Clinical characteristics: Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate-to-profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguish Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.
Diagnosis/testing: The diagnosis of Phelan-McDermid syndrome is established in a proband with typical clinical findings by detection of a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of SHANK3 or of a heterozygous pathogenic variant in SHANK3 on molecular genetic testing. Individuals diagnosed by chromosomal microarray should have a karyotype to evaluate for the presence of a ring chromosome 22.
Management: Treatment of manifestations: Early referral for developmental support / special education; assistive technology for communication, oral-motor therapy to alleviate chewing and swallowing problems; standard treatment of seizures, hearing loss, recurrent ear infection, visual problems, and other identified medical needs. Regular professional dental hygiene, routine brushing, and fluoride treatment are important as enamel may be damaged from persistent chewing.
Surveillance: Evaluation by a neurologist for epilepsy or if changes in behavior or regression of skills become evident; monitoring for lymphedema, which may appear in adolescence or adulthood; monitoring for symptoms of neurofibromatosis type 2 (NF2) in individuals with ring chromosome 22.
Agents/circumstances to avoid: Exposure to high temperatures and extended periods in the sun because of decreased perspiration; exposure to dangers such as sources of excessive heat or cold, sharp objects, or clothes/shoes that are too tight, due to decreased perception of pain.
Genetic counseling: Phelan-McDermid syndrome, caused by a deletion of 22q13.3 that includes at least a part of SHANK3 or a pathogenic variant in SHANK3, is inherited in an autosomal dominant manner. The deletion may be de novo or the result of a balanced translocation in one of the parents; pathogenic variants in SHANK3 are almost always de novo. Prenatal testing and preimplantation genetic testing for Phelan-McDermid syndrome are possible for a pregnancy at increased risk.
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