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 disturbance, 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. The majority of individuals function in the mild-to-moderate range of intellectual disability. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change until adulthood. Sensory issues are frequently noted; these may include avoidant behavior, as well as repetitive seeking of textures, sounds, and experiences. Toileting difficulties are common. Significant anxiety is common as are problems with executive functioning, 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 who has suggestive clinical findings and either a heterozygous deletion at chromosome 17p11.2 that includes RAI1 or a heterozygous intragenic RAI1 pathogenic variant.
Management: Treatment of manifestations: Early-childhood intervention programs; individualized special education for school-aged children; speech/language, physical, occupational, and behavior 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. Standard treatment for epilepsy, obesity, gastroesophageal reflux disease, constipation, hypercholesterolemia, palatal anomalies, scoliosis, ophthalmologic issues, recurrent otitis media, hearing loss, cardiac anomalies, renal anomalies, mild 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 (BHD). 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-aged 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 for complications of BHD 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 caused by a heterozygous deletion of or a heterozygous pathogenic variant in RAI1 on chromosome 17p11.2. The majority of 17p11.2 deletions are de novo, while deleterious variants in RAI1 can be de novo or inherited. Complex familial chromosome rearrangements leading to del(17)(p11.2) and SMS occur but are rare. Although SMS usually occurs as the result of a de novo deletion of 17p11.2, rare instances of vertical transmission from an affected parent to a child, parental germline mosaicism, and complex familial chromosome rearrangements leading to del(17)(p11.2) and SMS have been reported. If the SMS-related genetic alteration has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. In the rare instance of a complex familial chromosome rearrangement, prenatal testing is possible for a pregnancy at increased risk using prenatal chromosomal microarray analysis (CMA) and sequencing on fetal cells.
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