J. Biomedical Science and Engineering, 2013, 6, 1056-1061 JBiSE
http://dx.doi.org/10.4236/jbise.2013.611132 Published Online November 2013 (http://www.scirp.org/journal/jbise/)
GH treatment, BMI and different genotypes in patients
with Prader-Willi syndrome and scoliosis: Is there any
Tiziana Greggi1*, E. Pipitone1, K. Martikos1, F. Lolli1, F. Vommaro1, E. Maredi1, M. Di Silvestre1,
S. Giacomini1, L. Sangiorgi2
1Spine Surgery Department, Rizzoli Orthopaedic Institute—I.O.R., Bologna, Italy
2Medical Genetics, Rizzoli Orthopaedic Institute—I.O.R., Bologna, Italy
Email: *tiziana.greggi@ior.it
Received 25 August 2013; revised 25 September 2013; accepted 9 October 2013
Copyright © 2013 Tiziana Greggi et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The purpose of this study is to try to find a protocol de-
fining a clinical diagnostic procedure for the patients
to be admitted to the authors’ Institute to receive treat-
ment for either suspected or confirmed diagnosis of
spine deformity in Prader-Willi syndrome (PWS). The
aim is to evaluate every subject from the diagnostic
point of view, assessing variability of clinical expres-
sion and evolution of spinal deformity in the light of
the related genetic aspects, thus providing a univocal
protocol. The present series only includes patients (18
cases) with PWS, 7 hospitalized for surgical treat-
ment of scoliosis, 11 followed-up at the authors’ insti-
tute only for conservative treatment of scoliosis. Both
BMI tracks (weight/height2) and BMI Z-score (only
for children older than 2 years) were assessed. More-
over, the GH treatment was evaluated for each group
of patients as follows: being administered, suspended
or no treatment. Finally, the gene was compared with
BMI. No relationship was observed either between
GH treatment and mean BMI or between genetics
and mean BMI. More patients should be seen by the
authors to confirm or refute the current findings.
Keywords: Scoliosis; Prader-Willi; GH; BMI
The PWS is a rare and complex genetic disorder consid-
ered the most common genetic cause of morbid obesity,
first described by Prader et al. back in 1956 [1].
The prevalence reported in epidemiological studies
varies between 1 in 8000 and 1 in 134,000 whereas the
number of births identified as being PWS cases varies be-
tween 1 in 15,000 and 1 in 30,000. In 2010, the European
Organization for Rare Disease in partnership with Orpha-
net estimated the number of person living with PWS in
Europe to be around 10.7 per 100,000 (1:9346) [2,3].
Genes associated with PWS are known to be express-
ed from chromosome 15 derived from the father, but not
from the mother. Loss of the normal contribution from
paternally inherited genes in this interval leads to the
PWS phenotype, since maternal genes are normally inac-
tivated. This type of genetic regulation dependent on the
sex of the transmitting parent is termed genomic imprint-
ing [4].
The three genetic mechanisms involved in PWS are:
interstitial deletions of the paternal chromosome 15, which
are of two classes differing by their total length (T1 dele-
tion larger than T2 deletion) [5]; maternal uniparental di-
somy (mUPD, or two copies of chromosome 15 from
mother and none from father), [6] which can be either
hetero- or isodisomy (meaning two different maternal
chromosomes or two copies of the same maternal chro-
mosome), and imprinting defects [7] and translocations.
Recently it has been suggested that additional factors such
as maternal age, environmental variables causing genetic
errors, the use of reproductive technologies and diagnos-
tic methodology have influenced the previously recogni-
zed distribution of genetic subtypes, with mUPD occur-
ring more frequently than previously recognized [8,9].
In Italy PWS is related to deletion for 69% of the cases,
mUPD for 30% [10].
The original consensus diagnostic criteria of Holm et
al., 1993 [11] was recently revised [12] to indicate when
genetic analysis should be performed [13].
*Corresponding author.
T. Greggi et al. / J. Biomedical Science and Engineering 6 (2013) 1056-1061 1057
In the foetus and newborn, PWS is generally charac-
terized by decreased fetal movement, prenatal and post-
natal hypotonia (or diminish muscular tone) and poor
suckling, causing decreased movement, lethargy, abnor-
mal cry, breathing difficulties requiring special feeding
techniques and poor reflexes, and resulting in failure to
thrive. Whereas hypotonia improves over time, and dif-
ficulties in feeding are replaced by normal calorie intake
with a beginning of central obesity during the toddler
years [14,15].
Characteristic facial features including narrow bifron-
tal diameter with dolichocephaly (head disproportionally
long and narrow), almond-shaped eyes with ocular de-
fects (estropia, myopia), thin upper lip with down-turned
mouth and thick saliva.
In preadolescence, mild to moderate mental deficiency,
behavioral disorders (e.g. obsessive-compulsive charac-
teristics, self-injury behavior, skin-picking, temper tan-
trums, manipulative behavior, impulsivity, stubbornness)
and cognitive disabilities also become manifest and in-
tensify with age. Musculoskeletal problems may also be-
come apparent, such as scoliosis (abnormal back curva-
ture) [16-20]. Hyperkyphotic deformity can be observed
in nearly 40% of the patients [21-23].
The syndrome is associated with growth hormone de-
ficiency (GHD). According to cross-sectional, prospec-
tive and retrospective studies, GHD prevalence ranged
from 58% to 100% [24,25]. Similar prevalence rates (74%)
were observed in the international, observational KIGS
database [26].
Obesity is a primary cause of increased morbidity and
premature mortality in PWS. It leads to complications
such as type 2 diabetes mellitus, hypertension, atheros-
clerosis, hyperlipidemia, cardiovascular diseases, respi-
ratory insufficiencies, thrombophlebitis, leg edema, and
sleep apnea. Increased rates of scoliosis are also observed.
Although the pharmacological therapy with growth
hormone (GH) provides satisfactory results, its impact on
progression of spinal deformities still remains controver-
sial [21,27].
According to a study conducted in the UK population,
mortality rate of individuals with PWS not treated with
GH was estimated at 3% per year between age 6 and 56
years and at 7% per year above 30 years of age. Epide-
miological data from Italy noted 18 deaths over a 20-year
period of observation (4.2%), occurring in both the pedi-
atric and adult subjects (age range: 0.5 - 39.3). Causes of
death in children are usually associated with respiratory
infection or insufficiency, whereas mortality in adults is
found to be primarily circulatory and/or respiratory fail-
ure [10].
The various different clinical and pathological condi-
tions with onset during the pediatric and early adolescent
age, and affecting the general aspect and health status,
can change or delay treatment of spinal deformities and
subsequently entail negative consequences in terms of
life quality and expectation. Scoliosis is reported to re-
quire active treatment in 15% to 20% of the cases and to
behave as an idiopathic scoliosis, with high risk of pro-
gression during adolescence [1,22].
Absent, inadequate or delayed treatment of spinal de-
formities can jeopardize the patient’s respiratory and car-
diocirculatory “compliance”, which is already severely
compromised by the other remarkable phenotypic aspects
of the syndrome.
The present case series includes 18 patients, 11 of which
(9 males and 3 females) were seen at the Rare Disease
Outpatients’ Unit for conservative treatment; mean age
was 4.2 years (range, 0.5 to 16.1). Another 7 patients
were surgically treated: they were 5 males and 2 females,
aged 12.8 years on average (range, 10 to 14.6 years).
Regarding the patients’ origin, 87% came from outside
the region (Emilia-Romagna): 61% from the central south-
ern area and 44% from Latium, in particular (Figure 1).
For all of the 18 patients, both standard BMI (weight/
height2) and the BMI Z-score developed by the Centers
for Disease Control and Prevention (CDC) were calculat-
ed. The latter is to be preferred when assessing children
[28,29] to allow for their classification into underweight/
normal weight/overweight/obesity (Table 1), although
more recent studies tend to attach importance to the use
of BMI also for younger patients [30]. As a matter of fact,
the values of BMI Z-score are charted for specific
Figure 1. Patients’ Origin Region of origin of the patients be-
longing to the series with PWS.
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T. Greggi et al. / J. Biomedical Science and Engineering 6 (2013) 1056-1061
Table 1. Weight categories corresponding to percentile ranges.
Weight Status Category Percentile Range
Underweight Less than the 5th percentile
Healthy Weight 5th percentile to less than the 85th percentile
Overweight 85th to less than the 95th percentile
Obesity Equal to or greater than the 95th percentile
Z-scores (2, 1.5, 1, 0.5, 0, 0.5, 1, 1.5, 2), corres-
ponding to as many different growth curves for the chil-
dren. Scores are used to express the standard deviation
from the mean calculated on the reference population.
The corresponding percentiles in standard normal distri-
bution are calculated from Z-scores; the different weight
categories (underweight/normal weight/overweight/obesity)
derive from the percentile ranges. Percentiles are plotted
in “growth charts by age” (Figure 2) for each gender.
Proceeding this way, the BMI of a specific child is plot-
ted on the chart against the other children of the same sex
and age.
Anyway, BMI Z-score, can be calculated only for pa-
tients older than 2 years and therefore could not have
been applied in 5 cases, thus reducing the current case
series—which is small, the study involving a rare disease
and referring to a single diagnosis and treatment centre—
by 30% approximately. Therefore, both BMI indices were
The GH treatment was assessed in all of the 18 sub-
jects: being administered, suspended or no treatment.
The genotype is known only for the group of 12 PW
patients conservatively treated at the outpatients’ unit
(deletion of chromosome 15 or uniparental disomy), since
the genetic test was not routinely performed when the
surgically-treated patients’ data were recorded.
The purpose of the study was to evaluate the relation-
ship between BMI and GH treatment and, only for the
outpatients, the relationship between BMI and genotype.
The two groups of cases were assessed both separately
and as a whole. The statistical tests used were the follow-
ing: either the Chi-square test or the Fisher’s exact test
when the BMI-Z score was calculated, and the Wilcoxon
test to calculate the differences between the average val-
ues for the BMI.
Of the 12 outpatients with PWS (Ta ble 2 ), 9 were males
and 3 females; 87% came from outside the Region (Emi-
lia-Romagna): 61% from the central southern area, La-
tium in particular (44%); 11 had received conservative
treatment, 1 surgical treatment.
The BMI of the PW children seen at the Outpatients’
Unit turned out to be 17.54 (range, 11.49 to 29.48),
wherease the BMI Z-score was 0.7 (range, 0.7 to 1.7).
Their medical history revealed the presence, absence
Figure 2. BMI for age and sex body mass index for age percen-
tiles by sex.
Table 2. Characteristics of PWS outpatients.
Characteristics Values
Patients’ number
by sex
9 M
3 F
Mean age 4.2 yrs (range, 0.5 to 16.1)
BMI 17.54 (range, 11.5 to 29.5)
BMI Z-score 0.66 (range, 0.7 to 1.7)
70.4% percentile (range, 25.5% to 95.6%)
8 treated
2 suspended treatment
2 not recorded
Genotype 9 microdeletion of chromosome 15
3 uniparental disomy
of suspension of the GH treatment: GH had been admin-
istered to 8 patients, suspended in 2 cases and no infor-
mation was available for the 2 remaining cases.
Many studies (references 1 to 9) refer to the GH treat-
ment in PWS without reaching unambiguous conclu-
The present case series showed a statistically signifi-
cant (p < 0.05) difference in terms of mean BMI which
proved to be lower in children receiving GH treatment
(16.8, ±1.1) than in those who had had it suspended (24.7,
d.s. ±6.8) (Table 3).
In addition, genetics was compared with BMI as fol-
lows: mean BMI equal to 18 for the 9 patients with mi-
crodeletion of chromosome 15 versus mean BMI equal
to 15 for the 3 patients with uniparental disomy. The dif-
ference between BMI in the 2 groups did not result to be
statistically significant (Table 3).
Considering the other group of 7 PWS patients operat-
ed on for scoliosis (Table 4), 5 of them were males with
mean age of 12.8 yrs (range, 10 to 14.6) .
The BMI of the 7 patients with PW operated on for
scoliosis turned out to be equal to 29.41 (range, 21.03 to
41.72), whereas the BMI Z-score was 1.8 (range, 0.51 to
2.77). This value was notably higher than that observed
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T. Greggi et al. / J. Biomedical Science and Engineering 6 (2013) 1056-1061 1059
Table 3. BMI relationship with GH and genotype in PW outpa-
GH treated GH interrupted p
Mean BMI 16.8
(±6.8) 0.05
Microdeletion of
chromosome 15 Uniparental disomy
Mean BMI 18
4.1) 15
2.8) n.s.
Table 4. Characteristics of PWS surgically-treated patients.
Characteristics Values
Patients’ number
by sex
5 M
2 F
Mean age 12.8 yrs (range, 10 to 14.6)
BMI 29.41 (range, 21.0 to 41.7)
BMI Z-score 1.8 (range 0.5 to 2.8).
GH 4 treated
3 not treated
in outpatients who also were much younger.
The BMI Z-score could be calculated for all of the pa-
tients belonging to this group; subsequently, using growth
charts by age percentiles, the weight categories could be
assessed and the following results achieved: normal weight
in 2 cases, overweight in 1 and obesity in 4.
Focus was put on the relationship between weight
categories (obesity and overweight were considered as a
whole, due to the low number of subjects to be included
in the latter) and the corresponding GH treatment: of the
4 cases receiving Gh treatment, 3 (75%) were obese and
one overweight; of the 3 who did not receive the GH
treatment, 2 were normal weight (75%) and 1 obese. The
test proved to be not significant.
Besides, since surgery cannot be considered as an ef-
fect modifier of this relationship, outpatients and surgi-
cally-treated patients were assessed as a whole. In this
case, the authors compared the average BMI for the 2
groups instead of the weight categories deriving from the
BMI Z-score: no significant difference was found (Table
Before to begin GH treatment, many steps have to be
accomplished, starting from genetic confirmation of PWS,
On GH treatment regular clinical assessment of height,
weight, BMI, body composition, pubertal status, scolio-
sis, and side effects every 2 - 6 months should be done.
At cessation of GH, treatment uncontrolled progression
of obesity should be present in terms of how it has been re-
ported in the International—Second Expert Meeting of
the Comprehensive Care of Patients with PWS (2008)
Table 5. Mean BMI relationship with GH in PWS patients.
Not recordedp
(±2.6) n.s.
The only report that state scoliosis evolution and GH
treatment is a two-year open label study of Sode-Carlsen
et al. (2011) [32]. This study reported that scoliosis pro-
gressed in six of 38 patients, whereas three patients had a
decrease of Cobb angle of more than 5˚. It is unclear if
these observations are the results of GH treatment or the
natural history of progression of scoliosis in PWS adults.
Similar observations were reported for edema which is
often seen in clinical studies of GH treatment in adults
In our study, no significant difference in terms of BMI
was observed between patients receiving GH treatment
and patients who did not receive it. No relationship be-
tween GH treatment and mean BMI was seen. Anyway,
additional studies can be performed creating a subgroup
from the present case series which includes the patients
younger than 2 yrs, and replacing the BMI with the BMI
No relationship between genetics and mean BMI was
found in the outpatients’ group.
However, our case series is being too small, as it al-
ways happens with rare diseases, and for recording of da-
ta incomplete, more patients need to be examined by the
authors to confirm or refute these findings.
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