Knowledge on rare diseases and orphan drugs

Smith-Magenis syndrome (SMS) has an estimated prevalence of 1/15,000-25,000 and has been identified worldwide in all ethnic groups, but is probably underdiagnosed. Males and females are affected equally.

Patients have a recognizable clinical picture. Craniofacial features include brachycephaly, a broad square-shaped face, synophrys, mildy upslanted palpebral fissures, midface retrusion with relative prognathism with age, and an everted upper lip with a ''tented'' appearance. Short stature is common in young patients, with height typically in the normal range as adults. Excess weight and/or obesity in teens and adults are common. Other skeletal anomalies include brachydactyly, clinodactyly of the 5th finger, 2-3 toe syndactyly and scoliosis. Otolaryngological problems such as velopharyngeal insufficiency, laryngeal anomalies, a hoarse deep voice and otitis media occur frequently. Hearing loss is frequent and may be mild to moderate. Ophthalmologic features (>80%) include strabismus, myopia, iris anomalies and retinal detachment (often resulting from violent behaviors). The majority of individuals function in the mild to moderate range of intellectual disability. Significant speech delay and maladaptive behaviors (outbursts/temper tantrums, nail yanking, insertion of foreign objects into body orifices, self-injurious behaviors, attention seeking, and anxiety) are common. Sleep disturbance is due to an inversion of the circadian rhythm of melatonin. Organ malformations include cardiac, renal and central nervous system abnormalities.

SMS is typically a sporadic disorder caused either by a 17p11.2 deletion encompassing the retinoic acid-induced 1 (RAI1) gene (90%) or a mutation of the gene (10%). Patients with a mutation can have a less severe phenotype, and manifestations may have a later onset in the least severe cases.

Diagnosis is based on initial clinical suspicion followed by molecular confirmation of the genetic defect. Careful history-taking for birth defects, sleep disturbance, delayed milestones, chronic ear infections, self-injurious behaviors, and family history are important to recognize the characteristic features.

Differential diagnoses include Down syndrome, Williams syndrome, brachydactyly-intellectual deficit syndrome (del 2q37), and Kleefstra syndrome.

Almost all cases correspond to a single occurrence in a family, but prenatal testing can be offered for at-risk pregnancies where the genetic alteration has been previously identified in an affected family member.

The disorder is autosomal dominant with most cases arising sporadically. Genetic counseling is recommended to affected families due the possibility of vertical transmission, parental germline mosaicism, and complex familial chromosome rearrangements. When a chromosomal deletion is identified, parental chromosomal testing is recommended to rule-out any translocation or other rearrangements that might affect the recurrence risk.

Appropriate assessment of the degree of cognitive, developmental, and behavioral deficits and of systemic/organ abnormality is essential for appropriate and specific management. Treatment is symptomatic and may include psychotropics intended to increase attention, decrease hyperactivity and stabilize behavior and treatment for sleep disorders. However, no single regimen has shown consistent efficacy. Family psychosocial support is recommended.

Prognosis depends on age of diagnosis, disease severity, and precocity of therapeutic interventions.

Last update: November 2020 - Expert reviewer(s): Dr Laurence PERRIN | ITHACA*

* European Reference Network