Malan syndrome

Malan syndrome is a rare genetic disorder. It is generally inherited in an autosomal dominant manner, with most cases resulting from a de novo pathogenic variant, although inherited cases can occur. The phenotype may resemble Sotos syndrome and Weaver syndrome, particularly in its overgrowth and distinctive facial features, but these conditions are genetically distinct. Malan syndrome is associated with more significant intellectual and developmental impairment, a particularly prominent anxious behavioral phenotype, and more frequent ophthalmologic abnormalities. A distinctive presentation may include the combination of generalized overgrowth, Sotos-like facial features, intellectual disability, blue sclerae, and prominent anxiety.

It can present with psychiatric features such as generalized anxiety, separation anxiety, specific phobias, ADHD, behavioral dysregulation, impaired socialization, and sleep disturbance. Hypersensitivity to visual and auditory stimuli is also common. Autism spectrum disorder (ASD) may be considered because of social and communication difficulties, but many affected individuals do not have the characteristic social impairment of ASD, and difficulties with social interaction may instead reflect expressive language impairment. Panic episodes, aggression, and self-injurious behavior may also occur. Cognitive impairment, developmental delay, and speech and language impairment are common, typically ranging from moderate to severe.

From a morphologic lens perspective, other features include (but are not limited to):

• Macrocephaly

• Prominent forehead

• Deep-set eyes

• Downslanted palpebral fissures

• Short nose

• Long philtrum

Other characteristic features include prenatal and postnatal overgrowth, advanced bone age, hypotonia, and skeletal abnormalities, including scoliosis, pes planus, and pectus deformities. Ophthalmologic manifestations may include strabismus, refractive errors, nystagmus, blue sclerae, and optic nerve hypoplasia or atrophy, with visual impairment potentially being significant. Neurologic manifestations may include seizures/epilepsy, abnormal electroencephalographic findings, and structural brain abnormalities, including ventriculomegaly, corpus callosum abnormalities, and Chiari I malformation. Additional reported features include feeding difficulties, constipation, hearing impairment, noise hypersensitivity, renal abnormalities, cryptorchidism in males, and autonomic manifestations such as episodic ataxia or postural fainting. A low body mass index and slender habitus are also characteristic.

Early diagnosis is important to identify and monitor potentially significant developmental, behavioral, neurologic, ophthalmologic, skeletal, auditory, gastrointestinal, renal, and cardiac complications, recognize neuropsychiatric needs early, and institute tailored multidisciplinary surveillance and treatment.