Abstract
We report the first prospective longitudinal study of dietary intake, weight, height, and skinfold measurements during the early phase of four Prader–Labhart–Willi syndrome (PLWS) individuals (two males and two females). Although caloric intake ranged from 80 to 90 percent of recommended daily allowance during our study of the four PLWS infants, obesity still occurred. Our findings suggest that the onset of obesity in PLWS individuals occurs earlier than previously thought in spite of reduced caloric intake. The infants in our study reached the obese range judged by skinfold measurements greater than the 85th centile at an early age and before they were considered heavy based on weight for height criterion. We propose that skinfold measurements should be obtained on all individuals with PLWS and obesity judged by this criterion.
Keywords: skinfold measurements, Prader-Labhart-Willi syndrome, infants
Introduction
Prader–Labhart–Willi syndrome (PLWS) was first described in nine patients in 19561 and subsequently over 600 cases have been reported2–4. Prader–Labhart–Willi syndrome, generally sporadic in occurrence, is characterized by infantile hypotonia, early childhood obesity, mental deficiency, short stature, small hands and feet and hypogonadism. The first clinical phase from birth to 2 or 3 years of age consists of congenital hypotonia, feeding difficulties and poor weight gain. The second clinical stage is characterized by muscle tone improvement, an increased appetite and rapid weight gain5. Growth data and dietary intake are rare during the first phase of PLWS with only one previous report of a 10-month-old PLWS male but with no data on subcutaneous fat deposition6. Therefore, we report the first prospective longitudinal study of dietary intake, weight, height, weight/height ratio and skinfold measurements to monitor fat deposition in four PLWS individuals (two males and two females) during the early phase.
Materials and methods
Clinical assessment
Patient 1, a white female, was born at 38 weeks gestation to a 23-year-old G3P2Ab1 mother. Delivery was vaginal and the birth weight was 2.21 kg (5th centile), birth length was 48 cm (25th centile) and head circumference was 33.5 cm (30th centile). Severe hypotonia, a weak cry and an absent suck reflex were noted at birth. Tube feedings were required during the neonatal period, but gradually oral intake improved and by 3 months of age tube feedings were required for only one-third of the child’s dietary intake (115 kcal/kg per day).
On physical examination at 3 weeks of age, the head was dolichocephalic with a narrow bifrontal diameter and a small anterior fontanel. The eyes were almond-shaped with strabismus. The ears showed prominent antihelices with minor hypoplasia of the helices. There was mild micrognathia. Extremities showed small hands and feet but well formed nails and digits with normal palmar creases. Neurologically, she had overall decreased strength, hypotonia, absent deep tendon reflexes of the upper extremities, a weak suck reflex and lethargy. An EEG was abnormal but the rest of the laboratory and X-ray studies were normal. High resolution chromosome studies showed an interstitial deletion of the 15q12 band of chromosome 15 which is found in 50 percent of PLWS patients4.
In follow-up examinations, anthropometric measurements and caloric intake were recorded on 12 occasions from birth to 45 months of age with measurements obtained on eight separate occasions from birth to 1 year of age. Development testing at 1 year of age showed a 7 to 8 months age overall, 5 to 6 month gross motor age and 11 to 12 month fine motor skills.
Clinical features of patients 1, 2, 3, and 4 are summarized in Table 1. Caloric intake was also monitored for the PLWS patients (Table 2). For example, patient 1 consumed 115 and 80 kcal/kg per day at 6 and 12 months, respectively; patient 2 consumed 80 and 110 kcal/kg per day at 4 and 9 months, respectively; patient 3 consumed 90 and 100 kcal/kg per day at 3 and 14 months, respectively; and patient 4 consumed approximately 90 kcal/kg per day for the first 18 months of life.
Table 1.
Clinical features of individuals with Prader–Labhart–Willi syndrome.
| Clinical features | Patient 1 | Patient 2 | Patient 3 | Patient 4 |
|---|---|---|---|---|
| Sex | F | F | M | M |
| Gestation | 38w | 42 w | 40w | 40w |
| Reduced fetal activity | + | + | + | ? |
| Breech delivery | − | + | − | − |
| Neonatal period and infancy | ||||
| Birth weight | 2.21 kg | 2.31 kg | 2.98 kg | 3.10 kg |
| Birth length | 48.0 cm | 48.3 cm | 48.3 cm | 47.0 cm |
| Head circumference | 33.5 cm | 34.0 cm | 35.6 cm | ? |
| Neonatal feeding difficulty | + | + | + | + |
| Hypotonia | + | + | + | + |
| CNS function and behavior | ||||
| Seizures | − | + | − | − |
| Retarded psychomotor development | + | + | + | + |
| Hyperphagia | + | + | − | − |
| Strabismus | + | + | − | − |
| Growth | ||||
| Obesity* | + | − | + | + |
| Short stature (<5th%ile) | + | + | + | + |
| Facies | ||||
| Almond–shaped palpebral fissures | + | + | + | + |
| Narrow bifrontal diameter | + | + | + | + |
| Sexual development | ||||
| Hypogenitalism | + | + | + | + |
| Cryptorchidism | NA | NA | + | + |
| Limbs | ||||
| Small hands and feet (<5th%ile) | + | + | + | + |
| Chromosome status | del (15q) | normal | del (15q) | normal |
Obesity judged by skinfold measurements (>85th%ile).
Table 2.
Anthropometric measurements and caloric intake on four patients with Prader–Labhart–Willi syndrome.
| Case/Sex | Age (mos) | kcal/kg/d | Height* cm (%ile) | Weight* kg (%ile) | Weight/height* (%ile) | Triceps skinfold** (mm) (%ile) | Subscapular skinfold** (mm) (%ile) |
|---|---|---|---|---|---|---|---|
| 1/F | newborn | 115 | 48.0 (25) | 2.21 (5) | (<5) | ||
| 1 | 115 | 50.0 (10) | 2.36 (<5) | (<5) | 5.0 (10) | 4.0 (<5) | |
| 2 | 115 | 58.0 (50) | 3.80 (5) | (<5) | 9.0 (60) | 8.0 (40) | |
| 6 | 115 | 63.5 (20) | 5.95 (5) | (25) | 13.0 (85) | 10.5 (75) | |
| 7 | 85 | 63.7 (5) | 6.27 (5) | (40) | 14.0 (90) | 11.0 (85) | |
| 8 | 85 | 63.5 (5) | 6.68 (5) | (60) | 12.0 (60) | 10.0 (75) | |
| 10 | 67.6 (5) | 7.35 (5) | (35) | 14.5 (85) | 10.5 (80) | ||
| 12 | 80 | 69.3 (5) | 8.02 (5) | (40) | 13.0 (70) | 10.0 (80) | |
| 14 | 73.2 (10) | 8.72 (10) | (35) | 13.0 (70) | 8.5 (60) | ||
| 22 | 90 | 78.5 (5) | 10.03 (10) | (35) | 12.5 (60) | 7.5 (50) | |
| 34 | 78.9 (<5) | 10.10 (<5) | (40) | 8.5 (15) | 6.0 (35) | ||
| 45 | 83.9 (<5) | 10.40 (<5) | |||||
| 2/F | newborn | 80 | 48.3 (25) | 2.31 (5) | (5) | ||
| 4 | 80 | 58.0 (10) | 3.86 (<5) | (<5) | |||
| 9 | 110 | 64.1 (<5) | 4.77 (<5) | (<5) | |||
| 24 | 76.2 (<5) | 8.64 (<5) | (5) | ||||
| 31 | 100 | 83.0 (<5) | 9.98 (<5) | (10) | 11.5 (60) | 5.5 (20) | |
| 3/M | newborn | 90 | 48.3 (30) | 2.98 (25) | (30) | ||
| 1 | 54.5 (50) | 3.55 (15) | (25) | ||||
| 3 | 90 | 59.8 (40) | 4.92 (15) | (15) | |||
| 8 | 67.0 (5) | 6.92 (5) | (15) | 12.0 (50) | 5.5 (5) | ||
| 14 | 100 | 73.0 (5) | 8.80 (5) | (25) | 10.5 (30) | 6.5 (25) | |
| 26 | 81.0 (<5) | 11.20 (5) | (50) | 13.0 (85) | 9.0 (90) | ||
| 35 | >100 | 87.5 (<5) | 14.30 (40) | (>95) | 14.0 (90) | 9.0 (95) | |
| 48 | 96.0 (10) | 18.50 (85) | 14.5 (95) | 9.5 (95) | |||
| 4/M | newborn | 90 | 47.0 (10) | 3.10 (30) | (50) | ||
| 12 | 90 | 7.00 (<5) | |||||
| 18 | 90 | 78.0 (5) | 8.49 (<5) | (<5) | 11.0 (45) | 1.0 (5) | |
| 31 | 100 | 82.8 (<5) | 11.20 (<5) | (40) | 14.0 (90) | 5.0 (20) |
Anthropometric description
All of the anthropometric measurements were made by one of the authors (F.J.M.) according to standard techniques as presented by Weinerand Lourie7. Anthropometric measurements used in this study included weight, height (or length), subscapular and triceps skinfolds8,9. Up to the age of 2.5 years, length was measured in supine position using a horizontal calibrated board. Thereafter height measurements were taken. Skinfold measurements were obtained to the nearest half millimeter with a Lange skinfold caliper. Weight and height were measured using a balanced-beam scale and anthropometer, respectively.
Results
Weight, length, weight/height ratio, caloric intake, and triceps and subscapular skinfolds are found in Table 2. Birth weights, lengths and weight/height ratios ranged from less than the 5th to the 50th centile. During most of the period from birth to 36 months, height, weight and weight/height ratio were generally well below the 50th centile (excluding >95th centile for patient 3 at 35 months of age for weight/height) while triceps and subscapular skinfolds were usually at or above the 85th centile in three of the four patients (1,3 and 4) when caloric intakes were at or above 100 kcal/kg per day. Therefore, patients 1, 3 and 4 were generally in the obese range (>85th centile based on skinfold thickness)10 at times during the first 3 years of life when caloric intake was highest. Failure to thrive was apparent in these PLWS patients during the first 6 months.
Caloric intake was assessed during the early phase in the four PLWS patients. For example, the recommended daily dietary intake (115 kcal/kg per day) for patient 1 was followed during the first 6 months of life. At 6 months of age, a high-protein, low-fat diet consisting of Isomil formula, pureed cereal, fruit, vegetables and meat was followed. Her caloric intake was then adjusted due to her increased fat deposition as detected by skinfold measurements. At age 6 months the triceps skinfold in patient 1 was in the obese range while her weight, height and weight/height measurements were at the 25th centile or less. With continued diet intervention (caloric intake of 80 to 90 kcal/kg per day) from age 7 to 22 months her skinfold centile ratings dropped while her weight and height measurements were in the 5th to the 10th centile range and her weight/height measurement ranged from the 25th to the 60th centile.
Discussion
Dietary control of obesity of individuals with PLWS has met with limited success11. The first report of successful weight control in PLWS included four patients (ages 2¾–6 years) and weight control was achieved on a low-calorie diet containing 8.5 kcal/cm of height12. The four children maintained appropriate weight consuming calories below the 10th centile of intake of normal children. Therefore, the caloric requirement of PLWS individuals is thought to be about 60 percent of normal13.
At 34 months, patient 1 had a height and weight less than the 5th centile but her weight/height ratio was at the 40th centile and her triceps skinfold had dropped to the 15th centile. The reason for this weight and height deceleration, which was more pronounced than in the other three patients, was not clear, although limitation of nutritional intake or genetic factors may be involved. Growth deceleration during the first 3 years of life has also been previously noted in Down and Turner syndromes14,15.
A study that claims to demonstrate the development of progressive obesity in a child with PLWS by Char16 also suggests that excess fatness may precede overweight status in this condition. In this clinical study, heights and weights are reported for a female with PLWS from ages 10 months to 62 years. Unfortunately, skinfolds were not included. However, a photograph of the PLWS individual at 10 months of age certainly suggests that she may be obese by the skinfold criterion (>85th centile). The child’s weight for length at age 10 months plots at the 50th centile on standard charts8. By the next set of measurements reported at age 2 years and 4 months, the child’s weight for height is well above the 95th centile. Additional longitudinal studies of PLWS individuals in the early phase of this condition are clearly needed and should include skinfold assessments.
The finding of excess fatness before overweight status in the PLWS patients reported herein points to the difficulties in assessing obesity clinically as demonstrated in a recently published anthropometric survey by Griffiths and coworkers17 of 2300 boys aged 1 to 8 years. Griffiths and coworkers found no close relationship between obesity as assessed by triceps skinfolds and the development of heaviness as judged by weight for height. Therefore, individuals may be judged as heavy but not fat, fat but not heavy or both heavy and fat. Our patient 1 also emphasizes that an individual with PLWS may be fat but not heavy. While it may be of some benefit to use growth in height and weight in attempting to assess the development of obesity in suspected PLWS patients, the results from our study as well as others suggest that skinfold measurements should be taken and obesity judged by this criterion.
Caloric requirement in PLWS individuals is thought to be less than in normal individuals either because of a decreased metabolic rate and/or decreased physical activity18. Therefore additional prospective studies with monitoring of growth parameters and calorie intake at early ages should be useful in developing a dietary plan that allows brain and physical growth but prevents development of early obesity. In order to accomplish this goal early clinical diagnosis will be critical.
If the problem in PLWS patients is in part due to excess deposition of fat, it would seem pertinent to monitor carefully the development of fatness in suspected patients. If larger series of measurements and continued observations of the patients reported herein confirm these findings, measurements of skinfold thickness as well as metacarpophalangeal pattern profile analysis19,20 and highresolution chromosome analysis may provide early clinical diagnoses of infants suspected to have Prader–Labhart–Willi syndrome.
Acknowledgments
The authors thank Drs Rebecca Wappner, Bryan Hall, Patricia Baderand Andree Walczak for allowing us to evaluate their patients. This research was supported in part by CNRU (5P30AM26657). The authors acknowledge use of the facilities of Computing Services, Indiana University–Purdue University. Indianapolis. We thank Donna Hooper for expert preparation of the manuscript.
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