Weaver syndrome is a very rare genetic disorder that presents with a range of musculoskeletal, cutaneous, cognitive, and facial symptoms. Excessive growth in early life is the most prominent finding, followed by intellectual disability of various degrees and connective tissue disorders such as laxity of ligaments. The diagnosis rests on a thorough clinical assessment, which is the only tool to raise sufficient evidence for genetic testing.
Initially described in the 1970s, Weaver syndrome is a very rare congenital genetic disorder, with little over 50 cases described in the literature    . Until recently, the exact pathogenesis of this condition was unknown, but new results strongly point toward mutations of the Enhancer of Zeste Drosophila homolog 2 (EZH2) gene     . EZH2 is an important regulator of epigenetic functions and the process of transcription and is well-known for its prominent role in the maturation of skeletal, muscle, lymphoid, and blood cells  . The exact mechanism of mutation is yet to be solidified, although missense mutations were most frequently identified so far  . The clinical presentation involves several organ systems from early life and the most important component is excessive generalized growth leading to tall stature   . Hypertelorism and advanced bone age are frequent findings, whereas other notable findings of the musculoskeletal system are scoliosis, talipes equinovarus, and camptodactyly (fixed flexion of fingers)   . Cranial abnormalities, such as macrocephaly, and several characteristic features of the face (retrognathia, a broad forehead, round facies, large ears, and very wide eyes) are commonly present  . Intellectual impairment is an equally important component of the clinical presentation, varying from mild to severe and debilitating IQ deficits  . Poor coordination, owing to the extreme laxity of ligaments, and very loose skin are additional findings in patients suffering from Weaver syndrome .
Given the very rare occurrence of Weaver syndrome (and its still incompletely understood mechanism of inheritance), the diagnosis can be quite difficult to make. For this reason, the physician should obtain a comprehensive patient history that will cover the onset of symptoms and their progression, as well as severity. Because isolated cases of parent-to-child transmission were confirmed , a thorough family history may yield important information and should not be overlooked in patients with undisclosed complaints from early life. A detailed physical examination should follow history taking, during which the assessment of growth curves, facial features, and cognitive status must be evaluated. The initial recognition of Weaver syndrome primarily rests on clinical criteria, but the nonspecific clinical presentation that often lacks some of its main components significantly impedes recognition . In order to confirm the diagnosis, genetic testing needs to be employed . Detection of a pathogenic variant of EZH2 through molecular and proband testing strengthens the diagnosis . In addition to clinical and laboratory studies, imaging techniques, such as magnetic resonance imaging (MRI), may be useful for patients in whom macrocephaly is suspected, as ventriculomegaly and several other findings can be observed .