Natural history of Williams syndrome: Physical characteristics

Natural history of Williams syndrome: Physical characteristics C o l l e e n A. Morris, MD, Susan A. D e m s e y , MS, Claire O. L e o n a r d , MD, C o n s t a n c e Dilts, MA, a n d Brent L. Blackburn, BA From the Genetics Center, Southwest Biomedical Research InstitUte, Scottsdale, Arizona, and the Department of Pediatrics, University of Utah School of Medicine, Salt Lake City

The natural history of Williams syndrome, including medical complications, growth patterns, and problems in adulthood, was investigated. A growth pattern characterlzed by delay in the first 4 years of life, catch-up growth In childhood, and low ultimate adult height was found. Despite multiple medical problems in infancy, including feeding problems, failure to thrive, colic, and otitis media, mean a g e at diagnosis was 6.4 years. Developmental disabilities and cardiovascular disease were the major concerns in childhood. The older children developed progressive joint limitation and hypertonia. Adult patients were handicapped by their developmental disabilities. Hypertension, and gastrointestinal and genitourinary problems occurred frequently. Independent living and competitive employment were limited less by the individual's physical problems than by the psychologic and adaptive limitations. Williams syndrome is a progressive disorder with multisystem involvement. (J PEDIATR 1988;113:318-26)

Williams syndrome is a condition of unknown cause characterized by distinctive facial features, growth deficiency, mental retardation, learning disabilities, and birth defects, sometimes associated with infantile hypercalcemia. Previous reports identified the major features of the syndrome 1-~7 and described a characteristic personality.4. 5112.~s.19Preus2O developed a diagnostic index capable of discriminating Williams syndrome patients from other dysmorphie, developmentally impaired children. Craniofacial features include dolichocephaly, asymmetry, bitemporal depressions, flat mala, full cheeks, periorbital fullness, epicanthal folds, stellate or lacy iris patterns, full nasal tip, long philtrum, full lips, wide mouth, and dental malocclusion. Supravalvular aortic stenosis and other forms of arterial narrowing are frequently present. 2~26Developmen-

Supported by U.S. Public Health Service research grant No. RR-64 from the Division of Research Resources. Submitted for publication Oct. 6, 1987; accepted March 4, 1988. Reprint requests: Colleen A. Morris, MD, Associate Director of Clinical Genetics, The Genetics Center, Southwest Biomedical Research Institute, 6401 East Thomas Rd., Scottsdale, AZ 85251.

318

tal disabilities occur in most patients, but the overall intelligence quotient varies widely from the normal range to severe mental retardation/2, ~5,~g,19 The existence of a unique developmental profile with relative verbal strengths has been described by some is, 19.27,28 and questioned by others)9.30 The personality is typically outgoing and engaging. Williams syndrome is rarely familiaP~-34; most cases are sporadic. Pairs of monozygotic twins have been affected35,36; dizygptoc twins have been discordant. 37,3s Cases of classic Williams syndrome have occurred in families with documented autosomal dominant supravalvular aortic stenosis. 5,33,39-42 This study sought to ascertain the medical complications, growth patterns, and long-term prognosis of patients with Williams syndrome. METHODS

Subjects. Patients with Williams syndrome were identified from multiple sources, including the Utah State agencies for t h e mentally retarded (residential and day treatment), the files of the University of Utah Medical Center and Primary Children's Hospital pediatric cardiology and genetics clinics, the Idaho State genetics files, the Utah Birth Defects Registry, and by direct parent and

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Fig. 1. Pr•gressi•n•fthefacia•f•atures•f•i••iamssyndr•mefr•mthenewb•rnperi•dt•adu•th••d.A•Fema•esubject from infancy to 34 years of age. B, Male subject from infancy to 27 years of age.

teacher referrals. All diagnoses were confirmed by two medical geneticists (C.A.M. and C.O.L.), and each subject satisfied the diagnostic criteria of the Preus index. Of 48 individuals identified, two had moved, one family declined to participate, and three failed to complete the evaluations. The remaining subjects constituted group 1; there were 17

male and 25 female subjects ranging in age from 1 year to 34 years. All subjects were white. Findings from this group ~vere supplemented with data from an additional seven adults who attended the Williams Syndrome National Association meeting in 1986. These seven subjects and the 10 Utah subjects over 16 years of

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Table I. Medical problems of infants with Williams syndrome Incidence Problem

Early symptoms Feeding difficulty Failure to thrive Vomiting Constipation Colic Chronic otitis media Hypercalcemia Birth defects Congenital heart disease Umbilical hernia Inguinal hernia

No.

%

30/42 34/42 17/42 18/42 28/42 16/42 4/6

71 81 40 43 67 38 67

33/42 6/42 16/42

79 14 38

age constituted group 2. Of the 17 subjects, nine were men. The age range was 17 to 34 years (mean 23.5). Growth data were collected from the records of an additional 60 patients, 31 of whom attended the same Williams Syndrome National Association meeting and 29 of whom were the patients of Bryan Hall, MD, of Lexington, Ky, who allowed access to his files. The pooled sample of 109 individuals made up group 3. The protocols were approved by the University of Utah School of Medicine Institutional Review Board, and informed consent was obtained from parents, the individuals themselves, or both. Evaluations. Subjects in group 1 underwent a 1- or 2-day evaluation, including photographs; physical examination; measurement of height, weight, head circumference, and blood pressure; parent questionnaires and interviews; review of family photographs; and review of medical and educational records. A psychometric evaluation, including measures of behavior, adaptive functioning, cognitive ability, achievement, visual-motor skills, and language, 43-51was completed for 37 (three moved, two failed to complete the testing) and is the subject of another report. Radiographs of the hand and wrist to determine bone age (according to the method of Greulich and Pyle 52) were obtained on 21 prepubertal patients. For subjects in group 2, the diagnostic index of Preus was used to confirm the diagnosis, and measurements of height, weight, and head circumference were taken. Parent questionnaires were administered in person (10 subjects) or by mail (seven subjects), and interviews were conducted by telephone (seven) or as part of the protocol for group 1 (10). Medical records were reviewed for all 17 subjects. In group 3, current height, weight, and head circumference were measured in 80 subjects. All available growth

data from medical and family records were collected for the entire group of 109 subjects. These cross-sectional and longitudinal points were plotted on a scattergram, and a mean curve was derived by regression analysis. These curves were compared with those of normal children (head circumferences according to Nellhaus 53 and weight and height according to Hamill et al.54). RESULTS Group 1: Utah cohort. Prenatal and genetic factors were studied. The 42 patients had 112 siblings (60 younger). No parent or sibling had the facial features of Williams syndrome. One sibling had congenital heart disease (a ventricular septal defect), and another had mental retardation associated with trisomy 8 mosaicism. No consistent complications of pregnancy or prenatal exposures were documented in this group. Prenatal vitamins were taken by 77% of the mothers and doxylamine with pyridoxine (Bendectin) by 25%; only one mother received calcium supplementation. Mean paternal age was 27.3 years (range 21 to 41) and mean maternal age was 26.5 years (range 20 to 40), which did not differ from the Utah population means for the corresponding years. Half of the subjects were born after tern; 70% were small for gestational age, with birth weight and length less than the 10th percentile. 55 None of the subjects has reproduced. Diagnosis. The mean age at diagnosis was 6.4 years (median 4 years). The children who were less than 16 years old had been diagnosed somewhat earlier, at a mean age of 4.0 years (range 3 months to 12 years). Of the 14 children, eight with a diagnosis before 2 years of age had been hospitalized for severe failure to thrive, cardiac symptoms, or both. A review of infant photographs revealed that most subjects had discernible facial features by the age of 4 months and obvious Williams syndrome facies by 18 months. As individuals grew older, the typical childhood features were replaced by the coarse features seen in the adolescent and adult. The progression of facial features is illustrated in Fig. 1. Clinical features during infancy. Parents reported that the first 12 months of their child's life were "miserable," with feeding problems, vomiting, constipation, and colic. The problems described by the parents were substantiated by the pediatric records. Excluding well-child care, the average number of visits to a pediatrician was 9.6 in the first 12 months. The most common reasons for these visits, in order of decreasing frequency, were feeding problems or poor weight gain, colic, and otitis media. Early feeding difficulties occurred in 30 children (71%) and failure to thrive in 34 (81%). The mean duration of colic for the 28 affected infants was 7.4 months. Otitis media became a

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32 1

T a b l e II. Medical problems of children with Williams syndrome Incidence Organ system

Nervous Ocular Auditory Dental Cardiovascular

Genitourinary Gastrointestinal Musculoskeletal

Problem

No.

%

Developmental delay with specific learning disability Attention deficit disorder Esotropia Hyperopia Chronic otitis media Enamel hypoplasia Microdontia Malocclusion Congenital heart disease Supravalvular aortic stenosis Supravalvular pulmonic stenosis Ventricular septal defect Patent ductus arteriosus Hypertension Renal anomalies Enuresis Constipation Joint limitation Kyphosis Lordosis Scoliosis Awkward gait Extra sacral crease

36/37 Common 21/42 10/42 18/42 20/42 23/42 36/42 32/42 27/42 10/42 5/42 2/42 7/42

97 50 24 43 48 55 85 79 64 24 12 5 17

22/42 18/42 21/42 9/42 16/42 5/42 25/41 22/42

52 43 50 21 38 12 60 52

*Incidenceunknown in this age group.

chronic problem in 38% of the subjects. Although cardiac murmurs occurred in 79%, most were considered to be functional murmurs in infancy. Only six infants had symptoms, four requiring surgery before 1 year of age. Hernias (umbilical and inguinal) were equally common in male and female subjects, with 38% of patients requiring an inguinal herniorrhaphy. The frequencies of these and other problems of the infant are listed in Table I. Despite the frequency of symptoms suggesting hypercalcemia (vomiting, constipation, irritability), a serum calcium level was measured in only six infants, four of whom had hypercalcemia. Clinical features in childhood. Although delayed development was usually recognized, it was frequently attributed to the stormy early medical course by both the parents and professionals. Walking alone occurred at an average age of 21 months, talking at 21.6 months, and toilet training at 39 months. By the first grade, virtually every patient was experiencing academic problems, which stemmed from multiple developmental disabilities. Cognitive skills varied, with an IQ range from 20 to 106 (mean = 57). Subjects performed better on tasks requiring auditory input and verbal output than on tasks requiring complex visual analysis for receiving information and visual motor expression. Visual motor integration skills

involving paper-and-pencil tasks measured 3 standard deviations below the mean in 67% (20/30) of school-aged children. Distractibility was common, Attention deficit disorder was characteristic of 84% (21/25) of subjects 4 to 16 years of age. Only three children were being medicated for hyperactivity (all with methylphenidate). Two had received medication for hyperactivity in the past (one got pentobarbital and diphenhydramine, and one thioridazine). In conversation, the children had relative strength in expressive language skills, but this was not substantiated on formal language measures. Auditory comprehension problems and limited vocabulary were common. Grammar skills were typically normal: the speech of individuals with Williams syndrome sounded appropriate for their age. Acquisition of adaptive behavior skills requiring fine and gross motor performance was deficient for both age and cognitive level. The majority of the children and adolescents were unable to tie their shoes adequately, cut with a knife, or use a broom. This spectrum of strengths and weaknesses contributed t o , multiple school program changes in an attempt to address the child's needs. Vision' and hearing problems also contributed to the developmental disabilities (Table II). The most frequent visual problem was esotropia (50%), which required sur-

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Table III. Medical problems of adults with Williams syndrome Incidence Organ system

Nervous Ocular Cardiovascular

Genitourinary

Gastrointestinal

Integumentary

Problem

No.

%

Mental retardation (IQ <70) Borderline intellectual functioning (IQ 75-80) Hyperreflexia in lower extremities Hyperopia Supravalvular aortic stenosis Diminished peripheral pulse Pulmonary artery stenosis Hypertension Diffuse aortic hypoplasia Other documented arterial stenoses Renal anomalies Urinary tract infections Vesicoureter reflux Bladder diverticuli Nephrocalcinosis Constipation Peptic ulcer disease Cholelithiasis Diverticulitis Diabetes mellitus Obesity Prematurely gray hair

10/17 7/17 5/10 2/11 13/17 6/17 6/17 8/17 3/17 3/17 * 5/17 3/4t 3/41" :~ 7/17 3/17 2/17 3/17 2/17 5/17 6/10

59 41 50 18 76 35 35 47 18 18 29 75 75 41 18 12 12 12 29 60

*Incidenceunknown. 1"WithVCUG. :~Nonein our series,but previouslyreportedas a cause of renal failure in adults.

gery in 18% of the children. Hyperopia was common. The stellate or lacy iris pattern characteristic of the syndrome is caused by hypoplastic iris stroma but appears to have no clinical significance. Despite a high frequency of otitis media, hearing acuity was normal in all but two individuals. Ventilating tubes had been placed in the ears of eight patients (19%). A unique hypersensitivity to sound was noted by parents of 85% of the subjects; the children frequently demonstrated an exaggerated startle response to noise considered trivial to others. All but two patients had a low, hoarse voice. Two individuals had had direct laryngoscopy during surgical procedures; no anatomic explanation was found. In addition to the wide spacing between teeth, reported previously, most subjects (85%) had malocclusion. Small teeth, enamel hypoplasia, and missing teeth were also noted. Cardiac evaluations were usually undertaken during the childhood years. Of the 33 patients with murmurs (79%), one third had had a cardiac catheterization and six of these (18%) had required surgery. Diagnoses in patients with heart disease were supravalvular aortic stenosis in 64%, supravalvular pulmonary stenosis in 24%, and ventricular septal defect in 12%. In addition to the structural lesions,

17% of the children had hypertension and 35% had significantly higher blood pressure in the right arm than in the left. Documentation of age at menarche was available for eight female patients over 8 years of age. One was premenarchal, and the mean age of menarche for the remainder was 10.3 years (U.S. mean is 12.3 years). Enuresis and constipation were both common in the older children; half of the subjects 4 to 16 years of age had enuresis. Frequency of urination was noted at all ages. Urinary tract studies were generally not undertaken, although our finding of frequent urinary tract infections and anatomic abnormalities in the adults suggests that this problem needs further study. A previously unrecognized problem for this population is progressive joint limitation. Children with Williams syndrome are initially hypotonic, with joint laxity. Tone increases with age, and there is gradual tightening of the heel cords and hamstrings. Toe walking is characteristic of the school-aged child. Lordosis appears later, and the gait of the adolescent is stiff and awkward. Limitation of supination was present in five patients, one having radioulnar synostosis on x-ray study. Calcium metabolism. The calcium metabolism of our

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Natural history of Williams syndrome

70-

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323

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Fig. 2. Growth curve (height) for female subjects with Williams syndrome. The curve for male subjects is very similar.

subjects was not systematically studied during either infancy or childhood. Of the 42 patients, 30 had had one or more random serum calcium determinations; of the 30 patients, nine had hypercalcemia. In seven of the subjects, urine ealcium/creatinine ratios were determined, and six of these subjects showed hypercalciuria with normal serum calcium values. Group 2: adult cohort. The mean IQ of the adults was 58.5 (range 17 to 80). Seven were functioning in the borderline range, five were mildly retarded, two moderately, two severely, and one profoundly retarded. Of the 17 adults studied, all were handicapped by their developmental disabilities. Only two held competitive employment, and only one did not receive some form of public disability income. One was married and lived independently; the others lived with parents, in a group homes, or in a supervised apartment. The three lowest functioning individuals had been placed in institutions; two of these were adults who were moved to group homes during this study. Although the number of chronic medical problems was high (Table III), independent living was limited less by physical problems than by the psychologic and adaptive limitations. Cardiovascular conditions continued to be a problem for the adults and required ongoing care. These conditions included supravalvular aortic stenosis (13 subjects), pulmonary artery stenosis (6), aortic hypoplasia (3), other documented aortic stenoses (3), diminished peripheral pulses (6), and hypertension (8). Six of the ten patients over 22 years of age had hypertension.

Gastrointestinal and genitourinary problems occurred frequently. Five adults were obese, and two had diabetes mellitus. Also seen were chronic constipation (seven subjects), peptic ulcer disease (3), cholelithiasis (2), and diverticulitis (3). One third, including two men, had recurrent urinary tract infections. Four subjects had bad radiographic studies showing ureteral reflux and three had bladder diverticuli. None of our subjects was known to have nephrocalcinosis, a previously reported feature in Williams syndrome2 ,6,11,15,~7,56-63 Of the eight female adults, five had had sterilization procedures. Of the 10 adults who were examined, nine had lordosis and limitation of joint movement, which was more severe in men. Half had hyperreflexia in the lower extremities. These joint limitations adversely affected strength, coordination, and efficiency of movement. Two were treated with physical therapy. Only two of the adult subjects wore corrective lenses, both for hyperopia. Most have malocclusion, but only two had had orthodontic treatment. Enamel hypoplasia and multiple caries had resulted in extensive dental treatment in three adults. Prematurely gray hair was seen in 6 of the 10 adults examined. Three of the adults had had cranial computed tomography scans; all of these scans showed calcifications of the fatx or petroclonoid ligaments. One had calcifications of the abdominal aorta. GrouP 3: all subjects. Growth disturbance was greatest during infancy and early childhood. Weight gain was poor during the first year of life, and both weight and length

324

Morris et al.

were generally below the fifth percentile for the first 4 years. Thereafter, growth recovery was seen, although few subjects were found to be above the 50th percentile (Fig. 2). When the subjects' heights were compared with those expected for the combined mid-parental heights, 70% were below the 3rd percentile. Bone age determinations were within normal limits for the chronologic age. The ultimate height for the adults with Williams syndrome was usually in the low-normal or below normal range. Mean head circumference was at the 2nd percentile for the first 4 years and at the 25th percentile thereafter. Head size did not correlate with IQ but was usually proportionate to the height. Of the patients examined, only 16% (13/80) had microcephaly, which was most commonly found in younger children. Of eight children less than 4 years of age, four (50%) had a head circumference greater than two standard deviations below the mean. Head growth seemed to follow the same unusual pattern as somatic growth in these children. DISCUSSION Delineation of syndromes occurs in three partially overlapping stages: (1) the recognition of the existence of a unique association of clinical features, (2) clarification of the variability found within the disorder, including, determination of diagnostic criteria, and (3) elucidation of natural history and prognosis. Knowledge of the natural history of a syndrome is important in making a diagnosis and for the clinical management of the patient. Most subjects of earlier studies of Williams syndrome have been children. Our study has expanded knowledge about the syndrome in both younger and older individuals. Despite multiple medical problems and frequent contacts with physicians, the diagnosis of Williams syndrome is often delayed. The first cause for delay is that the typical facial features may not be obvious at birth but become more characteristic with time. Second, although the infants have symptoms that may be related to hypercalcemia, the symptoms are relatively nonspecific and serum calcium levels are not performed routinely. Third, although 80% of the children with Williams syndrome have cardiac murmurs, most are asymptomatic in childhood and their murmurs are dismissed as functional. Fourth, the developmental delays are frequently attributed to the chronic medical problems, and the small size and infantile facial features of children with Williams syndrome contribute toward making the patients seem younger than their chronologic age, thus further obscuring the developmental delays. Parents also may fail to seek a diagnosis or may deny an early diagnosis for similar reasons. The affected children may even seem to be "bright" because they are friendly, loquacious, and "cute."

The Journal of Pediatrics August 1988

Early diagnosis depends on a careful evaluation of infants who fail to thrive and are irritable, especially when these factors are associated with a cardiac murmur, hernias, delayed developmental milestones, or facial features that deviate from those of the parents or siblings. Once a diagnosis of Williams syndrome is made, the multisystem nature of the disorder dictates continued pediatric supervision, intervention, and treatment. Because several problems coexist, many subspecialists may be involved in the care of these children. Our subjects saw an average of three subspeciatists: cardiologists (70%), geneticists (51%), ophthalmologists (44%), and neurologists (37%) were the most frequently consulted. Equally important are the disciplines of audiology, dentistry (with orthodontics), psychology, and occupational and physical therapy. Psychoeducational testing should be done routinely so that appropriate early intervention and school placement are provided. Whenever clinical symptoms referable to the urinary tract appear (including enuresis), appropriate chemical, bacteriologic, and radiographic studies are indicated. Older patients have a high frequency of hypertension, gastrointestinal problems, and urinary tract abnormalities. The progressive joint limitation affects motor performance and makes difficult many of the unskilled jobs available to the intellectually handicapped. Despite the fact that many of our adults tested in mildly retarded or borderline ranges of intellectual functioning, independent living and competitive employment were rare. The older individual with Williams syndrome continues to need multidisciplinary care, and mechanisms for transition to the care of an internist while maintaining continuity should be developed. Tile pattern of growth in Williams syndrome is characteristic. Prenatal growth deficiency occurs frequently. Postnatal growth deficiency in the first 4 years of life may be a result of poor caloric intake and increased metabolic needs; weight is generally low even for the height. Weight gain and linear growth improve in childhood, and yet ultimate adult height is "still decreased. One possible explanation for this discrepancy would be the early onset of puberty, but most families could not recall this information. The ultimate short stature must also be partially a result of the progressive joint limitations. Contractures at the ankles, knees, and hips, as well as kyphosis and lordosis, contribute to the problem. The pattern of head growth, which parallels linear growth, is also unusual. Diminished head growth is usually a late finding only when failure to thrive results from inadequate caloric intake. We are not aware of any other microcephaly syndromes in which catch-up growth of the head occurs.

Volume 113 Number 2 The significance of the hypercalcemia associated with Williams syndrome has been a subject of debate; absolute hypercalcemia is typically found only in infancy, if at all. 12 Most patients have symptoms of hypercalcemia in both infancy (vomiting, constipation, and irritability) and adulthood (constipation, peptic ulcer disease, and frequent urination). Ectopic calcifications and nephrocalcinosis also suggest a relative hypercalcemia. There is some evidence for abnormal clearance of serum calcium after an intravenous load, 64'65 and hypercalciuria can be demonstrated in most patients. 66 Culler et al. 65 have suggested that an error in caleitonin production or release may result in the relative hypercalcemia seen in Williams syndrome. This relative hypercalcemia may result in an increased calcium load to the kidneys and in polyuria. The relationship of the abnormality in calcium metabolism to the pathogenesis of the other features of the syndrome is unknown. Williams syndrome can be diagnosed by the second year of life, when defined signs and symptoms should alert the pediatrician and lead to appropriate referrals. Many of the features of Williams syndrome cause an increasing number of problems for individuals during the adolescent and young adult years. Although much still needs to be learned about the natural history of this disorder in adults, we present a profile of the older patient that will assist in medical management and counseling. We thank Jane Kivlin, MD, for ophthalmologic evaluations, L. George Veasy, MD, for referral of cardiology patients, Bryan Hall, MD, for providing growth points, John C. Carey, MD, for suggestions and support, and the Williams Syndrome Association members for participation and cooperation.

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The Journal of Pediatrics August 1988

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