Smith-Magenis Syndrome

Excerpt

Clinical characteristics: Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly coarse facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbances, and childhood-onset abdominal obesity. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. Most individuals function in the mild-to-moderate range of intellectual disability. Behavioral manifestations, including significant sleep disturbances, stereotypies, and maladaptive and self-injurious behaviors, are generally not recognized until age 18 months or older and continue to change until adulthood. Sensory issues are frequently noted, including avoidant behavior and repetitive seeking of specific textures, sounds, and experiences. Significant anxiety is common as are problems with executive function, including inattention, distractibility, hyperactivity, and impulsivity. Maladaptive behaviors include frequent outbursts / temper tantrums, attention-seeking behaviors, opposition, aggression, and self-injurious behaviors including self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper body squeeze or "self-hug" seems to be highly associated with SMS. An underlying developmental asynchrony, specifically emotional maturity delayed beyond intellectual functioning, may also contribute to maladaptive behaviors in people with SMS.

Diagnosis/testing: The diagnosis of SMS is established in a proband with suggestive clinical findings and either a heterozygous deletion of chromosome 17p11.2 that includes RAI1 or a heterozygous intragenic RAI1 pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: Early childhood intervention programs; individualized special education for school-age children; speech-language, physical, occupational, and behavioral therapy and vocational training support later in life. Affected individuals may also benefit from monitored trials of psychotropic medication to increase attention and/or decrease hyperactivity, and therapeutic management of sleep disorders. Consider treating sleep disorders using acebutolol, melatonin, tasimelteon, and beta-1-adrenergic antagonists. Standard treatment for epilepsy, obesity, gastroesophageal reflux disease, constipation, hypercholesterolemia, palate anomalies, scoliosis, ophthalmologic issues, recurrent otitis media, hearing loss, cardiac anomalies, renal anomalies, immunodeficiency, hypothyroidism, and growth hormone deficiency. Individuals with a 17p11.2 deletion that includes FLCN may require management of features of Birt-Hogg-Dubé syndrome (BHDS). Respite care and psychosocial support for family members are recommended.

Surveillance: Annual multidisciplinary evaluations for general health and well-being and to plan for educational and vocational or other individualized interventions. In particular, periodic neurodevelopmental assessments and/or consultation with a developmental pediatrician to monitor progress and refer for additional services, evaluations, or support. School-age children should have periodic comprehensive evaluation to give input to the individualized education program. Annual otolaryngology, audiology, and ophthalmology evaluations. Measurement of growth parameters and nutritional status at each visit. Monitor for the development and/or progression of seizures and scoliosis. Annual fasting lipid profile, screening urinalysis for occult urinary tract infections, and thyroid function tests. Annual family psychosocial assessments are also recommended to assess support for caregivers and sibs. Repeat quantitative immunoglobulins / vaccine titers as clinically indicated. Surveillance in adulthood for complications of BHDS in those with a 17p11.2 deletion that includes FLCN.

Agents/circumstances to avoid: When starting a new medication, care should be taken to track sleep and behavior changes over several days or weeks to monitor for potential side effects (e.g., increased appetite, weight gain) and adverse reactions and/or to determine potential efficacy.

Genetic counseling: SMS is an autosomal dominant disorder typically caused by a de novo deletion of chromosome 17p11.2 that includes RAI1 or an intragenic RAI1 pathogenic variant. Almost all individuals reported to date with SMS whose biological parents have undergone genetic testing have the disorder as a result of a de novo genetic alteration. Rarely, individuals diagnosed with SMS have the disorder as the result of a 17p11.2 deletion or intragenic RAI1 pathogenic variant inherited from an unaffected or mildly affected mosaic parent; a 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent; or an intragenic RAI1 pathogenic variant inherited from a heterozygous affected parent. If neither parent is found to have the genetic alteration identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is likely less than 1%. Once the SMS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.