Clinical Pediatrics

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Rett Syndrome: An Update and Review for the Primary Pediatrician Stephen R. Braddock, Barbara A. Braddock and John M. Graham, JR Clin Pediatr (Phila) 1993; 32; 613 DOI: 10.1177/000992289303201011 The online version of this article can be found at: http://cpj.sagepub.com/cgi/content/abstract/32/10/613

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Rett An

Syndrome

Update and Review for the Primary Pediatrician

Stephen R. Braddock, M.D. Barbara A. Braddock, M.H.S. John M. Graham Jr., M.D., Sc.D.

Summary: Rett syndrome is a common developmental-neurologic disorder that has been reported almost exclusively in females. Recent work has improved recognition of this condition and helped to clarify the management of this disorder for affected individuals. The primary-care physician can become a major source of support and advocacy for the family of a girl with Rett syndrome. Many other resources are available to the primary care giver and the families of children with Rett syndrome; these may help to provide early diagnosis, psychological support, and preventive medical care for these individuals. The current state of knowledge regarding Rett syndrome is reviewed and a framework is provided for medical and developmental interventions.

Introduction

syndrome was first deby Dr. Andreas a Rett, neurologist who two mentally retarded fein his waiting room with

JL ~~

ett

scribed

noted males similar hand-wringing movements. Dr. Rett described these two patients, along with six others, in a pair of German publications in 1966.1°2 He later published his findings in English in 1977.~ Despite this early description, it was not until 1983 that this devastating disorder became widely known in

North America, following the publication by Hagberg et al4 of 35 cases in the Annals o, f Neurology. By early 1984, only two articles on Rett syndrome had appeared in English. In the past five years, more than 250 papers have been published. Thanks to the attention newly focused on this disorder, largely due to the efforts of the International Rett Syndrome Association (IRSA), a very active parent support group, girls with Rett syndrome in the 1990s have a brighter prospect for early identification

leading

to

more

appropriate

Clinical Genetics and Dysmorphology, Medical Genetics Birth Defects Center, Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California Address correspondence to: John M. Graham Jr., M.D., Sc.D., Director of Clinical Genetics and Dysmorphology, Medical Genetics Birth Defects Center, Cedars-Sinai Medical Center, 444 S. San Vicente Blvd., Suite 1001, Los Angeles, CA 90048

This work was supported by the UCLA Intercampus Training Program Grant #GM08243 from the National Institutes of Health and Grant #P01 HD22657-06 from the U.S. Department of Health and Human Services, Public Health Service.

health, education, and family support services at a younger age than the case in previous years. BeRett syndrome is a relatively recently characterized common developmental-neurologic disorder, many pediatricians are still learning to recognize the syndrome and to care for affected girls. Active neurology, genetic, pediatric, education, and care giver groups have collaborated to advance research efforts leading to was

cause

appropriate management girl with Rett syndrome. Family life remains an appropriate option for many girls with Rett syndrome today. Although families may feel overwhelmed by the various phases of development of the syndrome, most families caring for a girl with Rett syndrome more

for the

balance from which to carry normal family life. A loving family is usually the best advocate for appropriate health and educational services for such a child, but find

a

on a


613

if

particular family is unable or unready to incorporate a girl with Rett syndrome into its structure, specialized foster care or adoption a

may serve as a viable alternative. Since the initial description of Rett syndrome in 1966, accurate

diagnosis and access to high-quality health-care information and services have improved. Surveys document that a woman with Rett syndrome may survive into the fourth decade of life with excellent health; death in young girls with Rett syndrome is uncommon Improved early diagnosis and routine preventive medical care have led to the recognition that certain medical conditions affect the development of life skills in girls with Rett syndrome. Such conditions include variations in muscle tone, loss of purposeful hand movement, scoliosis and orthopedic complications, poor nutrition, now

constipation, growth retardation, seizure disorders, hyperventilation, and apnea. The discovery of survival into adulthood for girls with Rett syndrome has led to the awareness of possible pregnancy, along with such medical problems as increasing hypertonia leading to scoliosis and lower-limb deformities. Girls with Rett syndrome can take advantage of early, individualized developmental and educaSince the tional programs. of Public Law 94implementation 142 in 1977, all individuals with

handicaps are guaranteed a free, equal, and appropriate education in the least restrictive environment from ages 3 to 22 years. Public Law 99-457 reaffirmed the provision of Public Law 94-142 and allowed states the option of including early intervention services for infants and toddlers in the entitlement. Educators and parents have begun to realize that all children learn better when children with special needs are integrated with their

nondisabled peers. The literature on integration suggests that benefits are gained by the child with the disability, his or her family, his or her peers, and the educators employed in the integrated settings.66 The primary-care physician can become a major source of support and advocacy for the family of a girl with Rett syndrome, from the first informing interview about the diagnosis through the years of acute and preventive health-care man-

for parents and care givers was formed at that time. This organization has grown dramatically in size and influence over a few short years through the energy and enthusiasm of its leadership and its proximity to Washington, D.C.

agement. Primary-care physicians

etiology: 1) apparently exclusive oc-

often consultants for community-based programs and services for children with special needs. The remainder of this article will review the current state of knowledge regarding Rett syndrome and offer the primary-care physician a framework in which to provide care and information.

currence

are

History Dr. Andreas Rett of the L. Boltzman Institute for Research in

Brain Damage, in Vienna, first described Rett syndrome in 1966.1°2 It was not until 1983 that Dr. Bengt Hagberg of Sweden, with colleagues from France and Portugal, reported a comprehensive review of 35 cases in a widely read English-language neurology journal.~ This report led to an explosion of interest in the disorder, causing information about Rett syndrome to spread rapidly. The first International Rett Syndrome Conference was held in Vienna in 1984, resulting in the rapid dissemination and accumulation of clinical, biochemical, physiological, and genetic data. Dr. Hugo Moser of the John F. Kennedy Institute for Handicapped Children in Baltimore, Maryland, organized the first North American International Rett Syndrome Conference in 1985. The International Rett Syndrome Association


614

Genetics and Incidence Several features of Rett syndrome suggest a possible genetic in

females; 2)

concor-

dance in

monozygotic twins, with discordance in dizygotic twins; and 3) familial

higher at

rate

large.’

cases that than in the

Rett

occur at a

population

syndrome has ocentirely in females,

curred almost with few reports of affected males,8-10 and no unanimous agreement on the accuracy of those diagnoses. At this time it is felt that Rett syndrome is an X-linked dominant condition that is lethal in males. The overall incidence of Rett syndrome is about one in 10,000 girls from birth to 14 years.&dquo; Cytogenetic studies have revealed two patients with X-chromosome translocations. In one girl there a translocation between was and Xp11.22 22p11, which was also in a sister with atypical feapresent tures of the disorder and her unaffected mother.l2 Another patient has a de novo balanced translocation between Xp22.11 and chromosome 3.i3 To date, there have been seven pairs of concordant monozygotic twins and 11 pairs of discordant dizygotic twins. 1,16 Recurrences have been noted in several families, including three pairs of full sisters, two pairs of half-sisters (born to the same mother and unrelated fathers), and two other instances of inheritance through more distant maternal lines.’ In one instance, it has been documented that a woman with Rett

evolved since Dr. Rett first proTable 1

posed hyperammonemia as a cause.1 The progressive deterioration in these girls suggested a met-

OBLIGATE MANIFESTATIONS IN THE DIAGNOSIS OF CLASSIC RETT SYNDROME

has had an affected daughter.14 The explanation for these familial cases may lie in the maternal germ cell line mosaicism for the mutation or in nonrandom X-inactivation. A mother with the Rett gene could appear normal because her cells have nonrandomly inactivated the X-chromosome on which the mutant gene resides. 15 During gametogenesis, that chromosome is reactivated and available for reproduction. Thus, the Rett gene may be expressed in a female fetus or may result in the spontaneous abortion of a male fetus. The gene for Rett syndrome has not been located, nor has its gene product been identified. As

syndrome

more cases are

identified, espe-

cially familial

cases,

abolic cause, but hyperammonemia is not present.4.17,18 No other consistent biochemical findings have been described. More recently, there has been interest in the role of abnormal neurotransmitter function in Rett syndrome, with some studies suggesting decreased biogenic amine concentration in these patients. 19,20 Similarly, the role of endorphins is being investigated. These natural opioids might explain the happy, smiling disposition shown by some of these girls as well as their decreased sensitivity to pain.21 There have been conflicting reports between those finding elevated endorphin concentrations19,22 and those who have found such concentrations lower than in controls.23°24 The only agreement is that further study is necessary on a larger sample size in order to explore the etiopathogenesis of this disorder. The use of opioid antagonists has been attempted, but no conclusive results have yet been found.

linkage analy-

sis and molecular DNA probes will become useful in trying to understand this intriguing condition. Recently, two different families, each

with affected half-sisters who

maternally related,

were

were

examined

via DNA markers. The results were informative in both families. Multipoint linkage analysis showed that the region around the centromere, from Xp21.2 to Xq21q23, was excluded as a candidate gene region in these families.&dquo;

Etiology is

The etiology of Rett syndrome known. Many theories have

not

Suspecting the Diagnosis One frequent topic of concern addressed during pediatric office visits is normal child development. Parents are astute observers of their children, comparing their progress with that of siblings as well as of friends’ and neighbors’ children. If developmental concerns arise, the child is often brought to the primary-care physician for an evaluation and, if necessary, early intervention programming. It is not difficult to detect children who demonstrate recognizable syndromes associated with developmental variation or obvious delay in motor, visual, or cognitive areas,


615

Table 2

5DP1=©RTIYE CRITERIA IN THE DIAGNOSIS OF CLASSIC RETT SYNDROME

although the underlying diagnosis may sometimes be elusive. Hearing and speech-language delays are often identified by primary-care physicians during routine office visits. Children with normal initial progress and a subsequent loss of acquired skills are more difficult to identify, however; this is the group in which Rett syndrome girls are included.

and

genetic

disorders. No

dysmor-

associated with Rett syndrome, but there are several obligate manifestations (Table 1 ) .25 The normal prenatal and perinatal period is essential, as is the

phic

features

are

child’s

being normocephalic at subsequent deceleraof head growth beginning by

birth, with

tion 6 months of age. It is from this age that the more &dquo;classic&dquo; signs begin

appear, including psychomotor regression and the loss of purposeto

Diagnosis

and the exclusion of other known

ful hand movements. Some consider these signs to mark the onset of the clinical expression of the syndrome. To prevent bias against the reporting of male cases, female sex has been removed as an obli-

metabolic, neurologic, psychologic,

gate diagnostic criterion.26

The diagnosis of Rett syndrome is based upon the recognition of its

neurodevelopmental phenotype


616

Besides the obligate criteria, there are several supportive criteria in making the diagnosis, as set forth by the Rett Syndrome Diagnostic Criteria Work Group in 1988 (Table 2).27 In addition, there are also exclusion criteria, which must be absent, these include 1 ) evidence of intrauterine growth retardation; 2) organomegaly or other signs of metabolic disease; 3) retinopathy; 4) evidence of perinatally acquired brain damage; and 5) neurologic damage secondary to trauma or infection. In 1985, Kerr and Stephenson28 described cases of Rett syndrome based upon clinical severity that became apparent with increasing age. Naidu et a129 described 70 American cases in 1986, noting regressions in performance and developmental skills before the age of 2 years, with little gain thereafter. Hagberg and Witt-Engerstrom30 proposed a four-stage model (Table 3). Stage I is characterized by developmental stagnation, deceleration of head growth, disinterest in the surrounding environment, and hypotonia. Electroencephalogram (EEG) recordings at this period are normal or show minimal slowing. Stage II is characterized by

rapid developmental regression with irritability, loss of functional hand use, stereotypic hand-wringing, loss of expressive language, insomnia, self-abusive behaviors, occasional seizures, and background slowing on the EEG with gradual loss of the normal sleep patterns. The EEG pattern may be focal or multifocal spike and wave. Many children are diagnosed with autism at this stage. Screaming episodes and sleep disturbances are the major parental concerns. Stage III appears somewhat more stable, with some restitution of communication, typical hand stereotypes, and preserved ambulation, but with increasing ataxia,

.._

.

Table 3 THE FOUR CLINICAL STAGES OF RETT SYNDROME

however, these children appear to lose interest in toys completely, demonstrate progressive loss of their purposeful hand movements, and develop stereotypic hand movements.31.32 The typical handwringing and hand-to-mouth movements

generally originate

during stage

II and become

more

entrenched over the years (Figures 1 and 2). The etiology of these movements is unknown. One author has proposed that they arise as a result of the &dquo;motivation conflict,&dquo; reflecting a desire to perform coupled with an inability to generate purposeful activity.33 Case histories and natural history ofRett syndrome are well described by Moeschler et al. 51

Specific Concerns for the Girls With Rett

Syndrome

Neurologic Concerns to

Seizures may be present in up 75% of women with this disor-

der.26 Median years of age;

hyperreflexia, and rigidity. Hyperventilation when awake, followed by apnea, is also seen. Bruxism, weight loss despite good appetite, and scoliosis also characterize this stage. The earlier screaming and sleep problems are generally no longer present. The EEG shows gradual disappearance of the posterior rhythm and some epileptiform activity. These patients tend to appear happy and enjoy close physical contact. This stage may last for years. Stage IV is characterized by motor deterioration, with progressive

muscle wasting,

spasticity, scoliosis, decreasing mobility, and growth retardation. Many patients become wheelchair-bound by this stage. Venous stasis leading to cool, mottled extremities is common. Constipation also becomes a major problem during this stage. Seizures are less frequent. Despite the patients’ semental retardation and almost complete absence of language skills, parents report an ability to understand their children’s needs. As noted previously, Rett syndrome is frequently misdiagnosed as infantile autism. In contrast, vere

onset occurs at

severity

,

I

1

4

/

is most pro-

nounced early in the course.’ Carious types of seizures have been reported, but it is not clearwhether all &dquo;activity&dquo; is truly epileptiform or merely an expression of the truncal ataxia also present in these patients. The therapeutic efficacy of anticonvulsants is inconclusive. In some cases, the seizures are unresponsive to therapy.21 Carbamazepine has been the most frequently used medication for the treatment of clinical seizures.35 The convulsions may be-

responsive to therapy altogether as the girl

come more

or

abate

grows older .29,30 Haas et a136 reported that a ketogenic diet improved clinical seizure control while leading to mild behavioral and motor improvement.

Although not all girls have seizures, abnormal EEGs have been reported in almost 100% of cases.


617

Figure 1. Four girls with Rett syndrome, ranging from 2 to 3 years of age at diagnosis, when loss of purposeful hand movements was replaced by stereotypic hand movements, each slightly different. These characteristic changes led to the diagnosis.

Figure 2. These four different girls with Rett syndrome are aged 7 years (upper left),12 years (upper right and lower left), and 24 years (lower right). They demonstrate interest in their surroundings, with a cheerful disposition and progression into stages III or IV.

Source: Moeschler et al. 51 Reproduced with permission.

Source: Moeschler et al .51

the time of initial

EEG changes generally appear at the beginning of stage II and then follow a stepwise progression, with slowing, loss of normal sleep char-

acteristics, multifocal abnormalities, and, finally, generalized slow

spike and wave activity.34,37 Rett syndrome patients demonstrate manifestations of truncal ataxia, most apparent in small girls who are able to sit unsupported.44 In older children, it is masked by the severe lower motor neuron and basal ganglia abnormalities.25 Lower motor involvement is a late manifestation, and spinal cord im-

pairment has been reported.38

Gastroenterologic Concerns Rett syndrome has been associated with several different gastrointestinal

complaints. The leading of parental concern are weight loss and constipation. Constipation is a common finding and begins early in life. This is a functional disorder, not a problem with causes

as in Hirschsprung’s disease. Treatment consists of a high-fiber diet, and, if necessary, mineral oil and stool softeners. Other gastroenterologic prob-

innervation,


618

Reproduced with permission. lems that bring these children to the pediatrician include bruxism and gastroesophageal reflux. The bruxism may result in multiple dental erosions. Reflux adds to feeding difficulties and subsequent poor growth in these children. Swallowing difficulties are also common. It is not known whether growth failure is part of the disease process itself or secondary to inadequate caloric intake in the face of an increased metabolic rate. 34 The increased metabolic rate may be caused by the continuous motion that these children un-

Respiratory Abnormalities Respiratory problems sent an area

repre-

of frequent concern in

the early years. This is due to cyanotic spells that occur while the child is awake. This unusual breathing pattern consists of central apnea intermixed with hyperventilation.&dquo; The situation differs from that in other conditions because the apnea in Rett syndrome

only when the patient is awake. In Rett syndrome it is unclear whether apnea or hyperventilation is the primary problem. Acetazolamide may be helpful in severe cases of hyperventilation, although calcium supplementation should be discontinued during use of acetazolamide in order to prevent formation of renal stones. occurs

Figure 3. This 21-year-old hand-wringing,

and

woman

hypotrophic

with Rett

feet with

syndrome shows neuromuscular scoliosis, stereotypic right heel cords and peripheral vasomotor disturbances.

dergo when active and awake. Calcium homeostasis has been of interest recently. Haas et a136 have advocated an increased fat diet to offset poor growth, but with care to watch for calcium deficiency. Osteopenia and pathologic fractures have been reported. Low total body calcium results in lower bone density as well as lower body

weight. Currently, supplementation is recommended if hypocalcemia is documented; it may also be helpful in adolescents. All patients should be on multivitamins. feeding is a high priority for girls with Rett syndrome, since they tend to have difficulty with selffeeding as well as physiologic problems with swallowing.39 More

specifically, oropharyngeal feeding problems have been documented to include difficulty with chewing as well as swallowing and choking, with nasal regurgitation of food. It is reported that care givers spend prolonged amounts of time feeding these girls, relying on puréed foods, cutting food into small bites, and thickening liquids to prevent aspiration. 40

A feeding team consultation may be necessary to provide a total treatment program for the patient with Rett syndrome. A

videofluoroscopic swallowing procedure may be highly beneficial to assess oral, pharyngeal, and esophageal stages of swallowing. A nutritionist may be able to monitor the child’s caloric intake, since weight loss is a concern. Therapists can provide assistance in proper positioning for feeding as well as in tone reduction activities, if spasticity is problematic. Treatment for the purposeful use of hands for selffeeding requires behavioral methods using a physical-assist hand technique from which assistance is gradually removed. It usually takes years for girls with Rett syndrome to acquire this skill, if they are able to do so at all. Gastrostomy tube feeding may be a required alternative to oral feeding in cases of extreme

spasticity, improper positioning feeding, severe gastroesophageal reflux, or abnormalities resulting in an increased risk for aspiration. for

Sleep Disturbances Besides respiratory difficulties, sleep disturbances are common in these girls. Naidu et a129 noted that problems include night waking, screaming, and abbreviated sleep

patterns due

to

failure

to

nap. A

parental questionnaire found that 83% of parents observed that their

daughters awoke laughing at night.21 Piazza et a1,42 however, showed an overall increase in daytime sleep, correlating with increasing age. Also present was decreased night sleep compared with age-related peers. The same study revealed an overall increase in total sleep hours relative to peers and noted a delayed onset of sleep at night. Treatment of these sleep disorders uses behavioral modalities in an attempt to reorganize the sleep pattern. There has been some success with a bedtime fading procedure,43 although data are preliminary and larger studies are indicated. Various medications have been used to try to reverse the sleep cycles, with limited results. These agents should be used only with close observation for side effects.


619

transitions, prevent and reduce deformities, decrease irritability and discomfort, and maximize inde-

pendence. Many patients with Rett syndrome are considered hypotonic in early stages, then develop increased muscle tone with hyperreflexia and rigidity. Ambulation becomes hampered as the child begins to use a wide-based, stiff legged gait. Girls with Rett syndrome may have difficulty initiating steps. Postural instability, changing

Figure 4. A girl with Rett syndrome is shown at different ages, ranging from 3 months (upper left) to 8 years (lower right). Changes are demonstrated that are associated with developmental regression, loss of functional hand use, development of stereotypic hand movements, and continued happy disposition. As a teenager, the patient required surgical correction of scoliosis. She tolerated this procedure well and showed obvious delight at returning home after hospitalization.

Orthopedic Abnormalities and Motor Disturbances Girls with Rett syndrome commonly exhibit multiple orthopedic and motor movement disorders, which may vary in type through the different phases of the syndrome. Ataxia is

frequently an early motor disorder noted in girls with Rett syndrome. The type of ataxia is not a typical one, defined neurologically, but is best demovement

scribed as a manifestation of a general body dyspraxia. 25 This disruption of balance and motor planning leads to the girl’s marked fixing of her joints into positions of stability, reducing her ability to

change positions. Agitation is often present when movement is imposed upon the

with Rett syndrome. The legs may be fixed in wide abduction, with absent weight shift while sitting and standing. A truncal shakiness can be temporarily observable in small girls with Rett syndrome who are able to sit unsupported. This truncal shakiness appears to be best described as a delayed balance compensation reaction re-

girl

sulting in repeated body jerks. In later stages (III or IV) of this disorder, the ataxia may be concealed by prominent and disabling lower motor and basal ganglia abnormalities. There may be significant difficulty in the initiation and maintenance of ambulation. Intensive physical therapy programming is required to maintain and maximize ambulation and more


620

muscle tone, scoliosis, and this unusual movement disorder may result in the loss of ambulation as early as 4 years of age, although this may be delayed into adulthood. 31 With the passing of stage II, gait disturbances become prominent, and weight-bearing and walking should be emphasized therapeutically at each individual level. Overall, a combination of basal ganglial and spinal cord derangement is the proposed cause of the gait disturbance. Deformities requiring orthopedic and physical therapy management may include hip instability, heel cord shortening, foot malpositions, and scoliosis. Scoliosis in Rett syndrome may be accelerated by imbalance. Therapeutic services may incorporate space and midline orientation and perceptual exercises. Scoliosis is a progressive complication in girls with Rett syndrome, and the incidence increases with age (Figure 3), with a prevalence of 64% overall .4’ Bracing appears to be a temporary solution. Ultimately many girls with Rett syndrome may require surgical management. Surgery, strongly considered when the degree of spinal curvature is greater than 50 degrees, has shown benefit in reducing the curvature, preventing progression, and improving spinal balance for sitting and walking.44 In contrast to the loss of communication and deterioration of

of their surroundings. Causeeffect toys that lead to purposeful hand use may also open the pathway to communication. Diminished stereotypic hand movements with some purposeful hand use are generally noted by the end of the first decade of life. ness

Table 4

SKILLS OPTIMIZED THROUGH MUSIC AND PROSODY

Gynecologic Concerns The diagnosis of Rett syndrome does not prevent these girls from undergoing maturational changes. Progression through the stages of puberty generally occurs on

time, although precocious pu-

has occasionally been seen. Since menarche is partially related to body fat content, it is often delayed in girls with Rett syndrome because of their low ratio of body fat. Families should be aware, however, that menses will occur in these children. Families deal with their daughters’ menstrual periods in a variety of ways. Some use tampons or sanitary napkins, while others resort to increased diaper changes. Some families request hysterectomies for their children, but this is generally done only if the procedure is medically necessary. Girls with Rett syndrome are unable to make independent choices regarding their sexuality. Unfortunately, as with other neurologically impaired individuals, these girls are often at the mercy of their environment. Contraception is a major ongoing concern. Sterilization is not an accepted method of birth control. The ideal choice would stop menses and prevent pregnancy. Of the available technologies, barriers are an unrealistic choice, since they require premeditated action. Oral contraceptives are effective but difficult to swallow and require daily administration. Levonorgestrel (Norplant) has recently been made available. This technique is very effective in preventing con-

berty

gross

motor

skills, fine motor skills

to some degree with rehabilitation efforts.34 Occupational therapy is utilized to decrease finger and wrist flexor tightness through the fitting of hand splints; however, the tolerance for these devices may be limited. Splinting has been found to be successful in interrupting handto-mouth movements and, to a lesser degree, hand-wringing.45 Occan recover

cupational therapy incorporates development goals designed to decrease hand-wringing and

motor

hand-to-mouth behaviors, increase extended

reach, and maximize

purposeful

fine

to

motor movement

control the environment.

Technology is available for girls with Rett syndrome to promote and control over the environment by means of computers with adaptive switches. Toys that combine bright colors and orienting sounds requiring input from the child reinforce appropriate hand movements and aware-

purposeful play

ception

and lasts for five years.

However, prolonged bleeding has been reported. The optimal method of birth control for girls with Rett syndrome is medroxyprogesterone acetate (Depo-Provera), which has only recently been approved for this use. These injections, given every three months, suppress ovarian release of eggs. Side effects include moodiness and breast fullness as well as some pain from the injections. Two methods that are not widely available include endometrial ablation and electric cautery. Ablation is a nonsurgical technique in which a laser is used to destroy the endometrium. Compared with hysterectomy, it poses minimal risk to the patient, but any tissue that was &dquo;missed&dquo; can regrow and necessitate a second procedure. Electric cautery uses electricity to cauterize the uterine lining. This is faster and easier than ablation but permits less visualization during the procedure. Thus, neither of these two methods is adequate or recommended. Of special note is that the normal difficulties that many women have with urinary tract infections and monilial infections are also present in girls with Rett syndrome. Since the ability to communicate is not present, the clinician must always be suspicious, especially when presented with worsening behaviors or pain of unknown etiology. Therapy is the same as for other individuals.

Communication and

Cognition

The loss of acquired purposeful hand movements, along with the development of severe communicative dysfunction, is a salient feature in the diagnosis of Rett syndrome. Infantile autism associated with severe mental retardation and motor developmental retardation is

a common

misdiagnosis

in

girls


621

cortex. More

Table 5

) I

specifically,

it is

likely

that the cerebral hemispheres or the

NECESSITIES FOR THE FUTURE OF PATIENTS AND CARE GIVERS

interconnections to language-dominant centers of the brain are disrupted by the initial acquisition and subsequent loss of language

and

speech skills.

Patients may gradually change in the areas of social interaction and communication to become more quiet and placid, with im-

proved eye contact (Figure 4). Complete alalia is frequently observed in girls with Rett syndrome; however, in atypical variants, some girls may speak in fully formed phrases.48 In social interactions, girls with Rett syndrome generally

with Rett syndrome.31°32~46 The confusion of Rett syndrome with autism results from their total aloofness, characterized by an almost complete avoidance of gaze and hearing in the early period. These characteristics may, however, be more pronounced in Rett syndrome than in pure infantile autism contrasted at the initial stage. In the later years of development, autisticlike characteristics in Rett syndrome girls become less prominent and change in quality when compared to children with infantile autism. 31,32 In the majority of patients with Rett syndrome, language develops as babbling and single words by 10 to 12 months of age. A pronounced loss of these verbal skills is evi-

denced by 18 months. The sudden loss of language, with the skills never fully recovered, is often mistaken for hearing loss.34 It has been suggested by Bader et al47 that auditory perception remains functional and some discrimination properties are retained. Moreover, electrophysiologic evidence suggests dysfunction along the visual and auditory pathways, with slowed conduction.&dquo; Evoked potential evaluation techniques are often recommended to document problems in the brainstem and midbrain, as well as intracerebral cortical defects. The apparent dementias, loss of language with inconsolable screaming, and poor social interaction by the second year of life suggest impairment of the cerebral


622

establish and maintain eye contact for short periods of time, as contrasted with infantile autism.39 In contrast to a flat affect, some girls with Rett syndrome appear to be very happy, with frequent smiling between the ages of 1 and 3 years, around the time they begin to lose purposeful hand usage. This may lead to diagnostic confusion with Angelman syndrome; however, the child with Angelman syndrome has often been clearly developmentally delayed and hypotonic from birth. Girls with Rett syndrome appear normal initially and then develop aberrant behavior. Patients should have speechlanguage services to enhance cognitive-communicative function. services Speech-language emphasize functional receptive and expressive language skills, as well as cognitive, social pragmatic, and affective language skills. Early intervention strategies may focus on improved eye contact, visual and auditory attention to the environment, turn taking, appropriate facial expression and affective language, and cause-effect cognitive development. The shaping of the girl’s rudimentary nonverbal or verbal communicative intent requires close

Table 6

RESOURCES FOR PRIMARY-CARE PHYSICIANS AND PARENTS


623

observation and input from care givers and family members. Goals may include the implementation of augmentative or assistive communication devices to promote effective verbal and nonverbal communication. Facilitated communication using a method of fa-

cilitating language

expressive

symbolic

has been useful with some children, including those with autism and many forms of mental retardation, and may also prove to be of therapeutic value for girls with Rett syndrome. Music therapy, a relatively new therapeutic approach for girls with Rett syndrome, appears to offer a therapeutic vehicle to incorporate

many goals through a medium that neurologically and cognitively optimizes learning and attention. It appears that the inflection and timing found in a musical presentation may produce an orientation reaction

that is, an increase in sensory acuity for a more optimal level of input stimulation, such as increased tonus, shortened reaction time, and increased sensitivity of the skin. The musical stimuli work best if they are simple, varied, and repeatable. Initially, the child needs to learn to attend and perceive, as well as to prepare for the presentation of the acoustic signal. Through repetition, acoustic stimuli can be perceived as structure, preparing the child to anticipate the familiar.49 Music, as a means to set up the neurologic system for optimal learning, can be likened to the -

higher-pitched, exaggerated speech that adults use naturally when conversing with infants (referred to as Motherese has a and lower tempos higher pitch than normal speech, with exaggerated intonation. Vowels are pro-

&dquo;Motherese&dquo;).

longed carrying

and easily heard, thus communicative meaning.

Infants respond to this type of communication by showing precommunication skills such as increased gaze, eye contact, and joint referent. Similarly, a girl with Rett

syndrome, functioning

at a precommunication stage, would benefit from the prosodic linguistic units found in music and Motherese. The capacity for a girl with Rett syndrome to perceive and attend to rhythm and melody is a link to improved cognitive and communication skills (Table 4).

Prospects for Women Syndrome

With Rett

We have discussed many of the clinical features of Rett syndrome in terms of diagnosis. Since these girls are thought to have a good life expectancy, it is important to look toward the future. Currently, many women with Rett syndrome become wheelchair-bound as young adults due to disturbances of gait and increased muscle tone with hyperreflexia and rigidity. There is hope that early intervention and management of scoliosis and gait disturbances may delay or even prevent this progression. the affected Cognitively, woman continues to learn while her overall mental status remains unchanged. Even patients who live in a basically vegetative state are still apparently aware of their environment and willing to interact with it, particularly through eye contact. Nevertheless, maximum assistance with activities of daily living may be necessary. Difficulties with seizures, hyperventilation, stereotypic hand movements, crying outbursts, and failure to thrive may remain present throughout life. End-stage disease may result from cardiorespiratory compromise due to recurrent aspiration and progressive


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scoliosis. Status epilepticus may also lead to sudden death. Some women have electrocardiographic (ECG) abnormalities consisting of a problem with repolarization rather than conduction. In planning and providing for the adult life of a woman with Rett syndrome, Kerr’ provided a list of necessities for both the individual and her care givers (Table 5). With these in mind, it is possible to provide a brighter outlook for these women and their families. Clinicians and parents may draw upon a number of organizations that are dedicated to helping children with disabilities such as Rett syndrome (Table 6) .5° It is hoped that further research will lead to the discovery of a genetic marker to aid in prenatal diagnosis of this condition. There is also hope that a biochemical defect will be determined, which may then be treatable with medication or even gene therapy. Until this occurs, treatment will remain largely supportive, based on knowledge of the natural history of this disorder. 51 In a short span, much has been learned about this confusing condition. Perhaps over an equally short period many more answers will become apparent.

Acknowledgments We appreciate the generous sup-

port of SHARE’s Child Disability Center and the Stephen Spielberg Pediatric Research Center. We are also indebted to Ms. Ilene Mayo for expert secretarial assistance. This manuscript is dedicated to the Rett syndrome girls and their families who have helped to advance our

understanding of this disorder.

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