Abstract
Prader-Willi syndrome (PWS) is a complex genetic disorder with three molecular classes but clinical ascertainment is based on distinctive features. The prevalence of dysmorphic features was studied in 355 PWS participants (61% deletion, 36% maternal disomy UPD and 3% imprinting defects) from the National Institute of Health PWS Rare Diseases Clinical Research Network. The effect of growth hormone (GH) treatment on growth and dysmorphic features was compared. Among participants, upslanting palpebral fissures were seen in 23%; strabismus in 42%; abnormal dentition in 32%; small hands in 63% and small feet in 70%; hypopigmentation in 30%; striae in 32% and skin picking in 26%. Compared to those with UPD, participants with deletions were found to be heavier (p=0.002), had smaller head circumference (p=0.009), higher incidence of a flat occiput (p=0.005); low anterior hairline (p=0.04); abnormal dentition (p=0.009); abdominal striae (p=0.045), nail abnormalities (p=0.050), and fair-haired (p<0.001). Participants in both genetic groups receiving GH were taller (p=0.005), had larger head circumferences (p=0.005), and longer hands (p=0.049). This study suggested that PWS genetic subtypes and GH treatment can influence growth and dysmorphic features that may impact clinical diagnosis of PWS, such as stature, head shape and appearance of the eyes, nose and genitalia.
Keywords: Prader-Willi syndrome, genetic subtypes, growth hormone treatment, genotype-phenotype, growth, dysmorphology
INTRODUCTION
Prader-Willi syndrome (PWS) affects 1/15,000-1/30,000 live births and is genetically characterized by absence of expression of paternally inherited genes from the 15q11-q13 region, due to a paternal deletion, uniparental maternal disomy (UPD) 15, or imprinting defects (ID). Affected individuals have severe hypotonia, a poor suck with feeding difficulties and developmental delay during infancy and learning problems, hyperphagia with obesity in childhood, short stature, behavioral problems including frequent temper tantrums, skin picking, and possibly psychosis, schizophrenia, manic-depression and autism spectrum disorder (e.g., 1–8). Individuals with PWS have abnormal function of the endocrine system which includes growth hormone (GH)/insulin-like growth factor 1 axis dysfunction, hypogonadism, hypothyroidism, premature adrenarche, and adrenal insufficiency4–10. They also develop distinctive physical and dysmorphic facial features including small hands and feet, excessive body fat that often concentrates on the trunk and thighs, a narrow forehead, and deep-set almond-shaped eyes. Often these physical features and distinctive characteristics alert the clinician to the possible diagnosis of PWS but requires testing to identify the three known molecular genetic classes (i.e., paternally derived chromosome 15q11-q13 deletion, uniparental maternal disomy 15 or imprinting center defects) 11.
Distinct Facial and Physical Features
The facial and physical features seen in individuals with PWS were first described by Prader et al. in 1956 12. These facial features include a small narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, and thin upper lip with downturned corners of the mouth and decreased salivary secretions. Other physical features include short stature, small hands with flattened ulnar border, small feet, hypoplastic genitalia 1–8 and hypopigmentation in relationship to first degree relatives in those with the 15q11-q13 deletion 13.
Growth hormone deficiency has been documented in PWS with growth hormone treatment considered the standard of care 4,6,7,14. Overall, GH therapy affects linear growth by increasing adult height in addition to improvement of physical activity, strength and muscle mass that can impact craniofacial features, body habitus and quality of life with improved cognition and possibly behavior in PWS 6,8,15,16.
The aim of this study was to compare the physical and dysmorphic features in individuals with PWS in a large cohort and in relationship to genetic subtypes and growth hormone treatment to determine if growth hormone treatment effects are different for individuals with either deletion or UPD.
SUBJECTS AND METHODS
Data from 355 individuals with genetically confirmed PWS were collected at the University of California, Irvine, California; University of Florida Health Science Center, Gainesville, Florida; University of Kansas Medical Center, Kansas City, Kansas; and Vanderbilt University Medical Center, Nashville, Tennessee and entered into the National Institute of Health (NIH) funded Rare Disease Clinical Research Network (RDCRN) PWS registry 17. Written informed consent was obtained from all participants or their guardians prior to enrollment using approved human subjects research consent forms at the four sites. Clinical and genetic data were obtained over an eight-year period from 2006 to 2014 using standardized measurements of physical and growth variables including craniofacial features noted by PWS specialists with over 100 combined years of experience and training as dysmorphologists at the sites.
Dysmorphology Evaluation
Physical and facial features, including continuous and categorical variables, were assessed. Continuous variables included physical measurements of height, weight, body mass index (BMI), head circumference, craniofacial, arm span, hand, foot and penile length. Data were collected for analysis at the initial enrollment visit per participant. For statistical purposes, the data were converted into age and gender-adjusted centiles using the WHO (World Health Organization) and CDC (Center for Disease Control) reference tables 18,19. Categorical variables included esotropia, exotropia, head shape, narrow nasal bridge, flat philtrum, downturned corners of mouth, dental, genitalia, skin picking, hair texture and pigment. The data were summarized using mean and standard deviation (SD) for continuous variables. Participant groups were subdivided by PWS molecular genetic classes and growth hormone (GH) use, duration, and onset, and then compared using two-group t-tests for continuous variables and chi-square tests for categorical variables. The statistical analyses were accomplished using SPSS 20 Statistics software (Armonk, NY). Statistical significance was considered at p<0.05. This project was the focus of the Master’s thesis by one of our co-authors (AL)20
RESULTS
Dysmorphic and Clinical Features in Prader-Willi Syndrome
A total of 355 PWS study participants were analyzed and comprised of 160 males (45.1%) and 195 females (59.2%). Ninety-three percent of the PWS participants were Caucasian. The average age (±SD) for the 355 PWS participants was 13 (±1) years with a range of 2 months to 62 years. The mean age at diagnosis was 3.1 ± 6.7 years with a range from birth to 48 years. Sixty-two percent of the PWS participants were diagnosed at less than one year of age and 26% were diagnosed greater than three years of age. The PWS molecular genetic classes included 217 with 15q11-q13 deletions (61%), 127 with UPD (36%) and 11 with imprinting center defects (3%). Overall, 289 participants (81.4%) had a history of GH treatment with an average age of onset of 2 (±1) years, including 137 of 160 males (85.6%) and 152 of 195 females (77.9%). Additionally, 179 of 217 (82.4%) had deletions, 103 of 127 (81%) with UPD, and 7 of 11 (63.6%) individuals with imprinting center defects received growth hormone treatment (Table 1).
Table 1:
Phenotypic Characteristics According to Molecular Class for All Participants with Prader-Willi Syndrome with or without Growth Hormone Treatment
| Deletion | UPD | p-value | |||
|---|---|---|---|---|---|
| VARIABLES | N=217 (M=99,F=118) |
Mean (SD) or % frequency | N=127 (M=53,F=74) |
Mean (SD) or % frequency | |
| GROWTH PARAMETERS: | |||||
| Height percentile for age and gender | 160/217 | 42 (34) | 109/127 | 45 (35) | 0.510 |
| Weight percentile for age and gender | 207/217 | 75 (31) | 123/127 | 62 (35) | 0.002 |
| Head circumference (HC) percentile for age and gender | 192/217 | 51 (34) | 115/127 | 61 (31) | 0.009 |
| BMI percentile for age and gender | 209/217 | 86 (36) | 116/127 | 84 (38) | 0.137 |
| HEAD: | |||||
| Microcephaly HC (<3rd percentile) | 25/192 | 13% | 3 | 2% | 0.056 |
| Prominent occiput | 38 | 18% | 26 | 20% | 0.452 |
| Flat occiput | 59 | 27% | 18 | 14% | 0.005 |
| Round face | 74 | 34% | 34 | 27% | 0.157 |
| Bitemporal narrowing | 150 | 69% | 82 | 64% | 0.233 |
| Craniosynostosis | 2 | 0.9% | 1 | 0.8% | 0.550 |
| HAIR: | |||||
| Low anterior hair line | 56 | 26% | 19 | 15% | 0.04 |
| Fair colored for family members | 87 | 40% | 19 | 15% | <0.001 |
| Hypopigmented | 86 | 40% | 19 | 15% | <0.001 |
| EYES: | |||||
| Esotropia | 81 | 37% | 49 | 39% | 0.529 |
| Exotropia | 7 | 3% | 10 | 8% | 0.091 |
| Strabismus | 84 | 39% | 67 | 53% | 0.03 |
| Upslanting palpebral fissures | 57 | 26% | 23 | 18% | 0.156 |
| Downslanting palpebral fissures | 13 | 6% | 17 | 13% | 0.015 |
| Almond-shaped | 147 | 68% | 73 | 58% | 0.045 |
| Inter-canthal distance percentile for age and gender | 71 | 58 (33) | 49 | 61 (32) | 0.582 |
| Inter-pupillary distance percentile for age and gender | 70 | 65 (35) | 47 | 67 (35) | 0.685 |
| Outer-canthal distance percentile for age and gender | 71 | 50 (39) | 49 | 48 (41) | 0.749 |
| NOSE: | |||||
| Narrow | 36 | 17% | 18 | 14% | 0.638 |
| MOUTH: | |||||
| Philtrum flat | 50 | 23% | 31 | 24% | 0.957 |
| Upper lip downturned | 49 | 23% | 35 | 28% | 0.400 |
| Abnormal dentition | 91 | 42% | 31 | 25% | 0.009 |
| Dental caries | 41 | 19% | 20 | 16% | 0.045 |
| Dental grinding | 87 | 40% | 45 | 36% | 0.196 |
| EARS: | |||||
| Posterior angulated | 13 | 6% | 17 | 14% | 0.019 |
| Ear length percentile for age and gender | 71 | 44 (30) | 47 | 53 (29) | 0.075 |
| CHEST: | |||||
| Pectus excavatum | 32 | 15% | 24 | 19% | 0.314 |
| Pectus carinatum | 6 | 3% | 5 | 4% | 0.551 |
| ABDOMEN: | |||||
| Abdominal striae | 83 | 38% | 32 | 25% | 0.024 |
| Abdominal pale striae | 62 | 29% | 21 | 17% | 0.045 |
| EXTREMITIES: | |||||
| Hand length percentile for age and gender | 190 | 38 (31) | 114 | 36 (33) | 0.773 |
| Foot length percentile for age and gender | 185 | 24 (25) | 106 | 23 (26) | 0.841 |
| Shorter fifth finger | 86 | 40% | 35 | 28% | 0.024 |
| Nail abnormalities | 56 | 26% | 16 | 13% | 0.050 |
| Large thighs | 112 | 52% | 50 | 39% | 0.025 |
| SPINE: | |||||
| Scoliosis | 96 | 44% | 50 | 39% | 0.050 |
| GENITALIA: | |||||
| Bilateral cryptorchidism | 74/99 | 75% | 28/53 | 53% | 0.263 |
| Micropenis(<5th percentile) | 26/99 | 26% | 14/53 | 26% | 0.173 |
| Scrotum rugation poor | 32/99 | 32% | 18/53 | 34% | 0.920 |
| Scrotum hypoplastic | 46/99 | 46% | 25/53 | 47% | 0.570 |
| Labia minora hypoplastic | 53/118 | 45% | 37/74 | 50% | 0.526 |
| Clitoris hypoplastic | 48/118 | 41% | 27/74 | 36% | 0.531 |
| SKIN: | |||||
| Face skin picking | 14 | 6.5% | 6 | 4.7% | 0.010 |
Eleven participants with imprinting defects were not included in the analysis
F= Female, M= Male
In the entire PWS cohort (N=355 participants), microcephaly (head circumference less than third percentile) was found in 8% of participants, flat occiput in 22%, upslanting palpebral fissures in 23%, craniosynostosis in 0.8%; strabismus in 42%; abnormal dentition in 32%; small hands in 63% and small feet in 70%, hypopigmented hair in 30%; striae in 32% and skin picking in 26%. Bilateral cryptorchidism was present in 63% and hypoplastic scrotum in 44% of males. Hypoplastic clitoris and labia minora were found in 38% and 46% of females, respectively during the initial baseline clinic visit (Table 1). Forty of the 160 males had recorded penile stretched length and 15 (38%) were considered to have a micropenis (< 5th percentile).
Comparison Between the 15q11-q13 Deletion and Uniparental Maternal Disomy (UPD) 15 in the Entire Prader -Willi Syndrome Cohort
When comparing deletion with UPD, participants with deletions were found to be heavier (mean weight percentile of 75 ± 31 vs 62 ± 35, p=0.002), but BMI percentile was not significantly different (mean BMI percentile of 86 ± 36 vs 84 ± 38, p=0.137) . Those with deletions had a smaller head circumference (HC) with mean HC percentile of 51 ± 34 vs. 61 ± 31 (p= 0.009). However, height was not different between the two PWS molecular classes (p= 0.510). Almond-shaped eyes (68% vs 58%; p=0.045), a flat occiput (27 vs 14%; p=0.005), low anterior hairline (26% vs 15%; p=0.04), and abnormal dentition (42% vs 25%; p=0.009) were seen at a higher incidence in the deletion group compared with UPD. Individuals with the deletion had a higher incidence of shorter fifth fingers (40% vs 28%; p=0.024) and nail abnormalities (26% vs 13%; p=0.050). The participants with the deletion were more fair-haired (40% vs 15%; p<0.001) than their family members which may reflect the loss of a single biallelically expressed OCA2 gene allele found in the distal 15q11-q13 region and deleted in the deletion process leading to hypopigmentation 13,21. Interestingly, the UPD group had a higher incidence of strabismus (53% vs 39%; p=0.03), downward slanting of the fissures (13% vs 6%; p=0.015) and posterior angulated ears (14% vs 6%; p=0.019) than in the deletion group.
Comparison between Growth Hormone Treated and Non-Growth Hormone Treated Participants with Prader-Willi Syndrome
The study participants were categorized according to their history of growth hormone (GH) treatment (treated vs. not treated) regardless of their PWS molecular class. Table 2 tabulates the frequency of individuals taking growth hormone in different age groups. We found that 41.7 % of individuals began growth hormone by one year of age and 70% were started by 4 years of age. Not surprisingly, individuals who received GH were taller (p=0.005), had longer hands (p=0.049), and had larger head circumferences (p=0.005); however, weight was not statistically different. Mean BMI percentile was 83 ± 37 in the GH treated group vs 85 ± 44 in the non-GH treated group, (p=0.789). The data were standardized for gender and age, and each GH group had the same molecular class distribution (e.g., 62% deletion). We found that individuals on GH were taller (p=0.005), had larger head size (p=0.005), had a lower incidence of almond-shaped eyes (p=0.005), a narrow nose (p= 0.020), abdominal pale striae (p= 0.030), skin picking of the face (p=0.010), larger thigh circumferences (p=0.003), longer hand length (p= 0.049), increased incidence of esotropia (p=0.012), hypoplastic labia minora (p=0.005) and hypoplastic clitoris (p=0.044) (see Table 3).
Table 2:
Growth Hormone (GH) Intake Based on the Age of Onset of GH Treatment
| Age groups | Growth hormone treated cohort | ||
|---|---|---|---|
| Years | Frequency | % | |
| 1 | 0 - 1 | 121 | 41.7 |
| 2 | 1 - 4 | 84 | 29.2 |
| 3 | 4 - 12 | 52 | 18.1 |
| 4 | 12 - 21 | 19 | 6.6 |
| 5 | 21 - 70 | 13 | 4.5 |
| Total | 289 | 100 | |
Table 3:
Phenotypic Characteristics of the Study PWS Participants According to Growth Hormone Treatment Status
| Growth Hormone Treatment | No Growth Hormone Treatment | p-value | |||
|---|---|---|---|---|---|
| VARIABLES | N=289 (M=137,F=152) |
Mean (SD) or % frequency | N= 66 (M=23,F=43) |
Mean (SD) or % frequency | |
| GROWTH PARAMETERS: | |||||
| Height percentile for age and gender | 238/289 | 47 (33) | 36/66 | 17 (31) | 0.005 |
| Weight percentile for age and gender | 277/289 | 70 (32) | 60/66 | 74 (33) | 0.432 |
| Head circumference (HC) percentile for age and gender | 260/289 | 58 (32) | 55/66 | 52 (29) | 0.005 |
| BMI percentile for age and gender | 276/289 | 83 (37) | 57/66 | 85 (44) | 0.789 |
| HEAD: | |||||
| Prominent occiput | 37 | 13% | 16 | 24% | 0.004 |
| Flat occiput | 63 | 22% | 17 | 26% | 0.976 |
| Round face | 72 | 25% | 27 | 41% | 0.001 |
| Bitemporal narrowing | 192 | 66% | 28 | 42% | 0.906 |
| Craniosynostosis | 2 | 0.6% | 1 | 2% | 0.158 |
| HAIR: | |||||
| Low anterior hair line | 48 | 17% | 17 | 26% | 0.142 |
| Hypopigmented | 99 | 34% | 13 | 20% | 0.057 |
| EYES: | |||||
| Esotropia | 122 | 42% | 15 | 23% | 0.012 |
| Exotropia | 18 | 6% | 5 | 8% | 0.553 |
| Strabismus | 135 | 47% | 24 | 36% | 0.357 |
| Upslanting palpebral fissures | 59 | 20 % | 13 | 20% | 0.793 |
| Downslanting palpebral fissures | 25 | 9% | 5 | 8% | 0.955 |
| Almond-shaped | 156 | 54% | 43 | 65% | 0.005 |
| Inter-canthal distance percentile for age and gender | 99 | 54 (32) | 24 | 46 (25) | 0.246 |
| Inter-pupillary distance percentile for age and gender | 98 | 56 (36) | 22 | 37 (32) | 0.031 |
| Outer-canthal distance percentile for age and gender | 99 | 54 (38) | 24 | 41 (34) | 0.116 |
| Palpebral fissure percentile for age and gender | 97 | 58 (37) | 24 | 45 (38) | 0.145 |
| NOSE: | |||||
| Narrow | 79 | 27% | 25 | 38% | 0.020 |
| MOUTH: | |||||
| Philtrum flat | 112 | 39% | 27 | 41% | 0.317 |
| Upper lip downturned | 65 | 23% | 21 | 32% | 0.683 |
| Normal dentition | 172 | 60% | 41 | 62% | 0.265 |
| Dental caries | 52 | 18% | 10 | 15% | 0.294 |
| EARS: | |||||
| Posterior angulated | 23 | 8% | 6 | 9% | 0.583 |
| Ear length percentile for age and gender | 97 | 53 (31) | 24 | 48 (25) | 0.462 |
| CHEST: | |||||
| Pectus excavatum | 52 | 18% | 0 | 0 | 0.003 |
| Pectus carinatum | 6 | 2% | 3 | 6% | 0.187 |
| ABDOMEN: | |||||
| Abdominal pale striae | 54 | 19 % | 17 | 26% | 0.030 |
| EXTREMITIES: | |||||
| Hand length percentile for age and gender | 165 | 38 (33) | 55 | 34 (27) | 0.049 |
| Foot length percentile for age and gender | 167 | 23 (25) | 53 | 25 (26) | 0.649 |
| Nail abnormalities | 52 | 18% | 10 | 15% | 0.274 |
| Mid-thigh circumference percentile | 115 | 42 (14) | 43 | 35 (8) | 0.003 |
| Large thighs | 137 | 47% | 31 | 46% | 0.509 |
| SPINE: | |||||
| Scoliosis | 152 | 53% | 28 | 42% | 0.422 |
| GENITALIA: | |||||
| Bilateral cryptorchidism | 82/137 | 60% | 20/23 | 87% | 0.648 |
| Micropenis (<5th percentile) | 8/137 | 6% | 7/23 | 30% | 0.063 |
| Scrotum rugation poor | 46/137 | 34% | 9/23 | 39% | 0.613 |
| Scrotum hypoplastic | 66/137 | 48% | 9/23 | 39% | 0.390 |
| Labia minora hypoplastic | 79/152 | 52% | 11/43 | 26% | 0.005 |
| Clitoris hypoplastic | 64/152 | 42% | 11/43 | 26% | 0.044 |
| SKIN: | |||||
| Face skin picking | 14 | 5% | 6 | 9% | 0.010 |
These measurements are based on normative data.
Because of the wide age range of our participants, we studied the frequencies of dysmorphic features by age of initiation of GH treatment in different age groups (birth to 1 year, 1 to 4 years of age, 4 to 12 years, or 12 to 21 years), versus GH treatment initiated during adulthood (i.e., 21 years or older) (Table 4). This analysis was done to test the hypothesis that if growth hormone treatment was initiated at a younger age, then a stronger effect may be present by ameliorating the physical and dysmorphic features associated with PWS. Individuals who had GH treatment initiated at a younger age (from birth to 1 year) in contrast to an older age group showed lower incidences of micrognathia (p=0.039), slit-like eyes (p=0.025), a narrow nose (p=0.013), abdominal or central distribution of fat (p=<0.05), kyphosis (p=<0.05), and short fifth fingers (p=0.026). Participants who started GH treatment at a younger age had fewer dysmorphic features as they received treatment for a longer duration. However, no statistically significant difference was found when the duration of treatment was compared among these age groups (one-way ANOVA; p= 0.818), but both micrognathia and slit-like eyes were statistically more common in the older age groups.
Table 4:
Physical Features Compared with Age of Growth Hormone (GH) Treatment Initiation
| Age of initiation of GH (years) | 0 – 1 N= 121 |
1 – 4 N=84 |
4 – 12 N=52 |
12 – 21 N=19 |
21 – 70 N=13 |
Chi-Square p-value |
|||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | N | % | N | % | ||
| HEAD AND FACE: | |||||||||||
| Prominent occiput | 15 | 13.9 | 12 | 15.8 | 5 | 10.2 | 2 | 11.8 | 2 | 15.4 | 0.928 |
| Flat occiput | 34 | 31.5 | 19 | 25.0 | 15 | 30.6 | 2 | 11.8 | 3 | 23.1 | 0.471 |
| Round face | 25 | 23.1 | 23 | 30.3 | 18 | 36.7 | 5 | 29.4 | 1 | 7.7 | 0.198 |
| Narrow nose | 22 | 20.4 | 22 | 28.9 | 22 | 44.9 | 7 | 41.2 | 6 | 46.2 | 0.013 |
| Bitemporal narrowing | 81 | 75.0 | 54 | 71.1 | 32 | 65.3 | 13 | 76.5 | 12 | 92.3 | 0.355 |
| Craniosynostosis | 3 | 2.8 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0.360 |
| Hypopigmented hair | 50 | 46.3 | 23 | 30.3 | 15 | 30.6 | 8 | 47.1 | 3 | 23.1 | 0.089 |
| Hyperpigmented hair | 2 | 1.9 | 1 | 1.3 | 2 | 4.1 | 0 | 0.0 | 1 | 7.7 | 0.521 |
| CHIN: | |||||||||||
| Micrognathia | 24 | 22.2 | 18 | 23.7 | 5 | 10.2 | 6 | 35.3 | 6 | 46.2 | 0.039 |
| Prognathia | 11 | 10.2 | 5 | 6.6 | 8 | 16.3 | 2 | 11.8 | 0 | 0.0 | 0.317 |
| Retrognathia | 7 | 6.5 | 6 | 7.9 | 3 | 6.1 | 0 | 0.0 | 0 | 0.0 | 0.661 |
| EYES: | |||||||||||
| Almond-shaped | 61 | 56.5 | 46 | 60.5 | 31 | 63.3 | 10 | 58.8 | 8 | 61.5 | 0.945 |
| Slit-like eyes | 5 | 4.6 | 5 | 6.6 | 8 | 16.3 | 4 | 23.5 | 2 | 15.4 | 0.025 |
| Strabismus | 61 | 56.5 | 40 | 52.6 | 22 | 44.9 | 7 | 41.2 | 5 | 38.5 | 0.467 |
| Esotropia | 53 | 49.1 | 40 | 52.6 | 18 | 36.7 | 6 | 35.3 | 5 | 38.5 | 0.341 |
| Exotropia | 6 | 5.6 | 3 | 3.9 | 4 | 8.2 | 4 | 23.5 | 1 | 7.7 | 0.065 |
| Ptosis | 15 | 13.9 | 11 | 14.5 | 10 | 20.4 | 3 | 17.6 | 4 | 30.8 | 0.515 |
| Epicanthal folds | 38 | 35.2 | 22 | 28.9 | 11 | 22.4 | 5 | 29.4 | 3 | 23.1 | 0.549 |
| Hypertelorism | 8 | 7.4 | 7 | 9.2 | 3 | 6.1 | 1 | 5.9 | 0 | 0.0 | 0.809 |
| Hypotelorism | 9 | 8.3 | 11 | 14.5 | 7 | 14.3 | 2 | 11.8 | 0 | 0.0 | 0.424 |
| EXTREMITIES: | |||||||||||
| Short fifth fingers | 23 | 21.3 | 24 | 31.6 | 23 | 46.9 | 4 | 23.5 | 4 | 30.8 | 0.026 |
| BACK: | |||||||||||
| Kyphosis | 5 | 4.6 | 11 | 14.5 | 17 | 34.7 | 4 | 23.5 | 7 | 53.8 | <0.05 |
| ABDOMEN: | |||||||||||
| Abdominal (central) distribution of fat (Central) | 44 | 40.7 | 53 | 69.7 | 32 | 65.3 | 11 | 64.7 | 12 | 92.3 | <0.05 |
Comparison of Effect of Growth Hormone Treatment on Specific PWS Molecular Genetic Classes
Analysis of effects of growth hormone (GH) treatment was also undertaken for each individual molecular genetic class separately (Table 5). The duration of GH treatment was also calculated based on the reported age at initiation of GH treatment, if at first visit the participant was on GH or whether they were currently on GH, as well as at their current age, or age when discontinued. The mean age of starting GH treatment was 4 ± 0.4 years (range from birth to 49 years) with an average duration of 13 ± 0.8 years (range from birth to 53 years) with no significant differences in the two groups. Similar trends were noted in the molecular classes; individuals with the deletion versus UPD on GH treatment or non-GH treatment had a higher incidence of hypopigmented hair, or fairer hair color than their family members (p=0.029). There were no differences in the frequency of deletion or UPD participants on GH treatment or not on GH treatment or age difference found in the two molecular class groups. Other findings that showed differences when comparing effects of GH treatment on deletion versus UPD are included in Table 5. There was a greater weight percentile (p=0.021); hypopigmentation (p=0.030), a higher incidence of lower anterior hair line (p=0.046); almond-shaped eyes (p=0.023), dental caries (p=0.007) and kyphosis (p=0.001) in the deletion group without GH treatment; and a higher incidence of abdominal striae (p=0.006), hypopigmentation (p<0.001), scoliosis (p=0.011) and interestingly flattened occiput (p=0.002), in the deletion group on GH treatment. Interestingly the UPD group had a higher incidence of scoliosis (p=0.039), and broad nasal bridge (p=0.037) in those not on GH treatment; and more downslanting fissures (p=0.006) and posteriorly angulated ears (p=0.002) in the group on GH treatment.
Table 5:
Effect of Growth Hormone (GH) Treatment on PWS Molecular Classes
| GH treatment (N=282) | No GH treatment (N=62) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| PHYSICAL CHARACTERISTICS | Deletion (M=89, F=92) |
UPD (M=41, F=60) |
p-value | Deletion (M=10, F=26) |
UPD (M=12, F=14) |
p-value | ||||
| N=179 | Mean (SD) | N=103 | Mean (SD) | N=38 | Mean (SD) | N=24 | Mean (SD) | |||
| GROWTH PARAMETERS: | ||||||||||
| Height percentile for age and gender | 139/282 | 35 (30) | 78 | 42 (34) | 0.228 | 38/62 | 40 (35) | 24 | 21 (26) | 0.124 |
| Weight percentile for age and gender | 139/282 | 62 (35) | 78 | 58 (36) | 0.471 | 38/62 | 61 (36) | 24 | 30 (34) | 0.021 |
| Head circumference percentile for age and gender | 130/282 | 44 (31) | 75 | 51 (30) | 0.197 | 38/62 | 44 (29) | 24 | 42 (31) | 0.827 |
| BMI percentile for age and gender | 139/282 | 83 (38) | 78 | 82 (37) | 0.895 | 38 | 86 (48) | 24 | 83 (42) | 0.748 |
| HEAD: | ||||||||||
| Prominent occiput | 31 | 17 % | 19 | 18% | 0.547 | 7 | 18% | 7 | 29% | 0.382 |
| Round face | 56 | 31% | 22 | 21% | 0.083 | 13 | 34% | 10 | 41% | 0.657 |
| Flat occiput | 49 | 27% | 12 | 12% | 0.002 | 10 | 26% | 6 | 25% | 0.837 |
| Bitemporal narrowing | 116 | 65% | 61 | 59% | 0.143 | 34 | 89% | 21 | 87% | 0.882 |
| Craniosynostosis | 2 | 1% | 0 | 0.285 | 2 | 5% | 1 | 4% | 0.914 | |
| HAIR: | ||||||||||
| Hypopigmented | 69 | 38% | 16 | 16% | <0.001 | 17 | 45% | 3 | 13% | 0.030 |
| Low anterior hair line | 41 | 23% | 15 | 20% | 0.233 | 16 | 42% | 4 | 16% | 0.046 |
| Low posterior hair line | 64 | 36% | 35 | 47% | 0.638 | 18 | 47% | 8 | 33% | 0.250 |
| EYES: | ||||||||||
| Inter-canthal distance percentile for age and gender | 129 | 54 (33) | 70 | 57 (31) | 0.585 | 38 | 46 (26) | 24 | 63 (30) | 0.909 |
| Inter-pupillary distance percentile for age and gender | 139 | 57 (35) | 78 | 56 (37) | 0.923 | 38 | 40 (31) | 24 | 32 (38) | 0.626 |
| Outer-canthal distance percentile for age and gender | 139 | 58 (38) | 77 | 50 (38) | 0.345 | 38 | 40 (31) | 24 | 43 (38) | 0.864 |
| Palpebral fissure length percentile for age and gender | 139 | 55 (37) | 78 | 63 (37) | 0.339 | 38 | 40 (36) | 24 | 59 (40) | 0.279 |
| Almond-shaped | 99 | 55% | 53 | 51% | 0.245 | 30 | 70% | 12 | 50% | 0.023 |
| Strabismus | 63 | 35% | 54 | 52% | 0.011 | 21 | 55% | 13 | 54% | 0.461 |
| Esotropia | 64 | 36% | 41 | 40% | 0.734 | 17 | 45% | 8 | 33% | 0.157 |
| Exotropia | 6 | 3% | 8 | 7% | 0.187 | 1 | 2% | 2 | 8% | 0.454 |
| Ptosis | 19 | 12% | 12 | 10% | 0.872 | 6 | 16% | 5 | 21% | 0.666 |
| Hypotelorism | 8 | 4% | 12 | 16% | 0.276 | 6 | 16% | 3 | 13% | 0.200 |
| Hypertelorism | 8 | 4% | 2 | 3% | 0.330 | 3 | 7% | 2 | 8% | 0.209 |
| Telecanthus | 9 | 5% | 7 | 9% | 0.968 | 4 | 10% | 2 | 8% | 0.656 |
| Upslanting palpebral fissures | 43 | 24% | 18 | 18% | 0.345 | 14 | 36% | 5 | 21% | 0.165 |
| Downslanting palpebral fissures | 9 | 5% | 14 | 14% | 0.006 | 4 | 10% | 2 | 8% | 0.383 |
| NOSE: | ||||||||||
| Broad nasal bridge | 15 | 8% | 11 | 15% | 0.733 | 0 | 0% | 4 | 16% | 0.037 |
| Narrow nasal bridge | 31 | 17% | 13 | 17% | 0.580 | 2 | 5% | 5 | 21% | 0.344 |
| MOUTH: | ||||||||||
| Flat philtrum | 43 | 24% | 25 | 33% | 0.974 | 7 | 18% | 6 | 25% | 0.823 |
| Thin upper lip | 91 | 51% | 50 | 66% | 0.866 | 28 | 73% | 11 | 46% | 0.098 |
| Full upper lip | 20 | 11% | 13 | 17% | 0.918 | 4 | 10% | 1 | 4% | 0.311 |
| Wide-spaced dentition | 57 | 32% | 23 | 31% | 0.259 | 14 | 37% | 6 | 25% | 0.061 |
| Dental caries | 34 | 19% | 17 | 23% | 0.639 | 7 | 18% | 3 | 13% | 0.007 |
| Enamel hypoplasia | 68 | 38% | 36 | 48% | 0.922 | 16 | 42% | 6 | 25% | 0.061 |
| EARS: | ||||||||||
| Ear length percentile for age and gender | 139 | 48 (32) | 78 | 61 (25) | 0.074 | 38 | 51 (26) | 24 | 41 (24) | 0.376 |
| Low set ears | 22 | 12% | 18 | 19% | 0.252 | 7 | 18% | 1 | 4% | 0.246 |
| Posterior angulated ears | 4 | 3% | 12 | 14% | 0.002 | 3 | 7% | 1 | 4% | 0.731 |
| CHEST: | ||||||||||
| Pectus excavatum | 30 | 17% | 22 | 21% | 0.521 | 0 | 0 | 0 | 0 | 0.471 |
| Pectus carinatum | 4 | 2% | 2 | 2% | 0.321 | 2 | 5% | 3 | 12% | 0.572 |
| ABDOMEN: | ||||||||||
| Abdominal striae | 69 | 39% | 22 | 21% | 0.006 | 14 | 37% | 10 | 41% | 0.437 |
| SPINE: | ||||||||||
| Scoliosis | 65 | 47% | 29 | 37% | 0.011 | 31 | 82% | 21 | 88% | 0.039 |
| Kyphosis | 25 | 18% | 13 | 17% | 0.509 | 13 | 34% | 4 | 16% | 0.001 |
|
GENITALIA:
(N=137 males; N=152 females) | ||||||||||
| Bilateral cryptorchidism | 65 | 73% | 17 | 41% | 0.635 | 9 | 90% | 11 | 92% | 0.074 |
| Hypoplastic scrotum | 39 | 44% | 22 | 53% | 0.452 | 7 | 70% | 3 | 25% | 0.128 |
| Poor scrotal rugae | 27 | 30% | 15 | 37% | 0.747 | 5 | 50% | 3 | 25% | 0.749 |
| Hypoplastic labia minora | 45 | 49% | 34 | 85% | 0.513 | 8 | 31% | 3 | 21% | 0.416 |
| Hypoplastic clitoris | 39 | 42% | 25 | 62% | 0.721 | 9 | 35% | 2 | 14% | 0.218 |
DISCUSSION
The aim of our study was to analyze differences in phenotypic features seen in PWS between the two main PWS molecular classes and the effect of GH treatment on physical characteristics or dysmorphism. This study was based on the largest dataset to date consisting of 355 PWS participants whose phenotypical features were collected using standard forms and measures at four USA sites by PWS experts and trained dysmorphologists. Our study found that individuals with the 15q11-q13 deletion were heavier, had a smaller head circumference with a flattened occiput, were hypopigmented, had less strabismus, lower anterior hair line, less downslanting palpebral fissures, but more almond-shaped eyes, more dental problems, less posteriorly angulated ears, more abdominal striae, and shorter fifth fingers. However, no statistical differences in height between the two molecular classes were found. In another study of 64 individuals with PWS, participants with deletions were also heavier, and had smaller head circumferences, but were taller 22.
Our results are consistent with previous studies regarding a higher prevalence of characteristic facial features, including almond-shaped palpebral fissures, a narrow nasal bridge, and downturned mouth in individuals with the 15q11-q13 deletion when compared to UPD1,3,23,24. We also noted a higher incidence of abnormal dentition, low anterior hairline, shorter fifth finger, nail abnormalities, larger thighs, abdominal striae, hypoplastic labia minora, hypoplastic clitoris, and more facial skin picking in those with UPD. Not surprisingly, individuals with the deletion were more likely to have fair skin and hair than their family members13 compared to UPD, attributed to loss of a single copy of the OCA2 albinism gene in the 15q11-q13 region due to the deletion process 21. Individuals with UPD were noted to have an increased incidence of hypoplastic female genitalia, almond-shaped eyes, and more skin picking in the face region. More atypical presentations were also found in the UPD group. Involvement of abnormal maternal recessive gene alleles due to cross-over events in maternal meiosis with loss of heterozygosity and isodisomy of chromosome 15 regions may be present in those with UPD accounting for more variable presentation of clinical findings, behavior, and a later diagnosis11.
Surprisingly, we found that only 41% of individuals started GH treatment under the age of one year, 29% between the ages of 1-4 years, and 30% started GH over the age of 4 years. We studied the effects of GH on the incidence of dysmorphic features, understandably, those individuals who received GH treatment were taller, had larger head circumferences, and had longer hand lengths compared to the untreated PWS cohort participants in this study. Also, individuals who had GH treatment initiated at a younger age had lower incidences of micrognathia, slit-like eyes, narrow nasal bridge, abdominal distribution of fat, kyphosis and short fifth fingers. However, the duration of GH treatment had no significant effect on the frequencies or types of dysmorphic features. As in prior orthopedic reports, 25–27 we did see differences in the overall incidence of more scoliosis in the deletion group in the GH treatment, more scoliosis in the UPD group without GH treatment and more kyphosis in the deletion group without GH treatment as analysis of effects of GH treatment was done for each individual molecular class separately for each clinical variable. GH treated individuals in the deletion group had a more flattened occiput, hypopigmented or fairer hair, abdominal striae, or scoliosis. In contrast, the GH treated individuals in the UPD group had a higher incidence of hypoplastic labia majora and clitoris, downslanting eyes and strabismus. We also found that the overall incidence of scoliosis in patients on GH was significantly higher in the deletion group compared to UPD in our study.
In summary, PWS is a relatively rare condition and the strength of our study lies in the large size of the cohort increasing the power to show statistically significant PWS genetic subtype-phenotype correlations. We also found that GH treatment had different influences among the molecular classes as described in our report, but the authors encourage further studies to examine the effects of GH treatment in PWS and whether GH treatment which improves stature and foot size may also impact on more subjective characteristics such as facial features, both positively or negatively, and possibly other PWS findings or dysmorphic changes.
Acknowledgements
We thank the patients and families for their contribution to this study. We acknowledge support from the Prader-Willi Syndrome Association (USA) and the Angelman, Rett and Prader-Willi Syndromes Consortium (U54 HD06122), which was part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN) supported through collaboration between the NIH Office of Advancing Translational Science (NCATS) and the National Institute of Child Health and Human Development (NICHD).
Footnotes
Conflict of interest: There is no conflict of interest reported by the authors.
Data availability statement:
Data reported are available upon reasonable request from the authors.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data reported are available upon reasonable request from the authors.