Weaver Syndrome: Symptoms, Types, Causes and Treatment

Weaver syndrome is a rare genetic disorder that stands out for its distinctive combination of rapid growth, advanced bone age, unique facial features, and variable intellectual disability. As our understanding of genetics has evolved, so too has our knowledge of this complex condition, especially regarding its causes and the best approaches for management. In this article, we’ll explore the main symptoms, known types, underlying causes, and current treatment options for Weaver syndrome, providing a comprehensive guide for families, clinicians, and anyone interested in rare genetic disorders.

Symptoms of Weaver Syndrome

Weaver syndrome’s symptoms are wide-ranging, affecting physical appearance, growth, neurological development, and even musculoskeletal health. Its signs can be subtle in older children and adults, making diagnosis challenging without genetic testing.

Symptom	Description	Frequency/Severity	Source
Overgrowth	Tall stature, rapid growth	>90% of cases	1 2 6 8 9
Macrocephaly	Large head size	Common	2 6 8 11
Advanced bone age	Accelerated skeletal maturation	Prominent	2 6 7 8
Facial features	Large ears, broad forehead, hypertelorism, long philtrum, flat occiput	Subtle to prominent	1 2 5 8 11
Intellectual disability	Mild to moderate cognitive delay	~80% (variable)	1 6 8 11
Musculoskeletal	Camptodactyly, joint contractures, scoliosis, hip/foot anomalies	Variable	1 3 5 8 14
Skin changes	Soft, doughy or loose skin	Sometimes observed	1 3 5 11
Hoarse/low cry	Distinctive cry in infancy	Frequently present	1 2 3 7 8
Hernias	Umbilical or inguinal hernias	Not uncommon	1 3 5 11

Table 1: Key Symptoms

Growth and Skeletal Features

One of the most recognizable aspects of Weaver syndrome is rapid growth starting before birth, which continues after delivery. Children are often significantly taller than their peers and may have a large head (macrocephaly). Bone age (a measure of skeletal maturity) is advanced, meaning bones develop faster than expected for the child’s chronological age. This can lead to joint issues and, in some cases, musculoskeletal deformities such as scoliosis, congenital hip dislocations, or foot abnormalities (like talipes equinovarus) 2 6 7 8 14.

Distinctive Facial and Physical Characteristics

Facial features tend to be subtle in older patients but can include a broad forehead, large or prominent ears, widely spaced eyes (hypertelorism), a long groove between the nose and upper lip (philtrum), and a flat occiput. Some individuals may also have a “stuck-on” chin appearance (retrognathia with a chin crease) 1 5 8 11. Other physical changes can include soft, doughy or excessively loose skin and deep-set, thin nails.

Neurological and Developmental Aspects

Intellectual disability is seen in up to 80% of cases but is often mild. Hypotonia (reduced muscle tone) or, less commonly, hypertonia (increased tone) can be present, as well as poor coordination and delays in reaching developmental milestones. Some may have abnormalities of the brain (e.g., changes in the folds or gyri) visible on MRI, but the implications for cognition remain unclear 1 3 6 11.

Additional Symptoms

• Camptodactyly: permanent bending of fingers or toes.
• Joint contractures: limited movement, especially in elbows, knees, fingers, and toes.
• Hoarse or low-pitched cry in infancy.
• Hernias: umbilical and/or inguinal.
• Occasional hypothyroidism, macroglossia (enlarged tongue), or increased risk for certain tumors (especially neuroblastoma) 1 3 5 8 11 13.

Types of Weaver Syndrome

Although Weaver syndrome is generally considered a single disorder, advances in genetics have revealed a spectrum, with some patients showing classic features and others presenting milder or “Weaver-like” symptoms.

Type/Subtype	Main Features	Genetic Basis	Source
Classic Weaver	Full symptom spectrum	EZH2 mutation	1 6 8 10
Weaver-like	Partial/atypical symptoms	EED or SUZ12 mutations	4 6
Overlap with Sotos	Shared and distinguishing features	NSD1 mutation (rare in Weaver)	1 6 8
Sporadic vs. Familial	Most sporadic, rare familial cases	Autosomal dominant inheritance	5 8 11

Table 2: Types and Spectrum

Classic Weaver Syndrome

The “classic” form is linked to mutations in the EZH2 gene and displays the full range of typical symptoms, including overgrowth, advanced bone age, facial features, intellectual disability, and musculoskeletal involvement 1 6 8 10.

Weaver-like and Genetic Heterogeneity

Some patients have clinical features very similar to Weaver syndrome but do not have mutations in EZH2. Instead, they may have mutations in related genes, such as EED or SUZ12, both of which are also components of the polycomb repressive complex 2 (PRC2) 4 6. These Weaver-like forms may have slightly different or milder presentations but are considered part of the broader overgrowth spectrum.

Overlap with Sotos Syndrome

There is notable clinical overlap with Sotos syndrome, another overgrowth disorder. Both share features like tall stature, macrocephaly, and developmental delay, but Sotos is usually due to mutations in the NSD1 gene. Unique Weaver features include more pronounced chin crease, prenatal overgrowth, and specific bone maturation patterns 1 6 8.

Inheritance Patterns

Most cases are sporadic (occur as new mutations), but rare familial (autosomal dominant) inheritance has been reported. This means an affected parent has a 50% chance of passing the mutation to each child, but expression can be variable 5 8 11.

Causes of Weaver Syndrome

In recent years, our understanding of what causes Weaver syndrome has become much clearer. The disorder is now firmly established as being due to mutations in genes involved in chromatin remodeling and gene regulation.

Cause	Description	Inheritance	Source
EZH2 mutations	Mutations in histone methyltransferase EZH2	Usually de novo, sometimes familial	1 6 8 9 10 11
PRC2 complex defects	Includes EED and SUZ12 gene mutations	Rare, Weaver-like	4 6
NSD1 mutations	Occasionally in overlap with Sotos syndrome	Sporadic/familial	6 8
Unknown	Some cases without known mutation	Unknown	5 6 8

Table 3: Genetic Causes

EZH2 and the Polycomb Repressive Complex 2

The vast majority of cases are caused by mutations in the EZH2 gene, which encodes a histone methyltransferase that is the catalytic component of the polycomb repressive complex 2 (PRC2) 1 6 8 9 10 11. This complex plays a key role in regulating gene expression by modifying chromatin structure. Mutations in EZH2 reduce the enzyme’s activity, impairing the normal repression of certain genes during development, leading to the overgrowth and other symptoms seen in Weaver syndrome 9 10.

Other PRC2 Components: EED and SUZ12

A few patients with Weaver-like features have mutations in EED or SUZ12, also part of the PRC2 complex 4 6. These mutations often result in similar, though sometimes milder or atypical, clinical presentations.

NSD1 and Overlap with Sotos Syndrome

Rarely, mutations in NSD1—a gene more commonly associated with Sotos syndrome—have been found in individuals with Weaver-like features. This underlines the overlap between different genetic overgrowth syndromes 6 8.

Inheritance and Mutation Patterns

• Most cases are de novo (not inherited, but new in the child).
• Rare familial cases are autosomal dominant.
• Genetic counseling is advised for affected families, especially if a mutation is identified 5 8 11.

Treatment of Weaver Syndrome

There is currently no cure for Weaver syndrome. Management focuses on addressing specific symptoms, supporting development, and improving quality of life. A multidisciplinary approach is essential.

Symptom/Issue	Management Approach	Outcome/Goal	Source
Developmental delay	Early intervention, speech/behavioral therapy	Maximize potential	11 12
Musculoskeletal	Orthopedic surgery/physiotherapy	Improve mobility/function	14
Camptodactyly/joint contractures	Surgical release, physiotherapy	Improved joint use	11 14
Scoliosis	Routine orthopedic management	Prevent progression	11 14
Macroglossia	Partial glossectomy (rare)	Improve speech/swallowing	13
Aggressive behaviors	Deep brain stimulation (experimental)	Behavioral control	12
Tumor risk	Clinical surveillance (no routine screening)	Early detection	11
Genetic counseling	Risk assessment for families	Informed decision-making	11

Table 4: Treatment Approaches

Early Interventions and Developmental Support

• Developmental delay and learning disabilities benefit from early referral to speech, occupational, and behavioral therapy to maximize developmental outcomes 11.
• Physical therapy helps address hypotonia, joint contractures, and motor coordination issues.

Musculoskeletal Management

Musculoskeletal deformities, such as hip dislocations or significant joint contractures, may require surgical correction to improve mobility and independence. Early intervention, before bone maturity, gives the best outcomes 14. Camptodactyly (permanent finger/toe flexion) sometimes requires surgical release 11 14.

Management of Specific Symptoms

• Scoliosis: Managed like in other children, with monitoring and, if needed, bracing or surgery 11 14.
• Macroglossia: Rarely, surgical tongue reduction (partial glossectomy) may be performed to improve speech and swallowing 13.
• Aggressive Behavior: In rare, severe cases, deep brain stimulation has been used for uncontrollable aggression, with some success 12.

Surveillance and Tumor Risk

While neuroblastoma risk is slightly increased, routine tumor surveillance is not currently recommended due to insufficient data. However, clinicians should be vigilant and promptly investigate any suspicious symptoms 11.

Genetic Counseling and Family Planning

Families should be informed about inheritance risks and options for prenatal or preimplantation genetic diagnosis if a pathogenic variant has been identified 11.

Conclusion

Weaver syndrome is a rare but increasingly well-understood overgrowth disorder, thanks to advances in genetic research. With a constellation of symptoms ranging from rapid growth and distinctive facial features to developmental and orthopedic challenges, each person’s experience can be unique. Early diagnosis, a tailored multidisciplinary approach, and ongoing support are key to optimizing quality of life for those affected.

Key Points:

• Weaver syndrome is characterized by rapid growth, advanced bone age, unique facial features, and variable intellectual disability 1 2 6 8.
• It is usually caused by de novo mutations in the EZH2 gene, but can also result from changes in other PRC2 complex genes (EED, SUZ12) 4 6 8 9.
• Symptoms are highly variable, ranging from subtle to pronounced, and can include musculoskeletal, neurological, and dermatological findings 1 3 5 8 14.
• Treatment is symptomatic and multidisciplinary, focusing on developmental support, orthopedic management, and addressing individual needs 11 13 14.
• Most cases are sporadic; genetic counseling is recommended for affected families 5 8 11.

By fostering awareness and advancing research, we can continue to improve outcomes for individuals and families living with Weaver syndrome.