Differential Diagnosis of the Rett Syndrome and Autistic Syndromes Andreas Rett, MD, Bo Olsson, PhD and Wolfgang Killian, MD,PhD LudWig Boltzmann-Institut zur Erforschung Kindlicher Hirnschiiden, Wien, Austria

The most common wrong diagnosis of girls with the Rett syndrome (RS) is infantile autism associated with severe mental and motor developmental retardation. Therefore, results from clinical studies regarding characteristic de­velopment and non-behavioral symptoms in infancy and behavioral traits for three groups of patients over 2:5 (yrs:mos) of age were assembled: 1. The infantile autistic (Kanner) syndrome; 2. syndromes and diseases with severel mental and motor

retardation, 3. the Rett syndrome.

Check lists of the results from these studies may be helpful in differential diagnosis of RS and different groups of clinical pictures associated with autism. Here they are presented in two Tables:

Table 1 Characteristic development and non-behavioral symptoms in infancy

Infantile autism Severe mental retard. (Kanner) (autistic)

Predominantly boys More boys than girls

Variable growth de-velopment

Variable head growth development

Localized brain destruction

Seizures, abnormal EEG

Mild to moderate Severe mental re-mental retardation tardation

Variable motor re-tardation

Restricted mobility

Table 2 Characteristic behavioral traits

Infantile autism (Kanner)

Defence reactions to social stimuli

Looking without affectionate involve­ment

Severe mental retard. (autistic)

Variable

Variable

Rett syndrome

Only girls

Growth decelera-tion

Decelerating head growth

Diffuse brain at-rophy

Seizures, abnormal EEG

Profound mental retardation

Severe motor re-tardation

Gait apraxia

Truncal ataxia

Tendency to ky-phoscoliosis

Rett syndrome

Maintenance of eye contact-in some cases with an even­tual smile

Bright, wide open eyes

Short glances, swift Short glance at peo- Slow changes of the changing of the di- pIe direction of looking rection of looking

Focusing on close Variable Looking in the dis-objects tance

Rotating or swinging Monotonous stereo- Hand washing move-of objects between typies with or with- ments, wetting of the fingers out an object in the the hands with

hand saliva

Attraction to run- Rocking movements (younger children: ning water and ro- hand or fingers in tating objects the mouth)

Primary self-injuring Primary self-injuring Skin defects from activities activities the hand stereo-

typies

Tiptoe walking

Skilled motoricity Motor retardation Severe motor retard

Echolalia Alalia, at most a Alalia, at most a few words few words

Certain objects kept Variable Objects not or only in the hands for a briefly kept in the long time hands

References 1. Coleman M, Gillberg C. The biology of the autistic

syndromes. New York: Praeger, 1985. 2. Hagberg B, Aicardi J, Dias K, Ramos O. A progres­

sive syndrome of autism, dementia, ataxia and loss of purposeful hand use in girls: Rett syndrome: report of 35 cases. Ann Neurol 1983;14:471-9.

3. Olsson B. Autistic traits in the Rett syndrome. Brain Dev (Tokyo) 1987;9:491-8.

4. Rett A. Uber eip cerebral-atrophisches Syndrom bei Hyperammonaemie. Wien: Hollinek, 1966.

Classical Rett Syndrome Girl with "Forme Fruste" Vari­ant Maternal Aunt Bengt Hagberg, MD, Maria Anvret, MD and Jan Wahlstrom, MD Department of Pediatrics II, University of Gothenburg, Gothenburg (BH); Department of Clinical Genetics, Karolinska Hospital, Stockholm (MA); Department of Clinical Genetics, East Hospital, Gothenburg (JW)

At the 4th Rett Syndrome (RS) Conference in Vienna, October 1986, we reported in a short note the first known family with RS appearing in two consecutive generations [ 11. This family has now been studied in detail as to clinical family data, and with cytogenetic and molecular genetic technology.

Index case S68, a girl born in 1976, fulfills the cri­teria for a classical RS. She had early feeding problems; her development was arrested at age V2-l V2 years (stage I) and regressed at age 1 V2-2V2 years (stage II). She never learned to stand or walk. At the age of 13 she is badly multi-impaired, with severe weakness and limb atrophies

Abstracts 47

(stage IV). Case IK, born in 1944, is the maternal aunt of S68.

She is a small woman and was completely normal during her first year of life. Then an unexplained and rapid loss of communication, of acquired hand skill, and of speech occurred; but her acquired gross motor abilities were better retained. She became restless, agitated and severely retarded. When seen (BH) at age 43 she was a small­headed, still ambulant, teeth grinding, manneristic woman, unable to feed herself. She stereotypically put her hands on her breast. She had a peculiar gait dyspraxia, a mixed epilepsy, and a mild kyphoscoliosis. She was diagnosed as a forme fruste RS variant according to our definition [21.

Family data. A remarkable clustering of intestinal, psy­chiatric, and skin dysfunctions were revealed in the family of the mother of the index case S68.

Cytogenetic data. For both case S68 and her aunt the following was revealed. The chromosome analyses with good quality prometaphase chromosome revealed no large deletions or other chromosome abnormalities. No fragile Xp22 was found in the cultures with caffeine added.

Haplotyping data. Extensive family mapping revealed that the X-chromosome from the maternal grandfather of S68 was present in the two RS cases but not in her two healthy half-sisters.

Conclusions The findings in this family are not compatible with an X-linked dominant inheritance with the gene for RS on the short arm of the X-chromosome. A two-step mutation in the short arm of the X-chromosome was also found unlikely. Our analysis thus did not reveal how RS is inherited, nor its potential localization to a specific region on Xp. Data, however, gave the segregation pattern of the X-chromosome in the family, and also showed that the X-chromosome of the maternal grandfather in this family might have been of importance for the appearance of the RS phenotype in the two family members.

References 1. Hagberg B, Witt-Engerstrom 1. Rett syndrome: epide­

miology and nosology - progress in knowledge 1986 -A Conference Communication. Brain Dev (Tokyo) 1987;9:451-7.

2. Hagberg B, Witt-Engerstrom 1. Rett syndrome: a sug­gested staging system for describing impairment profile with increasing age towards adolescence. Am J Med Genet 1986;24:47-59.

3. Anvret M, Wahlstrom J, Hagberg B. Segretation ana­lysis of the X-chromosome in a family with Rett syndrome in two generations. Am J Med Genet (sub­mitted).

A full report on all genetic details has been submitted for publication in a genetic journal [31 .

48 Brain & Development, Vol 12, No 1, 1990

The Diagnosis and Classification of the Rett Syndrome in Clinical and Epidemiologic Research Edwin Trevathan, MD Center for Disease Control, Atlanta, Georgia, USA

Recently diagnostic criteria for the Rett syndrome (RS) were developed by a 4l-member consensus panel (Ann Neurol 1988;23:425-8). These diagnostic criteria were divided into necessary, supportive, and exclusion criteria. The necessary criteria, all of which must be met before diagnosis, are the following: apparently normal prenatal and perinatal period; apparently normal development through the first 6 months; normal head circumference at birth with deceleration of head growth between ages 5 months and 4 years; loss of acquired purposeful hand skills with development of communication dysfunction and social withdrawal; loss of language skills with ap­parent psychomotor retardation; stereotypic hand move­ments; and gait or truncal apraxia/ataxia. The diagnosis is tentative until 2 to 5 years of age. The exclusion criteria, all of which must be determined to be absent before di­agnosis, are: intrauterine growth retardation; signs of a storage disease; retinopathy or optic atrophy; micro­cephaly at birth; evidence of perinatally acquired brain damage; presence of other identifiable metabolic or pro­gressive neurologic disorders; and other acquired disorders resulting from severe trauma or infections. The supportive criteria serve to improve the recognition of the syndrome and provide confidence in the diagnosis once the neces­sary criteria have been met; a supportive criterion may not be substituted for a necessary criteria. The new di­agnostic criteria allow for the possibility of male RS cases. Should any males with the classic RS phenotype be identified, they should have detailed diagnostic evalua­tions, and for the purpose of clinical studies they should be analyzed separately from the more typical female cases. Atypical RS may define those with Rett-like char­acteristics, but who do not fulfill the diagnostic criteria for RS. Previously reported examples of children who might be considered to have atypical RS include cases with congenital microcephaly, those without deceleration of head growth and those with other associated neuro­metabolic disorders such as ornithine transcarbamylase de­ficiency. At this early stage of development of knowledge about RS in which no objective marker is available, in­vestigators are discouraged from making the diagnosis of atypical RS. But should children with atypical RS be used in clinical research, they should be analyzed separately from the typical RS cases. Once a marker for RS is available, the syndrome may be found to be more vari­able, or more narrow, than currently defined. For now, it is important to use these relatively rigid diagnostic criteria to define populations for clinical and epidemiologic research.

Nutrition in the Rett Syndrome; Report of Ongoing Studies Richard H Haas, MD and Marylynne A Rice, RD Departments of Neurosciences, Pediatrics and Clinical Nutrition, University of California San Diego, San Diego, California, USA

We report our continuing experience with the nutritional therapy of the Rett syndrome (RS). The study population consisted of 21 girls aged 2 to 23 years followed in the RS clinic from 1984 to 1988. Nineteen patients were typical and 2 atypical by 1985 criteria.

Use of a height/weight percentile comparison chart confirmed that 50% of our study population of 21 girls aged 2 to 23 years were abnormally thin for their height. Eighty-one percent were below the 5th percentile for weight but most of these girls were also very short. By calculating the height/weight ratio we found that half were below the 5th percentile for this ratio and thus were malnourished. Paradoxically these patients were malnour­ished in spite of an above normal calorie intake.

With information provided by the parents we found that 90% of the 21 patients studied had either an excel­lent or a good appetite. All the girls seemed to derive pleasure from eating but only 24% were able to feed themselves. Constipation was reported as a problem in 71 %. Ninety percent had definite food preferences and 66% were able to eat a normal diet while the others prefered soft or pureed foods. Only one patient was re­ported to have difficulty chewing and swallowing. In 15 patients for whom data was available the mean caloric inake on a normal home diet was 98 kcals/kg. The re­commended daily calorie requirement for girls aged 4-6 years is 90 kcals/kg and for 7-10 years the requirement for normal growth is 80 kcals/kg. Our Rett patients were eating more than the recommended number of calories for normal growth. A more detailed report of these studies has been published (J Child Neurol 1988 ;(suppl):S35-S42).

Our original reported experience was with the use of a ketogenic diet in RS to encourage weight gain and im­proved seizure control (Haas RH et aI, Am J Med Genet 1986 ;24 (suppl 1):22546). Medium chain triglyceride (MCT) based ketogenic diets are difficult to maintain and our more recent experience has suggested that a less rigorous high fat diet, using MCT oil when tolerated, en­courages weight gain. Five girls with RS who were below the normal weight/height growth curves were started on a high fat non-ketogenic diet. All 5 showed a weight gain in the first 3 months after starting the diet and in 4 this was dramatic. At I-year follow-up four girls had contin­ued to gain weight. One girl did not remain on the diet past the initial 3-month period due to a change in her caregiver.

High fat diets are often deficient in essential vitamins and minerals. Deficiencies of folate, calcium, iron and zinc may be expected. We recommend that patients on these diets should receive a good multivitamin supplement daily in addition to supplemental calcium if the diet excludes dairy products. Blood counts and chemistry panels should

be monitored every 6 months. At the present time we suggest that only girls with

serious weight concerns should be considered for this type of dietary therapy. We do not know the long-term cardio­vascular effects of high fat diets. Measurements of random cholesterol and triglyceride values were carried out in 26 Rett patients on an unmodified home diet. Mean cholesterol levels were 181 mg/dl±44 SD (range 127-290) and mean triglyceride levels were 98 mg/dl ± 39 SD (range 38-171). Our initial observations suggest that higher cholesterol and triglyceride levels are seen with high fat diets although the data does not reach statistical significance. We suspect that as the literature suggests these problems are minimal and may be transient when MCT oil is used as the major fat supplement. It is interest­ing that 12 of 26 girls with RS had elevated cholesterol (> 175 mg/dl) before dietary intervention. In the patients in whom values were obtained no elevation of HDL/LDL ratios was observed. Our studies of lipid levels in RS are ongoing.

The Incidence and Natural History of Scoliosis in the Rett Syndrome George S Bassett, MD Children's Hospital of Los Angeles, Los Angeles, Califor­nia, USA

The Rett syndrome (RS) is a progressive encephalopathy occuring in females and is associated with a neuromuscu­lar scoliosis. Thus far, the incidence and natural history has not been clearl}" delineated for this disorder. In 1 9 8 7, a spinal deformity survey was mailed to the 3 50 Amer­ican families who are members of the International Rett Syndrome Association. 258 questionnaires (74%) were completed and further information (medical records and radiographs) were received from treating physicians.

Results were analyzed according to four age groups. Scoliosis was present in 174 patients (68%) with the inci­dence increasing with age.

Group Age Number Scoliosis (+)

1-5 49 4 ( 8%) II 6-10 106 41 (39%) III 11-15 68 45 (66%) IV > 15 35 29 (83%)

113 patients (65%) had not received active treatment for their spinal deformities with curves ranging in size from 11 to 100 degrees. 45 patients have been braced using predominantly underarm orthoses for curves ranging in size from 11 to 56 degrees (ave 31 degrees). 17 patients (38%) have had continued curve progression averaging 26 degrees (range, 10-45 degrees) in spite of bracing. Most of these patients had a period of accelerated progression during their early teenage years in spite of an orthosis. 24 patients have undergone surgery (23 posterior/l com-

Abstracts 49

bined anterior-posterior procedures) for curves ranging in size from 40 to 120 degrees (ave 62 degrees). Post­operatively, curve magnitude has ranged from 6 to 50 degrees. 13 of these patients had previously been treated with orthoses. Three additional patients are scheduled for surgery.

Excessive kyphosis was present in 7 girls ranging from 65 to 100 degrees (ave 86 degrees) and three of these patients have undergone combined anterior-posterior fusions.

Patients with RS frequently develop spinal deformities which are typically progressive. The incidence increases with age occurring most commonly in the second decade. Bracing to control curve progression has been largely unsuccessful in adolescent patients.

The paper will appear in full in Developmental Medicine and Child Neurology.

50 Brain & Development, Vol 12, No 1, 1990

Communication and Oral-Motor Function in the Rett Syndrome Sarojini S Budden, MD, FRCP(C) and Merry M Meek, CCC,MS Child Development and Rehabilitation Center, The Oregon Health Sciences University, Portland, USA

One of the characteristics of females with the Rett syn­drome (RS) is the loss of expressive language. Families of the 20 girls with RS were interviewed to establish verbal comprehension and expression levels pre-diagnosis. The 20 girls were assessed to determine their expression, comprehension, oral-motor function and respiration post­diagnosis. The regression of both language comprehension and verbal expression appeared by Stage II of RS and stabilized. The oral-motor function and respiration status change as a function of the motoric progression of this disorder.

The paper will appear in full in Developmental Medicine and Child Neurology.