1. Introduction
1.1. Clinical Aspects of Prader–Willi Syndrome
1.2. Genetic Aspects of Prader–Willi Syndrome
2. Materials and Methods
Analysis
3. Results
4. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Baker, M.W.; Grossman, W.J.; Laessig, R.H.; Hoffman, G.L.; Brokopp, C.D.; Kurtycz, D.F.; Cogley, M.F.; Litsheim, T.J.; Katcher, M.L.; Routes, J.M. Development of a routine newborn screening protocol for severe combined immunodeficiency. J. Allergy Clin. Immunol. 2009, 124, 522–527. [Google Scholar] [CrossRef] [PubMed]
- Routes, J.M.; Grossman, W.J.; Verbsky, J.; Laessig, R.H.; Hoffman, G.L.; Brokopp, C.D.; Baker, M.W. Statewide newborn screening for severe T-cell lymphopenia. JAMA 2009, 302, 2465–2470. [Google Scholar] [CrossRef] [PubMed]
- Vogel, B.H.; Bonagura, V.; Weinberg, G.A.; Ballow, M.; Isabelle, J.; DiAntonio, L.; Parker, A.; Young, A.; Cunningham-Rundles, C.; Fong, C.T.; et al. Newborn screening for SCID in New York State: Experience from the first two years. J. Clin. Immunol. 2014, 34, 289–303. [Google Scholar] [CrossRef] [PubMed]
- Butler, M.G. Management of obesity in Prader-Willi syndrome. Nat. Clin. Pract. Endocrinol. Metab. 2006, 2, 592–593. [Google Scholar] [CrossRef]
- Butler, M.G.; Sturich, J.; Lee, J.; Myers, S.E.; Whitman, B.Y.; Gold, J.A.; Kimonis, V.; Scheimann, A.; Terrazas, N.; Driscoll, D.J. Growth standards of infants with Prader-Willi syndrome. Pediatrics 2011, 127, 687–695. [Google Scholar] [CrossRef] [PubMed]
- Cassidy, S.B.; Schwartz, S.; Miller, J.L.; Driscoll, D.J. Prader-Willi syndrome. Genet. Med. 2012, 14, 10–26. [Google Scholar] [CrossRef][Green Version]
- Angulo, M.A.; Butler, M.G.; Cataletto, M.E. Prader-Willi syndrome: A review of clinical, genetic, and endocrine findings. J. Endocrinol. Investig. 2015, 38, 1249–1263. [Google Scholar] [CrossRef]
- Butler, M.G. Prader-Willi syndrome: Current understanding of cause and diagnosis. Am. J. Med. Genet. 1990, 35, 319–332. [Google Scholar] [CrossRef][Green Version]
- Butler, M.G.; Manzardo, A.M.; Heinemann, J.; Loker, C.; Loker, J. Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey. Genet. Med. 2017, 19, 635–642. [Google Scholar] [CrossRef]
- Butler, M.G. Single Gene and Syndromic Causes of Obesity: Illustrative Examples. Prog. Mol. Biol. Transl. Sci. 2016, 140, 1–45. [Google Scholar] [CrossRef]
- Stevenson, D.A.; Heinemann, J.; Angulo, M.; Butler, M.G.; Loker, J.; Rupe, N.; Kendell, P.; Cassidy, S.B.; Scheimann, A. Gastric rupture and necrosis in Prader-Willi syndrome. J. Pediatr. Gastroenterol. Nutr. 2007, 45, 272–274. [Google Scholar] [CrossRef] [PubMed]
- Stevenson, D.A.; Heinemann, J.; Angulo, M.; Butler, M.G.; Loker, J.; Rupe, N.; Kendell, P.; Clericuzio, C.L.; Scheimann, A.O. Deaths due to choking in Prader-Willi syndrome. Am. J. Med. Genet. Part A 2007, 143, 484–487. [Google Scholar] [CrossRef] [PubMed]
- Shoffstall, A.J.; Gaebler, J.A.; Kreher, N.C.; Niecko, T.; Douglas, D.; Strong, T.V.; Miller, J.L.; Stafford, D.E.; Butler, M.G. The High Direct Medical Costs of Prader-Willi Syndrome. J. Pediatr. 2016, 175, 137–143. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Lindgren, A.C.; Lindberg, A. Growth hormone treatment completely normalizes adult height and improves body composition in Prader-Willi syndrome: Experience from KIGS (Pfizer International Growth Database). Horm. Res. 2008, 70, 182–187. [Google Scholar] [CrossRef] [PubMed]
- Nishi, Y.; Tanaka, T. Growth Hormone Treatment and Adverse Events. Pediatr. Endocrinol. Rev. 2017, 14 (Suppl. 1), 235–239. [Google Scholar] [CrossRef]
- Grugni, G.; Marzullo, P. Diagnosis and treatment of GH deficiency in Prader-Willi syndrome. Best Pract. Res. Clin. Endocrinol. Metab. 2016, 30, 785–794. [Google Scholar] [CrossRef]
- Irizarry, K.A.; Miller, M.; Freemark, M.; Haqq, A.M. Prader Willi Syndrome: Genetics, Metabolomics, Hormonal Function, and New Approaches to Therapy. Adv. Pediatr. 2016, 63, 47–77. [Google Scholar] [CrossRef]
- Butler, M.G.; Lee, J.; Cox, D.M.; Manzardo, A.M.; Gold, J.A.; Miller, J.L.; Roof, E.; Dykens, E.; Kimonis, V.; Driscoll, D.J. Growth Charts for Prader-Willi Syndrome During Growth Hormone Treatment. Clin. Pediatr. 2016, 55, 957–974. [Google Scholar] [CrossRef][Green Version]
- Heksch, R.; Kamboj, M.; Anglin, K.; Obrynba, K. Review of Prader-Willi syndrome: The endocrine approach. Transl. Pediatr. 2017, 6, 274–285. [Google Scholar] [CrossRef]
- Dykens, E.M.; Roof, E.; Hunt-Hawkins, H. Cognitive and adaptive advantages of growth hormone treatment in children with Prader-Willi syndrome. J. Child. Psychol. Psychiatry 2017, 58, 64–74. [Google Scholar] [CrossRef]
- Butler, M.G.; Matthews, N.A.; Patel, N.; Surampalli, A.; Gold, J.A.; Khare, M.; Thompson, T.; Cassidy, S.B.; Kimonis, V.E. Impact of genetic subtypes of Prader-Willi syndrome with growth hormone therapy on intelligence and body mass index. Am. J. Med. Genet. Part A 2019, 179, 1826–1835. [Google Scholar] [CrossRef] [PubMed]
- Butler, M.G.; Hartin, S.N.; Hossain, W.A.; Manzardo, A.M.; Kimonis, V.; Dykens, E.; Gold, J.A.; Kim, S.J.; Weisensel, N.; Tamura, R.; et al. Molecular genetic classification in Prader-Willi syndrome: A multisite cohort study. J. Med. Genet. 2019, 56, 149–153. [Google Scholar] [CrossRef] [PubMed]
- Manzardo, A.M.; Heinemann, J.; McManus, B.; Loker, C.; Loker, J.; Butler, M.G. Venous Thromboembolism in Prader-Willi Syndrome: A Questionnaire Survey. Genes 2019, 10. [Google Scholar] [CrossRef] [PubMed]
- Driscoll, D.J.; Miller, J.L.; Schwartz, S.; Cassidy, S.B. Prader- Willi Syndrome. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1330/ (accessed on 28 September 2019).
- Henkhaus, R.S.; Kim, S.J.; Kimonis, V.E.; Gold, J.A.; Dykens, E.M.; Driscoll, D.J.; Butler, M.G. Methylation-specific multiplex ligation-dependent probe amplification and identification of deletion genetic subtypes in Prader-Willi syndrome. Genet. Test. Mol. Biomark. 2012, 16, 178–186. [Google Scholar] [CrossRef]
- Hartin, S.N.; Hossain, W.A.; Francis, D.; Godler, D.E.; Barkataki, S.; Butler, M.G. Analysis of the Prader-Willi syndrome imprinting center using droplet digital PCR and next-generation whole-exome sequencing. Mol. Genet. Genomic Med. 2019, 7, e00575. [Google Scholar] [CrossRef] [PubMed]
- Bittel, D.C.; Kibiryeva, N.; Butler, M.G. Methylation-specific multiplex ligation-dependent probe amplification analysis of subjects with chromosome 15 abnormalities. Genet. Test. 2007, 11, 467–475. [Google Scholar] [CrossRef] [PubMed]
- Bar, C.; Diene, G.; Molinas, C.; Bieth, E.; Casper, C.; Tauber, M. Early diagnosis and care is achieved but should be improved in infants with Prader-Willi syndrome. Orphanet J. Rare Dis. 2017, 12, 118. [Google Scholar] [CrossRef] [PubMed]
- Inaba, Y.; Schwartz, C.E.; Bui, Q.M.; Li, X.; Skinner, C.; Field, M.; Wotton, T.; Hagerman, R.J.; Francis, D.; Amor, D.J.; et al. Early detection of fragile X syndrome: Applications of a novel approach for improved quantitative methylation analysis in venous blood and newborn blood spots. Clin. Chem. 2014, 60, 963–973. [Google Scholar] [CrossRef]
- Godler, D.E.; Inaba, Y.; Schwartz, C.E.; Bui, Q.M.; Shi, E.Z.; Li, X.; Herlihy, A.S.; Skinner, C.; Hagerman, R.J.; Francis, D.; et al. Detection of skewed X-chromosome inactivation in Fragile X syndrome and X chromosome aneuploidy using quantitative melt analysis. Expert Rev. Mol. Med. 2015, 17, e13. [Google Scholar] [CrossRef][Green Version]
- Butler, M.G.; Lee, J.; Manzardo, A.M.; Gold, J.A.; Miller, J.L.; Kimonis, V.; Driscoll, D.J. Growth charts for non-growth hormone treated Prader-Willi syndrome. Pediatrics 2015, 135, e126–e135. [Google Scholar] [CrossRef]
- Butler, M.G.; Sturich, J.; Myers, S.E.; Gold, J.A.; Kimonis, V.; Driscoll, D.J. Is gestation in Prader-Willi syndrome affected by the genetic subtype? J. Assist. Reprod. Genet. 2009, 26, 461–466. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Gold, J.A.; Ruth, C.; Osann, K.; Flodman, P.; McManus, B.; Lee, H.S.; Donkervoort, S.; Khare, M.; Roof, E.; Dykens, E.; et al. Frequency of Prader-Willi syndrome in births conceived via assisted reproductive technology. Genet. Med. 2014, 16, 164–169. [Google Scholar] [CrossRef] [PubMed]
- Miller, J.L.; Lynn, C.H.; Driscoll, D.C.; Goldstone, A.P.; Gold, J.A.; Kimonis, V.; Dykens, E.; Butler, M.G.; Shuster, J.J.; Driscoll, D.J. Nutritional phases in Prader-Willi syndrome. Am. J. Med. Genet. Part A 2011, 155, 1040–1049. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Butler, M.G.; Kimonis, V.; Dykens, E.; Gold, J.A.; Miller, J.; Tamura, R.; Driscoll, D.J. Prader-Willi syndrome and early-onset morbid obesity NIH rare disease consortium: A review of natural history study. Am. J. Med. Genet. Part A 2018, 176, 368–375. [Google Scholar] [CrossRef] [PubMed]
- Manzardo, A.M.; Loker, J.; Heinemann, J.; Loker, C.; Butler, M.G. Survival trends from the Prader-Willi Syndrome Association (USA) 40-year mortality survey. Genet. Med. 2018, 20, 24–30. [Google Scholar] [CrossRef] [PubMed]
- Mahmoud, R.; Singh, P.; Weiss, L.; Lakatos, A.; Oakes, M.; Hossain, W.; Butler, M.G.; Kimonis, V. Newborn screening for Prader-Willi syndrome is feasible: Early diagnosis for better outcomes. Am. J. Med. Genet. Part A 2019, 179, 29–36. [Google Scholar] [CrossRef] [PubMed]
- Angulo, M.A.; Castro-Magana, M.; Lamerson, M.; Arguello, R.; Accacha, S.; Khan, A. Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment. Am. J. Med. Genet. Part A 2007, 143, 1456–1461. [Google Scholar] [CrossRef]
- Carrel, A.L.; Myers, S.E.; Whitman, B.Y.; Allen, D.B. Sustained benefits of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome are dose-dependent. J. Pediatr. Endocrinol. Metab. 2001, 14, 1097–1105. [Google Scholar] [CrossRef]
- Butler, M.G.; Smith, B.K.; Lee, J.; Gibson, C.; Schmoll, C.; Moore, W.V.; Donnelly, J.E. Effects of growth hormone treatment in adults with Prader-Willi syndrome. Growth Horm. IGF Res. 2013, 23, 81–87. [Google Scholar] [CrossRef]
- Carrel, A.L.; Myers, S.E.; Whitman, B.Y.; Eickhoff, J.; Allen, D.B. Long-term growth hormone therapy changes the natural history of body composition and motor function in children with prader-willi syndrome. J. Clin. Endocrinol. Metab. 2010, 95, 1131–1136. [Google Scholar] [CrossRef]
- Mogul, H.R.; Lee, P.D.; Whitman, B.Y.; Zipf, W.B.; Frey, M.; Myers, S.; Cahan, M.; Pinyerd, B.; Southren, A.L. Growth hormone treatment of adults with Prader-Willi syndrome and growth hormone deficiency improves lean body mass, fractional body fat, and serum triiodothyronine without glucose impairment: Results from the United States multicenter trial. J. Clin. Endocrinol. Metab. 2008, 93, 1238–1245. [Google Scholar] [CrossRef] [PubMed]
- Hoybye, C. Five-years growth hormone (GH) treatment in adults with Prader-Willi syndrome. Acta Paediatr. 2007, 96, 410–413. [Google Scholar] [CrossRef] [PubMed]
- Myers, S.E.; Whitman, B.Y.; Carrel, A.L.; Moerchen, V.; Bekx, M.T.; Allen, D.B. Two years of growth hormone therapy in young children with Prader-Willi syndrome: Physical and neurodevelopmental benefits. Am. J. Med. Genet. Part A 2007, 143, 443–448. [Google Scholar] [CrossRef] [PubMed]
- Butler, M.G.; Roberts, J.; Hayes, J.; Tan, X.; Manzardo, A.M. Growth hormone receptor (GHR) gene polymorphism and Prader-Willi syndrome. Am. J. Med. Genet. Part A 2013, 161, 1647–1653. [Google Scholar] [CrossRef]
- Butler, M.G.; Manzardo, A.M.; Forster, J.L. Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches. Curr. Pediatr. Rev. 2016, 12, 136–166. [Google Scholar] [CrossRef]
- Khare, M.; Gold, J.A.; Wencel, M.; Billimek, J.; Surampalli, A.; Duarte, B.; Pontello, A.; Galassetti, P.; Cassidy, S.; Kimonis, V.E. Effect of genetic subtypes and growth hormone treatment on bone mineral density in Prader-Willi syndrome. J. Pediatr. Endocrinol. Metab. 2014, 27, 511–518. [Google Scholar] [CrossRef]
- Galassetti, P.; Saetrum Opgaard, O.; Cassidy, S.B.; Pontello, A. Nutrient intake and body composition variables in Prader-Willi syndrome—Effect of growth hormone supplementation and genetic subtype. J. Pediatr. Endocrinol. Metab. 2007, 20, 491–500. [Google Scholar] [CrossRef]
- Whitman, B.Y.; Myers, S.; Carrel, A.; Allen, D. The behavioral impact of growth hormone treatment for children and adolescents with Prader-Willi syndrome: A 2-year, controlled study. Pediatrics 2002, 109, e35. [Google Scholar] [CrossRef]
- Goldstone, A.P.; Holland, A.J.; Hauffa, B.P.; Hokken-Koelega, A.C.; Tauber, M. Recommendations for the diagnosis and management of Prader-Willi syndrome. J. Clin. Endocrinol. Metab. 2008, 93, 4183–4197. [Google Scholar] [CrossRef]
- Butler, M.G.; Miller, J.L.; Forster, J.L. Prader-Willi Syndrome—Clinical Genetics, Diagnosis and Treatment Approaches: An Update. Curr. Pediatr. Rev. 2019. [Google Scholar] [CrossRef]
- Lossie, A.C.; Whitney, M.M.; Amidon, D.; Dong, H.J.; Chen, P.; Theriaque, D.; Hutson, A.; Nicholls, R.D.; Zori, R.T.; Williams, C.A.; et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J. Med. Genet. 2001, 38, 834–845. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Dagli, A.I.; Mueller, J.; Williams, C.A. Angelman Syndrome; Adam, M.P., Ardinger, H.H., Pagon, R.A., Eds.; [Updated 2017 Dec 21]. GeneReviews® [Internet]; University of Washington: Seattle, WA, USA, 1993–2019. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1144/ (accessed on 28 September 2019).



Category | Frequency (%) |
---|---|
Age of Diagnosis (yrs.) | |
Mean = 3.1 | |
Median = 0.3 | |
SD = 6.7 | |
Min =0.0 | |
Max = 48.0 | |
Age of Diagnosis Category | |
<1 yr. | 217 (62%) |
≥1 yr. and <3 yrs. | 42 (12%) |
≥3 yrs. | 93 (26%) |
Gender | |
Female | 194 (55%) |
Male | 158 (45%) |
Ethicity | |
White | 328 (93%) |
Non-White | 24 (7%) |
Prader–Willi Molecular Class | |
Deletion | 216 (61%) |
Imprinting Defect | 11 (3%) |
Uniparental Disomy | 125 (36%) |
First Becoming Heavy | Increased Appetite | Actively Seeking Food | |
---|---|---|---|
Effect | Hazard Ratio (95% CI) p value | Hazard Ratio (95% CI) p value | Hazard Ratio (95% CI) p value |
Gender (ref = female) | 0.99 (0.73, 1.33) 0.990 | 1.13 (0.88, 1.46) 0.332 | 1.09 (0.83, 1.44) 0.525 |
PWS Molecular Class | |||
Deletion vs. UPD | 0.90 (0.66, 1.23) 0.499 | 1.31 (1.00, 1.72) 0.054 | 1.14 (0.85, 1.52) 0.393 |
ID vs. UPD | 1.45 (0.69, 3.07) 0.326 | 0.72 (0.33, 1.58) 0.415 | 1.05 (0.50, 2.20) 0.893 |
Ethnicity (ref = white) | 0.46 (0.28, 0.78) 0.004 | 0.76 (0.48, 1.21) 0.179 | 0.73 (0.44, 1.21) 0.224 |
Age of Diagnosis | |||
<1 vs. 1–3 | 0.67 (0.43, 1.04) 0.077 | 0.70 (0.47, 1.03) 0.067 | 0.72 (0.48, 1.09) 0.125 |
<1 vs. >3 yrs. | 0.48 (0.35, 0.66) < 0.001 | 0.90 (0.67, 1.20) 0.456 | 1.05 (0.77, 1.43) 0.754 |
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