Symptoms/Findings/Clinical Course
In females with classic RS, the disease course tends to follow a relatively predictable pattern, although the age at onset and symptom severity may be somewhat variable. Less commonly, patients may meet some but not all the diagnostic criteria for RS (atypical RS variants). For example, some may have congenital onset, late regression, or incomplete, milder symptoms (forme fruste), such as some preserved speech and hand use. In addition, in extremely rare cases, male children may appear to have "RS-like" symptoms. The following is an overview of the disease course typically associated with classic RS.
Prior to symptom onset
Growth and development before and shortly after birth are apparently normal. For example, newborns have a head circumference that is within normal limits. During the first months of life, infants tend to develop physical, mental, and behavioral skills—or reach "developmental milestones"—at the expected rate. These skills may include reaching for objects, smiling spontaneously, self-feeding with the fingers, or speaking single words or phrases.
Four stages of RS have been defined to help characterize the disorder and improve its recognition and diagnosis. These stages may be described as follows.
Stage I: Early onset
Beginning at approximately age 3 to 5 months (and continuing until about 4 years of age), there is a slowing of head growth (acquired microcephaly). Between about age 6 to 18 months, additional early abnormalities may develop that may not be recognized. Affected infants or children may attain certain developmental milestones—such as crawling or pulling themselves up to a sitting or standing position—later than otherwise expected. They may also cease to acquire new skills. Additional early findings may include increasingly diminished muscle tone (hypotonia), decreased eye contact, and inattentive behavior.
Stage II: Regressive stage
Between age 1 to 4 years, particularly from about 9 to 12 months, affected infants and children may have a gradual, sudden, or incremental loss of previously acquired skills. This is known as developmental regression. For example, by approximately age 3 years, spontaneous, purposeful use of the hands has been lost as well as most spoken language, such as previously acquired sounds, words, or word combinations. Conscious control of the hands and fingers is gradually replaced by distinctive, uncontrolled, stereotypic movements that are performed almost continually during waking hours yet cease during sleep. These may include repeated hand clapping, clenching, grasping and releasing, mouthing, patting, rubbing, tapping, or "washing and wringing." In addition, the tongue may repeatedly twist or contort in ineffective chewing movements, and there may be involuntary grinding, gnashing, or clenching of the teeth (bruxism). Children may also be prone to outbursts of laughter, screaming, or crying.
In infants and children with RS, an impaired ability to consciously coordinate purposeful movements, known as apraxia or dyspraxia, may gradually interfere with almost all voluntary motions. For example, relatively early in the disease course, this impaired ability may affect eye gaze, leading to poor eye contact. As mentioned previously, affected children also have severely impaired expressive--as well as receptive--language development. Verbal apraxia/dyspraxia is thought to contribute to the irritability and agitation seen in many RS patients. Affected girls may also have diminished interest in social interactions, often engage in repetitive rocking motions, and may develop other autistic-like behaviors. Although these RS characteristics interfere with the ability to obtain accurate assessments of intelligence, many reports suggest that patients with RS typically have severe mental retardation.
Children with RS also develop disturbances of balance and difficulties in purposefully performing the motor actions required for coordinating walking (gait apraxia) and trunk movements. As a result, they may have unsteady walking patterns, such as a widely based, stiff, jerky gait and unusual "toe-walking." In addition, some children may have severe delays in the ability to walk independently or never gain this ability. RS patients also develop episodes of "shakiness" or fine tremors of the torso and, possibly, the arms and legs, particularly during times of stress or excitement.
In many children, respiratory dysrhythmia becomes apparent during waking hours, including periodic apnea, hyperventilation, and air swallowing, which may lead to abdominal bloating. Hyperventilation episodes may also be associated with momentary lapses of awareness. Affected girls may also develop sleep irregularities and seizures.
Once neurodevelopmental regression occurs, most RS patients also begin to have growth delays and appear abnormally small and thin as compared to other females their age. Many develop chewing and swallowing difficulties and may have associated abnormalities of the digestive tract, resulting in insufficient food intake or impaired utilization of nutrients. There may be poor control of tongue movements and regular entry of foods or liquids into the airway during swallowing. Digestive abnormalities may include peristalsis, gastroesophageal reflux, and esophageal atony. Children with RS are also prone to infrequent, incomplete, or difficult passage of stools (constipation). In addition, although calcium and vitamin D intake and absorption may be adequate, many RS patients have decreased bone density and an associated increased risk of bone fractures. There may also be reduced bone density in the hands, shortening of certain bones of the hands and feet (e.g., fourth metacarpals and metatarsals), and shortening of the inner bones of the forearms (ulnae).
Stage III: Relative stabilization
During early to mid-childhood, such as from age 2 to 10 years, neurodevelopmental regression ceases and there is a relative stability of symptoms. However, motor difficulties and seizure activity may become more pronounced. In addition, before approximately 8 years of age, scoliosis may develop. Curvature may be mild or become progressively severe during late childhood to early adolescence. There may be modest developmental gains, such as increased attention span or more interest in surroundings. Relative improvements in communication skills may also be achieved and continue into adulthood. Many females with RS may remain in this stage of stabilization.
Stage IV: Late motor impairment
Beginning after approximately 10 years of age, some RS patients may develop increasing motor difficulties. Whereas some girls have never gained the ability to walk (Stage IVB), others may gradually lose this ability (Stage IVA). Other findings may include increasing muscle weakness, spasticity, or joint contractures. Sustained muscle contractions may cause involuntary, potentially painful, twisting or distorted posturing of affected muscles; this condition is known as dystonia. Additional abnormalities may include irregular, rapid, jerky movements (myoclonus), particularly of the forearms and lower legs, or athetosis. In addition, in patients with scoliosis, particularly those who are unable to walk or are affected by dystonia, the spinal curvature may become progressively severe during this stage.
However, abnormal breathing patterns and seizure episodes may tend to become less pronounced with age, and eye contact and attention span may continue to improve. In some patients, stereotypic hand movements also become less persistent during waking hours and some purposeful hand actions may be recovered.
Additional abnormalities
Many females with RS live well into adulthood. However, sudden or unexplained, life-threatening complications may develop. Increased risk of sudden death may be due to abnormalities in the transmission of electrical impulses that coordinate contractions of the heart (cardiac conduction system). For example, studies have demonstrated that girls with RS may have significantly longer "corrected QT intervals" compared with other girls of the same age. The QT interval, as seen on an electrocardiogram, represents the time required for "recharging" of the heart's electrical system following each heart beat. Thus, in those with an elongated QT interval, sometimes referred to as "long QT syndrome," there is prolongation of the resting pause of the heart. Long QT syndrome may lead to irregular heart rhythms (arrhythmias), potentially resulting in a sudden loss of consciousness (or syncope) due to insufficient blood supply to the brain and sudden death. Evidence of longer corrected QT intervals in RS patients suggests that cardiac electrical instability or dysfunction may play some role in the sudden death that may sometimes occur in association with RS. In addition, in some RS patients, life-threatening complications may occur as a result of weakened lung function (e.g., due to pneumonia, scoliosis, etc.), malnutrition, or other associated abnormalities.
Males with "RS-like" symptoms
A few cases have been reported in which males appear to have RS-like symptoms, such as unexplained developmental regression, loss of purposeful hand and finger movements, autistic-like behaviors, loss of the ability to walk, progressive scoliosis, and seizures. However, a few patients had classic RS and include certain patients with Klinefelter's syndrome (XXY) or those with MECP2 mosaicism, meaning that not all cells in the body carried the RTT mutation. Some researchers suggest that males with RS may have a more severe form of the disorder that has not yet been recognized.
