Smith-Kingsmore Syndrome

Excerpt

Clinical characteristics: Smith-Kingsmore syndrome (SKS) is characterized by varying degrees of overgrowth, developmental delay / intellectual disability, neurodevelopmental issues (autistic features, ADHD), and congenital anomalies. Developmental delay typically involves all aspects of development (gross motor, fine motor, speech/language). Virtually all individuals have speech delay, although speech abilities over time range from vocalizations to some verbal communication, with about 50% of individuals reportedly able to use verbal communication. Intellectual disability is frequently identified in affected individuals and typically ranges from moderate to severe. Regression in development has been reported in a minority of affected individuals. Other features of SKS include congenital hypotonia, epilepsy, sleep-wake disturbances (including insomnia and obstructive sleep apnea), macrocephaly, hyperphagia, eye anomalies, skeletal anomalies, cardiac findings (including stable aortic root dilatation), and genitourinary anomalies, most commonly in males (undescended testes and hypospadias).

Diagnosis/testing: The diagnosis of SKS is established in a proband with suggestive findings and a heterozygous constitutional or early postzygotic activating pathogenic variant in MTOR identified by molecular genetic testing. Because a significant subset (20%-25%) of individuals have a pathogenic variant that is postzygotic (and thus mosaic), more than one tissue may need to be tested, such as sequence analysis of DNA derived from a freshly obtained dermal biopsy.

Management: Treatment of manifestations: Feeding therapy with consideration of gastrostomy tube placement for persistent feeding issues; healthy lifestyle and referral to nutritionist to address obesity; standard treatment for epilepsy, developmental delay / intellectual disability, scoliosis and/or pes planus, mobility issues, vision issues, aortic dilatation, valvar and cardiac septal defects, sleep abnormalities, undescended testes / hypospadias, hypoglycemia, and hearing loss.

Surveillance: At each visit, measure growth parameters, evaluate nutritional status, monitor eating habits, assess for signs of hyperphagia, assess for new neurologic manifestations such as seizures and developmental regression, monitor developmental progress and educational needs, assess mobility and self-help skills, monitor for signs/symptoms of sleep disturbance, and assess for scoliosis clinically (until skeletal maturity). At least annually or as clinically indicated, obtain ophthalmology evaluation. As clinically indicated, monitor for hypoglycemia (typically in infancy), obtain behavioral assessment for anxiety, ADHD, autism, aggression, and self-injury, and perform audiology evaluation.

Therapies under investigation: Off-label sirolimus (rapamycin) has been used in seven individuals with SKS at low-to-moderate doses with parent-reported improvements in some behaviors, including verbal skills, attention span, decreased self-aggression, and improved hyperphagia. Before using mTOR inhibitors (e.g., rapamycin), it is advisable or necessary to assess the biochemical and functional impacts of the pathogenic variant in the affected individual to optimize dosing and timing. Of note, first-generation, second-generation, and third-generation inhibitors may have distinct mechanisms and off-target effects. Any off-label use of drugs should be done at the discretion of the treating physician in conjunction with the affected individual and/or caregiver and is not endorsed by GeneReviews or the authors of this chapter.

Genetic counseling: SKS is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Approximately 86% of individuals diagnosed with SKS have the disorder as the result of a de novo constitutional or early postzygotic pathogenic variant in MTOR. Some individuals have the disorder as the result of an MTOR pathogenic variant inherited from an unaffected parent with gonadal mosaicism (~11%) or, rarely, an affected parent (~3%). Sib recurrence has been reported in several families with presumed parental gonadal mosaicism. Once the MTOR pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.