrocephalus increasing pressure inside the skull
Extra fluid in the brain, called hydrocephalus, raises pressure inside the head. This high pressure can push on weak areas of the skull and make the abnormal shape worse. Hydrocephalus is common in babies with cloverleaf skull and adds to brain and eye problems. -
Genetic changes in FGFR2 and related genes
In some related syndromes, such as Pfeiffer syndrome, changes (mutations) in the fibroblast growth factor receptor genes FGFR1 and FGFR2 disturb how bone forms and when sutures close. These genes help tell bone cells when to grow and when to stop. Abnormal signals can make sutures close too early. -
Thanatophoric dysplasia type 2
Thanatophoric dysplasia type 2 is a severe skeletal (bone) disorder that affects limb length, chest size, and skull shape. It is strongly associated with cloverleaf skull because the skull sutures fuse early and the brain is large compared with the small skull. Many babies with this condition do not survive long after birth. -
Pfeiffer syndrome type 2
Pfeiffer syndrome is a genetic craniosynostosis syndrome. In the more severe type 2, the sutures fuse early and a cloverleaf skull can form, along with bulging eyes and hand and foot anomalies. The same genetic changes that cause Pfeiffer syndrome can therefore also cause the cloverleaf skull pattern. -
Crouzon syndrome
Crouzon syndrome is another craniosynostosis syndrome in which skull sutures close early. In some severe cases, the pattern of fusion and brain growth leads to a cloverleaf skull shape. These babies may also have shallow eye sockets, midface undergrowth, and airway problems. -
Carpenter syndrome
Carpenter syndrome is a rare disorder with craniosynostosis, extra fingers or toes, and heart or other organ defects. Because the skull sutures can fuse in many places, it has been reported together with cloverleaf skull in some children as part of a syndrome with many birth anomalies. -
Antley–Bixler syndrome
Antley–Bixler syndrome combines craniosynostosis, limb bending, and joint contractures. In some patients, the skull sutures close in a way that produces a cloverleaf-like shape. The broad pattern of bone abnormalities and joint problems shows that early bone formation is disrupted in many parts of the skeleton. -
Beare–Stevenson cutis gyrata syndrome
This rare genetic condition causes unusual folds in the skin of the scalp and forehead and craniosynostosis. Some babies with Beare–Stevenson syndrome have a cloverleaf skull, showing that abnormal skull bone fusion is part of a larger pattern of skin and bone changes. -
Cloverleaf skull–asphyxiating thoracic dysplasia syndrome
In this form, the cloverleaf skull occurs together with a very narrow chest (thorax) and short ribs. The small chest makes breathing very difficult and can be life-threatening. Here the same developmental problem affects skull bones and the bones of the chest. -
Cranioectodermal dysplasia
Cranioectodermal dysplasia is a condition that affects the skull, hair, teeth, and nails. It includes craniosynostosis, and in some patients a cloverleaf-like skull appears. Because skin and bone share early developmental pathways, both can be affected by the same genetic problem. -
Micromelic bone dysplasia with cloverleaf skull
This is a severe bone growth disorder with very short limbs and abnormal spine and rib bones. It has been reported in babies with cloverleaf skull, showing that when bone growth is severely disturbed, the skull is often affected as well. -
Mosaic trisomy 5
In mosaic trisomy 5, some of the baby’s cells have an extra copy of chromosome 5. This rare chromosomal problem has been linked to cloverleaf skull in some cases. The extra genetic material can upset normal skull and organ development and lead to multiple congenital anomalies. -
Muenke syndrome
Muenke syndrome is a craniosynostosis condition usually involving the coronal sutures. In rare, more severe cases, fusion of many sutures may lead to a cloverleaf-type skull. This shows that the same basic gene problem may produce mild or very severe skull shapes in different children. -
Osteoglophonic dysplasia
Osteoglophonic dysplasia is a rare skeletal disorder with abnormal facial bones and short stature. In some cases, craniosynostosis with a cloverleaf pattern has been reported. The gene problems here affect how bone matrix forms and how fast bones harden, including skull bones. -
Non-syndromic (isolated) multiple-suture craniosynostosis
Sometimes, cloverleaf skull appears without a known syndrome. In these “isolated” cases, several sutures close early but doctors do not find a wider pattern of symptoms. This form is still serious and is thought to result from unknown genetic or developmental errors affecting the skull only. -
De novo (new) dominant mutations
Many severe craniosynostosis syndromes arise from new mutations that are not present in either parent. These changes occur in the sperm or egg or very early embryo. Because they affect how bone and cartilage develop, they can lead to cloverleaf skull and many other anomalies even when no family history exists. -
Inherited autosomal dominant conditions
Some related syndromes, such as classic Pfeiffer syndrome, are inherited in an autosomal dominant way. This means one changed gene from an affected parent is enough to cause disease. In families with very severe forms, a baby may inherit a gene variant that leads to cloverleaf skull and multi-organ problems. -
Broad disturbance of early embryo development
Cloverleaf skull–multiple congenital anomalies syndrome often includes limb defects and internal organ problems, not just skull changes. This suggests a broad disturbance in early embryo development, where signals that guide bone, brain, and organ formation are all altered at the same time. -
Unknown or not yet identified genetic causes
In some babies, doctors still cannot find the exact gene change or trigger. Medical articles note that the cause of isolated cloverleaf skull is unknown in many cases. Ongoing research and more detailed genetic testing may discover new genes and pathways in the future.
Symptoms
-
Cloverleaf-shaped skull
The most obvious sign is the trilobed “cloverleaf” shape of the skull. The head looks very broad with three rounded parts, usually from the forehead and the sides bulging out. This happens because the brain grows against a stiff skull with fused sutures and pushes out in weak areas. -
Bulging, widely spaced eyes (proptosis)
The eye sockets are shallow and the bones around them are underdeveloped, so the eyes appear to bulge out and may be far apart. This is called proptosis. It can leave the eyes poorly protected and can lead to irritation, dryness, or damage to the cornea. -
Flat or underdeveloped midface
Many babies have midface hypoplasia, which means the bones of the middle face (cheeks, upper jaw) do not grow forward as they should. The face can look sunken or flat. This may cause problems with breathing through the nose and can affect how the teeth line up later. -
Large or abnormal soft spots and sutures
The soft spots (fontanels) on the baby’s head may be large or irregular. When doctors feel the skull, they may notice ridges or gaps where sutures have fused in unusual ways. These findings help them suspect craniosynostosis and a cloverleaf pattern. -
Signs of raised pressure in the head
Because of hydrocephalus and the tight skull, the baby may have vomiting, a very large head size, irritability, sleepiness, or a bulging soft spot. Over time, high pressure can damage the brain, leading to developmental delay or vision loss if not treated. -
Breathing problems
Some babies have a very narrow chest or severe midface undergrowth. This can cause breathing trouble soon after birth, such as fast breathing, noisy breathing, or episodes of stopping breathing. In skeletal dysplasia types, the small chest may not allow the lungs to expand well. -
Feeding difficulties
Problems with the jaw, palate, and breathing can make feeding hard. The baby may tire easily, cough, choke, or fail to gain weight. Sometimes a feeding tube is needed for safe nutrition. Poor feeding can worsen growth and development problems. -
Developmental delay and possible intellectual disability
Many children with severe cloverleaf skull and multiple anomalies have delays in sitting, walking, and talking. High pressure in the brain, hydrocephalus, and structural brain changes can affect learning and movement. In some associated syndromes, early death is common. -
Limb abnormalities
The arms and legs may be short or shaped differently. Some babies have bent elbows, joint stiffness, or very short limbs, especially in thanatophoric dysplasia and related syndromes. Fingers and toes can be broad, fused, or extra in number. -
Joint stiffness or abnormal positions
Joints, especially elbows and knees, may be fixed in one position (ankylosis) or have limited movement. This comes from abnormal bone growth around joints and may restrict normal movement and later function. -
Hearing loss
Many craniosynostosis syndromes include hearing problems. Hearing loss can come from middle ear fluid, abnormal ear bones, or nerve hearing loss. In cloverleaf skull–multiple anomalies syndrome, hearing loss may add to developmental delay because the child does not hear speech clearly. -
Vision problems and corneal damage
Because the eyes bulge and the eyelids may not close fully, the clear front part of the eye (cornea) can dry out, ulcerate, or scar. Recurrent corneal erosions and other eye complications are reported in kleeblattschädel. Early eye care is very important. -
Heart and other organ defects
In many cases with multiple congenital anomalies, babies may have heart defects, kidney problems, or abnormalities of the intestines or genitals. These add to the severity of the condition and can limit life span, especially when combined with breathing and brain problems. -
Seizures
Because the brain can be under pressure or malformed, seizures may occur. Seizures can appear as staring spells, jerking movements, or sudden stiffness. They are a sign that the brain is irritated or damaged and often require urgent treatment. -
Poor growth and failure to thrive
Due to feeding difficulties, repeated infections, and organ problems, many babies do not gain weight or grow as expected. This is called “failure to thrive.” It reflects how serious the overall condition is, not just the skull shape.
Diagnostic tests
Physical exam tests
-
Newborn physical examination
Right after birth, doctors examine the baby’s whole body. They look at the head shape, face, chest, limbs, and genital area. In cloverleaf skull–multiple congenital anomalies syndrome, they may see the characteristic skull shape along with limb differences and other organ problems. -
Head shape and circumference measurement
The doctor measures the head size with a tape measure and compares it to normal charts. They also visually inspect and feel the skull. A trilobed head, ridged sutures, and very large or odd head size suggest cloverleaf skull with possible hydrocephalus. -
Neurological examination
The baby’s muscle tone, reflexes, and movements are checked. The doctor looks for weakness, abnormal reflexes, or seizures. These findings can show brain pressure or damage from hydrocephalus and skull restriction. -
Eye and face inspection
The examiner looks at how far the eyes bulge, how wide apart they are, and whether the eyelids close fully. They also look at the midface and jaw. Proptosis, wide-set eyes, and midface undergrowth are typical clues to a craniosynostosis syndrome such as cloverleaf skull. -
Chest, heart, and lung examination
The doctor checks the chest size and shape and listens with a stethoscope. A narrow chest, signs of breathing effort, or heart murmurs may point to associated skeletal dysplasia or heart defects, which are part of the “multiple congenital anomalies.”
Manual tests
-
Palpation of cranial sutures and fontanels
By gently feeling the baby’s head, the doctor checks whether sutures are open, ridged, or fused. In cloverleaf skull, several sutures feel fused or abnormal, and the soft spots may be tense or bulging, suggesting high pressure. -
Manual eye protection and corneal check
The clinician may gently lift the eyelids and examine the cornea for dryness or ulcers using a light. Because the eyes are exposed and bulging, this test helps detect early eye damage and guides urgent eye lubrication or surgery. -
Limb and joint range-of-motion testing
The arms, legs, and joints are moved carefully through their normal ranges. Limited movement, fixed joints, or abnormal limb lengths suggest syndromes such as thanatophoric dysplasia or Antley–Bixler syndrome, which can be linked to cloverleaf skull. -
Anthropometric measurements
Doctors measure body length, arm span, chest circumference, and limb segment lengths. Short limbs, small chest, or unusual body proportions support a diagnosis of skeletal dysplasia, helping separate isolated skull problems from full-body syndromes. -
Developmental screening tests
Simple bedside checks of social smile, head control, and limb movements help detect early developmental delay. Although these tests are basic, they give early signs of how the brain is functioning and whether high intracranial pressure is affecting development.
Lab and pathological tests
-
Chromosomal microarray analysis
This blood test looks for missing or extra pieces of chromosomes. It can detect conditions such as mosaic trisomy 5, which has been linked with cloverleaf skull and multiple anomalies. The result helps confirm that a broad genetic error is present. -
Targeted gene panel for craniosynostosis
Special genetic tests can analyze many craniosynostosis-related genes at once, including FGFR1, FGFR2, and others. Finding a mutation in these genes can confirm a diagnosis such as Pfeiffer or Crouzon syndrome in a baby with cloverleaf skull. -
Whole-exome or whole-genome sequencing
When standard tests do not find a cause, broader sequencing can search all known genes for rare or new mutations. This is useful because many babies with cloverleaf skull–multiple anomalies have not yet identified gene changes. It can also help future family planning. -
Basic blood tests for organ function
Tests such as full blood count, kidney function, and liver enzymes help assess the baby’s overall health. Because multiple congenital anomalies may affect many organs, these tests guide safe use of medicines, anesthesia, and nutrition plans. -
Metabolic and endocrine screening
In some complex congenital conditions, doctors screen for metabolic or hormone problems that could worsen growth and development. Although not specific to cloverleaf skull, these tests help ensure there is no treatable metabolic disease on top of the structural anomalies.
Electrodiagnostic tests
-
Electroencephalogram (EEG)
An EEG records the electrical activity of the brain through electrodes on the scalp. In babies with seizures or suspected brain dysfunction, EEG helps detect abnormal brain waves. In cloverleaf skull–multiple anomalies, this can show whether seizures are occurring due to high pressure or structural brain problems. -
Auditory brainstem response (ABR) hearing test
ABR measures the brain’s response to sound using small electrodes. It is useful for babies who cannot cooperate with regular hearing tests. Because hearing loss is common in craniosynostosis syndromes, ABR helps identify early hearing problems so that hearing aids or other support can be planned.
Imaging tests
-
Prenatal ultrasound
During pregnancy, detailed ultrasound can sometimes show a cloverleaf skull shape, short limbs, or a narrow chest. These findings alert doctors that a severe skeletal or craniosynostosis syndrome may be present. Parents can then receive counseling and planning for birth and care. -
Fetal MRI
Fetal MRI can give clearer pictures of the brain, skull, and chest than ultrasound alone. It can show hydrocephalus, brain malformations, and the degree of skull deformity in suspected thanatophoric dysplasia or similar conditions with cloverleaf skull. -
Postnatal CT or MRI of the skull and brain
After birth, CT scans of the skull show exactly which sutures are fused and how the bones are shaped. MRI shows the brain structures and hydrocephalus. These images are essential for planning any possible skull surgery and for judging prognosis in cloverleaf skull–multiple congenital anomalies syndrome.
Non-pharmacological treatments (therapies and other approaches)
Note: In real life, the exact plan is customized for each baby. Below are 20 key non-drug approaches commonly used as part of multidisciplinary care.
-
Early multidisciplinary care
From the first hours of life, the baby is best cared for by a combined team (neonatology, neurosurgery, craniofacial surgery, ENT, cardiology, genetics, rehabilitation). The purpose is to quickly identify life-threatening problems like breathing difficulty and raised intracranial pressure. This team approach works by coordinating decisions and timing of operations so that every intervention supports overall survival and long-term function. -
Careful positioning and head support
Nurses and parents are taught special ways to position the head and body to protect the fragile skull, support the airway, and reduce pressure on bulging areas. The purpose is to keep venous drainage and breathing as easy as possible. It works by using soft supports, avoiding tight hats or pressure points, and regularly changing position, especially before definitive skull surgery is done. -
Airway management and respiratory support
Many babies have small midface bones, narrowed nasal passages, or chest problems, so they may need oxygen, non-invasive ventilation, or sometimes intubation and mechanical ventilation. The purpose is to keep blood oxygen levels safe and prevent strain on the heart and brain. It works by stabilizing breathing until surgical correction of facial bones and skull relieves pressure and improves airflow. -
Feeding and nutritional support
Because of breathing difficulty, weak suck, or reflux, some infants need feeding through a nasogastric tube or gastrostomy. The purpose is to give enough calories and protein to support brain growth and wound healing. This works by bypassing unsafe oral feeding, using thickened feeds or tube feeding, and involving dietitians to plan high-energy formulas or breast-milk fortification. -
Physiotherapy (physical therapy)
Physiotherapists assess muscle tone, movement, and posture. The purpose is to prevent joint stiffness, improve motor milestones, and support breathing mechanics. Therapy works through gentle range-of-motion exercises, positioning, and early motor play that is carefully adapted to protect the skull and any surgical sites, while helping the baby learn to roll, sit, and later walk as safely as possible. -
Occupational therapy
Occupational therapists focus on daily skills, sensory processing, and arm–hand coordination. The purpose is to help the child use their hands, interact with toys, and gradually participate in age-appropriate self-care. It works through customized play activities, adaptive tools, and caregiver training, helping to bypass physical limitations and support school readiness later in life. -
Speech and language therapy (including feeding therapy)
Speech therapists help with both swallowing and communication. The purpose is to reduce aspiration risk, support safe feeding, and encourage early communication (eye contact, gestures, sounds). Therapy works through oral-motor exercises, adjusting nipple types, pacing feeds, and later using play-based language stimulation or alternative communication systems if speech is delayed. -
Vision care and eye protection
Because the eyes may bulge forward (proptosis) and eyelids may not close fully, there is risk of dryness, ulceration, and vision loss. The purpose of non-surgical eye care is to keep the cornea moist and protected. It works via lubricating drops or ointments, moisture chambers, taping eyelids during sleep when necessary, and early referral to ophthalmology for monitoring and planning surgery if needed. -
Hearing evaluation and support
Midface and skull base anomalies can affect the Eustachian tube and middle ear, leading to fluid buildup and hearing loss. The purpose of early hearing screening is to detect problems before they delay language. It works through newborn hearing tests, repeated audiology, and early use of hearing aids or grommet insertion when appropriate, combined with speech therapy. -
Developmental and educational interventions
Developmental paediatrics and early intervention programs assess cognition, language, and behaviour. The purpose is to identify strengths and difficulties early and provide tailored stimulation. This works through structured play, early childhood education services, and Individualized Education Plans in school, helping the child reach their personal best level of independence and learning. -
Psychological support for parents and family
Parents often experience shock, fear, grief, and long-term stress caring for a child with a rare complex condition. The purpose of psychological support is to protect parental mental health and strengthen family coping. It works by offering counselling, peer support groups, clear communication from the team, and help with decision-making about high-risk surgeries and intensive care. -
Genetic counselling
Geneticists explain the underlying syndrome, inheritance patterns, and recurrence risk. The purpose is to help families understand why this happened and what future pregnancies might face. Counselling works by reviewing genetic test results, discussing options such as prenatal diagnosis or pre-implantation genetic testing, and connecting families with syndrome-specific support organizations. -
Seizure first-aid and monitoring education
Some children develop seizures because of brain malformations or hydrocephalus. The purpose of education is to make caregivers confident in recognizing seizures, keeping the child safe, and knowing when to seek urgent help. It works by teaching simple steps (protect the airway, timing the seizure, not putting anything in the mouth) and when to use prescribed rescue medications. -
Infection prevention and hygiene measures
Children with shunts, tracheostomies, or feeding tubes have higher infection risk. The purpose of strict hygiene is to prevent serious shunt infections, pneumonia, and wound infections. It works through handwashing, proper care of devices, up-to-date vaccinations, and early attention to fever or wound redness. -
Sleep positioning and monitoring
Raised intracranial pressure and airway obstruction can worsen during sleep. Parents may be advised to use slight head elevation or side-lying positions. The purpose is to keep breathing stable and reduce nighttime spikes in pressure. It works by combining safe-sleep rules with individualized plans, sometimes including home oximetry or hospital sleep studies. -
Custom helmets and orthotic supports (when appropriate)
In some milder or postsurgical situations, custom cranial helmets or orthoses may be used to gently guide skull shape or support posture. The purpose is cosmetic improvement and better balance of head weight. They work by applying soft, controlled pressure during growth, always under specialist supervision to avoid worsening pressure problems. -
Social work and practical support
Social workers help families access disability benefits, transport, equipment, and respite care. The purpose is to reduce financial and practical stress. It works by linking families to community resources, arranging home modifications, and coordinating with schools and local health services. -
Palliative care in lethal or very severe forms
Some forms, especially those linked to thanatophoric dysplasia, are often not compatible with long-term survival. Palliative care focuses on comfort, bonding, and quality of life rather than aggressive interventions that are unlikely to help. It works by controlling distressing symptoms, supporting family choices, and ensuring compassionate end-of-life care when needed. -
Telemedicine and remote follow-up
Because specialist centres may be far from home, telemedicine visits can help monitor development, surgical outcomes, and family wellbeing between in-person visits. The purpose is to maintain continuity of expert care. It works by using video consultations, sharing imaging and photos securely, and giving clear safety-net advice. -
Pre- and post-operative rehabilitation programs
Before major skull surgery, the team prepares the child with nutritional optimization and respiratory physiotherapy; afterwards, rehab focuses on wound care, safe handling, and gradual activity. The purpose is to reduce complications and speed recovery. It works by following structured protocols that combine nursing care, physiotherapy, and caregiver training around each operation.
Drug treatments
Very important: There is no specific medicine that cures cloverleaf skull syndrome itself. Drugs are used to manage symptoms (pain, seizures, infection, raised intracranial pressure, reflux, etc.) and to support the child around surgery. All dosing must be individualized by the treating specialists, especially in newborns and infants.
Because of length limits, below are 10 key medicine groups commonly used, with examples whose labels are available on [FDA prescribing information] for general reference.
-
Levetiracetam (antiepileptic, e.g., KEPPRA)
Levetiracetam is used to prevent and control seizures that can occur due to brain malformations, hydrocephalus, or after neurosurgery. It belongs to the antiepileptic drug class and is given by mouth or IV in weight-based doses, divided twice daily. It works by modulating synaptic neurotransmitter release via binding to the SV2A protein, helping stabilize brain electrical activity. Common side effects include sleepiness, irritability, and behavioural changes; rare but serious reactions include allergic reactions and mood or psychotic symptoms. -
Phenobarbital (antiepileptic and sedative)
Phenobarbital is another traditional antiepileptic often used in neonates for seizure control when levetiracetam is not enough or not available. It is a barbiturate that enhances GABA-mediated inhibition in the brain. Doses are usually started with a loading dose followed by daily maintenance, adjusted by blood levels. It can cause sedation, breathing depression, low blood pressure, and long-term effects on cognition, so monitoring in intensive care is essential. -
Acetaminophen (paracetamol) injection or oral
Acetaminophen is used to treat pain and fever after surgery or during infections. It is a non-opioid analgesic and antipyretic that works mainly by inhibiting prostaglandin synthesis in the central nervous system. Weight-based doses are given at set intervals, with a strict daily maximum to avoid liver damage, as described in [FDA-approved acetaminophen injection labeling]. Common side effects are usually mild, but overdose can cause severe liver injury. -
Ibuprofen or other NSAIDs
In selected cases, ibuprofen or other non-steroidal anti-inflammatory drugs (NSAIDs) may be used for additional pain relief and inflammation control after surgery. They work by blocking cyclo-oxygenase enzymes and reducing prostaglandin production. Doses are weight-based and limited by kidney function and bleeding risk. Side effects may include stomach irritation, kidney effects, and platelet dysfunction, so surgeons and anaesthetists decide carefully if NSAIDs are appropriate. -
Morphine sulfate (opioid analgesic)
Morphine sulfate is used for strong postoperative pain that does not respond to non-opioid medicines. It is a potent opioid agonist acting mainly on mu-receptors in the brain and spinal cord to reduce pain perception. According to [FDA labeling], dosing must be carefully weight-based and titrated, usually by IV in intensive care, with close monitoring for breathing depression, low blood pressure, nausea, constipation, and the long-term risks of dependence. -
Sedatives such as midazolam
Midazolam, a short-acting benzodiazepine, may be used in intensive care for sedation during ventilation or procedures. It enhances GABA activity, producing calming, amnesia, and muscle relaxation. Dosing is by infusion or intermittent IV bolus, adjusted to sedation scores. Side effects include respiratory depression, low blood pressure, and, rarely, paradoxical agitation; therefore it is used only under continuous monitoring. -
Diuretics (e.g., furosemide) in selected cases
When there is associated heart failure, lung congestion, or problematic fluid overload, diuretics like furosemide may be used. They act on the kidney tubules to increase salt and water excretion, reducing fluid volume and improving breathing. Dosing is weight-based and monitored via urine output and electrolytes. Side effects can include dehydration, low potassium, and metabolic alkalosis, so lab tests are checked regularly. -
Osmotic or other agents for raised intracranial pressure (under specialist control)
In acute crises of raised intracranial pressure before surgery, agents such as hypertonic saline or mannitol may be considered. These work by drawing fluid out of brain tissue into the bloodstream, temporarily lowering pressure. They are given IV with strict monitoring of serum sodium, osmolality, and kidney function. Over- or mis-use can cause electrolyte disturbance, rebound swelling, or kidney stress, so they are restricted to neurosurgical intensive care. -
Broad-spectrum antibiotics (e.g., ceftriaxone)
Children with ventricular shunts, cranial surgery, or airway/feeding devices are at higher risk of serious bacterial infections. Broad-spectrum antibiotics such as ceftriaxone are used when infection is suspected or proven. Ceftriaxone is a third-generation cephalosporin that inhibits bacterial cell wall synthesis and is given as IV or IM injections in weight-based doses, as detailed in [FDA ceftriaxone labeling]. Side effects include allergic reactions, diarrhoea, and rare blood or liver abnormalities. -
Gastric acid suppression (e.g., proton pump inhibitors)
Stress ulcers and reflux are common around major neurosurgery and prolonged ICU care. Proton pump inhibitors (PPIs) such as omeprazole reduce stomach acid by blocking the H⁺/K⁺-ATPase proton pump in gastric parietal cells. Weight-based doses, often once daily, are used to protect the stomach and oesophagus. Side effects may include diarrhoea, headache, and, with long-term use, altered mineral absorption or infection risk, so duration is kept as short as possible.
Dietary molecular supplements
There is no special “miracle” supplement for cloverleaf skull syndrome. Supplements are used to correct documented deficiencies, support bone and brain health, and optimize healing. Below are 10 commonly considered nutrients; all should be used only under medical and dietitian supervision.
-
Vitamin D – Supports calcium absorption and bone mineralization, important after cranial surgeries. Deficiency is corrected with weight-based doses of vitamin D drops or tablets. It works via activation of vitamin D receptors in gut and bone cells, improving calcium handling. Too much can cause high calcium, kidney stones, and vomiting, so blood levels are monitored.
-
Calcium – Adequate calcium intake helps maintain bone strength in a skull undergoing repeated surgeries. It is provided through formula, breast-milk fortifiers, or supplements when intakes are low. Calcium works by forming the mineral part of bone with phosphate. Over-supplementation can cause constipation, high blood calcium, or interfere with iron and zinc absorption, so dosing is carefully planned.
-
Protein supplements (whey or amino acid formulas)
Extra protein may be needed to support wound healing, immune function, and growth, especially after major surgery. Protein works by providing amino acids for tissue repair and enzyme production. Special high-protein formulas or modular powders are added to feeds; excess protein can strain immature kidneys, so dietitians adjust amounts to weight and lab results. -
Omega-3 fatty acids (DHA and EPA)
Omega-3s support brain development and may modulate inflammation. They are usually given as fish-oil-based supplements or formulas enriched with DHA. Mechanistically, they are incorporated into neuronal cell membranes and influence signalling pathways. Side effects can include fishy after-taste and, at high doses, mild effects on bleeding time, so surgeons time doses carefully around operations. -
Iron supplements
Children who undergo multiple surgeries or have feeding difficulties can become anaemic. Iron is crucial for haemoglobin and oxygen transport. Supplements are given as drops or syrups in weight-based doses. Iron works by providing the essential element for haem production in bone marrow. Side effects include dark stools, constipation, and stomach upset; overdoses are dangerous, so all bottles must be stored safely. -
Zinc
Zinc is important for wound healing, immune function, and taste. It acts as a cofactor for many enzymes involved in DNA synthesis and tissue repair. When deficiency is suspected or proven, zinc is added as syrup or part of a multivitamin. Too much zinc can upset copper balance and cause nausea, so doses are kept within recommended ranges. -
Multivitamin–mineral preparations
A complete paediatric multivitamin may be given when intake is limited or selective. These products provide a broad mix of vitamins and trace elements needed for metabolism and growth. They work by filling small deficits that are hard to cover with food alone during illness. Over-use can lead to vitamin excess, especially fat-soluble vitamins, so usually only one product is used at a time. -
Medium-chain triglyceride (MCT) oils
MCT oil adds extra calories in a small volume and is easier to absorb in some gut conditions. It provides rapidly available energy because it is transported directly to the liver and does not always need bile salts. It is mixed into feeds in small amounts; too much can cause diarrhoea or cramps, so doses are increased slowly. -
Probiotics (selected strains)
Probiotics may be considered to support gut flora and reduce antibiotic-associated diarrhoea. They work by introducing beneficial bacteria that compete with harmful organisms and influence immune signalling in the gut. Only strains with paediatric safety data are chosen. Rarely, in severely immune-suppressed patients, probiotics can cause infection, so they are avoided in the sickest children. -
Electrolyte solutions and oral rehydration
When vomiting, diarrhoea, or feeding interruptions occur, balanced electrolyte solutions help maintain fluid and mineral balance. They work by providing glucose and salts in ratios that promote absorption in the small intestine. Over- or under-dilution can disturb sodium balance, so caregivers follow exact mixing instructions.
Immune-booster, regenerative and stem-cell-related drugs
At present, there are no standard immune-booster or stem-cell drugs specifically approved for cloverleaf skull syndrome. Research in related craniofacial and skeletal disorders explores growth-factor modulation and stem-cell-based bone regeneration, but these remain experimental and are limited to trials. Examples include:
-
Haematopoietic or mesenchymal stem-cell therapies – experimental approaches to support bone or immune function in some syndromic or metabolic conditions; not routine care for cloverleaf skull.
-
Immune-modulating biologics or IVIG – used only when there is a separate immune disorder; they act on specific immune pathways or provide pooled antibodies.
-
Erythropoiesis-stimulating agents or growth-factor drugs – occasionally considered when there are coexisting marrow problems, but not standard for this syndrome alone.
Families should understand that, outside clinical trials, the main proven “regenerative” treatment is careful surgical reconstruction combined with good nutrition and rehabilitation.
Surgeries (procedures and why they are done)
-
Cranial vault expansion / cranial vault remodeling
This is the key operation where surgeons open and reshape large parts of the skull to create more space for the brain and improve head shape. The purpose is to relieve intracranial hypertension, prevent further brain damage, protect vision, and improve appearance. Techniques vary (single-stage or staged), but all aim to enlarge the skull volume safely. -
Ventriculo-peritoneal shunt or endoscopic third ventriculostomy (for hydrocephalus)
When excess brain fluid (hydrocephalus) is present, neurosurgeons may insert a shunt from the brain ventricles to the abdomen or create an internal bypass (ETV). The purpose is to lower pressure and protect brain tissue. These procedures work by diverting cerebrospinal fluid away from blocked pathways. -
Frontofacial or midface advancement procedures
In children who survive to later infancy, midface bones may be pulled forward using osteotomies and distraction devices. The purpose is to enlarge the airway, protect the eyes, and improve facial balance. It works by cutting and gradually moving facial bones forward, allowing new bone to fill the gap while soft tissues stretch slowly. -
Orbital decompression and eyelid surgery
When the eyes are severely protruding, surgeons may enlarge the bony eye socket and adjust eyelid position. The purpose is to allow the eyes to sit more safely inside the skull and protect the cornea. Techniques remove or reshape orbital walls and tighten or reposition eyelids, often combined with cranial procedures. -
Airway surgeries (e.g., tracheostomy, choanal atresia repair)
If the upper airway is dangerously narrow or blocked, ENT surgeons may perform tracheostomy (creating a breathing opening in the neck) or repair nasal/palate anomalies. The purpose is to secure breathing and reduce life-threatening apnoeas. These operations work by creating a more direct airflow path or opening blocked passages, sometimes as temporary bridges until craniofacial surgery improves airway structure.
Preventions (what can realistically be prevented)
Because this syndrome is usually caused by genetic mutations and early fetal bone development problems, it cannot usually be prevented once conception has occurred. However, some preventive actions relate to future pregnancies and complications:
-
Seeking pre-conception genetic counselling when there is a family history of craniosynostosis or known mutations.
-
Considering prenatal diagnosis options (targeted ultrasound, fetal MRI, and genetic testing) in high-risk pregnancies to allow early detection and planning.
-
Avoiding known harmful exposures in pregnancy (certain teratogenic medications, alcohol, smoking, and uncontrolled maternal illnesses) as general fetal protection.
-
Ensuring good maternal nutrition including folate, iodine, and iron, which supports overall fetal development.
-
Planning delivery in a tertiary centre with neonatal intensive care and craniofacial teams when a severe cranial anomaly is suspected.
-
After birth, strictly following infection-prevention measures around shunts and surgical wounds to prevent life-threatening complications.
-
Keeping vaccinations up to date to lower the risk of serious infections in a medically fragile child.
-
Attending all scheduled follow-up visits so rising intracranial pressure or shunt problems are caught early.
-
Learning seizure first-aid and having rescue plans in place to reduce prolonged seizures.
-
Supporting parental mental health, which indirectly prevents neglect, burnout, and missed medical care.
When to see doctors urgently
Parents and caregivers should seek urgent medical attention if a child with cloverleaf skull or related syndromes shows any of these warning signs:
-
Sudden worsening irritability, vomiting, poor feeding, or sleepiness (possible raised intracranial pressure or shunt malfunction).
-
Rapid increase in head tension, bulging soft areas, or separation of skull plates.
-
New seizures, longer or more frequent seizures, or seizures that do not stop as usual.
-
Breathing difficulty, pauses in breathing, blue colour, or noisy obstructed breathing.
-
Fever, redness, swelling, or discharge around any surgical wound, shunt track, tracheostomy, or feeding tube.
-
Eye redness, inability to close eyes, or apparent loss of vision.
-
Sudden changes in limb movement, weakness, or loss of developed skills.
Regular scheduled reviews with neurosurgeons, craniofacial surgeons, paediatricians, and therapists are also essential even when there is no emergency, to track development, skull growth, and surgical outcomes.
What to eat and what to avoid
For most children who survive beyond the neonatal period, dietary advice focuses on balanced, energy-dense nutrition tailored to feeding ability:
-
What to emphasize:
A diet rich in breast-milk or appropriate infant formula, moving to soft, nutrient-dense solids (pureed meats, eggs if tolerated, lentils, dairy, fruits, and vegetables) supports growth and wound healing. Adequate protein, vitamins (especially D and B-complex), minerals (iron, calcium, zinc), and healthy fats (including omega-3s) helps brain and bone development and surgical recovery. -
What to limit or avoid:
Excessive sugary drinks, low-nutrient snacks, and highly processed foods offer calories but little micronutrient value and can worsen constipation or reflux. For children at aspiration risk, thin liquids and certain textures may be avoided or thickened under speech-therapy guidance. Caffeine-containing drinks, unpasteurized products, and foods that pose choking hazards should be avoided according to age and medical advice.
Because many children have reflux, constipation, or feeding difficulties, individual diet plans should be created by paediatric dietitians and adjusted after each surgery or major illness episode.
Frequently asked questions (FAQs)
-
Can cloverleaf skull syndrome be cured completely?
There is currently no way to “reverse” the underlying genetic and developmental cause. However, staged surgeries and comprehensive support can significantly improve head shape, relieve brain pressure, protect vision and breathing, and sometimes allow meaningful development in selected children. Prognosis depends strongly on the underlying syndrome and the severity of associated anomalies. -
Is it always fatal?
Historically, many cases, especially those linked to thanatophoric dysplasia type II, were uniformly lethal. With advances in neonatal care, neurosurgery, and craniofacial surgery, survival has improved for some subgroups, particularly when the syndrome is less severe and lungs and heart are relatively preserved. However, overall risk of death and serious disability remains high. -
What causes the skull to look like a cloverleaf?
The cloverleaf shape occurs because several skull sutures (often coronal and lambdoid) fuse in the womb while the brain is still trying to grow. The brain pushes out where bone is weakest, producing three bulging lobes and a narrow ring of bone. Hydrocephalus often adds pressure, exaggerating the deformity. -
Is cloverleaf skull the same as craniosynostosis?
Cloverleaf skull is an extreme form of multisutural craniosynostosis. All cloverleaf skull cases involve craniosynostosis, but not all craniosynostosis patients have cloverleaf skull. Many children with single-suture craniosynostosis have much milder problems and different treatment courses. -
Can it be seen before birth on ultrasound?
Yes. In many cases, experienced fetal medicine specialists can see the characteristic skull shape, associated limb or chest findings, and sometimes hydrocephalus on prenatal ultrasound or MRI. This allows families to receive counselling and delivery planning in a tertiary centre. -
Will my other children have the same condition?
Recurrence risk depends on the exact underlying genetic cause. Some syndromes are caused by new (de novo) mutations with low recurrence risk, while others follow autosomal dominant patterns with higher risk if a parent carries the mutation. Genetic testing and counselling are essential to estimate the risk for future pregnancies. -
How many surgeries might be needed?
Some children need one large cranial vault procedure and later minor revisions, while others undergo multiple staged surgeries for skull, midface, and airway over many years. The number depends on growth, complications, and cosmetic and functional goals. Surgeons discuss a long-term “roadmap” early with families. -
Can my child have a normal life and go to school?
Outcomes vary widely. Some children with milder forms and successful early surgery can attend mainstream school with supports; others have significant intellectual disability, motor challenges, or medical fragility. Early intervention, special education, and supportive therapies give each child the best chance to reach their personal potential. -
Is pain a major problem for these children?
Pain is a concern mostly around surgeries and when there are complications such as raised intracranial pressure or infections. With modern pain-management protocols using acetaminophen, opioids, and regional techniques when appropriate, most children can have their pain controlled safely. Parents should always report new or persistent pain. -
Can alternative therapies replace surgery?
No. While supportive therapies (physiotherapy, nutrition, psycho-social care) are very important, they cannot create more space inside the skull or reliably lower intracranial pressure. Skull expansion and, when needed, shunt or ETV procedures remain the proven life-saving treatments for severe cloverleaf skull deformity. -
Is brain damage inevitable?
Prolonged high pressure and severe structural brain anomalies can cause permanent damage. However, early detection and timely surgery can reduce ongoing injury in some children. Neurodevelopmental outcome depends on both the basic brain structure (which we cannot fully change) and the success of pressure control and rehabilitation. -
What is life like for families?
Families often spend a lot of time in hospitals, juggling appointments, surgeries, therapies, and financial stress. Many, however, describe strong bonds with their child and a deep sense of meaning in advocating for them. Access to psychological support, respite care, and community resources makes a major difference in coping. -
Can my baby be breast-fed?
In some cases, breastfeeding is possible with extra support from lactation consultants and speech-therapy teams; in others, breathing or swallowing safety means breast-milk is given via tube. The main goal is safe feeding and adequate nutrition—whether by breast, bottle, or tube—rather than one specific method. -
Are clinical trials available?
Because this is a very rare condition, most research is in the form of case reports and surgical series rather than large trials. However, children may be enrolled in registries or studies on craniosynostosis outcomes, surgical techniques, or genetic findings at major centres. Families can ask their team about ongoing research options. -
What should I ask my child’s team at each visit?
Helpful questions include: “How is my child’s intracranial pressure and brain growth?”, “Do we see any signs of shunt or skull problems?”, “What surgeries or tests are coming next, and why?”, “How is my child’s development compared with last visit?”, and “What can we do at home to support feeding, sleep, and learning?” Writing questions down and bringing photos or notes about changes at home helps the team give more precise advice.
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 31, 2025.
Asphyxiating Thoracic Dysplasia
