American Journal of Medical G e n e t i c s 44720-729 (1992)
Williams Syndrome in Adults E. Lopez-Rangel, M. Maurice,
B. McGillivray, and J.M. Friedman
Department of Medical Genetics, University of British Columbia and University Hospital, Vancouver, Canada
There are few published reports of adults with Williams syndrome (WS). We have evaluated ten adult WS patients. The patients in our study were very variable in clinical presentation, ranging from severely affected patients with complicated medical histories to mildly affected patients who are generally in good health. Cardiovascular anomalies and hypertension were frequent. Supravalvular aortic stenosis was seen in four patients, mitral valve prolapse in three, bicuspid aortic valve in one, valvular aortic stenosis in one, a n d pulmonary stenosis with right ventricular hypertrophy in one. vpical facial features included stellate irides, prominent cheeks, full lips, and micrognathia. Mental retardation was seen in all patients. Verbal skills were better developed than motor skills. All patients in our study lead active lives, and most are involved in sports. Some hold supervised jobs. Eight of our patients live with their parents and two in group homes. Independent living is restricted by their mental and adaptive limitations. 0
1992 Wiley-Liss, Inc.
KEY WORDS: Williams syndrome, cardiovascular, facial anomalies, developmental delay INTRODUCTION Williams syndrome (WS)in children is a well characterized entity [Williams et al., 19611, but there have been few previous reports of affected adults [Morris et al., 1988, 1990, F’ryns et al., 19911. We report on ten adults with WS in order to delineate better the longterm outcome, medical complications, and adaptive and social skills of adults with this condition.
Received for publication September 16, 1991; revision received May 14, 1992. Address reprints request to Dr. J.M. E’riedman, Department of Medical Genetics, University Hospital, Shaughnessy Site, 4490 Oak Street, Vancouver, B.C., Canada V6H 3V5.
0 1992 Wiley-Liss, Inc.
MATERIALS AND METHOD Patients with a diagnosis of WS who were above the age of 18 years were identified from the records of the Department of Medical Genetics, University of British Columbia and University Hospital, Vancouver. We recalled five men and five women for evaluation. Their mean age was 26.4 years; the age range was from 18 to 43 years. All patients were examined by a medical geneticist. Family history and medical records were reviewed, and chromosome studies were done. The families were asked to provide photographs of the patients at various ages. A summary of phenotypic and cognitive manifestations of the patients is provided in Tables I and 11. CLINICAL REPORTS Patient 1 (Fig. 1) P.H. was the product of a normal term pregnancy; her birth weight was 2.025 kg (< 5%). The patient was kept in the nursery for a month after birth in order to gain weight. During childhood, her weight gain was slow: she is said to have always been “half the size” of a normal child her age. At age 4 she had surgery for congenital bowel obstruction. She also underwent bilateral inguinal herniorrhaphy and two haemorrhoidectomies. Tonsillectomy and adenoidectomywere performed for recurrent tonsillitis. At age 12 she had surgery for correction of supravalvular aortic stenosis (WAS). At 14 she developed hypertension that required a cardiopulmonary bypass, resection of SVAS, and repair of arch stenosis; since then there has been no recurrence of the hypertension. Hysterectomy was performed at age 14 because it was thought pregnancy would complicate her cardiac status. Chromosome analysis was normal. On physical examination a t age 30 years, the patient was a small, friendly woman. Her height was 149.1 cm (< 3%), her weight was 42 kg (< 5%) and her head circumference was 52 cm (< 3%).She had a low anterior hairline, small jaw with a high-arched palate, unusual dentition with duplication of the anterior incisors, prominent lips, stellate irides, and facial asymmetry. Her fingernails were short; she had short fifth metacarpals and camptodactyly of the fifth finger on both hands. There was mild scoliosis. Her blood pressure was 122/80. There was a grade 2/6 systolic ejection murmur at the upper sternal border. P.H.’s intellectual development was slow. She walked
Patient 1
Yes Yes No Yes Yes Yes Lordosis No
No
Yes No Yes Yes Yes Scoliosis
No
None Congenital bowel obstruction herniorrhaphy heamorroidectomy tonsillectomy adenoidectomy correction of SVAS hysterectomy
High blood pressure Stellate irides Strabismus High cheeks f i l l lips Micrognathia Skeletal anomalies
Contractures
Surgical procedures
Other medical concerns
Bicuspid aortic valve
SVAS
Bony cyst of left superior pubic ramus
Strabismus bilateral herniorrhaphy
No
No Adenoidectomy correction of SVAS cosmetic facial surgery to correct micrognathia
Yes Yes Yes Yes Yes None
Yes Yes Yes Yes Yes Scoliosis
Yes
Mitral valve prolapse
55.7 cm (50%)
171 cm (10%)
Yes Yes Yes Yes Yes Lordosis and cervical fusion Knees and hips Strabismus correction of SVAS
(< 3%)
Yes
SVAS
166.5 cm
Patient 5
43 2.700 kg 57 kg (25%)
Yes
153 cm (< 3%) 54.5 cm (25%) SVAS
Patient 4
18 2.970 krr 49.5 kg-(5%)
Patient 3
27 1.935 ka 52 kg CiOW)
Patient 2
22 2.925 ka97 kg (> 97%) 160 cm (25%) 54 cm (25%)
Heart disease
52 cm (< 3%)
OM:
(< 3%)
149.1 cm
height
Current age 30 2.025 kg Birth weight Current weight 42 kg (< 5%)
Patient 7
160 cm (< 3%) 52 em (< 3%) Pulmonary stenosis and right ventricular hypertrophy Yes
24 2.300 kg 50 kg (10%)
tuba1 ligation
Nephrocalcinosis
Strabismus tonsillectomy
Yes Yes Yes Yes Yes Yes Mild lordosis Scoliosis & mild pectus No No No No Yes Yes
No
SVAS
26 2.7 kg 62.5 kg (75%) 138 cm ( 97%),her height 160 cm (25%),and her head circumference 54 cm (25%).She had prominent cheeks and very full lips, anteverted nares, and a long philtrum. The irides exhibited a stellate pattern. Her blood pressure was 140/90. There was a soft systolic ejection murmur over the precordium. There was mild
lordosis with central obesity and striae over the abdomen. The patient had slow development from early childhood. She did not sit until 10 months of age, and she walked at age 2. Her first words were spoken a t the same time, and she did not have three word sentences until age 3. Her education occurred in a special school; she finished grade 12. She cannot read and writes very sloppily. She can do simple sums and use a calculator. She speaks clearly and can follow a conversation. She is presently living a t home and working in a sheltered workshop.
Patient 3 (Fig. 1) D.S.was the product of a 30-week pregnancy complicated by vaginal bleeding during the third and fifth months of gestation. He was delivered prematurely by cesarean section because of ruptured membranes, fetal distress, and transverse lie. His birth weight was 1.8kg (90th centile for gestational age). He was placed in an incubator for 3 weeks in order to gain weight. He was always a very small child. Shortly after birth he was noted to have a cardiac murmur and was placed on iron therapy for anaemia. At age 2 months a diagnosis of SVAS was made. At 12 months he had surgery to correct a strabismus. He was chronically ill until age 10 years and was hospitalized
724
Rangol et al.
repeatedly for recurrent bronchiolitis. At age 18 he underwent cardiac surgery and had patch repair for WAS. At 22 years he developed a large bone cyst involving the left superior pubic ramus which spontaneously regressed and ossified. On physical examination at age 27 years, he was a small, talkative man in no distress. His weight was 52 kg (lo%), his height 153 cm (< 3%), and his head circumference 54.5 cm (25%). He had a round face with prominent cheeks, full lips, and malformed teeth. His irides were blue with a stellate pattern. There was hyperlordosis of the spine attributed to his pubic lesion. His blood pressure was 118181.Radiographs showed fusion of the cervical vertebrae. His chromosomes were normal. His intellectual development was always slow. He sat at 10 months and walked and talked at 4 years. He scored in the severely retarded range on a recent IQ test. He is hyperactive and talkative. D.S. can neither read nor write, but his verbal skills are highly developed. He is actively involved in sports and is part of a bowling team in the Special Olympics. He is currently living a t home where his mother runs a boarding house for mentally and physically handicapped people. He works in a sheltered workshop.
Patient 4 (Fig. 1) S.F. was the product of a 40-week pregnancy that was complicated by mild vaginal bleeding at approximately 3 months of gestation. He was born by repeat cesarean section. He weighed 2.970 kg (10%) at birth and was cyanotic. He was found to have SVAS. He fed and slept poorly and was always small as a child. Adenoidectomy was performed at age 7. At 14 he underwent surgery for correction of WAS. He also had surgery to correct his strabismus. He recently underwent cosmetic facial surgery for micrognathia. He complains of chronic abdominal pain with occasional nausea, but investigations to date have been non-diagnostic. On physical examination at age 18, S.F. was a small, friendly young man. His weight was 49.5 kg (5%)and his height 166.5 cm (< 3%).His blood pressure was 1421120. He had a narrow head with a relatively long face. There was mid-face hypoplasia with a high palate and mildly prominent lips. He had left-sided profound congenital sensori-neural hearing loss. He had an asymmetrical chest and mild scoliosis. Chromosome analysis was normal. S.F.’s psychomotor development was delayed. He stood at one year, walked a t 19 months and said single words at 3I/z. At age 13 he was found to have an IQ of 69. He can read and write and is still attending high school. He has been playing soccer a t his own age level for almost 10 years and enjoys sports. He lives at home.
and a trileaflet aortic valve with eccentric closure. This has always been asymptomatic. He had surgery to correct bilateral congenital esotropia as an infant. Bilateral inguinal herniorrhaphies were done a t age 4. Cytogenetic studies were not performed. On physical examination at age 43 years, K.M. was a tall, thin, pleasant man. His weight was 57 kg (25%),his height 171 cm (lo%), and his head circumference 55.7 cm (50%).He had a very long narrow face with very high arched palate, marked micrognathia, and prominent lips. His eyes showed stellate patterned irides and right esotropia. His ears were large, measuring greater than the 97th centile. His blood pressure was 150182.He had a loud 316 systolic ejection murmur radiating to the back. His skin was very soft and lax with multiple nevi and tags. His shoulders were down-slanting, and he had joint limitation in the knees and hips. He exhibited bilateral short fourth and fifth metacarpals. K.M.’s psychomotor development was delayed. He stood a t 1 year and walked a t 18 months. He started using single words a t 2 and complete sentences at 3 years. He attended special classes and has completed 12 years of schooling. K.M. reads and writes but has a hard time with calculations. He spends more than 10 hours a week reading in the public library. He worked at a sheltered workshop for 18 years. His present job involves sorting, pricing, and stacking shelves. He plays floor hockey, bowling, and soccer and is on a Special Olympics baseball team. K.M. recently moved to a group home; before that he lived with his parents.
Patient 6 (Fig. 1) L.C. was born at term after an uncomplicated pregnancy. Her birth weight was 2.7 kg (10%).She was a sickly baby and a very poor feeder. Her growth was always slow. She was noted to have a cardiac murmur at age 6 weeks and underwent cardiac catheterizations at 3 months and at age 8 years. Mild SVAS was diagnosed. As a child L.C. had chronic constipation and recurrent respiratory infections. Tuba1 ligation was performed at the age of 22. Chromosome analysis was normal. On physical examination at age 26, L.C. was a short, overweight woman. Her weight was 62.5 kg (75%),her height 138 cm (
Williams Syndrome in Adults E. Lopez-Rangel, M. Maurice,
B. McGillivray, and J.M. Friedman
Department of Medical Genetics, University of British Columbia and University Hospital, Vancouver, Canada
There are few published reports of adults with Williams syndrome (WS). We have evaluated ten adult WS patients. The patients in our study were very variable in clinical presentation, ranging from severely affected patients with complicated medical histories to mildly affected patients who are generally in good health. Cardiovascular anomalies and hypertension were frequent. Supravalvular aortic stenosis was seen in four patients, mitral valve prolapse in three, bicuspid aortic valve in one, valvular aortic stenosis in one, a n d pulmonary stenosis with right ventricular hypertrophy in one. vpical facial features included stellate irides, prominent cheeks, full lips, and micrognathia. Mental retardation was seen in all patients. Verbal skills were better developed than motor skills. All patients in our study lead active lives, and most are involved in sports. Some hold supervised jobs. Eight of our patients live with their parents and two in group homes. Independent living is restricted by their mental and adaptive limitations. 0
1992 Wiley-Liss, Inc.
KEY WORDS: Williams syndrome, cardiovascular, facial anomalies, developmental delay INTRODUCTION Williams syndrome (WS)in children is a well characterized entity [Williams et al., 19611, but there have been few previous reports of affected adults [Morris et al., 1988, 1990, F’ryns et al., 19911. We report on ten adults with WS in order to delineate better the longterm outcome, medical complications, and adaptive and social skills of adults with this condition.
Received for publication September 16, 1991; revision received May 14, 1992. Address reprints request to Dr. J.M. E’riedman, Department of Medical Genetics, University Hospital, Shaughnessy Site, 4490 Oak Street, Vancouver, B.C., Canada V6H 3V5.
0 1992 Wiley-Liss, Inc.
MATERIALS AND METHOD Patients with a diagnosis of WS who were above the age of 18 years were identified from the records of the Department of Medical Genetics, University of British Columbia and University Hospital, Vancouver. We recalled five men and five women for evaluation. Their mean age was 26.4 years; the age range was from 18 to 43 years. All patients were examined by a medical geneticist. Family history and medical records were reviewed, and chromosome studies were done. The families were asked to provide photographs of the patients at various ages. A summary of phenotypic and cognitive manifestations of the patients is provided in Tables I and 11. CLINICAL REPORTS Patient 1 (Fig. 1) P.H. was the product of a normal term pregnancy; her birth weight was 2.025 kg (< 5%). The patient was kept in the nursery for a month after birth in order to gain weight. During childhood, her weight gain was slow: she is said to have always been “half the size” of a normal child her age. At age 4 she had surgery for congenital bowel obstruction. She also underwent bilateral inguinal herniorrhaphy and two haemorrhoidectomies. Tonsillectomy and adenoidectomywere performed for recurrent tonsillitis. At age 12 she had surgery for correction of supravalvular aortic stenosis (WAS). At 14 she developed hypertension that required a cardiopulmonary bypass, resection of SVAS, and repair of arch stenosis; since then there has been no recurrence of the hypertension. Hysterectomy was performed at age 14 because it was thought pregnancy would complicate her cardiac status. Chromosome analysis was normal. On physical examination a t age 30 years, the patient was a small, friendly woman. Her height was 149.1 cm (< 3%), her weight was 42 kg (< 5%) and her head circumference was 52 cm (< 3%).She had a low anterior hairline, small jaw with a high-arched palate, unusual dentition with duplication of the anterior incisors, prominent lips, stellate irides, and facial asymmetry. Her fingernails were short; she had short fifth metacarpals and camptodactyly of the fifth finger on both hands. There was mild scoliosis. Her blood pressure was 122/80. There was a grade 2/6 systolic ejection murmur at the upper sternal border. P.H.’s intellectual development was slow. She walked
Patient 1
Yes Yes No Yes Yes Yes Lordosis No
No
Yes No Yes Yes Yes Scoliosis
No
None Congenital bowel obstruction herniorrhaphy heamorroidectomy tonsillectomy adenoidectomy correction of SVAS hysterectomy
High blood pressure Stellate irides Strabismus High cheeks f i l l lips Micrognathia Skeletal anomalies
Contractures
Surgical procedures
Other medical concerns
Bicuspid aortic valve
SVAS
Bony cyst of left superior pubic ramus
Strabismus bilateral herniorrhaphy
No
No Adenoidectomy correction of SVAS cosmetic facial surgery to correct micrognathia
Yes Yes Yes Yes Yes None
Yes Yes Yes Yes Yes Scoliosis
Yes
Mitral valve prolapse
55.7 cm (50%)
171 cm (10%)
Yes Yes Yes Yes Yes Lordosis and cervical fusion Knees and hips Strabismus correction of SVAS
(< 3%)
Yes
SVAS
166.5 cm
Patient 5
43 2.700 kg 57 kg (25%)
Yes
153 cm (< 3%) 54.5 cm (25%) SVAS
Patient 4
18 2.970 krr 49.5 kg-(5%)
Patient 3
27 1.935 ka 52 kg CiOW)
Patient 2
22 2.925 ka97 kg (> 97%) 160 cm (25%) 54 cm (25%)
Heart disease
52 cm (< 3%)
OM:
(< 3%)
149.1 cm
height
Current age 30 2.025 kg Birth weight Current weight 42 kg (< 5%)
Patient 7
160 cm (< 3%) 52 em (< 3%) Pulmonary stenosis and right ventricular hypertrophy Yes
24 2.300 kg 50 kg (10%)
tuba1 ligation
Nephrocalcinosis
Strabismus tonsillectomy
Yes Yes Yes Yes Yes Yes Mild lordosis Scoliosis & mild pectus No No No No Yes Yes
No
SVAS
26 2.7 kg 62.5 kg (75%) 138 cm ( 97%),her height 160 cm (25%),and her head circumference 54 cm (25%).She had prominent cheeks and very full lips, anteverted nares, and a long philtrum. The irides exhibited a stellate pattern. Her blood pressure was 140/90. There was a soft systolic ejection murmur over the precordium. There was mild
lordosis with central obesity and striae over the abdomen. The patient had slow development from early childhood. She did not sit until 10 months of age, and she walked at age 2. Her first words were spoken a t the same time, and she did not have three word sentences until age 3. Her education occurred in a special school; she finished grade 12. She cannot read and writes very sloppily. She can do simple sums and use a calculator. She speaks clearly and can follow a conversation. She is presently living a t home and working in a sheltered workshop.
Patient 3 (Fig. 1) D.S.was the product of a 30-week pregnancy complicated by vaginal bleeding during the third and fifth months of gestation. He was delivered prematurely by cesarean section because of ruptured membranes, fetal distress, and transverse lie. His birth weight was 1.8kg (90th centile for gestational age). He was placed in an incubator for 3 weeks in order to gain weight. He was always a very small child. Shortly after birth he was noted to have a cardiac murmur and was placed on iron therapy for anaemia. At age 2 months a diagnosis of SVAS was made. At 12 months he had surgery to correct a strabismus. He was chronically ill until age 10 years and was hospitalized
724
Rangol et al.
repeatedly for recurrent bronchiolitis. At age 18 he underwent cardiac surgery and had patch repair for WAS. At 22 years he developed a large bone cyst involving the left superior pubic ramus which spontaneously regressed and ossified. On physical examination at age 27 years, he was a small, talkative man in no distress. His weight was 52 kg (lo%), his height 153 cm (< 3%), and his head circumference 54.5 cm (25%). He had a round face with prominent cheeks, full lips, and malformed teeth. His irides were blue with a stellate pattern. There was hyperlordosis of the spine attributed to his pubic lesion. His blood pressure was 118181.Radiographs showed fusion of the cervical vertebrae. His chromosomes were normal. His intellectual development was always slow. He sat at 10 months and walked and talked at 4 years. He scored in the severely retarded range on a recent IQ test. He is hyperactive and talkative. D.S. can neither read nor write, but his verbal skills are highly developed. He is actively involved in sports and is part of a bowling team in the Special Olympics. He is currently living a t home where his mother runs a boarding house for mentally and physically handicapped people. He works in a sheltered workshop.
Patient 4 (Fig. 1) S.F. was the product of a 40-week pregnancy that was complicated by mild vaginal bleeding at approximately 3 months of gestation. He was born by repeat cesarean section. He weighed 2.970 kg (10%) at birth and was cyanotic. He was found to have SVAS. He fed and slept poorly and was always small as a child. Adenoidectomy was performed at age 7. At 14 he underwent surgery for correction of WAS. He also had surgery to correct his strabismus. He recently underwent cosmetic facial surgery for micrognathia. He complains of chronic abdominal pain with occasional nausea, but investigations to date have been non-diagnostic. On physical examination at age 18, S.F. was a small, friendly young man. His weight was 49.5 kg (5%)and his height 166.5 cm (< 3%).His blood pressure was 1421120. He had a narrow head with a relatively long face. There was mid-face hypoplasia with a high palate and mildly prominent lips. He had left-sided profound congenital sensori-neural hearing loss. He had an asymmetrical chest and mild scoliosis. Chromosome analysis was normal. S.F.’s psychomotor development was delayed. He stood at one year, walked a t 19 months and said single words at 3I/z. At age 13 he was found to have an IQ of 69. He can read and write and is still attending high school. He has been playing soccer a t his own age level for almost 10 years and enjoys sports. He lives at home.
and a trileaflet aortic valve with eccentric closure. This has always been asymptomatic. He had surgery to correct bilateral congenital esotropia as an infant. Bilateral inguinal herniorrhaphies were done a t age 4. Cytogenetic studies were not performed. On physical examination at age 43 years, K.M. was a tall, thin, pleasant man. His weight was 57 kg (25%),his height 171 cm (lo%), and his head circumference 55.7 cm (50%).He had a very long narrow face with very high arched palate, marked micrognathia, and prominent lips. His eyes showed stellate patterned irides and right esotropia. His ears were large, measuring greater than the 97th centile. His blood pressure was 150182.He had a loud 316 systolic ejection murmur radiating to the back. His skin was very soft and lax with multiple nevi and tags. His shoulders were down-slanting, and he had joint limitation in the knees and hips. He exhibited bilateral short fourth and fifth metacarpals. K.M.’s psychomotor development was delayed. He stood a t 1 year and walked a t 18 months. He started using single words a t 2 and complete sentences at 3 years. He attended special classes and has completed 12 years of schooling. K.M. reads and writes but has a hard time with calculations. He spends more than 10 hours a week reading in the public library. He worked at a sheltered workshop for 18 years. His present job involves sorting, pricing, and stacking shelves. He plays floor hockey, bowling, and soccer and is on a Special Olympics baseball team. K.M. recently moved to a group home; before that he lived with his parents.
Patient 6 (Fig. 1) L.C. was born at term after an uncomplicated pregnancy. Her birth weight was 2.7 kg (10%).She was a sickly baby and a very poor feeder. Her growth was always slow. She was noted to have a cardiac murmur at age 6 weeks and underwent cardiac catheterizations at 3 months and at age 8 years. Mild SVAS was diagnosed. As a child L.C. had chronic constipation and recurrent respiratory infections. Tuba1 ligation was performed at the age of 22. Chromosome analysis was normal. On physical examination at age 26, L.C. was a short, overweight woman. Her weight was 62.5 kg (75%),her height 138 cm (
