Summaries of the number of subjects with PWS in each of the three age categories (<1 year, >1 years and <3 years, and ≥3 years) and other covariates are shown in Table 1
. Kaplan–Meier curves for the age when the child first became heavy as determined by their primary care providers, age the child developed an increased appetite, and age the child began to actively seek food are shown in Figure 1
, Figure 2
and Figure 3
, respectively. The Cox proportional hazards analyses for these three variables are shown in Table 2
. For example, individuals with PWS having an imprinting defect had a hazard ratio (HR) of 1.45 of becoming heavy, compared to UPD15 or 15q11–q13 deletion molecular genetic classes, but the number of subjects tested with imprinting defects was low. The 15q11–q13 deletion group had the highest HR of 1.31 for an increased appetite, as well as for actively seeking food, with an HR of 1.14.
Both the age of diagnosis (p
< 0.001) and race (p
= 0.004) were significant factors influencing the age when the child was first reported to be heavy. The earlier the diagnosis of PWS, the later the age at which individuals became heavy. The estimated median age for when the child first became heavy was 10 years for an age of diagnosis of < 1 year, 6 years for an age of diagnosis between 1 and 3 years, and 4 years for an age of diagnosis greater than 3 years. Additional partitions of age of diagnosis ≥ 3 years category were also examined, but no evidence was found that further partitioning into separate categories produced significant statistical differences. Non-white individuals became heavier at an earlier age, compared with whites, with an estimated median age of 4 years for non-whites and a median age of 8 years for whites. However, age of diagnosis and race did not influence the age at which individuals first developed an increased appetite or began actively seeking food. In addition, our data analysis indicates that the age the individual became heavy, age of increased appetite and age of seeking food were not significantly different across the three PWS molecular classes (deletion, UPD or imprinting defects), except for a difference between the 15q11–q13 deletion and UPD15 subjects regarding increased appetite (Figure 1
, Figure 2
and Figure 3
Early diagnosis of Prader–Willi syndrome, particularly in the newborn period, is critical for changing the lives of those with this disorder and further supported by our study results, showing that those with earlier diagnosis developed obesity at a later age. We firmly believe that early diagnosis in the first few weeks of the newborn period is critical for individuals with PWS to receive appropriate intervention and anticipatory guidance. This should happen at an early an age as possible. For example, GH treatment at an early age affords the opportunity to take proactive strategies for regulating caloric intake and delaying the onset and reducing the risk of early obesity, with associated co-morbidities such as diabetes, hypertension, and respiratory compromise. The earlier diagnosis would also impact the cost of medical care, by decreasing diagnostic evaluations and the length of hospital stays, as noted by Shoffstall et al. [13
The typical time of diagnosis for individuals with PWS was noted approximately three decades ago to be between 7 and 9 years of age, depending on the genetic subtype (deletion vs. non-deletion status [8
]). In our cohort of 352 analyzed subjects with PWS, the age of diagnosis in our younger subjects had decreased to a mean age of 3.1 years, but often not enough to avoid extensive and costly evaluations, with health concerns leading to ineffective medical care and treatment. We believe that it is critical to detect those with PWS in the newborn period, in order for treatment to begin as early as possible. Significant progress has been made in awareness and early diagnosis of PWS, but further efforts could be made to diagnose at earlier stages.
Better acceptance of expanded newborn screening programs nationwide regarding metabolic and genetic disorders may impact this problem. Early diagnosis and treatment can significantly improve prognosis in other disorders not readily detected at birth by routine physical examination, but sensitive, specific, inexpensive tests do exist, using expanded newborn screening programs with filter paper cards, a gold standard for newborn testing and diagnosis of genetic disorders [2
]. As an example, on 21 May 2010, the Secretary of Health and Human Services added Severe Combined Immunodeficiency (SCID), an immune disorder with a frequency of 1/53,000 to the Recommended Uniform Newborn Screening Panel (RUSP) [1
]. Pompe disease, another rare metabolic disorder was also added to the newborn screening list in several states. Since the clinical presentation and available treatment of PWS meets or fulfills the criteria for newborn screening, it is expected that newborn screening for PWS will become available in the future, depending on cost-effective genetic testing methods, where early diagnosis can impact medical care, treatment and quality of life [37
]. Early diagnosis can also transform medical management of PWS, by eliminating extensive and expensive evaluations, along with the uncertainty generated by not having a diagnosis early in infancy. If the diagnosis is not made early, the patient is deprived of the benefits of optimal treatment and anticipatory strategies to avoid morbid obesity.
The benefits of lifelong GH therapy in infants, children and adults with PWS have been demonstrated in multiple well-designed and controlled studies [14
]. For example, GH treatment for 2 years in children showed major increases in height and weight, and a decrease in body fat [44
]. GH replacement therapy also improves linear growth velocity and, ultimately, height, and results in healthier body composition (increased lean body mass, decreased fat mass), muscle function and level of activity [4
]. GH treatment in children with PWS ultimately improves growth, adult height and body composition, and nearly normalizes stature by 18 years of age, with a significant improvement in obesity status, as noted in PWS-specific standardized growth charts [10
]. Evidence further supports treating PWS adults with GH, with it leading to increased muscle strength and physical activity, improved lipid levels and better quality of life measures after one year of treatment (e.g., [40
]). The improvements with GH treatment are also demonstrated in bone mineral density [47
]. When treatment occurs from infancy, facial appearance and body habitus also normalizes in conjunction with good dietary management, and there is an improvement in quality of life and psychosocial status in PWS individuals [45
]. The benefits of initiating treatment before the age of 2 years are well recognized, and further improvement are possible, when the diagnosis and treatment is earlier particularly in the newborn period [50
]. Early diagnosis, good dietary control, exercise and GH treatment with better therapeutic approaches [46
] can reduce the risk and age of onset of obesity, and many of the associated co-morbidities, such as diabetes, hypertension, and respiratory compromise, common in PWS without early recognition and treatment. Despite significant advances in diagnosing PWS, the mean age of diagnosis is still delayed. As seen in our current study, there was a wide range of age at diagnosis, spanning birth–48.0 years. (mean ± SD = 3.1 yr. ± 6.7 yr.; median = 0.3 yr.).
We believe it is important for individuals to be diagnosed in the newborn period, to receive better treatment and appropriate, syndrome-specific medical care, beginning as early as the first few weeks of life. The current genetic testing methods (e.g., mPCR, high resolution chromosomal microarrays) which are useful for diagnosing PWS in the newborn period, would also have the added benefit of detecting the majority of newborns with Angelman syndrome (AS), as well. AS is caused by a maternal chromosome 15q11–q13 deletion, whereas PWS is associated with a paternal 15q11–q13 deletion. AS is associated with severe intellectual disability, electroencephalographic (EEG) abnormalities and epilepsy, limited or absent language development, an abnormal gait, inappropriate laughter and autistic behaviors, with a frequency of 1/12,000 [52
]. The combined frequency for the two genomic imprinting disorders of PWS and AS would be about 1/6000. This frequency is more common than nearly all other disorders for which newborn screening is currently available. The benefits for early detection for Angelman syndrome would also be substantial, as early diagnosis avoids the unnecessary diagnostic odyssey (and expense), as seen in PWS, and anxiety that families experience prior to an accurate diagnosis, permitting early therapy with anticonvulsants and interventions with support. Early diagnosis, identifying abnormal DNA methylation, which has a 99% accuracy rate for the diagnosis of PWS and a 78% chance of accuracy identifying AS, would also allow for the detection of imprinting defects for both PWS or AS, which can be associated with a 50% recurrence risk, thereby permitting early and accurate genetic counseling [22
]. Large-scale newborn screening programs for PWS/ Angelman syndrome would also give us a much more accurate frequency of the disorder, which may be more prevalent than we previously thought.
In summary, early diagnosis could lead to significant improvements, with decreased costs and better medical care of affected newborns (in both PWS and AS), leading to an enhanced quality of life. More research is needed to further investigate the feasibility of lowering costs of testing, including DNA methylation analysis and its application in the newborn setting.