Prader Willi syndrome often has a rather confusing clinical presentation and many referrals do not fulfill the diagnostic criteria. Identification of appropriate patients for testing remains a challenge for clinicians because many features of the disorder are not specific, while others are subtle or evolve over time [12]. In the present series only 35% of the referred PWS cases had typical presenta­tion of the syndrome, while the remaining had obesity, hypotonia or mental retardation of other etiology. This is in concordance with previous reports that PWS is often inaccurately suspected in obese and mentally retarded patients [12]. In the present study, 30% of newborns with hypotonia were shown to have PWS, while the rest either developed various neurological or metabolic diseases or were normal. Molecular alterations were also identified in 15% of the non typical PWS cases. This is comparable with the 16.7% frequency reported in the literature [12] and supports the idea that revision of the criteria for PWS according to age may be warranted [12]. Most of our AS patients (56%) had a characteristic behavioral phenotype and facial features [13].

In agreement with previous reports, this study indi­cates that molecular abnormalities in PWS and AS are in most cases de novo deletions [2]. In general, smaller dele­tions were detected in PWS (Figs. 1 and 2). Non typical presentation without obesity and short stature was ob­served in one patient with PWS who had a deletion inside the critical region. The other six patients with molecular findings and non typical presentation were younger than 3 years old, and it is possible that they had not as yet devel­oped the full phenotype. In all AS patients with detected deletions, the deletion included the region between the D15S11 and D15S10 loci, where the UBE3A gene has been mapped [13]. Six out of 10 patients with deletion of the GABRb3 locus presented with spasms. The GABA_A (g-aminobutyric acid) receptor b₃ subunit is one of the major inhibitory neurotransmitters in the mammalian brain, and both in vivo and in vitro studies indicate that it is involved in the suppression of seizure activity [14].

Deletions near the D15S113 marker with normal bi­parental inheritance of the other markers were detected in four out of 28 PWS patients. The clinical presentation of PWS in 54 and 39 patients was non typical with mild behavioral problems, learning difficulties and insignificant obesity or short stature. It has been reported that some times an unamplified allele in the D15S113 locus may be misinterpreted as a small deletion. In our cases, however, heterozygosity in both parents excluded the possibility of a “null” allele [15].

The incidence of PWS and AS among twins is very rare, although there are only a few relevant reports in the literature [16-18]. In our series there was a pair of identi­cal twin PWS boys with a deletion of the paternal alleles in the 15q11-13 region, who had neonatal hypotonia, obe­sity after the fifth year and were developmentally delayed. There was also a pair of identical twin girls with AS who were born after in vitro fertilization (IVF) and were both severely retarded, with spasms and absence of speech. Both of them had a deletion of the maternal alleles in the 15q11-13 region. Increased maternal age is often the rea­son for referral for IVF, as was the case in our AS twins, and there is a positive relationship between maternal age and non-disjunction [19]. According to the literature, non-disjunction is also increased in experimental models in IVF due to in vitro conditions. After chromosome 21, chromosome 15 is the most commonly involved chromo­some in this type of aneuploidy [19].

Clinical evaluation of patients referred for investiga­tion of PWS and AS should always be performed by a specialist to classify patients as typical or non typical. Molecular investigation using DNRP or methylation tests would be necessary for all patients. Although only few patients had cytogenetic findings, it is worthwhile to per­form a karyotype analysis in all patients, since the detec­tion of possible chromosomal aberrations may be impor­tant in family counseling. In uninformative patients FISH analysis could detect deletions in some cases.