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Clinical Report−−Health Supervision for Children With Prader-Willi Syndrome
          Shawn E. McCandless and THE COMMITTEE ON GENETICS
            Pediatrics; originally published online December 27, 2010;
                           DOI: 10.1542/peds.2010-2820



 The online version of this article, along with updated information and services, is
                        located on the World Wide Web at:
    http://pediatrics.aappublications.org/content/early/2010/12/27/peds.2010-2820




   PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
   publication, it has been published continuously since 1948. PEDIATRICS is owned,
   published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
   Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy
   of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.




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FROM THE AMERICAN ACADEMY OF PEDIATRICS
                                                                                                                    Guidance for the Clinician in
                                                                                                                        Rendering Pediatric Care




Clinical Report—Health Supervision for Children With
Prader-Willi Syndrome
Shawn E. McCandless, MD, and THE COMMITTEE ON
GENETICS                                                           abstract
KEY WORDS                                                          This set of guidelines was designed to assist the pediatrician in caring
Prader-Willi syndrome, Prader-Labhart-Willi syndrome,
uniparental disomy, genetic testing                                for children with Prader-Willi syndrome diagnosed by clinical features
ABBREVIATIONS
                                                                   and confirmed by molecular testing. Prader-Willi syndrome provides
PWS—Prader-Willi syndrome                                          an excellent example of how early diagnosis and management can
UPD—uniparental disomy                                             improve the long-term outcome for some genetic disorders. Pediatrics
GH—growth hormone
                                                                   2011;127:195–204
IGF—insulin-like growth factor
This document is copyrighted and is property of the American
Academy of Pediatrics and its Board of Directors. All authors
                                                                   INTRODUCTION
have filed conflict of interest statements with the American         Prader-Willi syndrome (PWS) (also Prader-Labhart-Willi syndrome) is a
Academy of Pediatrics. Any conflicts have been resolved through     recognizable pattern of physical findings with significant cognitive,
a process approved by the Board of Directors. The American
Academy of Pediatrics has neither solicited nor accepted any
                                                                   neurologic, endocrine, and behavioral abnormalities caused by lack of
commercial involvement in the development of the content of        expression of genes from an imprinted region of the paternally inher-
this publication.                                                  ited chromosome 15q11-q13, near the centromere. Originally de-
The guidance in this report does not indicate an exclusive         scribed in 1958,1 PWS was the first recognized disorder related to
course of treatment or serve as a standard of medical care.        genomic imprinting in humans2 and provides an excellent example of
Variations, taking into account individual circumstances, may be
appropriate.                                                       how early diagnosis and meticulous management can markedly im-
                                                                   prove the long-term outcome for people with some genetic disorders.
                                                                   PWS affects both genders equally and occurs in people from all geo-
                                                                   graphic regions; its estimated incidence is 1 in 15 000 to 1 in 25 000 live
                                                                   births.3,4 Affected infants uniformly have significant hypotonia, early
                                                                   feeding problems, and difficulty with weight gain. Later, a second
                                                                   phase of the disorder ensues with hyperphagia (excessive appetite for
                                                                   food), which leads to obesity and characteristic behavior problems.
                                                                   Without adequate weight control and management of eating behaviors,
                                                                   massive obesity and associated complications of diabetes, obstructive
www.pediatrics.org/cgi/doi/10.1542/peds.2010-2820                  sleep apnea, and right-sided heart failure occur; death typically occurs
doi:10.1542/peds.2010-2820                                         in the fourth decade of life. With careful weight control, people with
All clinical reports from the American Academy of Pediatrics
                                                                   PWS can remain healthy well into older adult life, and some people are
automatically expire 5 years after publication unless reaffirmed,   known to live into their seventh decade.
revised, or retired at or before that time.
                                                                   The findings of PWS are listed in Table 1. Clinical diagnostic criteria
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
                                                                   have been developed and validated5 (Table 2), but now that reliable
Copyright © 2011 by the American Academy of Pediatrics             molecular testing is readily available, these clinical criteria should be
                                                                   considered guidelines to help define people for whom further diagnos-
                                                                   tic testing is indicated.6 In general, PWS should be considered in any
                                                                   infant with significant hypotonia, particularly in the setting of poor
                                                                   feeding, reduced spontaneous arousal for feeding, and hypogonadism
                                                                   (undescended testes, small phallus, or small clitoris). In older chil-
                                                                   dren, the diagnosis should be considered when there is impaired sati-
                                                                   ety for food, especially with rapid weight gain. Likewise, poor linear
                                                                   growth, especially in the presence of excessive caloric intake, should
                                                                   also raise suspicion for PWS. Hypogonadism, hypotonia, developmental


PEDIATRICS Volume 127, Number 1, January 2011                                                                                                195
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TABLE 1 Clinical Findings in PWS                  TABLE 1 Continued                                           when assisting in the provision of a
Fetal                                             Sleep                                                       comprehensive medical home for chil-
   Breech position                                   Snoring/obstructive sleep apnea
   Reduced fetal activity                            Central apnea during sleep
                                                                                                              dren and adults with PWS. They are
   Polyhydramnios                                    Excessive daytime sleepiness                             based on a thorough review of the per-
Growth                                               Early-morning waking                                     tinent medical literature and incorpo-
   Short stature                                     Night-awakening for food-seeking
   Failure to thrive in infancy                   Voice                                                       rate experimental data and the experi-
   Central obesity                                   Hypernasal speech                                        ence of clinicians with expertise in
Head and neck                                        Weak or squeaky cry in infancy
   Dolichocephaly                                                                                             caring for people with PWS. As with all
                                                  Endocrine
   Narrow bitemporal diameter                        Hyperinsulinemia                                         chronic medical conditions, establish-
   Almond-shaped eyes                                GH deficiency                                             ing a medical home is essential to the
   Strabismus                                        Hypogonadotropic hypogonadism
   Up-slanting palpebral fissures                     Diabetes mellitus (type 2)
                                                                                                              smooth and effective provision of care
   Myopia                                         Behavior/mental health                                      to the individual person and support to
   Hyperopia                                         Skin picking
   Thin upper lip                                                                                             his or her family, which is best
                                                     Rectal picking
   Small-appearing mouth                             Food related behavioral problems                         achieved when the primary care pro-
   Down-turned corners of mouth
   Thick, viscous (reduced) saliva
                                                     Temper tantrums                                          vider and consultants communicate ef-
                                                     Difficulty with transitions
   Enamel hypoplasia                                 Stubbornness
                                                                                                              fectively and clearly delineate their re-
   Early dental caries                                                                                        spective roles in the care of the
                                                     Obsessive behaviors
   Dental crowding and malocclusion
                                                     Perseverant speech                                       person.
Ocular
                                                     Obsessive-compulsive disorder
   Strabismus
                                                     Psychosis
   Nystagmus
                                                     Elopement                                                GENETICS AND GENOMICS OF PWS
   Cataracts (rare)
                                                  Miscellaneous
   Retinal hypopigmentation
                                                     Temperature instability
                                                                                                              PWS is associated with lack of expres-
   Foveal hypoplasia                                                                                          sion of several genes on the paternally
                                                     High pain threshold
   Hyperopia
                                                     Unusual skill with jigsaw puzzles                        inherited chromosome 15. This region
   Myopia
Respiratory                                                                                                   contains genes that are normally “im-
   Hypoventilation
   Obstructive sleep apnea
                                                                                                              printed,” which means that they are
   Central sleep apnea                            delays, speech-articulation defects,                        differentially expressed (used to make
Gastrointestinal                                  and characteristic physical appear-                         RNA and proteins) depending on
   Feeding problems in infancy                    ance should all raise the index of sus-
   Gastroesophageal reflux                                                                                     whether the chromosome was inher-
   Decreased vomiting                             picion. Significant neonatal hypotonia                       ited from the father or the mother. On
Genitourinary                                     is present in essentially all children for                  the maternally inherited chromosome
   Small penis
   Scrotal hypoplasia
                                                  whom molecular testing eventually                           15, these genes are transcriptionally
   Cryptorchidism                                 confirms the diagnosis of PWS7; there-                       silenced by hypermethylation of their
   Hypoplastic labia minora                       fore, this history should be actively
   Hypoplastic clitoris                                                                                       promoter regions. Therefore, only the
Skeletal                                          sought during evaluation of older                           paternally inherited chromosome pro-
   Osteoporosis                                   children.                                                   duces the gene products. These
   Osteopenia
   Scoliosis                                      These guidelines are intended to be                         changes are referred to as “epige-
   Kyphosis                                       suggestions for health care providers                       netic,” because they do not involve a
   Small hands and feet
   Narrow hands with straight ulnar border
   Clinodactyly
Skin, nails, hair                                 TABLE 2 Suggested Criteria for Prompting Molecular Testing for PWS
   Hypopigmentation                                 Age at Assessment                                Features Sufficient to Prompt DNA Testing
   Blonde to light-brown hair
                                                  Birth to 2 y                      Significant hypotonia with poor suck and difficulty with weight gain
   Frontal hair upsweep
Neurologic                                        2–6 y                             Congenital hypotonia with history of poor suck; global developmental
   Severe neonatal hypotonia that improves with                                        delay
      age                                         6–12 y                            History of congenital hypotonia with poor suck (hypotonia often persists),
   Poor neonatal suck and swallow reflexes                                              global developmental delay, and excessive eating (hyperphagia;
   Poor gross motor coordination                                                       obsession with food) with central obesity if uncontrolled
   Poor fine motor coordination                    13 y through adulthood            Cognitive impairment, usually mild mental retardation, excessive eating
   Mild-to-moderate mental retardation                                                 (hyperphagia; obsession with food) with central obesity if
   Learning disabilities                                                               uncontrolled, and hypothalamic hypogonadism and/or typical behavior
   Increased risk of seizures                                                          problems (including temper tantrums and obsessive-compulsive
   Global developmental delay                                                          features)
   Speech-articulation problems                   Adapted from Gunay-Aygun M, Schwartz S, Heeger S, O’Riordan MA, Cassidy SB. Pediatrics. 2001;108(5). Available at:
   Hyperphagia                                    www.pediatrics.org/cgi/content/full/108/5/e92.



196     FROM THE AMERICAN ACADEMY OF PEDIATRICS
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FROM THE AMERICAN ACADEMY OF PEDIATRICS


change in the sequence of the DNA but,             of chromosome 15 from the mother          chromosome 15, both of which origi-
instead, involve a change to the                   and no copy from the father.              nate from the mother. Alternatively,
genomic structure that affects regula-          3. Imprinting errors, which occur in         the sperm could have no copy of chro-
tion of expression.                                5% or fewer cases, involve a defect       mosome 15 as a result of a paternal
The part of chromosome 15 involved in              of the process of switching the im-       meiotic error, and the resulting con-
PWS contains several segments of du-               print when the father passes on a         ceptus would have only 1 chromosome
plicated DNA that predispose to rear-              copy of the chromosome 15 that he         15. Such an embryo would also be
rangements, either deletion or dupli-              inherited from his mother.                spontaneously aborted unless a sec-
cation, of the PWS region. Absence of                                                        ond, mitotic error occurred after fer-
                                                4. Finally, PWS has been described as
the paternally inherited contribution                                                        tilization that duplicates the mater-
                                                   a result of a balanced translocation
of the PWS region of chromosome 15                                                           nally contributed chromosome 15. In
                                                   involving chromosome 15 that
leads to lack of the gene products and                                                       either case, an infant born from such a
                                                   moves the genes in the region away
causes the findings of PWS. In contrast,                                                      pregnancy would be missing the pater-
                                                   from the imprinting center.
several other genes in the region are                                                        nally contributed chromosome 15 and,
                                                Several recent reports suggested that        therefore, would only have inactive,
silenced by methylation on the pater-
                                                the essential PWS phenotype may be           maternally imprinted copies of the
nally inherited allele. Absence of the
                                                caused by loss of the imprinted HBII-85      genes in the PWS region.
maternally inherited contribution of
                                                cluster of small nucleolar RNAs
this region causes Angelman syn-                                                             The third mechanism, an “imprinting
                                                (snoRNAs), which, if confirmed, will be
drome, a completely different disorder                                                       error,” leads to a situation in which the
                                                one of the first developmental disor-
caused by lack of expression of a sin-                                                       imprinted (silenced) genes that the fa-
                                                ders shown to be caused by loss of
gle gene in the region (UBE3A).                                                              ther inherited from his mother cannot
                                                microRNA.8,9
A short sequence of DNA in the region                                                        be reactivated. The infant inherits 1
                                                The PWS region of chromosome 15 is           copy of chromosome 15 from each par-
called the “imprinting center” seems
                                                flanked by segments of duplicated             ent, but the PWS region is fully methyl-
to control switching and maintenance
                                                DNA, which predisposes to deletion, or       ated on both copies of chromosome 15
of the imprinting pattern, which is crit-
                                                duplication, during recombination in         and, thus, is silenced in both copies.
ical, because half of a male’s copies of
                                                meiosis. This seems to be the reason         This mechanism, although rare, is im-
chromosome 15 carry the silenced
                                                for the high frequency of the typical        portant to identify, because the inabil-
genes inherited from his mother. When
                                                deletion in PWS and in some other re-        ity to switch the imprint can be an in-
he, in turn, passes copies of his moth-
                                                current microdeletions. It is important      herited trait, which means that a man
er’s chromosome 15 to his own off-
                                                to recognize that the normal chromo-         with an inherited imprinting defect
spring, those genes must be reacti-
                                                some structure in the region plays a         has up to a 50% recurrence risk with
vated, which “switches” the imprint.
                                                significant role in the development of        each pregnancy to sire another child
It becomes clear, then, that there are          the genetic defect; thus, PWS has been       with PWS. The rare case of PWS attrib-
multiple mechanisms by which a per-             described as a “genomic disorder” to         utable to a balanced translocation also
son may end up with no functional               distinguish it from other genetic disor-     may have an increased recurrence
(transcriptionally active) copies of the        ders that are specifically caused by an       risk if the father carries the same
genes in this critically important re-          alteration in the sequence of the DNA.10     translocation on the chromosome 15
gion of chromosome 15 and, thus, have                                                        he inherited from his mother. Neither
                                                UPD is thought to result most often
PWS.                                                                                         deletion nor UPD is known to be asso-
                                                from meiotic nondisjunction that leads
1. The most common situation ( 70%              to trisomy for chromosome 15 and,            ciated with increased recurrence risk.
   of cases) is that the paternally in-         thus, is associated with increased ma-       Although subtle differences have been
   herited chromosome 15 contains a             ternal age. Trisomy 15 is the most com-      shown between groups of people with
   microdeletion of 3 to 4 megabases            mon trisomy at the time of conception        deletions compared with UPD,11–16 for
   of genetic material spanning the             but can only survive if there is a second    the most part, there are no major dif-
   PWS region.                                  mitotic division error after fertilization   ferences in phenotype among the var-
2. In approximately 20% of cases, the           that eliminates 1 of the 3 chromo-           ious causes. The exception is the find-
   affected infant has maternal unipa-          somes 15. If the paternally contributed      ing of hypopigmentation, which is
   rental disomy (UPD), which means             chromosome is lost, the embryo will          most notable in people with PWS who
   that the child inherited both copies         revert to having the normal 2 copies of      have a deletion of the OCA2 gene (a


PEDIATRICS Volume 127, Number 1, January 2011                                                                                     197
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often helpful. Later, after hyperphagia
        Methylation
                                                                                                begins, the diet must be quite calori-
         analysis                                 FISH
                                                                                                cally restricted, often to as little as
                                    Yes                         Yes        PWS due to           60% of the calories that similarly sized
            Abnormal?                            Abnormal?
                                                                        deletion 15q11-13
                                                                                                children without PWS might require
                                                                                                for adequate growth. This diet re-
            No                                   No                                             quires careful attention to the balance
                                                                                                of essential nutrients, which is often
Consider other disorders                         Molecular analysis for UPD                     best achieved by referral and regular
  Infant hypotonia:
                                                                Yes        PWS due to           follow-up with a dietitian who is knowl-
  •chromosome rearrangement                      Abnormal?
  •spinal muscular atrophy type I                                         maternal UPD          edgeable about PWS.
  •myotonic dystrophy
  •other myopathy/neuropathy
                                                 No                                             Feeding Tubes (Nasogastric or
  Older children (obesity):
  •fragile X syndrome                                                                           Gastrostomy Tubes)
  •Bardet Biedl syndrome
  •microscopic chromosome             PWS due to imprinting defect;                             Infants with PWS have poor feeding be-
   rearrangement                        family studies needed                                   cause of weak suck, easy fatigability,
FIGURE 1                                                                                        and low muscle tone. The need for as-
Flowchart of recommended molecular testing strategy for PWS.
                                                                                                sisted feeding is nearly universal in the
                                                                                                first 4 to 6 months; use of nursing sys-
nonimprinted gene in the PWS region                (FISH) reveal no evidence of deletion or     tems with 1-way valves and manual as-
of chromosome 15 associated with au-               balanced rearrangement, the next             sistance of sucking, originally de-
tosomal recessive oculocutaneous al-               step is to obtain blood from the par-        signed for infants with cleft palate (eg,
binism type II).17,18 Recently, some au-           ents and the child to evaluate for UPD.      Haberman nipple, Pigeon feeder), can
thors suggested that there may be                  If biparental inheritance is discovered      greatly reduce reliance on feeding
subtle differences in neurocognitive               in the face of abnormal methylation          tubes. Nasogastric tubes, when
development in children with deletions             and normal FISH results, then, by pro-       needed, are generally well tolerated
depending on the location of the prox-             cess of elimination, the cause is as-        and rarely required for more than 3 to
imal break point.19 Others have not ob-            sumed to be an imprinting defect. The        6 months. The use of a gastrostomy
served such a difference13; therefore,             possible role of testing for defects of      tube (generally with placement of a
the clinical utility of defining the break          the HBII-85 small nucleolar RNA cluster      button-style device) can be avoided in
points is not clear at this time.                  remains to be elucidated.                    most cases, but if, after considering
DIAGNOSTIC TESTING                                                                              the risks and benefits of both ap-
                                                   SPECIAL CONSIDERATIONS FOR THE               proaches, a decision to use a gastros-
Diagnostic testing for PWS, as outlined            INFANT AND CHILD IN WHOM PWS                 tomy tube is made, the device should
in Fig 1, should begin with methylation            IS DIAGNOSED                                 be promptly removed when no longer
analysis to confirm the absence of pa-
                                                   Nutrition                                    needed. Poor feeding is a transient
ternally imprinted genes in the PWS re-
                                                   Maintenance of adequate and appro-           problem in PWS, and the increased ab-
gion of chromosome 15. When only a
                                                   priate nutrition is central to the care of   dominal fat mass with reduced muscle
maternal methylation pattern is seen,
PWS is confirmed, but additional test-              people with PWS at every age. Infants        that characterizes this disorder en-
ing is needed to identify the specific              may require support of feeding for sev-      sures a cosmetically disfiguring scar
cause, which allows for appropriate                eral months. Caloric needs may be, but       at the site of the gastrostomy tube
counseling regarding recurrence risk.              are not always, somewhat reduced in          (families sometimes refer to this as
The recurrence risk for spontaneous                infants with PWS, and infants with PWS       the “second belly-button”). These 2 fac-
deletions or UPD is low ( 1%),                     typically do not spontaneously demand        tors, relatively specific to PWS, may
whereas the recurrence risk of im-                 feedings. Therefore, the infant’s diet       significantly alter the risk/benefit anal-
printing mutations can be as high as               must be adjusted as needed to main-          ysis regarding the approach to tube
50%. If the methylation analysis is con-           tain appropriate weight gain as deter-       feedings compared with the decision-
sistent with PWS and the karyotype                 mined by frequent weight checks. In-         making process for children with dis-
and fluorescence in situ hybridization              creased caloric density of feedings is       abilities attributable to other causes.


198    FROM THE AMERICAN ACADEMY OF PEDIATRICS
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Endocrine Considerations and                    perience has suggested that treat-           bone density27,29 and possible stabiliza-
Recombinant Human Growth                        ment can begin at as early as 2 to 3         tion of behavior decline.30 Studies are
Hormone                                         months of age. It is important that par-     in progress to evaluate the use of GH in
Generalized hypothalamic insuffi-                ents be thoroughly informed about the        adults with PWS.31 However, there is
ciency is characteristic of PWS and             potential benefits and the potential for      nothing to suggest that endogenous
manifests as dysregulation of the               undesired effects. Specifically, there        GH insufficiency improves in later life;
hypothalamic-pituitary axis (including          have been several deaths in children         therefore, it is reasonable to consider
growth hormone [GH], thyroid func-              as young as 3 years with PWS within 6        continuing therapy into adulthood.
tion, and possibly regulation of the ad-        months of initiating GH therapy. The         Pretreatment laboratory evaluation to
renal cortex), appetite, thermoregula-          role of GH in those deaths, if any, is not   document sequelae of GH insufficiency,
tion, and respiratory control. Recent           known. Adenotonsillar hypertrophy            to exclude other causes of slow linear
work demonstrated the possibility that          and obstructive apnea may occur dur-         growth in people with PWS, and to de-
centrally mediated adrenal insuffi-              ing GH therapy; therefore, current rec-      fine baseline parameters related to
ciency may be an underrecognized                ommendations for management in-              potential complications of therapy of-
contributor to premature deaths                 clude polysomnography (sleep study)          ten includes:
among people with PWS.20,21 It is rec-          before and 6 to 10 weeks after begin-        ● polysomnography;
ommended that early-morning serum               ning GH treatment, regardless of age.        ● measurement of plasma insulin-like
adrenocorticotropic hormone and cor-            Polysomnography results are fre-                growth factor 1 (IGF1), IGF-binding
tisol concentrations be evaluated               quently abnormal in people with PWS,            protein 3 (IGFBP3), thyroxine, and
when the child is well and repeated             and both central and obstructive hy-            thyrotropin levels, a complete blood
during any severe illness. Consider-            popnea are common.24 Evidence of ob-            count, and a basic metabolic profile
ation should be given to prophylactic           structive sleep apnea should be man-            (with calcium); and
therapy with hydrocortisone during              aged according to accepted standards
                                                                                             ● left hand and wrist radiography for
rare episodes of critical illness in chil-      of care25 (this American Academy of
                                                                                                bone age (in older children).
dren with PWS, pending measurement              Pediatrics clinical practice guideline
                                                was published in 2002 and has not            Follow-up should include:
of adrenocorticotropic hormone and
serum cortisol. Discussion with a pedi-         been updated) and, specifically, should       ● repeat polysomnography 6 to 10
atric endocrinologist is helpful in de-         lead to referral to an otolaryngologist         weeks after initiation of therapy
termining whether provocative testing           for evaluation of airway, increased ef-         (consider repeating in 1 year and
is indicated in early childhood.                fort to reduce weight, and consider-            any time at which there are new or
                                                ation of delaying (or stopping) GH              worsening symptoms);
GH insufficiency is considered to be
                                                treatment until polysomnography re-          ● monitoring of IGF1 at least twice
universal in PWS, so provocative diag-
nostic testing is not required in the           sults improve. It has also been sug-            yearly, dosing GH to keep IGF1 in
face of reduced growth velocity. In the         gested that GH could be associated              physiologic range; and
first year of life, reduced growth veloc-        with unexpected death by increasing          ● monitoring of head circumference
ity may not be readily identified, but           resting energy expenditure (through             at each visit, because GH treatment
both controlled clinical trials22,23 and        increased muscle bulk) in children              can cause abnormal growth of the
clinical experience have demonstrated           with underlying abnormalities of cen-           head, especially if the fontanelles
that there is often significant response         tral respiratory drive attributable to          are open when GH is started.
to treatment with GH, primarily in im-          PWS, although there is a suggestion in
proved lean mass, improved motor de-            the literature that treatment with GH        Behavioral Food Controls
velopment, and normalization of body            may be associated with modest im-            After the onset of hyperphagia, chil-
habitus. Decisions about use of GH              provement in the central respiratory         dren with PWS may develop a wide
therapy and management are best                 drive.26                                     range of food-related behaviors, in-
made in consultation with a pediatric           There is mounting evidence from con-         cluding actively seeking food, eating
endocrinologist. Although GH treat-             trolled clinical trials that GH therapy in   nonfood items (eg, animal chow,
ment has been approved by the US                children improves linear growth, lean        spoiled food, decorative items that
Food and Drug Administration for chil-          mass and lean-to-fat ratio,27 and respi-     look like food, searching in garbage
dren with PWS older than 2 years with           ratory drive,26,28 and there has been        cans, etc), stealing money to buy food,
documented growth failure, clinical ex-         suggestion of beneficial effects on           and even running away from home to


PEDIATRICS Volume 127, Number 1, January 2011                                                                                     199
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search for food in a wider area. Con-           behaviors, particularly skin-picking,        adults with PWS develop depression,
trol of these behaviors is complex but          become prominent. In later childhood         anxiety, and, in some cases, true psy-
centers on strategies to limit access to        and the early adolescent years, food-        chosis. Parents should be counseled to
food (eg, locks on cabinets and refrig-         seeking behaviors may increase and           identify early indicators of these pro-
erators), limit exposures that make             are often associated with lying, and oc-     cesses to facilitate appropriate medi-
the child think about food (eg, birthday        casionally stealing, to obtain food.         cal intervention.
treats sitting on the teacher’s desk            Some teenagers with PWS have a dis-
during the school day), and instill con-        turbing tendency to sneak off to             HEALTH SUPERVISION FROM BIRTH
fidence that the next meal will be               search for food, which is potentially        TO 1 MONTH: NEWBORN INFANTS
served on time by scrupulously main-            quite dangerous and difficult to man-
                                                                                             Evaluation
taining mealtime routines. Relatives            age. Typical of the adolescent years, the
and social contacts must be educated            teenager with PWS is often overly confi-      ● Confirm the diagnosis of PWS (Fig 1)
to realize that “sneaking” food to the          dent of his or her ability to handle risks     and review the implications of the
child with PWS is not an appropriate            and dangerous situations. It is important      molecular testing results with the
method of demonstrating affection,              to recognize that teenagers with PWS           parents.
and, in fact, undermines the child’s            deal with many of the same neurodevel-       ● Review history for:
nutritional regimen and sense of                opmental and hormonal issues that all          ●   growth and development;
well-being.                                     adolescents encounter, and, similar to
                                                                                               ●   feeding problems; and
                                                their typically developing peers, many of
Hypogonadism                                                                                   ●   symptoms of obstructive apnea.
                                                their behavioral issues seem to stabilize,
Both males and females are affected,            although not disappear entirely, as they     ● Physical examination should in-
although the primary external mani-             reach adulthood.                               clude evaluation of:
festations in females (clitoral and la-                                                        ●   hypotonia, and
                                                Management of the many complex be-
bia minora hypoplasia) may not be ob-
                                                havioral issues is best accomplished           ●   hypogonadism.
vious with cursory evaluation. A
                                                through an active partnership of the
therapeutic trial of human chorionic
                                                parents, the primary care provider,          Anticipatory Guidance
gonadotropin (hCG) is indicated for
                                                and a developmental/behavioral spe-          ● Review the phenotype, discuss the
treatment of undescended testes be-
                                                cialist (pediatrician or psychologist).        specific findings with both parents
fore surgery, because avoidance of
                                                Behavioral management that focuses             whenever possible, and talk about
general anesthesia is desirable for in-
                                                on rewarding desired behaviors and             potential clinical manifestations as-
fants with low muscle tone and poten-
tial for underlying respiratory compro-         ignoring, when possible, undesirable           sociated with the syndrome; these
mise. Added benefits of a course of hCG          behaviors seems to be most effective.          issues may have to be reviewed
may include increased scrotal size and          Early recognition of developing behav-         again at a subsequent meeting.
partial normalization of phallus length,        ior problems is critical for maximizing
                                                                                             ● Point out both early and late feeding
thereby improving surgical outcomes             the effectiveness of such an approach.
                                                Parents should be counseled that of-           issues and the dichotomous nature
for undescended testes and facilitat-                                                          of feeding problems (ie, too little as
ing later standing micturition.                 fering food as a reward or withholding
                                                food as a punishment is almost always          a neonate, too much as an older
Behavior Management                             counterproductive and should be                child), and, as appropriate, discuss
                                                avoided. Positive reinforcers are gen-         use of nasogastric feedings with in-
As the child with PWS ages, there is a                                                         creased caloric-density formula to
progression of behavioral issues,               erally not difficult to identify, and re-
                                                ward systems that use small, short-            minimize volume and use of special
many of which can be anticipated,                                                              nipples/feeders (eg, Pigeon feeder,
identified early, and managed pro-               term goals that progress to larger
                                                goals are quite effective.                     Haberman nipple, other nursers de-
spectively. Early childhood is often
                                                                                               signed to reduce work of sucking).
characterized by rigidity, particularly         Finally, young adults with PWS seem to
                                                                                               Special attention should be paid to:
related to daily routines and long-term         be prone to a variety of compulsive be-
persistence of temper tantrums and              haviors including smoking cigarettes,          ●   avoidance of prolonged oral feed-
oppositional behaviors typical of the           and some of them develop frank                     ing time (usually not 20 min-
normally developing 2-year-old. Later,          obsessive-compulsive disorder. Like-               utes per feeding);
perseverant speech and compulsive               wise, a significant minority of young           ●   transition from tube feeding;


200   FROM THE AMERICAN ACADEMY OF PEDIATRICS
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FROM THE AMERICAN ACADEMY OF PEDIATRICS


   ●   maintenance of adequate caloric          ● Monitor time/work of feeding and              ●   benefits of early behavioral mon-
       intake; and                                 caloric density of foods to maintain             itoring and establishment of rou-
   ●   development of appropriate eat-             appropriate growth.                              tines; and
       ing habits; discuss the impor-           ● Perform developmental evaluation,             ●   importance of limit-setting and
       tance of normal fat and calorie             and refer to early-intervention ser-             enforcement.
       intake for brain development                vices (if not already done).              ● At 6 to 12 months of age, review the
       (some parents may start restrict-        ● Evaluate boys for undescended tes-            psychological support and in-
       ing too early).                             tes (or cryptorchidism) and ingui-           trafamily relationships, including
● Refer infants to early-intervention              nal hernia; consider trial of human          long-term planning, financial plan-
   services in the community.                      chorionic gonadotropin injections            ning, and guardianship; reinforce
                                                   (may be performed in conjunction             need for parents to work in partner-
● Discuss the importance of stimulat-
                                                   with pediatric endocrinologist); re-         ship, and discuss early relationship-
   ing the infant, because he or she is                                                         counseling for parents if problems
                                                   fer to pediatric urologist or a urolo-
   likely to be undemanding.                                                                    arise.
                                                   gist who has special expertise and
● Inform the family of the availability            experience with infants with disabil-     ● Review early-intervention services
   of support and advice from the par-             ities if the infant’s testes are             relative to the strengths and needs
   ents of other children with PWS.                abnormal.                                    of the infant and family.
● Supply contact information for PWS            ● Check the infant’s vision at each          ● Review the family’s understanding
   support groups (see “Resources for              visit by using developmentally ap-           of the risk of recurrence of PWS
   Parents”).                                      propriate subjective and objective           and the availability of prenatal
● Point out the strengths of the child             criteria; if evidence of strabismus          diagnosis.
   and positive family experiences.                or other concern arises, refer the        ● Discuss increased risk of seizures
● Discuss individual resources for sup-            infant to a pediatric ophthalmolo-           during childhood (5%–10% of those
   port, such as family, clergy, and               gist or an ophthalmologist who has           with PWS), which may be associated
   friends.                                        special expertise and experience             with fever and are generally respon-
                                                   with infants with disabilities.              sive to monotherapy.
● Talk about how and what to tell
                                                ● Administer vaccines recommended
   other family members and friends;                                                         HEALTH SUPERVISION FROM 1 TO 5
                                                   for all children unless there are spe-
   review methods of coping with long-                                                       YEARS: EARLY CHILDHOOD
                                                   cific contraindications.
   term disabilities.
                                                ● Assess the emotional status of par-        Evaluation
● Review the recurrence risk in sub-
                                                   ents and intrafamily relationships;       ● Obtain a history and perform a
   sequent pregnancies and the avail-                                                           physical examination with attention
                                                   educate and support siblings and
   ability of prenatal diagnosis and ge-                                                        to growth and developmental sta-
                                                   discuss sibling adjustments.
   netic counseling.                                                                            tus. PWS-specific growth curves
● Give overview of the long-term                Anticipatory Guidance                           should only be used for children
   management plan.                             ● Review feeding issues (see above)             who are not treated with GH; regular
                                                   and the infant’s growth and devel-           curves should be used for children
HEALTH SUPERVISION FROM 1                                                                       who are treated with GH.
                                                   opment relative to other children
MONTH TO 1 YEAR: INFANCY                           with PWS.                                 ● Feeding issues: monitor food intake
                                                                                                and behaviors, and consider refer-
Evaluation                                      ● Review GH deficiency and review
                                                                                                ral to dietitian who has experience
● Review and note clinical features                benefits and potential risks of GH
                                                                                                with PWS; calorie needs must be
   and confirm diagnosis, if not done               therapy; consider referral to pediat-
                                                                                                based on growth rate and are usu-
   previously.                                     ric endocrinology specialist.
                                                                                                ally less than those for similarly
● Review routine health maintenance.            ● Discuss:                                      sized children without PWS.
● Plot growth by using standard                    ●   need for careful dietary manage-      ● Annual hearing and vision screen-
   pediatric growth charts, and pay                    ment later in childhood;                 ing evaluation before 3 years of age;
   special attention to weight-for-                ●   probability of mild-to-moderate          refer the child to a pediatric oph-
   length measurements.                                cognitive impairment;                    thalmologist or ophthalmologist


PEDIATRICS Volume 127, Number 1, January 2011                                                                                     201
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who has special expertise and expe-           ● Discuss need for all family mem-         ● Discuss socialization, family status,
  rience with children with disabili-             bers, child care providers, and             and relationships, including finan-
  ties for a thorough evaluation for              school staff members to learn               cial arrangements and guardian-
  ocular findings during the second                about the disorder, the need for            ship; begin discussion of adult living
  or third year of life or earlier if there       strict food management, and devel-          arrangements; advise parents to
  is evidence of cataracts, nystagmus,            opment of routines.                         consider joining waiting list for
  or strabismus.                                ● Discuss future pregnancy planning,          placement in a group home specifi-
● Evaluate annually for scoliosis, and            risk of recurrence of PWS, and pre-         cally organized for people with PWS
  regularly assess muscle tone; refer             natal diagnosis; remind parents of          and recognize that placement may
  to pediatric orthopedist for man-               positive aspects for typically func-        take several years (or more).
  agement of scoliosis as indicated.              tioning children of having a sibling     ● Discuss the development of age-
● Discuss reduced salivation and in-              with special needs.                         appropriate social and self-help
  creased caries risk by 1 year of age;                                                       skills and the development of a
                                                HEALTH SUPERVISION FROM 5 TO                  sense of responsibility.
  refer to a pediatric dentist or a gen-        13 YEARS: LATE CHILDHOOD
  eral dentist who has special train-                                                      ● Discuss psychosexual development,
  ing to manage children with special           Evaluation                                    physical and sexual development,
  needs; consider need for more-                ● Obtain a history, and perform a             menstrual hygiene and manage-
  frequent dental cleanings (every                physical examination with attention         ment, fertility, and contraception;
  3– 4 vs every 6 months) because of              to growth and developmental sta-            explain that people with PWS often
  the increased caries risk.                      tus; evaluate for scoliosis.                have strong feelings of desire for an
                                                                                              infant.
● Ask about symptoms related to ob-             ● Specifically evaluate for behavior is-
  structive sleep apnea, including                sues that may arise in this age          ● Discuss symptoms related to ob-
  snoring, restless sleep, and exces-             group, including binge-eating, run-         structive sleep apnea, including
  sive daytime sleepiness; refer to a             ning away, and worsening of                 snoring and restless sleep, and
  sleep or pulmonary specialist as                skin-picking.                               evaluate for signs of excessive day-
  indicated.                                                                                  time sleepiness; refer to a sleep or
                                                ● Perform vision screening annually
                                                                                              pulmonary specialist as indicated.
                                                  with attention to recurrence of
Anticipatory Guidance                             strabismus.                              ● Discuss increased pain tolerance
● Review early intervention, including                                                        common in people with PWS, particu-
                                                ● Perform thyroid-screening tests ev-
  physical therapy, occupational ther-                                                        larly with regard to evaluating for ill-
                                                  ery 2 to 3 years or if symptomatic.
  apy, and speech therapy, in the pre-                                                        ness or injury; special attention
                                                ● Look for signs of premature adren-          should be given to risk of intestinal
  school program and discuss future
                                                  arche (which often occurs without           necrosis after binge-eating, because
  school placement and performance.
                                                  progression of other aspects of pre-        the high pain tolerance can mask
● Assess the child’s behavior, discuss            cocious puberty; thus, reassurance          symptoms and delay treatment,
  behavioral management, and ask                  is often the only intervention              which can lead to death; people with
  specifically about common behav-                 needed).                                    PWS rarely vomit, so parents should
  iors seen in those with PWS (eg,              ● Discuss    management of skin-              be aware that vomiting after binge-
  skin-picking, temper tantrums,                  picking (primarily behavioral; medi-        eating can be an ominous sign.
  food-seeking, etc), which may begin             cations, including topiramate, are
  during this period.                             used only in the most severe cases).     HEALTH SUPERVISION FROM 13 TO
● Discuss sibling adjustments, social-                                                     21 YEARS OR OLDER:
  ization, and recreational skills.             Anticipatory Guidance                      ADOLESCENCE TO EARLY
● Encourage families to establish op-           ● Review the child’s development           ADULTHOOD
  timal dietary and physical exercise             and appropriateness of school
                                                                                           Evaluation
  patterns to prevent obesity; sched-             placement and developmental
                                                  intervention.                            ● Perform physical examination with
  ule annual (or more often) meetings
                                                                                              particular emphasis on evidence of:
  with dietitian to review caloric in-          ● Continue to stress the need for di-
  take and suggest ways to provide                etary management and daily exer-            ●   heart failure;
  less calorically dense foods.                   cise to avoid obesity.                      ●   peripheral edema;


202   FROM THE AMERICAN ACADEMY OF PEDIATRICS
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FROM THE AMERICAN ACADEMY OF PEDIATRICS


   ●   skin-picking (perianal areas and            sumed to be infertile, although the          through adult life (eg, the medical
       intertriginous folds should be              possibility of fertility should always       geneticist); when new providers are
       examined); and                              be considered.                               needed, the transferring physician
   ●   scoliosis.                               ● Discuss sexuality and socializa-              should clearly communicate the
                                                   tion, the need for and degree of             person’s needs, and care should
● Evaluate diet, caloric intake, and ex-
                                                   supervision and/or the need for              overlap until all providers, as well
   ercise program, and stress obesity
                                                   contraception.                               as patients and their family, are
   prevention; initiate weight-loss
                                                                                                comfortable with the care needed.
   strategy if needed.                          ● Explain to the patient and her family
● Vision screening should be per-                  the risk of genetic abnormalities if      RESOURCES FOR PARENTS
   formed annually.                                she were to become pregnant.              Prader-Willi Syndrome Association,
● Look for early signs of developing            ● Discuss       group homes and              8588 Potter Park Dr, Suite 500, Sara-
   psychosis or increasing obsessive-              independent-living opportunities          sota, FL 34238; telephone: 800-926-4797
   compulsive behaviors seen in a mi-              specifically for people with PWS,          or 941-312-0400; fax: 941-312-0142;
   nority of patients (risk is apparently          workshop settings, and other              Web: www.pwsausa.org
   higher in cases attributable to UPD             community-supported employment            Foundation for Prader-Willi Research
   than deletion, but may occur with               (group homes specifically designed         Canada (formerly Canadian Prader-
   either of them).                                for people with PWS are desirable,        Willi Syndrome Organization), 19-
                                                   but they often have long waiting          13085 Yonge St, Suite 370, Richmond
● Evaluate pubertal status and con-
                                                   lists, so applying during the adoles-     Hill, Ontario, Canada L4E 0K2; tele-
   sider referral to pediatric endocri-
                                                   cent years is helpful in securing a       phone: 866-99-FPWRC (866-993-7972);
   nology for discussion about pros
                                                   spot for the future).                     Web: www.onesmallstep.ca
   and cons of sex hormone therapy.
                                                ● Discuss intrafamily relationships, fi-      Foundation for Prader-Willi Research,
Anticipatory Guidance                              nancial planning, and guardianship.       104 Hume Ave, Alexandria, VA 22301;
● Discuss skin care, especially in the          ● Facilitate transfer to adult medical       telephone: 703-683-7500; fax: 703-836-
   presence of truncal obesity.                    care.                                     0959; Web: www.fpwr.org
● Discuss issues related to transition                                                       International Prader-Willi Syndrome
   into adulthood.
                                                TRANSITION TO ADULT CARE                     Organisation, Web: www.ipwso.org
                                                ● Identify health care providers in the
● Discuss possible compulsive behav-                                                         LEAD AUTHOR
                                                  community who are willing to learn
   iors, including use of tobacco.                                                           Shawn E. McCandless, MD – Section on
                                                  about the special situations of peo-         Genetics and Birth Defects Member
● Discuss appropriateness of school
                                                  ple with PWS; ideally, use providers
   placement, and emphasize ade-                  with training or experience in the         COMMITTEE ON GENETICS, 2010 –2011
   quate vocational training within the           care of people with special needs.
                                                                                             Howard M. Saal, MD, Chairperson
                                                                                             Stephen R. Braddock, MD
   school curriculum while keeping in
                                                ● Regular evaluation is needed for:          Gregory Enns, MB, ChB
   mind the special issues related to                                                        Jeffrey R. Gruen, MD
   the need to scrupulously avoid expo-           ● weight control (maintenance or           James M. Perrin, MD
   sure to opportunities to obtain food.             loss);                                  Robert A. Saul, MD
                                                                                             Beth A. Tarini, MD
● Provide information on how to rec-              ● diabetes;
                                                                                             LIAISONS
   ognize the signs of psychosis.                 ● hypertension;
                                                                                             W. Allen Hogge, MD
● Discuss the need for gynecologic                ● sleep apnea;                             American College of Obstetricians and
   care for pubescent girls. Talk about                                                         Gynecologists
                                                  ● heart failure;                           James W. Hanson, MD – American College of
   the risk of Angelman syndrome (at-                                                           Medical Genetics – Eunice Kennedy Shriver
                                                  ● peripheral edema; and
   tributable to deletion of maternally                                                         National Institute of Child Health and Human
   inherited chromosome 15q11-13)                 ● behavior management, including              Development
                                                     the use of medications such             Michele A. Lloyd-Puryear, MD, PhD – Health
   with the patient and her family if she                                                       Resources and Services Administration
   were to become pregnant; review                   as selective serotonin-reuptake         Sonja A. Rasmussen, MD, MS – Centers for
   the fact that there have been 2 case              inhibitors.                                Disease Control and Prevention
   reports in which a woman has re-             ● Some providers may continue to             STAFF
   produced. Men with PWS are as-                 care for the person with PWS               Paul Spire


PEDIATRICS Volume 127, Number 1, January 2011                                                                                           203
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    Clarke D, Boer H. Population prevalence and            specific differences. Am J Med Genet. 1996;              childhood obstructive sleep apnea syn-
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    in one UK Health Region. J Med Genet. 2001;            Thompson T, Butler MG. Intellectual charac-             erad J. Growth hormone treatment in-
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    Evidence for the role of PWCR1/HBII-85 C/D             deh Z, Thompson T. Behavioral differences               J Clin Endocrinol Metab. 2003;88(5):
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    669 – 678                                              disomy. Pediatrics. 2004;113(3 pt 1):                   Benefits of long-term GH therapy in Prader-
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    Prader-Willi phenotype caused by paternal        20.   de Lind van Wijngaarden RF, Otten BJ, Fes-              crinol Metab. 2002;87(4):1581–1585
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    arrangements and human disease traits.                 al. Unexpected death and critical illness in            able at: www.pediatrics.org/cgi/content/
    Trends Genet. 1998;14(10):417– 422                     Prader-Willi syndrome: report of ten individ-           full/109/2/e35
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    ann D, Kaya-Westerloh S, Passarge E,                   158 –164                                                adults with Prader-Willi syndrome. Treat
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204     FROM THE AMERICAN ACADEMY OF PEDIATRICS
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Clinical Report−−Health Supervision for Children With Prader-Willi Syndrome
          Shawn E. McCandless and THE COMMITTEE ON GENETICS
            Pediatrics; originally published online December 27, 2010;
                           DOI: 10.1542/peds.2010-2820
 Updated Information &                including high resolution figures, can be found at:
 Services                             http://pediatrics.aappublications.org/content/early/2010/12/27
                                      /peds.2010-2820
 Permissions & Licensing              Information about reproducing this article in parts (figures,
                                      tables) or in its entirety can be found online at:
                                      http://pediatrics.aappublications.org/site/misc/Permissions.xht
                                      ml
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 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
 publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
 and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
 Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All
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Health supervision for children with Prader-Willi syndrome

  • 1. Clinical Report−−Health Supervision for Children With Prader-Willi Syndrome Shawn E. McCandless and THE COMMITTEE ON GENETICS Pediatrics; originally published online December 27, 2010; DOI: 10.1542/peds.2010-2820 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2010/12/27/peds.2010-2820 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 2. FROM THE AMERICAN ACADEMY OF PEDIATRICS Guidance for the Clinician in Rendering Pediatric Care Clinical Report—Health Supervision for Children With Prader-Willi Syndrome Shawn E. McCandless, MD, and THE COMMITTEE ON GENETICS abstract KEY WORDS This set of guidelines was designed to assist the pediatrician in caring Prader-Willi syndrome, Prader-Labhart-Willi syndrome, uniparental disomy, genetic testing for children with Prader-Willi syndrome diagnosed by clinical features ABBREVIATIONS and confirmed by molecular testing. Prader-Willi syndrome provides PWS—Prader-Willi syndrome an excellent example of how early diagnosis and management can UPD—uniparental disomy improve the long-term outcome for some genetic disorders. Pediatrics GH—growth hormone 2011;127:195–204 IGF—insulin-like growth factor This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors INTRODUCTION have filed conflict of interest statements with the American Prader-Willi syndrome (PWS) (also Prader-Labhart-Willi syndrome) is a Academy of Pediatrics. Any conflicts have been resolved through recognizable pattern of physical findings with significant cognitive, a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any neurologic, endocrine, and behavioral abnormalities caused by lack of commercial involvement in the development of the content of expression of genes from an imprinted region of the paternally inher- this publication. ited chromosome 15q11-q13, near the centromere. Originally de- The guidance in this report does not indicate an exclusive scribed in 1958,1 PWS was the first recognized disorder related to course of treatment or serve as a standard of medical care. genomic imprinting in humans2 and provides an excellent example of Variations, taking into account individual circumstances, may be appropriate. how early diagnosis and meticulous management can markedly im- prove the long-term outcome for people with some genetic disorders. PWS affects both genders equally and occurs in people from all geo- graphic regions; its estimated incidence is 1 in 15 000 to 1 in 25 000 live births.3,4 Affected infants uniformly have significant hypotonia, early feeding problems, and difficulty with weight gain. Later, a second phase of the disorder ensues with hyperphagia (excessive appetite for food), which leads to obesity and characteristic behavior problems. Without adequate weight control and management of eating behaviors, massive obesity and associated complications of diabetes, obstructive www.pediatrics.org/cgi/doi/10.1542/peds.2010-2820 sleep apnea, and right-sided heart failure occur; death typically occurs doi:10.1542/peds.2010-2820 in the fourth decade of life. With careful weight control, people with All clinical reports from the American Academy of Pediatrics PWS can remain healthy well into older adult life, and some people are automatically expire 5 years after publication unless reaffirmed, known to live into their seventh decade. revised, or retired at or before that time. The findings of PWS are listed in Table 1. Clinical diagnostic criteria PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). have been developed and validated5 (Table 2), but now that reliable Copyright © 2011 by the American Academy of Pediatrics molecular testing is readily available, these clinical criteria should be considered guidelines to help define people for whom further diagnos- tic testing is indicated.6 In general, PWS should be considered in any infant with significant hypotonia, particularly in the setting of poor feeding, reduced spontaneous arousal for feeding, and hypogonadism (undescended testes, small phallus, or small clitoris). In older chil- dren, the diagnosis should be considered when there is impaired sati- ety for food, especially with rapid weight gain. Likewise, poor linear growth, especially in the presence of excessive caloric intake, should also raise suspicion for PWS. Hypogonadism, hypotonia, developmental PEDIATRICS Volume 127, Number 1, January 2011 195 Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 3. TABLE 1 Clinical Findings in PWS TABLE 1 Continued when assisting in the provision of a Fetal Sleep comprehensive medical home for chil- Breech position Snoring/obstructive sleep apnea Reduced fetal activity Central apnea during sleep dren and adults with PWS. They are Polyhydramnios Excessive daytime sleepiness based on a thorough review of the per- Growth Early-morning waking tinent medical literature and incorpo- Short stature Night-awakening for food-seeking Failure to thrive in infancy Voice rate experimental data and the experi- Central obesity Hypernasal speech ence of clinicians with expertise in Head and neck Weak or squeaky cry in infancy Dolichocephaly caring for people with PWS. As with all Endocrine Narrow bitemporal diameter Hyperinsulinemia chronic medical conditions, establish- Almond-shaped eyes GH deficiency ing a medical home is essential to the Strabismus Hypogonadotropic hypogonadism Up-slanting palpebral fissures Diabetes mellitus (type 2) smooth and effective provision of care Myopia Behavior/mental health to the individual person and support to Hyperopia Skin picking Thin upper lip his or her family, which is best Rectal picking Small-appearing mouth Food related behavioral problems achieved when the primary care pro- Down-turned corners of mouth Thick, viscous (reduced) saliva Temper tantrums vider and consultants communicate ef- Difficulty with transitions Enamel hypoplasia Stubbornness fectively and clearly delineate their re- Early dental caries spective roles in the care of the Obsessive behaviors Dental crowding and malocclusion Perseverant speech person. Ocular Obsessive-compulsive disorder Strabismus Psychosis Nystagmus Elopement GENETICS AND GENOMICS OF PWS Cataracts (rare) Miscellaneous Retinal hypopigmentation Temperature instability PWS is associated with lack of expres- Foveal hypoplasia sion of several genes on the paternally High pain threshold Hyperopia Unusual skill with jigsaw puzzles inherited chromosome 15. This region Myopia Respiratory contains genes that are normally “im- Hypoventilation Obstructive sleep apnea printed,” which means that they are Central sleep apnea delays, speech-articulation defects, differentially expressed (used to make Gastrointestinal and characteristic physical appear- RNA and proteins) depending on Feeding problems in infancy ance should all raise the index of sus- Gastroesophageal reflux whether the chromosome was inher- Decreased vomiting picion. Significant neonatal hypotonia ited from the father or the mother. On Genitourinary is present in essentially all children for the maternally inherited chromosome Small penis Scrotal hypoplasia whom molecular testing eventually 15, these genes are transcriptionally Cryptorchidism confirms the diagnosis of PWS7; there- silenced by hypermethylation of their Hypoplastic labia minora fore, this history should be actively Hypoplastic clitoris promoter regions. Therefore, only the Skeletal sought during evaluation of older paternally inherited chromosome pro- Osteoporosis children. duces the gene products. These Osteopenia Scoliosis These guidelines are intended to be changes are referred to as “epige- Kyphosis suggestions for health care providers netic,” because they do not involve a Small hands and feet Narrow hands with straight ulnar border Clinodactyly Skin, nails, hair TABLE 2 Suggested Criteria for Prompting Molecular Testing for PWS Hypopigmentation Age at Assessment Features Sufficient to Prompt DNA Testing Blonde to light-brown hair Birth to 2 y Significant hypotonia with poor suck and difficulty with weight gain Frontal hair upsweep Neurologic 2–6 y Congenital hypotonia with history of poor suck; global developmental Severe neonatal hypotonia that improves with delay age 6–12 y History of congenital hypotonia with poor suck (hypotonia often persists), Poor neonatal suck and swallow reflexes global developmental delay, and excessive eating (hyperphagia; Poor gross motor coordination obsession with food) with central obesity if uncontrolled Poor fine motor coordination 13 y through adulthood Cognitive impairment, usually mild mental retardation, excessive eating Mild-to-moderate mental retardation (hyperphagia; obsession with food) with central obesity if Learning disabilities uncontrolled, and hypothalamic hypogonadism and/or typical behavior Increased risk of seizures problems (including temper tantrums and obsessive-compulsive Global developmental delay features) Speech-articulation problems Adapted from Gunay-Aygun M, Schwartz S, Heeger S, O’Riordan MA, Cassidy SB. Pediatrics. 2001;108(5). Available at: Hyperphagia www.pediatrics.org/cgi/content/full/108/5/e92. 196 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 4. FROM THE AMERICAN ACADEMY OF PEDIATRICS change in the sequence of the DNA but, of chromosome 15 from the mother chromosome 15, both of which origi- instead, involve a change to the and no copy from the father. nate from the mother. Alternatively, genomic structure that affects regula- 3. Imprinting errors, which occur in the sperm could have no copy of chro- tion of expression. 5% or fewer cases, involve a defect mosome 15 as a result of a paternal The part of chromosome 15 involved in of the process of switching the im- meiotic error, and the resulting con- PWS contains several segments of du- print when the father passes on a ceptus would have only 1 chromosome plicated DNA that predispose to rear- copy of the chromosome 15 that he 15. Such an embryo would also be rangements, either deletion or dupli- inherited from his mother. spontaneously aborted unless a sec- cation, of the PWS region. Absence of ond, mitotic error occurred after fer- 4. Finally, PWS has been described as the paternally inherited contribution tilization that duplicates the mater- a result of a balanced translocation of the PWS region of chromosome 15 nally contributed chromosome 15. In involving chromosome 15 that leads to lack of the gene products and either case, an infant born from such a moves the genes in the region away causes the findings of PWS. In contrast, pregnancy would be missing the pater- from the imprinting center. several other genes in the region are nally contributed chromosome 15 and, Several recent reports suggested that therefore, would only have inactive, silenced by methylation on the pater- the essential PWS phenotype may be maternally imprinted copies of the nally inherited allele. Absence of the caused by loss of the imprinted HBII-85 genes in the PWS region. maternally inherited contribution of cluster of small nucleolar RNAs this region causes Angelman syn- The third mechanism, an “imprinting (snoRNAs), which, if confirmed, will be drome, a completely different disorder error,” leads to a situation in which the one of the first developmental disor- caused by lack of expression of a sin- imprinted (silenced) genes that the fa- ders shown to be caused by loss of gle gene in the region (UBE3A). ther inherited from his mother cannot microRNA.8,9 A short sequence of DNA in the region be reactivated. The infant inherits 1 The PWS region of chromosome 15 is copy of chromosome 15 from each par- called the “imprinting center” seems flanked by segments of duplicated ent, but the PWS region is fully methyl- to control switching and maintenance DNA, which predisposes to deletion, or ated on both copies of chromosome 15 of the imprinting pattern, which is crit- duplication, during recombination in and, thus, is silenced in both copies. ical, because half of a male’s copies of meiosis. This seems to be the reason This mechanism, although rare, is im- chromosome 15 carry the silenced for the high frequency of the typical portant to identify, because the inabil- genes inherited from his mother. When deletion in PWS and in some other re- ity to switch the imprint can be an in- he, in turn, passes copies of his moth- current microdeletions. It is important herited trait, which means that a man er’s chromosome 15 to his own off- to recognize that the normal chromo- with an inherited imprinting defect spring, those genes must be reacti- some structure in the region plays a has up to a 50% recurrence risk with vated, which “switches” the imprint. significant role in the development of each pregnancy to sire another child It becomes clear, then, that there are the genetic defect; thus, PWS has been with PWS. The rare case of PWS attrib- multiple mechanisms by which a per- described as a “genomic disorder” to utable to a balanced translocation also son may end up with no functional distinguish it from other genetic disor- may have an increased recurrence (transcriptionally active) copies of the ders that are specifically caused by an risk if the father carries the same genes in this critically important re- alteration in the sequence of the DNA.10 translocation on the chromosome 15 gion of chromosome 15 and, thus, have he inherited from his mother. Neither UPD is thought to result most often PWS. deletion nor UPD is known to be asso- from meiotic nondisjunction that leads 1. The most common situation ( 70% to trisomy for chromosome 15 and, ciated with increased recurrence risk. of cases) is that the paternally in- thus, is associated with increased ma- Although subtle differences have been herited chromosome 15 contains a ternal age. Trisomy 15 is the most com- shown between groups of people with microdeletion of 3 to 4 megabases mon trisomy at the time of conception deletions compared with UPD,11–16 for of genetic material spanning the but can only survive if there is a second the most part, there are no major dif- PWS region. mitotic division error after fertilization ferences in phenotype among the var- 2. In approximately 20% of cases, the that eliminates 1 of the 3 chromo- ious causes. The exception is the find- affected infant has maternal unipa- somes 15. If the paternally contributed ing of hypopigmentation, which is rental disomy (UPD), which means chromosome is lost, the embryo will most notable in people with PWS who that the child inherited both copies revert to having the normal 2 copies of have a deletion of the OCA2 gene (a PEDIATRICS Volume 127, Number 1, January 2011 197 Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 5. often helpful. Later, after hyperphagia Methylation begins, the diet must be quite calori- analysis FISH cally restricted, often to as little as Yes Yes PWS due to 60% of the calories that similarly sized Abnormal? Abnormal? deletion 15q11-13 children without PWS might require for adequate growth. This diet re- No No quires careful attention to the balance of essential nutrients, which is often Consider other disorders Molecular analysis for UPD best achieved by referral and regular Infant hypotonia: Yes PWS due to follow-up with a dietitian who is knowl- •chromosome rearrangement Abnormal? •spinal muscular atrophy type I maternal UPD edgeable about PWS. •myotonic dystrophy •other myopathy/neuropathy No Feeding Tubes (Nasogastric or Older children (obesity): •fragile X syndrome Gastrostomy Tubes) •Bardet Biedl syndrome •microscopic chromosome PWS due to imprinting defect; Infants with PWS have poor feeding be- rearrangement family studies needed cause of weak suck, easy fatigability, FIGURE 1 and low muscle tone. The need for as- Flowchart of recommended molecular testing strategy for PWS. sisted feeding is nearly universal in the first 4 to 6 months; use of nursing sys- nonimprinted gene in the PWS region (FISH) reveal no evidence of deletion or tems with 1-way valves and manual as- of chromosome 15 associated with au- balanced rearrangement, the next sistance of sucking, originally de- tosomal recessive oculocutaneous al- step is to obtain blood from the par- signed for infants with cleft palate (eg, binism type II).17,18 Recently, some au- ents and the child to evaluate for UPD. Haberman nipple, Pigeon feeder), can thors suggested that there may be If biparental inheritance is discovered greatly reduce reliance on feeding subtle differences in neurocognitive in the face of abnormal methylation tubes. Nasogastric tubes, when development in children with deletions and normal FISH results, then, by pro- needed, are generally well tolerated depending on the location of the prox- cess of elimination, the cause is as- and rarely required for more than 3 to imal break point.19 Others have not ob- sumed to be an imprinting defect. The 6 months. The use of a gastrostomy served such a difference13; therefore, possible role of testing for defects of tube (generally with placement of a the clinical utility of defining the break the HBII-85 small nucleolar RNA cluster button-style device) can be avoided in points is not clear at this time. remains to be elucidated. most cases, but if, after considering DIAGNOSTIC TESTING the risks and benefits of both ap- SPECIAL CONSIDERATIONS FOR THE proaches, a decision to use a gastros- Diagnostic testing for PWS, as outlined INFANT AND CHILD IN WHOM PWS tomy tube is made, the device should in Fig 1, should begin with methylation IS DIAGNOSED be promptly removed when no longer analysis to confirm the absence of pa- Nutrition needed. Poor feeding is a transient ternally imprinted genes in the PWS re- Maintenance of adequate and appro- problem in PWS, and the increased ab- gion of chromosome 15. When only a priate nutrition is central to the care of dominal fat mass with reduced muscle maternal methylation pattern is seen, PWS is confirmed, but additional test- people with PWS at every age. Infants that characterizes this disorder en- ing is needed to identify the specific may require support of feeding for sev- sures a cosmetically disfiguring scar cause, which allows for appropriate eral months. Caloric needs may be, but at the site of the gastrostomy tube counseling regarding recurrence risk. are not always, somewhat reduced in (families sometimes refer to this as The recurrence risk for spontaneous infants with PWS, and infants with PWS the “second belly-button”). These 2 fac- deletions or UPD is low ( 1%), typically do not spontaneously demand tors, relatively specific to PWS, may whereas the recurrence risk of im- feedings. Therefore, the infant’s diet significantly alter the risk/benefit anal- printing mutations can be as high as must be adjusted as needed to main- ysis regarding the approach to tube 50%. If the methylation analysis is con- tain appropriate weight gain as deter- feedings compared with the decision- sistent with PWS and the karyotype mined by frequent weight checks. In- making process for children with dis- and fluorescence in situ hybridization creased caloric density of feedings is abilities attributable to other causes. 198 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 6. FROM THE AMERICAN ACADEMY OF PEDIATRICS Endocrine Considerations and perience has suggested that treat- bone density27,29 and possible stabiliza- Recombinant Human Growth ment can begin at as early as 2 to 3 tion of behavior decline.30 Studies are Hormone months of age. It is important that par- in progress to evaluate the use of GH in Generalized hypothalamic insuffi- ents be thoroughly informed about the adults with PWS.31 However, there is ciency is characteristic of PWS and potential benefits and the potential for nothing to suggest that endogenous manifests as dysregulation of the undesired effects. Specifically, there GH insufficiency improves in later life; hypothalamic-pituitary axis (including have been several deaths in children therefore, it is reasonable to consider growth hormone [GH], thyroid func- as young as 3 years with PWS within 6 continuing therapy into adulthood. tion, and possibly regulation of the ad- months of initiating GH therapy. The Pretreatment laboratory evaluation to renal cortex), appetite, thermoregula- role of GH in those deaths, if any, is not document sequelae of GH insufficiency, tion, and respiratory control. Recent known. Adenotonsillar hypertrophy to exclude other causes of slow linear work demonstrated the possibility that and obstructive apnea may occur dur- growth in people with PWS, and to de- centrally mediated adrenal insuffi- ing GH therapy; therefore, current rec- fine baseline parameters related to ciency may be an underrecognized ommendations for management in- potential complications of therapy of- contributor to premature deaths clude polysomnography (sleep study) ten includes: among people with PWS.20,21 It is rec- before and 6 to 10 weeks after begin- ● polysomnography; ommended that early-morning serum ning GH treatment, regardless of age. ● measurement of plasma insulin-like adrenocorticotropic hormone and cor- Polysomnography results are fre- growth factor 1 (IGF1), IGF-binding tisol concentrations be evaluated quently abnormal in people with PWS, protein 3 (IGFBP3), thyroxine, and when the child is well and repeated and both central and obstructive hy- thyrotropin levels, a complete blood during any severe illness. Consider- popnea are common.24 Evidence of ob- count, and a basic metabolic profile ation should be given to prophylactic structive sleep apnea should be man- (with calcium); and therapy with hydrocortisone during aged according to accepted standards ● left hand and wrist radiography for rare episodes of critical illness in chil- of care25 (this American Academy of bone age (in older children). dren with PWS, pending measurement Pediatrics clinical practice guideline was published in 2002 and has not Follow-up should include: of adrenocorticotropic hormone and serum cortisol. Discussion with a pedi- been updated) and, specifically, should ● repeat polysomnography 6 to 10 atric endocrinologist is helpful in de- lead to referral to an otolaryngologist weeks after initiation of therapy termining whether provocative testing for evaluation of airway, increased ef- (consider repeating in 1 year and is indicated in early childhood. fort to reduce weight, and consider- any time at which there are new or ation of delaying (or stopping) GH worsening symptoms); GH insufficiency is considered to be treatment until polysomnography re- ● monitoring of IGF1 at least twice universal in PWS, so provocative diag- nostic testing is not required in the sults improve. It has also been sug- yearly, dosing GH to keep IGF1 in face of reduced growth velocity. In the gested that GH could be associated physiologic range; and first year of life, reduced growth veloc- with unexpected death by increasing ● monitoring of head circumference ity may not be readily identified, but resting energy expenditure (through at each visit, because GH treatment both controlled clinical trials22,23 and increased muscle bulk) in children can cause abnormal growth of the clinical experience have demonstrated with underlying abnormalities of cen- head, especially if the fontanelles that there is often significant response tral respiratory drive attributable to are open when GH is started. to treatment with GH, primarily in im- PWS, although there is a suggestion in proved lean mass, improved motor de- the literature that treatment with GH Behavioral Food Controls velopment, and normalization of body may be associated with modest im- After the onset of hyperphagia, chil- habitus. Decisions about use of GH provement in the central respiratory dren with PWS may develop a wide therapy and management are best drive.26 range of food-related behaviors, in- made in consultation with a pediatric There is mounting evidence from con- cluding actively seeking food, eating endocrinologist. Although GH treat- trolled clinical trials that GH therapy in nonfood items (eg, animal chow, ment has been approved by the US children improves linear growth, lean spoiled food, decorative items that Food and Drug Administration for chil- mass and lean-to-fat ratio,27 and respi- look like food, searching in garbage dren with PWS older than 2 years with ratory drive,26,28 and there has been cans, etc), stealing money to buy food, documented growth failure, clinical ex- suggestion of beneficial effects on and even running away from home to PEDIATRICS Volume 127, Number 1, January 2011 199 Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 7. search for food in a wider area. Con- behaviors, particularly skin-picking, adults with PWS develop depression, trol of these behaviors is complex but become prominent. In later childhood anxiety, and, in some cases, true psy- centers on strategies to limit access to and the early adolescent years, food- chosis. Parents should be counseled to food (eg, locks on cabinets and refrig- seeking behaviors may increase and identify early indicators of these pro- erators), limit exposures that make are often associated with lying, and oc- cesses to facilitate appropriate medi- the child think about food (eg, birthday casionally stealing, to obtain food. cal intervention. treats sitting on the teacher’s desk Some teenagers with PWS have a dis- during the school day), and instill con- turbing tendency to sneak off to HEALTH SUPERVISION FROM BIRTH fidence that the next meal will be search for food, which is potentially TO 1 MONTH: NEWBORN INFANTS served on time by scrupulously main- quite dangerous and difficult to man- Evaluation taining mealtime routines. Relatives age. Typical of the adolescent years, the and social contacts must be educated teenager with PWS is often overly confi- ● Confirm the diagnosis of PWS (Fig 1) to realize that “sneaking” food to the dent of his or her ability to handle risks and review the implications of the child with PWS is not an appropriate and dangerous situations. It is important molecular testing results with the method of demonstrating affection, to recognize that teenagers with PWS parents. and, in fact, undermines the child’s deal with many of the same neurodevel- ● Review history for: nutritional regimen and sense of opmental and hormonal issues that all ● growth and development; well-being. adolescents encounter, and, similar to ● feeding problems; and their typically developing peers, many of Hypogonadism ● symptoms of obstructive apnea. their behavioral issues seem to stabilize, Both males and females are affected, although not disappear entirely, as they ● Physical examination should in- although the primary external mani- reach adulthood. clude evaluation of: festations in females (clitoral and la- ● hypotonia, and Management of the many complex be- bia minora hypoplasia) may not be ob- havioral issues is best accomplished ● hypogonadism. vious with cursory evaluation. A through an active partnership of the therapeutic trial of human chorionic parents, the primary care provider, Anticipatory Guidance gonadotropin (hCG) is indicated for and a developmental/behavioral spe- ● Review the phenotype, discuss the treatment of undescended testes be- cialist (pediatrician or psychologist). specific findings with both parents fore surgery, because avoidance of Behavioral management that focuses whenever possible, and talk about general anesthesia is desirable for in- on rewarding desired behaviors and potential clinical manifestations as- fants with low muscle tone and poten- tial for underlying respiratory compro- ignoring, when possible, undesirable sociated with the syndrome; these mise. Added benefits of a course of hCG behaviors seems to be most effective. issues may have to be reviewed may include increased scrotal size and Early recognition of developing behav- again at a subsequent meeting. partial normalization of phallus length, ior problems is critical for maximizing ● Point out both early and late feeding thereby improving surgical outcomes the effectiveness of such an approach. Parents should be counseled that of- issues and the dichotomous nature for undescended testes and facilitat- of feeding problems (ie, too little as ing later standing micturition. fering food as a reward or withholding food as a punishment is almost always a neonate, too much as an older Behavior Management counterproductive and should be child), and, as appropriate, discuss avoided. Positive reinforcers are gen- use of nasogastric feedings with in- As the child with PWS ages, there is a creased caloric-density formula to progression of behavioral issues, erally not difficult to identify, and re- ward systems that use small, short- minimize volume and use of special many of which can be anticipated, nipples/feeders (eg, Pigeon feeder, identified early, and managed pro- term goals that progress to larger goals are quite effective. Haberman nipple, other nursers de- spectively. Early childhood is often signed to reduce work of sucking). characterized by rigidity, particularly Finally, young adults with PWS seem to Special attention should be paid to: related to daily routines and long-term be prone to a variety of compulsive be- persistence of temper tantrums and haviors including smoking cigarettes, ● avoidance of prolonged oral feed- oppositional behaviors typical of the and some of them develop frank ing time (usually not 20 min- normally developing 2-year-old. Later, obsessive-compulsive disorder. Like- utes per feeding); perseverant speech and compulsive wise, a significant minority of young ● transition from tube feeding; 200 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 8. FROM THE AMERICAN ACADEMY OF PEDIATRICS ● maintenance of adequate caloric ● Monitor time/work of feeding and ● benefits of early behavioral mon- intake; and caloric density of foods to maintain itoring and establishment of rou- ● development of appropriate eat- appropriate growth. tines; and ing habits; discuss the impor- ● Perform developmental evaluation, ● importance of limit-setting and tance of normal fat and calorie and refer to early-intervention ser- enforcement. intake for brain development vices (if not already done). ● At 6 to 12 months of age, review the (some parents may start restrict- ● Evaluate boys for undescended tes- psychological support and in- ing too early). tes (or cryptorchidism) and ingui- trafamily relationships, including ● Refer infants to early-intervention nal hernia; consider trial of human long-term planning, financial plan- services in the community. chorionic gonadotropin injections ning, and guardianship; reinforce (may be performed in conjunction need for parents to work in partner- ● Discuss the importance of stimulat- with pediatric endocrinologist); re- ship, and discuss early relationship- ing the infant, because he or she is counseling for parents if problems fer to pediatric urologist or a urolo- likely to be undemanding. arise. gist who has special expertise and ● Inform the family of the availability experience with infants with disabil- ● Review early-intervention services of support and advice from the par- ities if the infant’s testes are relative to the strengths and needs ents of other children with PWS. abnormal. of the infant and family. ● Supply contact information for PWS ● Check the infant’s vision at each ● Review the family’s understanding support groups (see “Resources for visit by using developmentally ap- of the risk of recurrence of PWS Parents”). propriate subjective and objective and the availability of prenatal ● Point out the strengths of the child criteria; if evidence of strabismus diagnosis. and positive family experiences. or other concern arises, refer the ● Discuss increased risk of seizures ● Discuss individual resources for sup- infant to a pediatric ophthalmolo- during childhood (5%–10% of those port, such as family, clergy, and gist or an ophthalmologist who has with PWS), which may be associated friends. special expertise and experience with fever and are generally respon- with infants with disabilities. sive to monotherapy. ● Talk about how and what to tell ● Administer vaccines recommended other family members and friends; HEALTH SUPERVISION FROM 1 TO 5 for all children unless there are spe- review methods of coping with long- YEARS: EARLY CHILDHOOD cific contraindications. term disabilities. ● Assess the emotional status of par- Evaluation ● Review the recurrence risk in sub- ents and intrafamily relationships; ● Obtain a history and perform a sequent pregnancies and the avail- physical examination with attention educate and support siblings and ability of prenatal diagnosis and ge- to growth and developmental sta- discuss sibling adjustments. netic counseling. tus. PWS-specific growth curves ● Give overview of the long-term Anticipatory Guidance should only be used for children management plan. ● Review feeding issues (see above) who are not treated with GH; regular and the infant’s growth and devel- curves should be used for children HEALTH SUPERVISION FROM 1 who are treated with GH. opment relative to other children MONTH TO 1 YEAR: INFANCY with PWS. ● Feeding issues: monitor food intake and behaviors, and consider refer- Evaluation ● Review GH deficiency and review ral to dietitian who has experience ● Review and note clinical features benefits and potential risks of GH with PWS; calorie needs must be and confirm diagnosis, if not done therapy; consider referral to pediat- based on growth rate and are usu- previously. ric endocrinology specialist. ally less than those for similarly ● Review routine health maintenance. ● Discuss: sized children without PWS. ● Plot growth by using standard ● need for careful dietary manage- ● Annual hearing and vision screen- pediatric growth charts, and pay ment later in childhood; ing evaluation before 3 years of age; special attention to weight-for- ● probability of mild-to-moderate refer the child to a pediatric oph- length measurements. cognitive impairment; thalmologist or ophthalmologist PEDIATRICS Volume 127, Number 1, January 2011 201 Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 9. who has special expertise and expe- ● Discuss need for all family mem- ● Discuss socialization, family status, rience with children with disabili- bers, child care providers, and and relationships, including finan- ties for a thorough evaluation for school staff members to learn cial arrangements and guardian- ocular findings during the second about the disorder, the need for ship; begin discussion of adult living or third year of life or earlier if there strict food management, and devel- arrangements; advise parents to is evidence of cataracts, nystagmus, opment of routines. consider joining waiting list for or strabismus. ● Discuss future pregnancy planning, placement in a group home specifi- ● Evaluate annually for scoliosis, and risk of recurrence of PWS, and pre- cally organized for people with PWS regularly assess muscle tone; refer natal diagnosis; remind parents of and recognize that placement may to pediatric orthopedist for man- positive aspects for typically func- take several years (or more). agement of scoliosis as indicated. tioning children of having a sibling ● Discuss the development of age- ● Discuss reduced salivation and in- with special needs. appropriate social and self-help creased caries risk by 1 year of age; skills and the development of a HEALTH SUPERVISION FROM 5 TO sense of responsibility. refer to a pediatric dentist or a gen- 13 YEARS: LATE CHILDHOOD eral dentist who has special train- ● Discuss psychosexual development, ing to manage children with special Evaluation physical and sexual development, needs; consider need for more- ● Obtain a history, and perform a menstrual hygiene and manage- frequent dental cleanings (every physical examination with attention ment, fertility, and contraception; 3– 4 vs every 6 months) because of to growth and developmental sta- explain that people with PWS often the increased caries risk. tus; evaluate for scoliosis. have strong feelings of desire for an infant. ● Ask about symptoms related to ob- ● Specifically evaluate for behavior is- structive sleep apnea, including sues that may arise in this age ● Discuss symptoms related to ob- snoring, restless sleep, and exces- group, including binge-eating, run- structive sleep apnea, including sive daytime sleepiness; refer to a ning away, and worsening of snoring and restless sleep, and sleep or pulmonary specialist as skin-picking. evaluate for signs of excessive day- indicated. time sleepiness; refer to a sleep or ● Perform vision screening annually pulmonary specialist as indicated. with attention to recurrence of Anticipatory Guidance strabismus. ● Discuss increased pain tolerance ● Review early intervention, including common in people with PWS, particu- ● Perform thyroid-screening tests ev- physical therapy, occupational ther- larly with regard to evaluating for ill- ery 2 to 3 years or if symptomatic. apy, and speech therapy, in the pre- ness or injury; special attention ● Look for signs of premature adren- should be given to risk of intestinal school program and discuss future arche (which often occurs without necrosis after binge-eating, because school placement and performance. progression of other aspects of pre- the high pain tolerance can mask ● Assess the child’s behavior, discuss cocious puberty; thus, reassurance symptoms and delay treatment, behavioral management, and ask is often the only intervention which can lead to death; people with specifically about common behav- needed). PWS rarely vomit, so parents should iors seen in those with PWS (eg, ● Discuss management of skin- be aware that vomiting after binge- skin-picking, temper tantrums, picking (primarily behavioral; medi- eating can be an ominous sign. food-seeking, etc), which may begin cations, including topiramate, are during this period. used only in the most severe cases). HEALTH SUPERVISION FROM 13 TO ● Discuss sibling adjustments, social- 21 YEARS OR OLDER: ization, and recreational skills. Anticipatory Guidance ADOLESCENCE TO EARLY ● Encourage families to establish op- ● Review the child’s development ADULTHOOD timal dietary and physical exercise and appropriateness of school Evaluation patterns to prevent obesity; sched- placement and developmental intervention. ● Perform physical examination with ule annual (or more often) meetings particular emphasis on evidence of: with dietitian to review caloric in- ● Continue to stress the need for di- take and suggest ways to provide etary management and daily exer- ● heart failure; less calorically dense foods. cise to avoid obesity. ● peripheral edema; 202 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 10. FROM THE AMERICAN ACADEMY OF PEDIATRICS ● skin-picking (perianal areas and sumed to be infertile, although the through adult life (eg, the medical intertriginous folds should be possibility of fertility should always geneticist); when new providers are examined); and be considered. needed, the transferring physician ● scoliosis. ● Discuss sexuality and socializa- should clearly communicate the tion, the need for and degree of person’s needs, and care should ● Evaluate diet, caloric intake, and ex- supervision and/or the need for overlap until all providers, as well ercise program, and stress obesity contraception. as patients and their family, are prevention; initiate weight-loss comfortable with the care needed. strategy if needed. ● Explain to the patient and her family ● Vision screening should be per- the risk of genetic abnormalities if RESOURCES FOR PARENTS formed annually. she were to become pregnant. Prader-Willi Syndrome Association, ● Look for early signs of developing ● Discuss group homes and 8588 Potter Park Dr, Suite 500, Sara- psychosis or increasing obsessive- independent-living opportunities sota, FL 34238; telephone: 800-926-4797 compulsive behaviors seen in a mi- specifically for people with PWS, or 941-312-0400; fax: 941-312-0142; nority of patients (risk is apparently workshop settings, and other Web: www.pwsausa.org higher in cases attributable to UPD community-supported employment Foundation for Prader-Willi Research than deletion, but may occur with (group homes specifically designed Canada (formerly Canadian Prader- either of them). for people with PWS are desirable, Willi Syndrome Organization), 19- but they often have long waiting 13085 Yonge St, Suite 370, Richmond ● Evaluate pubertal status and con- lists, so applying during the adoles- Hill, Ontario, Canada L4E 0K2; tele- sider referral to pediatric endocri- cent years is helpful in securing a phone: 866-99-FPWRC (866-993-7972); nology for discussion about pros spot for the future). Web: www.onesmallstep.ca and cons of sex hormone therapy. ● Discuss intrafamily relationships, fi- Foundation for Prader-Willi Research, Anticipatory Guidance nancial planning, and guardianship. 104 Hume Ave, Alexandria, VA 22301; ● Discuss skin care, especially in the ● Facilitate transfer to adult medical telephone: 703-683-7500; fax: 703-836- presence of truncal obesity. care. 0959; Web: www.fpwr.org ● Discuss issues related to transition International Prader-Willi Syndrome into adulthood. TRANSITION TO ADULT CARE Organisation, Web: www.ipwso.org ● Identify health care providers in the ● Discuss possible compulsive behav- LEAD AUTHOR community who are willing to learn iors, including use of tobacco. Shawn E. McCandless, MD – Section on about the special situations of peo- Genetics and Birth Defects Member ● Discuss appropriateness of school ple with PWS; ideally, use providers placement, and emphasize ade- with training or experience in the COMMITTEE ON GENETICS, 2010 –2011 quate vocational training within the care of people with special needs. Howard M. Saal, MD, Chairperson Stephen R. Braddock, MD school curriculum while keeping in ● Regular evaluation is needed for: Gregory Enns, MB, ChB mind the special issues related to Jeffrey R. Gruen, MD the need to scrupulously avoid expo- ● weight control (maintenance or James M. Perrin, MD sure to opportunities to obtain food. loss); Robert A. Saul, MD Beth A. Tarini, MD ● Provide information on how to rec- ● diabetes; LIAISONS ognize the signs of psychosis. ● hypertension; W. Allen Hogge, MD ● Discuss the need for gynecologic ● sleep apnea; American College of Obstetricians and care for pubescent girls. Talk about Gynecologists ● heart failure; James W. Hanson, MD – American College of the risk of Angelman syndrome (at- Medical Genetics – Eunice Kennedy Shriver ● peripheral edema; and tributable to deletion of maternally National Institute of Child Health and Human inherited chromosome 15q11-13) ● behavior management, including Development the use of medications such Michele A. Lloyd-Puryear, MD, PhD – Health with the patient and her family if she Resources and Services Administration were to become pregnant; review as selective serotonin-reuptake Sonja A. Rasmussen, MD, MS – Centers for the fact that there have been 2 case inhibitors. Disease Control and Prevention reports in which a woman has re- ● Some providers may continue to STAFF produced. Men with PWS are as- care for the person with PWS Paul Spire PEDIATRICS Volume 127, Number 1, January 2011 203 Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 11. REFERENCES 1. Prader A, Labhart A, Willi A. Ein syndrom von lation in a series of 167 deletion and non- mone and Prader-Willi syndrome. In: Butler adipositas, kleinwuchs, kryptorchismus deletion patients with Prader-Willi syn- MG, Lee PDK, Whitman BY, eds. Management und oligophrenie nach myotonieartigem drome. Hum Genet. 1995;96(6):638 – 643 of Prader-Willi Syndrome. 3rd ed. New York, zustand im neugeborenenalter [in Ger- 12. Gunay-Aygun M, Heeger S, Schwartz S, NY: Springer; 2006:201–244 man]. Schweiz Med Wochen. 1956;86:1260 Cassidy SB. Delayed diagnosis in patients 23. Eiholzer U, Schlumpf M, Nordmann Y, 2. Driscoll DJ, Waters MF, Williams CA, et al. with Prader-Willi syndrome due to maternal l’Allemand D. Early manifestations of A DNA methylation imprint, determined by uniparental disomy 15. Am J Med Genet. Prader-Willi syndrome: influence of growth the sex of the parent, distinguishes the An- 1997;71(1):106 –110 hormone. 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Unexpected death and critical illness in able at: www.pediatrics.org/cgi/content/ Trends Genet. 1998;14(10):417– 422 Prader-Willi syndrome: report of ten individ- full/109/2/e35 11. Gillessen-Kaesbach G, Robinson W, Lohm- uals. Am J Med Genet A. 2004;124A(2): 31. Höybye C, Thorén M. Somatropin therapy in ann D, Kaya-Westerloh S, Passarge E, 158 –164 adults with Prader-Willi syndrome. Treat Horsthemke B. Genotype-phenotype corre- 22. Carrel AL, Lee PDK, Mogul HR. Growth hor- Endocrinol. 2004;3(3):153–160 204 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on February 4, 2012
  • 12. Clinical Report−−Health Supervision for Children With Prader-Willi Syndrome Shawn E. McCandless and THE COMMITTEE ON GENETICS Pediatrics; originally published online December 27, 2010; DOI: 10.1542/peds.2010-2820 Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2010/12/27 /peds.2010-2820 Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Reprints Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from pediatrics.aappublications.org by guest on February 4, 2012