Diagnostic Criteria for Prader-Willi Syndrome 2

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2

Diagnostic Criteria for Prader-Willi Syndrome

Shawn E. McCandless and Suzanne B. Cassidy

Diagnostic criteria for Prader-Willi syndrome (PWS) were originally established in 1993 by consensus of a group of highly experienced physicians and psychologists.⁷ These criteria were developed to care- fully establish the basis for diagnosis to allow for accurate management and genetic counseling, and to ensure uniform clinical diagnosis for future molecular investigations in defi ning the cause of the syndrome and development of diagnostic tests. As diagnostic testing with FISH (fl uorescence in situ hybridization) and other molecular techniques became a reality, the validity of the criteria was confi rmed.3,4,5,8,13,18 At the same time, the need for precise clinical diagnostic criteria was superseded by the need for guidelines to identify appropriate indica- tions for molecular testing.⁶ Today, this is the most important use of diagnostic criteria. This chapter will review the diagnostic criteria, evaluate the current status of these criteria, and review approaches to diagnosis in light of the natural history of the disorder. The goal of diagnostic criteria now should be to maximize early identifi cation while limiting costs for unnecessary testing.

Diagnosing Prader-Willi Syndrome Using Diagnostic Criteria

The diagnostic criteria developed in 1993 through a consensus process are shown in Table 2.1.⁷ Clinical diagnosis is based on a scoring system that assigns one point each for major criteria and one half point for minor criteria. The diagnosis is confi rmed in an individual of 3 years or older when at least fi ve major criteria are present and there is a total of at least eight points. Because many of the diagnostic criteria are not present in the fi rst several years of life, diagnosis in a child under 3 years of age requires the presence of only four major criteria and at least fi ve total points.

Experience demonstrated that the diagnostic criteria allowed for con- ﬁ dence that the diagnosis was correct but that they did not conﬁ rm the diagnosis in some individuals who truly did have the disorder.⁵ This

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Table 2.1. Consensus Diagnostic Criteria for Prader-Willi Syndrome*

Major criteria

1. Neonatal and infantile central hypotonia with poor suck, gradually improving with age 2. Feeding problems in infancy with need for special feeding techniques and poor weight gain/

failure to thrive

3. Excessive or rapid weight gain on weight-for-length chart (excessive is deﬁ ned as crossing two centile channels) after 12 months but before 6 years of age; central obesity in the absence of intervention

4. Characteristic facial features with dolichocephaly in infancy, narrow face or bifrontal diameter, almond-shaped eyes, small-appearing mouth with thin upper lip, down-turned corners of the mouth (3 or more required)

5. Hypogonadism—with any of the following, depending on age:

a. Genital hypoplasia (male: scrotal hypoplasia, cryptorchidism, small penis and/or testes for age [<5^th percentile]; female: absence or severe hypoplasia of labia minora and/or clitoris) b. Delayed or incomplete gonadal maturation with delayed pubertal signs in the absence of intervention after 16 years of age (male: small gonads, decreased facial and body hair, lack of voice change; female: amenorrhea/oligomenorrhea after age 16)

6. Global developmental delay in a child younger than 6 years of age; mild to moderate mental retardation or learning problems in older children

7. Hyperphagia/food foraging/obsession with food

8. Deletion 15q11–q13 on high resolution (>650 bands) or other cytogenetic/molecular abnormality of the Prader-Willi chromosome region, including maternal disomy Minor criteria

1. Decreased fetal movement or infantile lethargy or weak cry in infancy, improving with age 2. Characteristic behavior problems—temper tantrums, violent outbursts and obsessive/

compulsive behavior; tendency to be argumentative, oppositional, rigid, manipulative, possessive, and stubborn; perseverating, stealing, and lying (5 or more of these symptoms required)

3. Sleep disturbance or sleep apnea

4. Short stature for genetic background by age 15 (in the absence of growth hormone intervention)

5. Hypopigmentation—fair skin and hair compared to family

6. Small hands (<25^th percentile) and/or feet (<10^th percentile) for height age 7. Narrow hands with straight ulnar border

8. Eye abnormalities (esotropia, myopia)

9. Thick, viscous saliva with crusting at the corners of the mouth 10. Speech articulation defects

11. Skin picking

Supportive ﬁ ndings (increase the certainty of diagnosis but are not scored) 1. High pain threshold

2. Decreased vomiting

3. Temperature instability in infancy or altered temperature sensitivity in older children and adults

4. Scoliosis and/or kyphosis 5. Early adrenarche

6. Osteoporosis

7. Unusual skill with jigsaw puzzles 8. Normal neuromuscular studies

* Scoring: Major criteria are weighted at one point each. Minor criteria are weighted at one half point. Children 3 years of age or younger: Five points are required for diagnosis, four of which should come from the major group.

Children 3 years of age to adulthood: Total score of eight is necessary for the diagnosis. Major criteria must comprise ﬁ ve or more points of the total score.

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was further confi rmed in a critical review of the diagnostic criteria by Gunay-Aygun et al.,⁶ who showed that 15 of 90 patients with a molecularly confi rmed diagnosis of PWS did not meet the requirements of the diagnostic criteria. The authors pointed out that the criteria were developed to precisely identify affected individuals for counseling and for involvement in studies to develop molecular tests. Now that highly sensitive and specifi c molecular testing is available, the purpose of diagnostic criteria has shifted to identifying those individuals for whom diagnostic testing is indicated.⁶ Therefore, new criteria were suggested to prompt specifi c genetic testing for PWS (see Table 2.2). Other authors¹⁸ have identifi ed “core” criteria, the absence of any one of which strongly predicts negative molecular genetic testing. These criteria are: a weak suck in the neonatal period, a weak cry and reduced activity in the neonatal period, absence or rarity of vomiting, and thick saliva. Again, the presence of these criteria is age dependent, limiting their usefulness in the very young patient.

The new criteria shown in Table 2.2 take into account the evolving clinical course of the disorder. Recognition of the natural history of a condition is especially important now that speciﬁ c management strategies are known to alter the long-term consequences of the disorder.

Other chapters in this book will document the importance of early diagnosis in maximizing potential growth and performance in individuals with PWS while minimizing long-term complications.

As noted previously, there are two distinct phases recognized in the life of an individual with PWS. The ﬁ ndings associated with these two phases affect the likelihood that an individual with PWS will satisfy

Table 2.2. Proposed Revised Criteria To Prompt Diagnostic Testing for Prader-Willi Syndrome

Age Features Suggesting PWS

Birth to 2 years Hypotonia and weak suck

Early childhood Appropriate neonatal history of hypotonia and weak suck

Global developmental delay

Later childhood Appropriate neonatal history of hypotonia and weak suck

Global developmental delay

Excessive appetite and lack of satiety

(hyperphagia), obesity (if food not limited) Adult Mild or borderline mental retardation

Excessive appetite and lack of satiety (hyperphagia), obesity (if food not limited)

Hypothalamic hypogonadism

Typical behavior (especially obsessive-compulsive features, skin picking, or temper tantrums) Adapted from M. Gunay-Aygun et al., Pediatrics, 2001;108(5):E92.⁶

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the diagnostic criteria. Phase 1 begins in the uterine environment with decreased fetal movement and a high rate of malposition (breech), leading to the need for uterine manipulation (e.g., external version to move the breech fetus to a headﬁ rst position for delivery) and surgical delivery (Caesarian section). In the newborn and in early infancy there is profound hypotonia, excessive sleepiness, failure to wake for feeding, and lack of crying. This is generally accompanied by a poor or weak suck, difﬁ culty latching on to the breast leading to high failure rate for breast-feeding, poor intake from a bottle, and poor weight gain. Most infants require tube feedings for weeks to months, rarely persisting beyond 6 to 9 months, in order to avoid or minimize the poor weight gain.

Of the eight major diagnostic criteria put forward by the consensus group,⁷ only four relate to clinical ﬁ ndings found in the ﬁ rst 2 years of life (numbers 1, 2, 4 and 5 in Table 2.1). Another major criterion, presence of a cytogenetic abnormality, may be found in some but is unlikely to be found unless the diagnosis of PWS is already being considered.

Therefore, the diagnostic criteria are much less useful in the fi rst 2 years of life, at the time when the proper diagnosis is critical for early intervention to prevent complications. This recognition of the limitations of the original diagnostic criteria has prompted the current recommenda- tion that testing be considered for all infants with hypotonia and a poor suck (Table 2.2). PWS appears to be one of the most common identifi - able causes of marked neonatal hypotonia. This was shown in a German study that identifi ed PWS, confi rmed molecularly, in 29 of 65 hypotonic infants tested.⁵ This was subsequently confi rmed by Richer et al.¹⁶ in an 11-year retrospective study of newborns admitted to the neonatal intensive care unit of a children’s hospital, which showed that PWS was second only to hypoxia as a cause of hypotonia (6 of 33 patients with central hypotonia).

The differential diagnosis in the ﬁ rst phase of neonatal hypotonia includes a wide variety of other chromosomal rearrangements that are mostly detectable by high resolution chromosome analysis or subtelomeric FISH in addition to spinal muscular atrophy type I (Werdnig- Hoffmann disease), congenital myotonic dystrophy, peroxisome biogenesis disorders (e.g., Zellweger syndrome), congenital central nervous system malformations or anoxic injury, and rarely benign congenital hypotonia.¹ Many other disorders may present with congenital hypotonia, most of which are easily distinguished by other clinical ﬁ ndings. The differential diagnosis of infantile hypotonia is beyond the scope of this chapter.

By the later part of the fi rst year and early second year of life, the feeding diffi culties are usually resolving, the infant begins to have better weight gain, and there is slow but steady developmental progress. This “honeymoon period” may last 2 or 3 years before the onset of the second phase of the clinical course of PWS, the hyperphagic phase. At this time recognition of signifi cant developmental delay may bring the child with PWS to medical attention, although there is a tendency to delay diagnostic testing at this point because the feeding

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problems and hypotonia appear to be improving relative to the ﬁ rst year of life.

The second distinct phase in the life of a person with PWS is charac- terized by the onset of excessive appetite, or more accurately, lack of satisfaction of hunger after eating. This is accompanied by a failure to progress beyond several normal behavioral phases of the 2-year-old, including the need for routines in the schedule, difﬁ culty with transi- tions between activities, and rapidly escalating loss of emotional control (tantrums) during disagreements or disappointments. At the same time there may be recognition of unusual food-related behaviors such as foraging or hoarding food. Often there is obsessive thinking about food and verbal repetition of questions about food (e.g., “When will it be time for lunch?”). The combination of rapid weight gain and behavioral issues often brings the child to medical attention and suggests the diagnosis of PWS to the medical provider. Unfortunately, this often occurs after the child has become massively obese. It is not uncommon to see the plot of the child’s weight on a standard growth curve go from below the 3rd percentile to above the 95th percentile in less than a year.

At this time, the consensus clinical diagnostic criteria are more likely to be positive. The hypogonadism is clearly present, though it may be overlooked by physicians, especially in prepubertal females. It is generally more obvious in males than females because of the high rate of undescended or nonpalpable testes and small penis. The female external genitalia may be underdeveloped, with very small labia minora and clitoris. If not appreciated in childhood, the hypogonadism becomes readily apparent in late adolescence with the lack or arrest of development of secondary sexual characteristics. Interestingly, there is often premature adrenarche, with development of ﬁ ne pubic hair, underarm hair, odoriferous sweat, and sometimes acne.

The characteristic facial appearance is often more readily distinguished in later childhood as well, particularly in the presence of obesity. Anecdotally, it appears that treatment with growth hormone may alter the facial appearance somewhat, making diagnosis more difﬁ cult based on that ﬁ nding. The presence of the minor criteria of short stature and small hands and feet may also be altered by therapy with growth hormone.

Later in childhood the global developmental delay becomes more obvious as the motor issues begin to resolve. In the school-age child speciﬁ c learning strengths and weaknesses may be recognized on the background of global cognitive dysfunction, leading the informed edu- cator to raise the possibility of the diagnosis.

How Sensitive and Speciﬁ c Are the Diagnostic Criteria?

The consensus diagnostic criteria are highly speciﬁ c for the diagnosis in later childhood. There are few convincing reports in the literature of individuals who clearly meet the diagnostic criteria but have normal molecular studies,¹⁸ but it is possible that injury to the developing

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hypothalamus or pituitary could cause some of the typical PWS fi ndings (e.g., Cushing syndrome). Experience suggests that these patients can be distinguished from molecularly confi rmed patients with PWS on the basis of clinical grounds, although we are aware of no confi rmation studies.

The published consensus diagnostic criteria are less sensitive for molecularly confi rmed subjects with PWS. Gunay-Aygun et al.⁶ found that 15 of 90 (16.7%) patients confi rmed by methylation testing or FISH studies did not meet consensus diagnostic criteria. These included 14 subjects with deletions and 1 subject with uniparental maternal disomy, and all were over 3 years of age. Other authors have found better sensitivity.³ Some investigators have tried to refi ne the diagnostic criteria retrospectively by identifying those features found in all confi rmed subjects.¹⁸ These so-called core criteria have not been evaluated prospectively. What is clear from all of these studies, though, is the importance of the characteristic neonatal fi ndings of hypotonia and poor feeding. Absence of these fi ndings makes the likelihood of molecular confi rmation of PWS very low, although validation studies are needed.

Another interesting fi nding by Gunay-Aygun et al.⁶ is the recognition that many of the so-called minor diagnostic features of the consensus criteria (see Table 2.1) are actually more sensitive in identifying PWS than some of the major criteria. Specifi cally, the characteristic facial appearance is not highly sensitive for the diagnosis of PWS, nor does it appear to be highly specifi c.

It seems most appropriate, in light of the highly sensitive and speciﬁ c molecular genetic testing available, to use clinical indicators to help select individuals for laboratory testing. The newer proposed indica- tions, as suggested by Gunay-Aygun et al.,⁶ are shown in Table 2.2.

Several conditions other than PWS are associated with obesity, hyperphagia, developmental delay, and hypotonia in older children and adults. Among the more commonly seen are Albright hereditary osteo- dystrophy (Online Mendelian Inheritance in Man¹⁵ #103580), fragile X syndrome (OMIM #309550), Bardet-Biedl syndrome (OMIM #209900), Alstrom syndrome (OMIM #203800), Cohen syndrome (OMIM #216550), Beckwith-Wiedemann syndrome (OMIM #130650), and other chromosomal rearrangements. Generally, these disorders can be distinguished clinically, although in some cases molecular testing to rule out PWS may be indicated in the process of making another diagnosis of exclu- sion (e.g., some cases of Cohen syndrome). There are other less common syndromes involving obesity and developmental abnormalities that also should be distinguished, but because they are less readily recog- nizable they may require conﬁ rmation that PWS is not the correct diagnosis. These include MOMO (macrosomia, obesity, macrocephaly, ocular abnormalities) syndrome (OMIM #157980), Urban-Rogers- Meyer syndrome (OMIM #264010), and syndromes reported by Camera et al.² and Vasquez et al.¹⁷ In addition, as with neonatal hypotonia, there are a number of chromosomal abnormalities associated with these ﬁ ndings that are detectable by high resolution chromosome analysis and subtelomeric FISH.

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Role of Diagnostic Criteria in the Laboratory Evaluation of PWS

Because of the need for early initiation of appropriate management strategies, diagnostic assessment ideally should occur early in life, when the primary clinical abnormality is profound hypotonia. Finding an individual with infantile hypotonia, for example, should prompt obtaining diagnostic laboratory testing for PWS.

The diagnostic evaluation for possible PWS is most cost-effective when performed in stepwise fashion.¹² The ﬁ rst step is conﬁ rmation of PWS using a methylation-sensitive DNA method, utilizing either methylation-sensitive PCR-based or Southern blotting.^9,10,13 We note that in practice both approaches occasionally have false negative and false positive results, so it is reasonable to consider repeating diagnostic testing using a different methodology in individuals who meet diagnostic criteria but have a previous negative test result. The recently developed diagnostic approach that measures expression of the SNRPN gene by reverse transcription PCR has not yet been shown to be as complete in ascertaining PWS.¹⁴

Once abnormal methylation is established the pattern will deﬁ ne whether the abnormality is consistent with PWS or Angelman syndrome. The next step is to perform FISH analysis to identify microdele- tions of chromosome 15q11–q13 utilizing, at minimum, the SNRPN probe that can identify both the common large deletions as well as some smaller deletions involving the region around the imprinting center. If no deletion is found, the DNA is obtained from the affected individual and both parents, if possible (although it can often be done with DNA from only one parent), for uniparental disomy studies. If this is also normal, then the only remaining explanation for the abnormal methylation pattern is an imprinting defect, which may be inher- ited or a new event (de novo).

As noted elsewhere in this textbook, rarely PWS can result from chromosome translocations involving the PWS critical region of chromosome 15, again with potentially signiﬁ cant implications for recur- rence risk in the parents and extended family. Since full chromosome analysis is also needed if the methylation pattern is abnormal, in order to conduct FISH for the deletion and to rule out a translocation, the authors routinely order chromosome analysis at the same time as PWS methylation analysis. This also serves to identify other chromosomal abnormalities causing a phenotype similar to that of PWS (see, e.g., McCandless et al.¹¹).

Changes in the availability of specifi c molecular testing for PWS make documentation of the specifi c cause mandatory to confi rm the diagnosis and prevent recurrences in those rare families with an inher- ited form of the disorder. Likewise, the development of effective treatment strategies, such as growth hormone therapy, means that early diagnosis is critical to providing the best possible outcome. Therefore, the role of the clinical diagnostic criteria has changed from that of care- fully defi ning the disorder to one of identifying those individuals for whom further testing is indicated. Judicious interpretation of the

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medical literature and further critical study will allow the diagnosis of PWS to be made early in the vast majority of patients while limiting the expense of testing in those at low likelihood of being affected. The priority for testing is in infants with marked hypotonia and feeding problems, two highly sensitive markers of PWS.

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