The Prader Willi Syndrome

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An excellent clinical summary of Prader-Willi syndrome (PWS) is provided in the literature (Holm et al., 1993; Cassidy, 1997). PWS is a multisystemic disorder with numerous manifestations of hypothalamic insufficiency. The neonatal and infantile period is marked by hypotonia, poor suck, feeding problems, and poor weight gain with a failure to thrive. In contrast, between 1 and 6 years of age, excessive weight gain with central obesity occurs, resulting from a voracious appetite. There is global developmental delay, mild to moderate mental retardation, and various learning problems. Characteristic cranio-facial features include dolichocephaly, narrow face or narrow forehead, almond-shaped eyes, small mouth with thin upper lip and downturned corners. Hypogonadism is marked, with hypoplasia of the genitals in both sexes and hypomaturity later on.

The minor diagnostic criteria include poor fetal movements, infantile lethargy, weak cry, and compulsive behavior with tantrums and outbursts. Also of note are sleep disturbances or apnea, short stature, hypopigmentation, small or narrow hands and feet, ocular anomalies, thick but scant saliva, speech articulation defects, and a tendency to skin ''picking.'' Other findings that often support the diagnosis include a high pain threshold, decreased vomiting, body temperature instability, kypho-scoliosis, osteoporosis, early adrenarche, unusual visual-spatial skills as seen from the ability to complete jigsaw puzzles, and normal neuromuscular abilities.

The study of the DNA from PWS patients and their families revealed four different classes of molecular lesions in the 15q11-q13 region (Nicholls et al., 1998; Jiang et al., 1998) as summarized in Table 2. These are: (1) patients with paternally inherited deletions of about 4Mb in the chromosome 15q11-q13 region. The deletions are thought to occur via unequal crossing-over between copies of the HERC2 gene (see Chapter 7, also Ji et al., 1999) and account for 70% of PWS patients. The recurrence risk is extremely low. (2) The category of maternal UPD15 in which no paternally derived alleles are present accounts for approximately 2530% of patients; the recurrence risk is negligible, unless there is a parental translocation that predisposes to UPD15. It is of interest that maternal UPD15 is

TABLE 2 Molecular Subclassification of PWS (according to Nicholls et al., 1998)

PWS

Recurrence

Class

Chr15 Mechanism

Frequency

Methylation

Risk

I

Paternal deletion 15q11—q13

70%

Abnormal

Extremely low

II

Maternal UPD15

25-30%

Abnormal

Extremely low

IIIa

Imprinting mutation with IC deletion

1-2%

Abnormal

Significant

Illb

Imprinting mutation without IC deletion

1-2%

Abnormal

Low

IV

Balanced translocation involving 15q11—q13

<1%

?

Significant

much more common than paternal UPD15 which results in AS. This is probably due to the higher rates of maternal nondisjunction that results in trisomy 15 which is subsequently ''corrected'' to maternal UPD15 and loss of the paternally derived chromosome. (3) Another fraction of PWS patients, approximately 1-3%, shows ''imprinting'' mutations in which there is a maternal type of methylation on 15q11-q13 loci from the paternally inherited chromosome 15. In about half of these patients, there is a small deletion of the telomeric portion of the bipartite imprinting center (IC) at exon 1 of the SNRNP gene, which causes the inability to establish the normal methylation status (subcategory IIIa) (Ohta et al., 1999). The recurrence risk of these small deletions is high because most such cases are familial. The subcategory IIIb consists of cases with imprinting mutations but without any detectable deletion in the IC region. Their molecular mechanism is unknown, but their recurrence risk is low (Ohta et al., 1999). (4) There are a few rare PWS cases with a balanced translocation in 15q11-q13; the mechanism of PWS in these cases is unknown but it might involve a disruption of chromatin structure (Saitoh et al., 1997).

Phenotype-genotype correlations in PWS In order to detect phenotypic differences between PWS patients with different types of molecular lesions on chromosome 15q, analysis of a series of 167 cases, including 116 deletions and 51 nondeletion cases, was performed (Gillessen-Kaesbach et al., 1995). The diagnosis of the nondeletion cases was based on the methylation test. In the nondeletion group, molecular methods did not distinguish between maternal UPD15 and the rare cases of IC (imprinting center) mutations. No substantial (statistically proven) differences were found between the deletion and nondeletion cases. Weight and length of newborn PWS patients were significantly lower than those of healthy controls, but head circumferences were normal; however, male and female deletion cases had lower birthweights than nondeletion cases. The frequency of hypopigmentation was also different between the molecular classes, being present in about 50% of deletion cases (48 of 93) and only 25% (9 of 39) of nondeletion cases (Gillessen-Kaesbach et al., 1995).

There is an increase in maternal age in nondeletion cases as expected, since both trisomy rescue and gamete complementation follow maternal 15 meiotic nondisjunc-tion. In one study of 128 cases with maternal UPD15, the mean maternal age was 34.9 versus 28 years in the general population (Robinson et al., 1998). Similarly in another study, the average maternal age was increased (34.4 years) among 17 PWS patients with maternal UPD15, as compared to 26.8 years in 37 PWS patients with deletions (Cassidy et al., 1997).

In another series of PWS patients, FISH for D15S11, SNRPN, or GABRB3 was used to detect chromosome 15 deletions and microsatellite analysis using at least six markers to detect maternal UPD15 (Cassidy et al., 1997). Statistically significant differences in the occurrence of PWS symptoms between 37 PWS patients with deletion of chromosome 15 and 17 PWS with maternal UPD15 cases were not observed, except for two features: The first was a trend to hypopigmentation, present in 50% of the cases with deletion compared to 15% with maternal UPD15. The second feature that may reflect the thorough and expert clinical dysmorphology assessment relates to facial appearance, which was judged to be somewhat less characteristic in UPD15 cases (typical facies in 10 of 17) than in deletions (33 of 36). The characteristic narrow frontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, and downturned mouth were less often present in maternal UPD15 cases of PWS (Cassidy et al., 1997). Skin picking, high pain threshold, jigsaw puzzle skills, and articulation abnormalities were also more commonly reported in the deletion cases, although the differences were not statistically significant.

The age at diagnosis was also delayed in PWS patients with UPD15. In males, the mean age of diagnosis was 9 years in PWS with UPD15 versus 4 in PWS with deletions; in females, the ages were 9 versus 2, respectively, also suggesting a milder phenotype in maternal UPD15 versus deletion 15 PWS cases.

Significant differences were observed between females PWS with maternal UPD15 and those with deletions 15, particulary in the length of gavage feeding and a later onset of hyperphagia (Mitchell et al., 1996). These features suggest a milder presentation in the female UPD15 group. In both deletion 15 and UPD15 PWS patients, the length of time of gavage feeding was shorter in female than male babies (Cassidy et al., 1997).

A study of sleep anomalies, including onset of REM periods and excessive daytime sleepiness, did not reveal a consistent significant association with one or the other molecular type of PWS, although such disturbances were more common in patients with paternal deletions (Vgontzas et al., 1996).

The differences in the phenotypes of PWS patients with varying genomic alterations may result from factors such as: (i) preservation of the biallelic expression of nonimprinted gene pairs in UPD15 versus hemizygous expression in deletion (haploinsufficiency for nonimprinted loci); (ii) lack of possible interactions between regions of imprinted domains when deletions are present (LaSalle and Lalande, 1995, 1996); (iii) homozygosity for recessive alleles in the case of maternal isodisomy UPD15.

The molecular laboratory analysis of the 15q11-q13 region (methylation, FISH, and microsatellite analysis) of patients suspected to have PWS has contributed to the recognition of a phenotypic spectrum much broader than that with the consensus diagnostic criteria (Holm et al., 1993). Thus, among 50 cases, 35 with deletions of the 15q11-q13 region, 11 with maternal UPD15, and 4 with maternal methylation, nearly one-half had unusual findings. These consisted of normal height (seven cases), normal puberty (two cases), normal cognitive ability (five cases), and minimal speech acquisition (three cases). Macro- and microcephaly occurred in four and two cases, respectively, while other malformations such as gastroschisis, hypospadias, cataract, autism, and kidney stones were observed in single cases (Cassidy et al., 1997).

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