Phelan-McDermid Syndrome- SHANK3 Related

Clinical characteristics: Phelan-McDermid syndrome-SHANK3 related (PMS-SHANK3 related) 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 relatively large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguish PMS-SHANK3 related from other autosomal chromosome disorders. Neurobehavioral characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior. Some individuals experience regression / loss of skills, epilepsy, ataxic/abnormal gait, and sleep disturbance (difficulty falling asleep and staying asleep, hypersomnia, and parasomnias). Less commonly, affected individuals may have strabismus, vision problems (hyperopia or myopia), cardiac anomalies, renal anomalies, and lymphedema. Those who have PMS-SHANK3 related due to a ring chromosome 22 also have a high risk of developing features of NF2-related schwannomatosis (NF2).

Diagnosis/testing: The diagnosis of PMS-SHANK3 related is established in a proband with suggestive findings and either (1) a <50-kb to >9-Mb heterozygous deletion at chromosome 22q13.3 with involvement of at least part of SHANK3; (2) a heterozygous pathogenic variant in SHANK3; OR (3) a chromosomal rearrangement with breakpoints disrupting SHANK3 identified by molecular genetic testing.

Management: Treatment of manifestations: Standard treatment for developmental delay / intellectual disability, epilepsy, hearing loss, recurrent ear infections, refractive error, strabismus, gastroesophageal reflux disease, autoimmune hepatitis / liver failure, renal anomalies, vesicoureteral reflux, hypothyroidism, pubertal abnormalities, bruxism, malocclusion, and cardiac issues. Those who experience poor feeding may benefit from feeding therapy or, if the feeding issues are persistent, placement of a gastrostomy tube. Immunomodulation therapy (such as intravenous immunoglobulins) may be considered in those with autoimmune encephalitis. Sleep hygiene, healthy habits, light therapy, and potential medical management may be considered to treat sleep disturbance. More complex vision issues, such as optic nerve hypoplasia or cortical visual impairment, may require input from an ophthalmic subspecialist. Use of pressure stockings and elevation of the foot of the bed may be helpful for those who have lymphedema; depending on the stage of the symptom, compression therapy, weight reduction, and stimulation mobility may also be indicated. In those who have a ring chromosome 22, see the GeneReview on NF2-related schwannomatosis for further information about treatment of manifestations.

Surveillance: At each visit, measurement of growth parameters; evaluation of nutritional status and safety of oral intake; monitor for signs/symptoms of GERD; monitor for new manifestations, such as seizures, changes in tone, and developmental regression; monitor developmental progress and educational needs; evaluate for neurobehavioral issues, such as anxiety, ADHD, autism, aggression, and self-injury; monitor for signs/symptoms of sleep apnea and sleep disturbance. Annually, perform audiology evaluation and ophthalmology evaluation. At each visit in childhood and adolescence, monitor for signs and progression of puberty. At regular intervals, perform dental evaluation for evidence of tooth decay, malocclusion, and crowding. In those with poor growth or as clinically indicated, assess thyroid function. In those with a ring chromosome 22, perform annual neurologic examination by a provider with experience with NF2; brain MRI annually beginning at age 10-12 years until fourth decade of life; annual audiology evaluation, including BAER, to assess for the earliest symptoms of vestibular schwannomas; annual ophthalmology evaluation.

Agents/circumstances to avoid: Exposure to high temperatures and extended periods in the sun due to reduced perspiration and tendency to overheat easily; exposure to excessive heat or cold, sharp objects, or clothes/shoes that may be too tight and cause skin lesions due to decreased perception of pain; radiotherapy for NF2-associated tumors in those with a ring chromosome 22.

Genetic counseling: PMS-SHANK3 related is an autosomal dominant disorder most often caused by a de novo genetic alteration. Recurrence risk in family members depends on the genetic mechanism underlying PMS-SHANK3 in the proband and the genetic status of the parents of the proband.

22q13.3 deletion: Most probands have a de novo deletion; some probands have the deletion as the result of an unbalanced structural rearrangement that includes 22q13 (about half of these individuals have a parent who is a carrier of a balanced translocation) or a ring chromosome 22 (karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by CMA). Rarely, a proband inherited the genetic alteration from a heterozygous or mosaic parent. If a parent has (1) a non-mosaic 22q13.3 deletion, the risk to each sib of inheriting the deletion is 50%; (2) a mosaic 22q13.3 deletion, the risk to each sib is increased but impossible to quantify because the level of mosaicism in gonadal tissue is unknown; (3) a chromosomal rearrangement, the risk to sibs is increased and depends on the specific chromosomal rearrangement and the possibility of other variables.

Intragenic SHANK3 pathogenic variant: Most probands have a de novo pathogenic variant; rarely, a proband inherited the pathogenic variant from a heterozygous or mosaic parent. If a parent of the proband is affected and/or known to have an intragenic SHANK3 pathogenic variant, the risk to the sibs is 50%.

Once a 22q13.3 deletion involving SHANK3 or a SHANK3 intragenic pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Prenatal test results cannot reliably predict the phenotype.