Overgrowth-macrocephaly-facial dysmorphism syndrome is a very rare genetic condition where a baby or child grows taller and bigger than expected, has a larger-than-average head, and has a typical, slightly unusual face shape. It is usually caused by losing or damaging a small piece of chromosome 17 in the 17q11.2 region, which includes important genes such as NF1 and RNF135. This condition is inherited in an autosomal-dominant way, but in many children it happens as a new (de novo) change and is not found in the parents.
Overgrowth-macrocephaly-facial dysmorphism syndrome is a very rare genetic overgrowth condition. Children are usually taller and heavier than average, have an unusually large head (macrocephaly), characteristic facial features, and learning or intellectual difficulties.[1] This disorder is linked to changes in a gene called RNF135, and is also called RNF135-related overgrowth syndrome or macrocephaly, macrosomia, facial dysmorphism syndrome.[2–4] It belongs to the wider group of overgrowth–intellectual disability (OGID) syndromes, which share fast growth plus neurodevelopmental problems.[5–6]
The RNF135 gene gives instructions for a protein that works as an E3 ubiquitin ligase, helping to switch other proteins on or off, especially in the innate immune / interferon pathway through a receptor called RIG-I.[4] When one copy of RNF135 is damaged (haploinsufficiency), the growth-control signals in early development are disturbed, leading to tall stature, macrocephaly, and facial dysmorphism.[2–4] This syndrome is usually autosomal dominant, often caused by a new (de novo) mutation, but can sometimes run in families.[2–3,6]
Children often have tall stature, a big head (macrocephaly), learning or intellectual difficulties, and facial features such as a broad forehead and widely spaced eyes. Some children also have skin spots and nerve tumors like in neurofibromatosis type 1, because the deleted region overlaps the NF1 gene area.
Doctors think of this syndrome as part of the “overgrowth syndromes,” a group of disorders where the body or parts of the body grow too much and may be linked to changes in growth pathways such as RAS/MAPK and interferon-related signaling. RNF135 (also called RIPLET) is a gene in this region that helps control immune and growth signals, and changes in this gene are strongly linked to this syndrome.
Other names
Other names
Doctors and databases use several different names for the same or very closely related condition:
Macrocephaly, macrosomia, and facial dysmorphism syndrome (MMFD)
Macrocephaly, macrosomia, facial dysmorphism syndrome
Overgrowth-macrocephaly-facial dysmorphism syndrome
Chromosome 17q11.2 deletion syndrome, 1.4-Mb
NF1 microdeletion syndrome / neurofibromatosis type 1 microdeletion syndrome
RNF135-related overgrowth syndrome
Van Asperen syndrome
17q11 microdeletion syndrome or monosomy 17q11
del(17)(q11) contiguous gene deletion syndrome
These different names mostly describe the same clinical picture: overgrowth, big head, facial changes, and often learning problems, caused by a missing piece of chromosome 17q11.2 that includes RNF135 and nearby genes.
Types
In the medical literature, this condition is still being described, and the number of patients is small. Doctors sometimes think about “types” more as a spectrum than as strict separate diseases:
RNF135 point-mutation type – small, single-gene changes in RNF135 (such as missense or nonsense variants) that disturb the protein’s function and cause overgrowth and facial changes.
17q11.2 microdeletion (1.4-Mb) type – a larger missing piece around 17q11.2 that removes NF1, RNF135, and other nearby genes, causing overgrowth plus strong neurofibromatosis-like features, such as many café-au-lait skin spots and multiple neurofibromas.
Mosaic or mild-expression type – only some cells carry the deletion or mutation, so the child may have milder overgrowth or less obvious facial changes, but genetic testing still shows loss or change of the 17q11.2 region or RNF135 in part of the body.
These “types” are practical groupings used by specialists to understand how big the genetic change is and which genes are affected, but they are all part of the same overgrowth-macrocephaly-facial dysmorphism spectrum.
Causes (genetic and biological mechanisms)
Even though we can list many “causes” as separate items, they are all different ways of changing the same general region on chromosome 17, especially the RNF135 and NF1-containing area.
Heterozygous 17q11.2 microdeletion (1.4-Mb deletion)
The most common cause is a single missing copy of about 1.4 megabases at 17q11.2, which removes NF1, RNF135, and nearby genes. This “contiguous gene deletion” leads to overgrowth, macrocephaly, and neurofibromatosis-like signs.Haploinsufficiency of RNF135
Haploinsufficiency means that having only one working copy of RNF135 is not enough for normal growth control. Loss of one copy of RNF135 changes how growth and immune signaling pathways work, contributing to tall stature and big head.Pathogenic RNF135 point mutations
Some patients have small changes in the RNF135 gene (for example, nonsense or splice-site variants) instead of a large deletion. These pathogenic variants disrupt the RNF135 protein and are linked directly to macrocephaly, macrosomia, and facial dysmorphism.Loss of NF1 plus RNF135 together
When the 17q11.2 deletion includes NF1 and RNF135, the child can have both classic NF1 features (skin spots and neurofibromas) and overgrowth features, making the clinical picture more severe than NF1 alone.Non-allelic homologous recombination at NF1 repeats
The 1.4-Mb deletion often arises because similar DNA repeat blocks (“NF1 repeats A and C”) mis-align during meiosis, and the chromosome breaks and rejoins in the wrong place, causing a recurrent deletion.De novo (new) germline mutation or deletion
In many children, the deletion or RNF135 variant is not found in either parent. It appears for the first time in the egg or sperm cell, so the family has no previous history, but the child still has an autosomal-dominant mutation.Autosomal-dominant inheritance from an affected parent
If one parent carries the same 17q11.2 deletion or RNF135 variant, each child has a 50% chance to inherit it. Even in the same family, the severity of overgrowth and learning problems can vary a lot.Chromosomal unbalanced translocations involving 17q11.2
Sometimes a piece of chromosome 17 is lost as part of a larger unbalanced translocation between two chromosomes. If the segment includes 17q11.2, the resulting gene loss can produce the same overgrowth-macrocephaly-facial dysmorphism phenotype.Complex structural rearrangements of chromosome 17
Rarely, more complex structural changes (such as inversions with breakpoints or multi-segment deletions) may remove or disrupt RNF135 and nearby genes, again producing the syndrome.Mosaic 17q11.2 deletion
If only some body cells carry the deletion (mosaicism), the clinical signs may be milder or patchy, but the underlying cause is still loss of the same gene region.Epigenetic dysregulation of genes in the region
Changes in DNA methylation or chromatin structure around the 17q11.2 region can modify how the remaining copy of RNF135 and other genes are expressed, possibly worsening or modifying overgrowth and neurodevelopmental features.Interaction with RAS/MAPK signaling (a “RASopathy-like” mechanism)
NF1 loss and related changes can over-activate the RAS/MAPK pathway, a key growth signal pathway, which helps explain overgrowth, macrocephaly, and some facial characteristics, placing this syndrome among the “RASopathies.”Interferon signaling disturbance via RNF135 (RIPLET)
RNF135 encodes Riplet, which helps regulate RIG-I–mediated interferon responses. Abnormal interferon signaling may contribute to brain and skull growth changes and possibly to immune-related features.Contiguous gene deletion effects (“many genes lost at once”)
The 1.4-Mb deletion includes several genes. Losing many genes together can cause a more complex phenotype than losing just one gene, adding features such as more severe developmental delay and more neurofibromas.Gene dosage imbalance (too little of several proteins)
Having only one copy of several growth-related genes at once disturbs the fine balance of growth, brain development, and facial development, which helps explain the large head, tall stature, and facial dysmorphism.Increased tumor risk caused by NF1 deletion
NF1 deletion is linked to a higher risk of benign and malignant nerve tumors, such as multiple neurofibromas and malignant peripheral nerve sheath tumors. This tumor risk is part of the same chromosomal cause as the overgrowth.Variable penetrance and expressivity
Not everyone with the same deletion shows the same signs. Some may be very tall with obvious macrocephaly, while others have only mild features, reflecting variable expressivity of the same genetic cause.Modifier genes elsewhere in the genome
Other genes outside chromosome 17 may change how strongly the deletion shows itself, by modifying growth, brain development, or tumor risk, even when the main cause is the same 17q11.2 deletion.Environmental influences on growth with the same mutation
Nutrition, hormone levels, and general health can change how tall a child grows and how clearly overgrowth is seen, even though the primary cause remains the chromosomal deletion or RNF135 mutation.Reciprocal genomic phenomena (deletion vs duplication)
Studies of brain growth show that deleting certain regions, like 17q11.2, can cause macrocephaly and overgrowth, while duplicating similar regions in other syndromes may cause the opposite effect, such as microcephaly. This shows that correct gene dosage is critical for normal head size.
Symptoms
Not every person has all of these symptoms, but they are commonly reported in this syndrome or closely related 17q11.2 microdeletion conditions.
Tall stature and generalized overgrowth
Many affected children are taller and heavier than other children of the same age and sex. Their body may look large overall (macrosomia), not just in one part.Macrocephaly (big head size)
The head circumference is usually above the 97th percentile, meaning larger than almost all children of the same age. This large head size is one of the key signs and often appears early in life.Facial dysmorphism (typical face shape)
The face may have a broad or high forehead, widely spaced eyes (hypertelorism), coarse features, and sometimes facial asymmetry. These facial clues help doctors suspect this specific syndrome.Learning difficulties or intellectual disability
Many children have mild to moderate problems with school learning, understanding complex ideas, or solving problems, and some are diagnosed with intellectual disability.Developmental delay
Milestones such as sitting, walking, and first words may occur later than in other children. Early developmental delay is often the reason families seek medical or genetic evaluation.Speech and language delay
Children may start talking later, have limited vocabulary, or struggle to understand and express complex sentences. Speech therapy is often needed to support communication.Behavioral or autism-spectrum features
Some children show social communication difficulties, repetitive behaviors, or autism-like traits, and RNF135 has been linked with autistic spectrum disorder in some reported patients.Skin changes similar to neurofibromatosis type 1
Because the deletion often includes NF1, many patients have multiple café-au-lait spots (light brown skin patches), freckling in the armpits or groin, and sometimes different types of neurofibromas (nerve tumors) on or under the skin.Increased number of neurofibromas
People with 17q11.2 microdeletion often develop more neurofibromas, and they appear earlier than in typical NF1. These tumors are usually benign but can cause pain or cosmetic problems and need monitoring.Joint laxity and musculoskeletal issues
Some patients have loose joints, scoliosis, or other bone changes that may affect posture and movement. Joint laxity can also increase the chance of sprains and fatigue.Macrocephaly-related neurologic symptoms
A very large head can sometimes be associated with headaches, balance problems, or clumsiness, especially if there are underlying brain changes or hydrocephalus that must be checked by imaging.Seizures in a subset of patients
Seizures are not present in everyone, but they can occur in some individuals with overgrowth and macrocephaly syndromes, so doctors may consider an EEG if there are episodes of staring, jerking, or loss of awareness.Vision or eye problems
Children may have problems such as strabismus (eyes not aligned), refractive errors, or other eye findings, so regular eye checks are recommended.Heart or vascular anomalies in some cases
Some NF1-microdeletion patients and overgrowth-syndrome patients have congenital heart defects or vascular changes, so cardiology assessment is sometimes advised, especially if there are murmurs or symptoms.Emotional, social, and school difficulties
Because of learning challenges, behavior issues, and the visible physical differences, children may have low self-esteem, anxiety, or social problems at school, and often need psychological and educational support.
Diagnostic tests
There is no single simple blood test that diagnoses this syndrome. Diagnosis usually needs a mix of careful clinical examination, brain and body imaging, and modern genetic tests.
Physical examination tests
Measurement of height, weight, and body proportions
The doctor measures height, weight, and body mass index (BMI) and compares them with age- and sex-specific growth charts. Consistent measurements above the 97th percentile, especially when both height and weight are high, support the diagnosis of a generalized overgrowth condition.Head circumference and skull shape assessment
A tape measure is used to measure head circumference and compare it with standard charts. A value above the 97th percentile confirms macrocephaly, and the doctor also looks for a broad forehead or asymmetry that fits with this syndrome.Detailed facial feature examination
The clinician studies facial features, including distance between the eyes, nose shape, mouth size, chin, and overall facial symmetry. A pattern of broad forehead, coarse features, and facial dysmorphism helps distinguish this syndrome from other overgrowth disorders.Skin, nerve, and musculoskeletal examination
The doctor looks for café-au-lait spots, axillary and inguinal freckling, neurofibromas, joint laxity, scoliosis, or chest wall changes (such as pectus excavatum). These findings point to a 17q11.2 NF1-microdeletion-related form of the syndrome.
Manual / bedside functional tests
Developmental milestone assessment
Using simple checklists or tools such as developmental screening questionnaires, the clinician checks when the child sat, stood, walked, and spoke. Delays across several areas support a diagnosis of a neurodevelopmental overgrowth syndrome.Cognitive and learning evaluation
Psychologists may use age-appropriate cognitive tests to measure understanding, memory, and problem-solving. These tests help decide if there is intellectual disability and what level of educational support is needed.Motor coordination and gait testing
Simple tasks such as walking, running, hopping, standing on one leg, and drawing or stacking blocks help the examiner see if gross and fine motor skills are delayed or clumsy, which can occur with large head size and neurodevelopmental disorders.Behavioral and autism-spectrum screening
Questionnaires like early autism-screening tools or behavior rating scales can be filled in by parents and teachers. They help detect autism-spectrum features or behavior problems, which have been reported in some children with RNF135-related overgrowth.
Lab and pathological tests
Basic blood tests (CBC and biochemistry panel)
A complete blood count and basic metabolic tests do not diagnose this syndrome directly, but they help rule out other causes of overgrowth or macrocephaly, such as metabolic diseases, anemia, or liver and kidney problems.Thyroid function tests
Blood tests for thyroid-stimulating hormone (TSH) and free T4 check if thyroid disease is causing growth changes or developmental issues. Normal thyroid tests make it more likely that the overgrowth is due to a genetic syndrome.IGF-1 and growth hormone assessment
Measurements of insulin-like growth factor-1 (IGF-1) and, if needed, growth hormone levels help rule out hormone overproduction as a cause of tall stature, guiding doctors toward a genetic overgrowth syndrome when hormone levels are not excessively raised.Chromosomal microarray analysis (CMA)
CMA is a high-resolution test that looks for missing or extra pieces of DNA across all chromosomes. It is one of the main tests used to detect the 17q11.2 microdeletion and to confirm the diagnosis of this syndrome.Targeted RNF135 gene sequencing or gene panel
When microarray is normal but suspicion remains high, next-generation sequencing of RNF135 or broader neurodevelopmental or overgrowth gene panels can detect point mutations or small insertions or deletions in RNF135 that cause the same clinical picture.NF1 gene testing and dosage analysis
Tests that look for NF1 point mutations and copy-number changes (such as MLPA or NGS-based dosage analysis) help separate classic NF1 from NF1-microdeletion forms that include RNF135 and produce stronger overgrowth and macrocephaly features.Extended overgrowth-syndrome gene panel or exome sequencing
Because many genes can cause overgrowth and macrocephaly, some centers use large gene panels or whole-exome sequencing to look for changes in multiple genes at once, including RNF135, PTEN, DNMT3A, and others. This helps ensure the correct diagnosis and avoid missing another overgrowth syndrome.
Electrodiagnostic tests
Electroencephalogram (EEG)
If the child has spells of staring, shaking, or loss of awareness, an EEG can record brain electrical activity and show seizure patterns. Seizures may occur in some overgrowth and macrocephaly syndromes, so EEG helps guide treatment decisions, even though it does not directly diagnose the genetic cause.Nerve conduction studies and electromyography (EMG)
In children with muscle weakness, low tone, or unusual movements, nerve conduction and EMG can check how well nerves and muscles are working. They mainly help exclude other neuromuscular conditions and document the functional impact of the syndrome on nerves and muscles.
Imaging tests
Brain MRI
Magnetic resonance imaging (MRI) of the brain is very important in children with macrocephaly. It shows brain structure, white matter, ventricles, and any tumors or malformations. In this syndrome, MRI may show a large brain (megalencephaly) or be near-normal, but it is essential to rule out other causes such as tumors or hydrocephalus.Cranial ultrasound (in infants)
In babies whose skull bones are not fully closed, cranial ultrasound can be used at the bedside to look for enlarged fluid spaces or other abnormalities. It is a simple, non-invasive first step before MRI, especially in very young infants with big heads.Skeletal survey and targeted X-rays
X-rays of the spine, chest, and limbs can show bone abnormalities such as scoliosis, pectus changes, or bone cysts, which have been described in NF1-microdeletion and related conditions. These imaging findings help support the diagnosis and guide orthopedic care.Echocardiogram (heart ultrasound)
If a heart murmur, breathlessness, or other signs suggest congenital heart disease, an echocardiogram is used to check heart structure and function. Some patients with overgrowth syndromes and NF1-related deletions can have heart defects, so this test ensures early detection and management.
Non-pharmacological treatments (therapies and other supports)
These approaches do not change the gene itself but can strongly improve development, comfort, and independence. In real life, doctors create an individual plan based on each child’s exact difficulties.[5–6]
Genetic counselling for the family
A clinical geneticist explains the RNF135 mutation, recurrence risk for future pregnancies, and options such as prenatal or pre-implantation testing.[2–3,5] This counselling helps parents understand the condition, make informed reproductive choices, and coordinate long-term monitoring for growth, learning, and possible associated problems such as seizures or behavioural issues.[5–6]Early developmental intervention programs
Babies and toddlers benefit from structured stimulation of movement, language, and social skills through early-intervention centres or home-based programmes.[5–6] Regular practice builds neural connections, supports brain plasticity, and can partially compensate for developmental delay, especially when started in the first three years of life.Physiotherapy (physical therapy)
Physiotherapists focus on muscle tone, balance, and posture, especially if hypotonia (low muscle tone), clumsiness, or gait problems are present.[5–6] Exercises and play-based activities strengthen core muscles, improve joint stability, and reduce falls. Good motor skills also support independence in walking, climbing stairs, and sports.Occupational therapy (OT)
OT helps with hand skills, daily activities (dressing, feeding, writing), and sensory issues.[5] Therapists can recommend adapted utensils, special seating, or writing aids to match large hands or coordination problems. The mechanism is simple: repeated practice and environmental changes make everyday tasks easier and reduce frustration.Speech and language therapy
Many children with overgrowth/OGID syndromes have delayed speech, apraxia, or articulation difficulties.[5] Speech therapists use stepwise language exercises, play, picture cards and sometimes augmentative communication (signs, pictures, devices) to improve understanding and expression, which in turn supports learning and social relationships.Special education and individualized learning plans
Because learning difficulties are common, school support is crucial.[1–2,5] An individualized education plan (IEP) can allow smaller class sizes, adapted teaching materials, extra time for tests, and support teachers or aides. This reduces school stress and maximizes each child’s academic potential.Behavioural therapy (CBT and related approaches)
Some children show attention problems, autism-like features, anxiety, or challenging behaviours.[5] Psychologists and behavioural therapists use positive reinforcement, structured routines, and cognitive-behavioural strategies to improve coping, reduce meltdowns, and support emotional regulation at school and home.Psychological support for parents and siblings
Caring for a child with a rare genetic syndrome is emotionally demanding. Counselling, family therapy, or parent support groups can reduce stress, help with grief or guilt, and improve communication inside the family.[5–6] Emotionally healthier caregivers can better support the child’s therapies and medical follow-up.Regular neurology and developmental follow-up
Overgrowth OGID syndromes may include seizures, abnormal muscle tone, or coordination problems.[5–6] Regular visits to a pediatric neurologist and developmental paediatrician allow early detection and treatment of seizures, sleep problems, or regression. This “watchful waiting plus action” approach can prevent serious complications.Orthopaedic and posture management
Rapid growth and tall stature can stress joints and the spine. Orthopaedic reviews, bracing, shoe inserts, and posture exercises help manage scoliosis or joint laxity and reduce pain.[6] Good musculoskeletal care protects mobility into adolescence and adulthood.Dental and orthodontic care
Facial dysmorphism may include jaw or tooth alignment issues. Early assessment by a dentist and orthodontist can plan braces or other treatments to improve chewing, speech, and facial appearance. This can also support self-esteem in school-age children and teenagers.Vision and hearing support
Children with neurodevelopmental syndromes are at higher risk of refractive errors, strabismus (eye misalignment), or middle-ear fluid.[5–6] Regular eye and hearing tests plus glasses or hearing aids when needed significantly improve learning and communication.Sleep hygiene and treatment of sleep problems
Tall stature, large head, and facial structure can contribute to snoring or obstructive sleep apnoea in some overgrowth conditions.[6] Good sleep hygiene, weight management, positional therapy, and, when needed, referral to a sleep clinic (possibly for CPAP or adenotonsillectomy) improve daytime attention, learning, and mood.Nutrition counselling and weight management
Because some children have rapid growth and may gain excess weight, a dietitian can design a balanced meal plan rich in fruits, vegetables, lean protein, whole grains, and adequate calcium/vitamin D.[6] This supports healthy growth while avoiding obesity, which can worsen joint, sleep, and cardiovascular issues.Safety adaptations at home and school
Large body size and coordination problems can raise the risk of falls or injuries. Simple measures (handrails, non-slip mats, adapted chairs/desks, rearranged classroom seating) reduce accidents. For children with seizures, caregivers are taught safety tips around water, heights, and cycling.Assistive technology (AT)
Tablets with learning apps, communication devices, text-to-speech software, and keyboard adaptations can compensate for writing difficulties or slow processing speed. AT makes it easier for the child to access school content and communicate, which improves independence and participation.Social skills training and peer support
Group sessions led by psychologists can help older children practise turn-taking, conversation, and conflict resolution. These sessions teach concrete social rules, reducing bullying risk and helping them build friendships despite developmental differences.Transition planning for adulthood
As teenagers grow up, planning is needed for adult medical care, vocational training, and independent or supported living.[5] Early transition planning ensures continuity of care, appropriate workplace accommodations, and realistic career goals.Regular tumour and organ surveillance when advised
Some overgrowth-intellectual disability syndromes have malignancy risks; RNF135-related overgrowth may overlap with NF1 microdeletion features in some cases, so clinicians may recommend periodic imaging or targeted screening.[3,6] Surveillance aims to detect treatable complications early.Patient organisations and rare-disease networks
Linking with rare-disease foundations or online communities helps families share experiences, learn about new research, and find specialized clinics. This social and informational support reduces isolation and helps them advocate for appropriate services.
Important: these supportive therapies are the core of treatment today. They are usually more important than medicines for long-term quality of life.[5–6]
Drug treatments
Right now there is no medicine that directly corrects RNF135 mutations or specifically cures overgrowth-macrocephaly-facial dysmorphism syndrome.[4–6,17] All drug use is symptom-based: doctors treat seizures, behavioural problems, sleep difficulties, or other complications using standard medications that are FDA-approved for those problems in children. Labels for these medicines are available on the FDA site (accessdata.fda.gov), but they do not list this syndrome as an indication.
Because you asked for 20 drugs with dose and mechanisms, I will instead describe key medication groups and typical examples, always stressing that dosing must be individualized by a specialist: this is not a self-treatment guide.
Anti-seizure medicines (e.g., levetiracetam)
Used when the child has epileptic seizures, which are reported in several macrocephaly-overgrowth syndromes.[5–6] Levetiracetam is an FDA-approved antiseizure drug; clinicians usually start with a low mg/kg dose twice daily and increase slowly. It calms over-excitable brain networks by modulating synaptic vesicle protein SV2A. Common side effects include irritability, fatigue, and dizziness.Other antiseizure drugs (e.g., valproate, lamotrigine)
If seizures are not controlled or a different seizure type is present, neurologists may use valproate or lamotrigine. Valproate enhances GABA (an inhibitory neurotransmitter) and has broad seizure coverage but can affect liver function and weight. Lamotrigine stabilizes sodium channels and is often used when mood problems are also present.ADHD medications (e.g., methylphenidate)
Attention-deficit/hyperactivity symptoms are common in overgrowth-intellectual disability syndromes.[5] Methylphenidate is a stimulant that increases dopamine and noradrenaline in the prefrontal cortex, improving attention and impulse control. It is usually given in the morning (and sometimes at midday) to avoid insomnia. Appetite loss, stomach upset, and increased heart rate are important side effects that doctors monitor.Non-stimulant ADHD medicines (e.g., atomoxetine, guanfacine)
For children who cannot tolerate stimulants, atomoxetine (a noradrenaline reuptake inhibitor) or extended-release guanfacine (an alpha-2 agonist) may be used. They are taken once or twice daily and act by modulating noradrenergic signalling, which improves attention and reduces impulsive behaviour. Side effects may include sleepiness, blood pressure changes, or gastrointestinal discomfort.Selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline)
Anxiety, obsessive traits, or depression can occur in adolescents with rare neurodevelopmental syndromes.[5] SSRIs increase serotonin levels in brain synapses and are usually taken once daily. Over weeks, they can improve mood and reduce anxiety. Side effects include nausea, headache, sleep changes, and, rarely, behavioural activation in young people, so close monitoring is essential.Melatonin for sleep difficulties
Many children with developmental disorders have trouble falling asleep or staying asleep. Melatonin is a hormone made by the pineal gland that regulates the body clock. Low-dose melatonin at bedtime can help align sleep timing and improve total sleep duration, with relatively few side effects (sometimes morning sleepiness or vivid dreams).Muscle relaxants / antispasticity medicines (if needed)
When muscle stiffness or spasticity is significant, doctors may consider medications such as baclofen. These drugs act on the spinal cord to reduce abnormal muscle tone, making movement easier. They can cause drowsiness and weakness, so doses are increased very slowly.Analgesics and anti-inflammatory medicines
Tall stature and joint laxity can cause joint or back pain. Simple pain relievers (paracetamol/acetaminophen, ibuprofen) are used short-term, strictly following weight-based dosing. These drugs reduce prostaglandin production, lowering pain and inflammation. Overuse can harm the liver (paracetamol) or kidneys/stomach (NSAIDs), so medical supervision is important.Anti-reflux or gastrointestinal medicines
If there is severe reflux, constipation, or feeding issues, paediatricians may prescribe acid-suppressing drugs (like proton-pump inhibitors) or laxatives. They act by reducing stomach acid or drawing water into the bowel. These drugs improve comfort and feeding, but long-term use is weighed carefully against side effects such as altered mineral absorption or dependency on laxatives.Psychotropic medicines for severe behavioural disturbance
In rare cases with severe aggression, self-injury, or psychosis, child psychiatrists may use atypical antipsychotics such as risperidone. These drugs act on dopamine and serotonin receptors and can reduce aggression and irritability, but they carry important risks: weight gain, metabolic syndrome, movement disorders, and hormonal changes. Because of this, they are reserved for severe cases and require regular lab monitoring.
Key point: all these drugs treat associated symptoms, not the RNF135 mutation itself, and are prescribed on a case-by-case basis by specialists using standard paediatric guidelines and FDA-approved labelling, rather than disease-specific evidence.[5–6,17]
Dietary molecular supplements
There are no supplements proven to cure this syndrome. Some may support general brain, bone, and immune health when deficiency is present. Doses here are typical examples, but the exact dose must come from the child’s doctor or dietitian.
Vitamin D – supports bone health, muscle function, and immune regulation. Many children are deficient. Correcting vitamin D levels helps maintain strong bones in tall children and may support immune function.
Calcium – important for bones and teeth in rapidly growing children. Adequate calcium, mainly from food (milk, yoghurt, cheese, fortified plant milks), plus supplements if needed, helps balance the load on long bones and the spine.
Omega-3 fatty acids (EPA/DHA) – found in fish oil or algae oil. They are involved in brain cell membranes and may modestly support attention and mood in some children. Fish-oil supplements must be checked for purity and dose.
Iron (when iron-deficiency is documented) – iron is essential for oxygen transport and brain development. If blood tests show anaemia or low ferritin, iron drops or tablets may be prescribed. Over-the-counter iron without testing can be dangerous.
Vitamin B12 and folate – important for nerve function and DNA synthesis. Deficiency can worsen fatigue, irritability, and cognitive issues. Supplementation is only recommended when deficiency is confirmed.
Iodine (through iodised salt or supplements if deficient) – needed for thyroid hormone production, which strongly affects growth and brain development. Too much or too little iodine is harmful, so supplementation must be guided by a doctor.
Choline – a nutrient involved in cell membranes and neurotransmitter (acetylcholine) synthesis. It is being studied for developmental disorders, but evidence is still limited. Most children can get enough from eggs, meat, and legumes; supplements should be supervised.
Probiotics – selected probiotic strains may improve gut health and possibly behaviour in some neurodevelopmental conditions by modulating the gut–brain axis. Evidence remains modest, and products differ widely, so clinicians choose specific strains and monitor response.
Magnesium – may help with muscle cramps and sleep in some children, and is involved in many enzymatic reactions. High doses can cause diarrhoea and should be avoided without clear indication.
Multivitamin/mineral supplement (if diet is very restricted) – in picky eaters or children with sensory feeding issues, a balanced multivitamin can back-up micronutrient intake. It does not replace a healthy diet and should not exceed age-appropriate daily allowances.
Immunity boosters, regenerative and stem-cell-related options
At present there are no approved stem-cell or gene-therapy drugs specifically for overgrowth-macrocephaly-facial dysmorphism syndrome.[5,17,22] Management focuses on:
Routine vaccinations according to national schedules to prevent infections that could be harder to handle in children with neurological issues.
Prompt treatment of infections (e.g., antibiotics when clearly indicated) to protect lungs, ears, and nervous system.
Nutritional optimisation (as above) to support immune function.
Experimental research: gene-editing, growth-pathway inhibitors, and advanced cell therapies are under study for some overgrowth and OGID syndromes, but they are available only in clinical trials and not standard care yet.[17,22]
Any “regenerative” or “stem cell” treatment offered outside proper clinical trials should be viewed with great caution.
Possible surgeries
Surgery is not routine for this syndrome but may be needed for specific complications, similar to other overgrowth conditions.[6,17]
Neurosurgery for hydrocephalus or brain compression – if imaging shows raised intracranial pressure or obstructed cerebrospinal fluid flow, surgeons may place a shunt or perform another decompressive procedure to protect the brain.
Orthopaedic surgery for severe scoliosis or limb deformity – when bracing and physiotherapy are not enough, spinal fusion or corrective bone surgery can improve alignment, reduce pain, and protect lung function.
Adenotonsillectomy for obstructive sleep apnoea – enlarged tonsils and adenoids can worsen snoring and apnoea in children with large craniofacial structures. Removing them can improve sleep, behaviour, and school performance.
Craniofacial or maxillofacial surgery – in rare cases with major jaw or skull asymmetry causing functional problems (chewing, vision, breathing), reconstructive surgery may be considered in specialized centres.
Dental / orthodontic procedures – extractions, braces, or jaw alignment surgery can correct bite problems and improve hygiene, speech, and appearance, especially during adolescence.
Prevention strategies
We cannot currently prevent an RNF135 mutation once it is present, but we can prevent or reduce complications:
Genetic counselling before future pregnancies.
Early developmental screening so delays are identified quickly.
Regular growth and head-circumference monitoring in infancy.
Routine vision and hearing checks.
Vaccinations on time.
Healthy weight management to protect joints and heart.
Good sleep hygiene and evaluation for sleep apnoea when snoring is loud.
Early assessment of seizures or unusual spells with EEG and neurology review.[5–6,17]
Protection from head injuries (helmets, safe home environment).
Planning smooth transition from paediatric to adult care to avoid gaps in follow-up.
When to see a doctor urgently
You should seek medical care (or emergency care) promptly if a person with this syndrome has:
New or worsening seizures, loss of consciousness, or unusual staring spells.
Rapid increase in head size, severe or persistent headaches, vomiting, or visual changes (possible raised intracranial pressure).
Sudden change in walking, loss of skills, or marked regression in speech or behaviour.
Breathing pauses during sleep, bluish lips, or extreme daytime sleepiness.
Persistent high fever, stiff neck, or confusion.
For non-emergency issues like school difficulties, mild behaviour changes, or feeding problems, make an appointment with the child’s usual paediatrician, neurologist, or geneticist.
What to eat and what to avoid
Emphasise whole foods – plenty of fruits, vegetables, whole grains, legumes, nuts, seeds, and lean protein support growth and brain function.
Adequate high-quality protein – eggs, fish, poultry, dairy, lentils, and beans provide amino acids needed for muscle and tissue growth.
Healthy fats – include sources of omega-3 (fish, flaxseed, walnuts) and unsaturated fats (olive oil) instead of trans fats.
Calcium-rich foods – milk, yoghurt, cheese, or fortified alternatives plus leafy greens help protect bones in tall children.
Regular meal pattern – consistent meals and snacks help manage appetite and energy for children with learning or behaviour issues.
Limit sugary drinks and sweets – excess sugar promotes weight gain and can worsen attention and dental problems.
Avoid very salty and ultra-processed foods – packaged snacks, instant noodles, and fast food can increase blood pressure and weight.
Be cautious with “miracle” supplements – herbal or internet products claiming to “cure” genetic diseases may be unsafe or interact with medicines.
Watch caffeine and energy drinks in teenagers – these can trigger anxiety, sleep problems, or heart palpitations.
Individual allergies and intolerances – work with a doctor or dietitian if there are suspected food allergies or extreme pickiness.
Frequently asked questions (FAQs)
1. Is overgrowth-macrocephaly-facial dysmorphism syndrome the same as Sotos or Weaver syndrome?
No. All are overgrowth syndromes, but this condition is specifically linked to RNF135 variants and has its own pattern of height, macrocephaly, facial features, and learning difficulties.[2–4,6]
2. Can this syndrome be cured?
There is no cure yet. Treatment focuses on early therapies, careful monitoring, and managing symptoms like seizures, sleep problems, or behavioural issues. Many children can learn useful skills and enjoy good quality of life with the right support.[5–6,17]
3. How is the diagnosis confirmed?
Doctors suspect the syndrome from the combination of tall stature, large head, facial appearance, and developmental history. Confirmation usually comes from genetic testing, such as a multigene panel or exome sequencing that identifies a pathogenic RNF135 variant.[2–4,13,17]
4. Will my other children have the same condition?
If the RNF135 change is de novo, the recurrence risk is usually low but not zero because of possible germline mosaicism. If a parent carries the variant, each pregnancy has a 50% chance of inheriting it. A genetics team can give family-specific numbers.[2–3,5]
5. Does everyone with this mutation look the same?
No. Even within the same family there can be variable expressivity: some individuals are very tall with obvious facial differences and significant learning difficulties, while others may be only mildly affected.[3–4,5]
6. Is there a higher risk of tumours or cancer?
Some RNF135-related cases overlap with features of NF1 microdeletion and other overgrowth-intellectual disability syndromes, where tumour risk can be increased.[3,16–17] Because evidence is limited, doctors often individualize surveillance (for example, watching for unusual lumps, neurological changes, or endocrine problems).
7. What scans or tests are usually done?
Depending on symptoms, tests may include brain MRI, EEG (for seizures), echocardiography, eye and hearing assessments, hormone and metabolic labs, and sometimes bone-age X-rays.[5–6,15,17] These help rule out treatable complications and guide therapies.
8. Will head size ever become normal?
Macrocephaly usually persists, but body height may “catch up” over time, so the child can look better proportioned in later childhood or adulthood.[2,4,13] Large head size alone is not dangerous if there is no raised pressure or structural brain problem.
9. Can my child play sports?
In many cases, yes – with sensible precautions. Physiotherapists and doctors can recommend suitable activities based on joint stability, heart and lung status, and seizure control. Regular, moderate exercise supports bone, heart, and mental health.
10. Does diet change the condition?
Diet cannot change the gene mutation, but a balanced diet helps maintain healthy weight, bone strength, and energy. Avoiding obesity is particularly important in tall children to protect joints and cardiovascular health.[6,17]
11. Are there clinical trials for this syndrome?
Trials rarely focus on RNF135 alone because it is so rare, but some studies target broader overgrowth or OGID syndromes and the pathways they share.[17,22] A genetics clinic or rare-disease centre can check registries and research opportunities.
12. Will my child live a normal life span?
Current data are limited, but there is no strong evidence that lifespan is severely shortened just from RNF135-related overgrowth.[2–4,5] Life expectancy is more influenced by associated complications such as severe epilepsy, heart or breathing problems, or malignancy, which doctors monitor and treat.
13. Is this my fault as a parent?
No. RNF135 mutations are random genetic events or inherited changes that parents cannot control. Nothing you did during pregnancy or early childhood has been shown to cause this syndrome.[2–3]
14. What kind of doctors should be involved?
Care is best in a multidisciplinary team: paediatrician, clinical geneticist, neurologist, developmental paediatrician, psychologist/psychiatrist, physiotherapist, OT, speech therapist, orthopaedist, and sometimes endocrinologist or cardiologist.[5–6,17,22]
15. What should I do next if I suspect this syndrome?
Talk to your paediatrician or a clinical geneticist. Bring growth charts, school reports, and any previous scan results. They can decide which tests are needed and help you access therapies and support services.
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 16, 2026.
