Smith-Magenis syndrome

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BACKGROUND AND CLINICAL INFORMATION: Head

Summary: Smith-Magenis syndrome is characterized by mental retardation and multiple congenital anomalies. A deletion at chromosome 17p11.2 is seen in most patients by cytogenetics or, in smaller deletion, by FISH. The deletion occurs in only one chromosome and almost all of the patients have de novo deletions. Smith-Magenis syndrome is characterized by typical craniofacial features, peripheral neuropathy, mental retardation, and hyperactivity disorder or ADHD. Other typical problems include onychotillomania, spasmodic upper body squeezing, and sleep behavior. Typically, these patients also have aggression, self–destruction, and tantramus. Renal, musculoskeletal, cardiac, and ophthalmological abnormalities may also be present.

Incidence:  1/25,000 in the general population. This can be an underestimation.

Genetics:

• Deletion at chromosome 17p11.2. The deletion vary from 1.5 MB to 9 MB but they typically are about 5 MB in size.

• Haplotype insufficiency: Deletion occurs on only one chromosome.

• Pathogenesis: Most cases are due to de novo deletion.

• FISH: Can be diagnosed by high-resolution cytogenetics studies or FISH.

• Genes involved: Only a few genes have been demonstrated to be consistently deleted in Smith-Magenis syndrome. These genes include the human homologue (FLII) of Drosophila melanogaster flightless-1 gene, the human microfibril-associated protein (MFAP4) gene. The cytosolic serine hydroxymethyl-transferase (cSHMT) gene. Other genes in this regions that may be related to Smith-Magenis syndrome include the adenosine A2b receptor subtype gene (ADORA2B), a gene for one form o f nonsyndromal recessive deafness (DFNB3), and a human gene RIGUI.

Mental and behavial:

• Salient features: They usually have profound mental retardation. About 80% of the patients have hyperactivity or ADHD and is usually associated with aggression, self –destruction, and tantramus.

• Intelligence: Cognitive abilities range from profound mental retardation to borderline functioning. Their IQ scores is usually between 40 and 50.

• Self-hug or spasmodic upper body squeezing: This is seen in about 50% of patients,

• Speech delay: They have speech delay with or without hearing loss.

• Onychotillomania (pulling out of hair, fingernails and toe nails): common in older patients, may be related to their decrease in sensitivity to pain resulted from peripheral neuropathy.

• Sleep disturbance: seen in about 70% of patients. These patients often have difficulties in falling asleep and frequent night awakenings that lead to exhaustion.

• Seizure: seen in about 20% of patients.

• Failure to thrive in infancy.

Physical features/clinical features:

• Relation to deletion: More severe clinical involvement may be seen with a large deletion that removes more genes than are typrically removed in cases of Smith-Magenis syndrome.

• Craniofacial: brachycephaly, microcephaly, midface hypoplasia, broad nasal bridge, prognathism, low-set and/or posteriorly rotated ears, synophrys (the growing together of the two eyebrows), and dowturned mouth with a cupid’s bow shape. Delayed eruption of theeth and malocclusion are common. Facial features may suggest Down syndrome.

• Peripheral neuropathy: Peripheral neuropathy is present in about 75% of patients and may manifest as one or more of the following: decreased sensitivity to pain or temperature, pes cavus or planus, and decreased deep tendon reflexes.

• Musculoskeletal: short stature, scoliosis, a variety of hand abnormalities. Short, broad hand and fingers with partial syndactyly are typical. Hypotonia is present in about half of the patients and is seen in infancy.

• Hearing: Both conducting and sensory hearing loss are common.

• Ophthalmological: strabismus, myopia and high myopia, and cataracts.

• Cardiovascular: ASD, VSD, subvalvular aortic stenosis, and others.

• Renal malformations are also common.

NEUROIMAGING: Head  

In a small study, about half of the cases have abnormalities. The most common one is ventriculomegaly. Less common abnormalities include by enlargement of cisterna magna and partial absence of the cerebellar vermis.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

Autopsy cases area rarely reported. Abnormal cortical architecture has been described in one case. [Smith AC et al., 1986; Greenberg F et al., 1996]

REFERENCES: Head

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Background    Neuroimaging    Histopathology & Immunohistochemistry    Reference