Rett syndrome is a pervasive developmental disorder affecting predominantly females. After a period of apparently normal development, affected children experience a plateau in development and then a rapid decline in motor and cognitive function, usually between the ages of 6 to 18 months. The principal clinical features are loss of purposeful hand use; development of stereotypic hand movements, such as hand washing, hand wringing, and hand tapping (Fig. 413.1); and loss of communication and socialization skills. Generally, these children say a few words initially, but meaningful verbal communication is lost with onset of the disorder. In addition, eye contact is very poor, leading to interpretation of their behavior as being autistic. Acquired deceleration of head growth is noted as early as 3 months of life; other features include periodic breathing, including breath holding or hyperventilation or both, while awake. Seizures occur in many of these children and may consist of staring spells, complex partial, and generalized tonic-clonic events. Pervasive growth failure, including poor weight gain, short stature, and small hand and foot size, is evident. In addition, the hands and feet tend to be markedly cooler and discolored (bluish) when compared to the remainder of the extremities. Diminished response to pain often is noted. Gastrointestinal dysfunction manifested as gastroesophageal (GE) reflux and constipation may be prominent. In later childhood and early adolescence, scoliosis is a common finding.

Although the behavioral mannerisms (hand stereotypies and periodic breathing) seen in Rett syndrome are confined to wakefulness, sleep often is interrupted, and uncontrollable screaming is a common occurrence, especially during the first few years of life. A lengthy, relatively stable phase, during which the episodes of screaming and the behavioral mannerisms may become milder, follows the early period of decline. Attentiveness and eye contact improve such that communication may occur through gaze or eye pointing or augmentative communication. Survival into adulthood is typical. Because Rett syndrome has been recognized for only 40 years, and accurate clinical diagnosis only since the 1980s, the natural history including survival of Rett syndrome has not been elucidated fully.

In 1999, our understanding of Rett syndrome advanced dramatically, with the identification of mutations in the gene MECP2, which encodes methyl-CpG-binding protein 2. Mutations in MECP2 have been identified in up to 95% of females fulfilling the clinical criteria for Rett syndrome (Box 413.1). As such, the diagnosis of Rett syndrome still is based on well-established clinical criteria. Further, the spectrum of clinical expression in females has widened considerably, with descriptions of several variant forms being based on different patterns of expression. With the identification of mutations in MECP2, affected males also have been detected. However, they generally present a quite different clinical picture, ranging from severe, fatal encephalopathy both sporadically and in the male siblings of affected females to typical Rett syndrome in males with Klinefelter syndrome or somatic mosaicism. Familial X-linked mental retardation has been noted in males with MECP2 mutations, but lacking other features of Rett syndrome.