Fragile X Syndrome

Most common form of X-linked mental retardation. Affects males more often and more severely than females. Only subtle dysmorphic features. Behavioral issues may be more pronounced.

FRAXA Syndrome; Martin Bell Syndrome; X-linked Mental Retardation with Macroorchidism.

The incidence for boys is estimated to be 1:1000-5000 live births, making it the most common chromosomal cause of mental retardation second only to trisomy 21. The clinical picture can vary significantly.

Inheritance is X-gonosomal dominant. The genetic defect has been mapped to Xq27.3. Advanced maternal age seems to be a risk factor for this disorder.

The clinical picture may be suggestive of the disease, although the dysmorphic features are rather subtle. The diagnosis can be confirmed using molecular genetic testing (Southern blot) and relies on the detection of an altered fragile X mental retardation-1 (FMR1) gene. In almost all patients, the mutation is caused by a significantly increased number of CGG (C = cytosine, G = guanosine) trinucleotide repetitions, which is also associated with abnormal methylation of the FMR1 gene. The absence of or mutation in the fragile mental retardation protein (FMRP) is responsible for the Fragile X syndrome. FMRP is an RNA binding protein that shuttles between the nucleus and the cytoplasm. It seems that FMRP is located at synapses, where it is involved in signal transduction and encoding of cytoskeletal proteins. It also appears that lack of FMRP affects synaptic plasticity. Prenatal diagnostic is possible.

This progressive X-linked mental retardation affects boys (moderate mental retardation) more often and more severely than girls (mild mental retardation). The main neurologic symptoms include delayed language skills, delayed motor development, autism or autistic-like behavior, behavioral problems (attention deficit hyperactivity disorder, oppositional defiant disorder, enuresis, encopresis), and poor sensory skills. Anatomical features may include macrocephaly, a long face with prognathism (which in fact is often just a prominent symphysis of the mandibula rather than real prognathism), strabismus, prominent large ears, high arched palate, and a high-pitched voice. The external male genitalia show pronounced growth during puberty, which results in macroorchidism. Overall, muscle tone is low with generalized joint laxity (particularly of the fingers). Pectus excavatum, flat feet, shortening of the tubular bones of the hands, and hyperlordosis may be present. Heart defects (e.g., mitral valve prolapse), dilatation of the aortic root, and seizures have been described. Researchers found that the hippocampus often shows an age-related increase in size, whereas the superior temporal gyrus and the posterior cerebellar vermis are diminished in size. After age 50 years, patients show an increased rate of progressive parkinsonism, cognitive decline, and generalized brain atrophy.

The cardiovascular findings may prompt the anesthetist to request an echocardiography. If pectus excavatum is present and significant, a chest radiograph should be obtained. Because these patients are mentally retarded and may have some additional behavior issues, preoperative sedation is most often helpful and therefore recommended.

Careful positioning and padding are needed in the presence of joint laxity to prevent luxations. Facial anomalies are not expected to be severe enough to cause airway management problems. The dose of neuromuscular blockers can probably be reduced in the face of generalized muscular hypotonia. Depending on the procedure, postoperative mechanical ventilation may be indicated.

If mitral valve prolapse is present and associated with mitral regurgitation, subacute bacterial endocarditis prophylaxis is indicated.

Allan-Herndon Syndrome: Although most neonates and infants with this disorder appear to develop normally in the first few months of life, the presence of poor muscle tone is most often present at birth. By age 6 months, hypotonia, inability to hold the head, and severe muscle atrophy are detectable. Severe mental retardation is associated with multiple congenital anomalies.

Juberg-Marsidi Syndrome: X-linked recessive inherited syndrome characterized by severe mental retardation, deafness, failure to thrive, microgenitalism, and early death.

Happy Puppet Syndrome: Rare disorder characterized by developmental delay, ataxia, dysmorphic facial features, and seizures associated with a happy, sociable disposition.

MASA Syndrome: Extremely rare inherited disorder that is one of several disorders known as X-linked mental retardation (XLMR) syndromes.

Renpenning Syndrome (Escalante Syndrome): Extremely rare form of X-linked (moderate-to-severe) mental retardation. It has been linked to Xp11.2-p11.4. Other findings may include short stature, moderate microcephaly, prognathism, and small testes. Affected patients may use repetitive speech and show an aggressive behavior. Longevity seems not to be impaired, and female carriers do not show any heterozygous signs.

Sutherland-Haan Syndrome (Sutherland-Haan X-Linked Mental Retardation Syndrome; X-Linked Mental Retardation With Spastic Diplegia): Extremely rare form of X-linked severe mental retardation. Features include short stature, spastic diplegia, significant congenital heart defects, and craniofacial abnormalities (microcephaly, cleft palate or high arched palate, abnormal ears, bulbous nose, broad nasal bridge, malar hypoplasia, micrognathia, and a small mouth. No reports exist about anesthesia in these patients; however, difficult airway management seems likely.