Mosaic in PWS appears to be very rare and there are few reports. Izumi et al. [
15] reported two infants with PWS caused by mosaic maternal UPD15. Patient 1 has mosaic uniparental isodisomy of the entire chromosome 15, and Patient 2 has mosaic uniparental mixed iso/heterodisomy 15. Wey et al. [
16] reported a young woman with an almost typical expression of the PWS due to a mosaic imprinting defect. Huang et al. [
17] reported a mosaic de novo
SNRPN gene variant in a 10-year-old girl who presented with phenotypes that are consistent with the clinical diagnosis of PWS. We know of only two cases of mosaicism of the proximal 15q deletion [
18,
19]. On one hand, this may be because that patients with a high proportion of normal cells have milder features, which result in missed diagnosis. On the other hand, it is due to the widespread use of non-quantitative assays to determine methylation status. Our case is interesting mainly because it reports a rare case of PWS caused by a mosaic deletion in the 15q11.2-q13 region of paternal origin. It can enrich the clinical understanding of the atypical clinical phenotype of PWS patients caused by chimerism deletion, help clinical early diagnosis and intervention of the disease, so as to improve the quality of life of patients.
The clinical manifestations of PWS are complex and diverse, covering growth, development, metabolism and other aspects in the life process. Patients in different age groups have different manifestations. For example, one of the typical symptoms in patients, severe obesity due to overeating if uncontrolled, usually occurs between 1 and 6 years of age, so differential diagnosis should be made according to the clinical characteristics of the corresponding age group [
1,
5,
20,
21]. In addition, PWS has clinical overlap with other disorders, particularly those with other genetic variants or chromosomal imbalances but with a partially similar clinical presentation to PWS. Sometimes they are referred to as Prader-Willi syndrome-like (PWS-like) [
10,
22,
23]. The mosaic of PWS makes phenotypic prediction more difficult. This is not difficult to find by reviewing the clinical phenotypes of previous mosaic deletion cases. Boyd et al. [
18] reported a female with clinical features typical of PWS. The karyotype from blood lymphocytes is written as follows: 45,XX, der(1)t(1;15)(p36.3;q12)[50] /46,XX,der(1)t(1;15)(p36.3;q12),+idic(15)(q12)[50]. The methylation studies of exon 1 of SNRPN were normal. The distribution of the deleted cell line appears sufficient to induce the classic PWS symptoms expressed in the individual. Anderlid et al. [
19] reported an atypical male patient who had no hypotonia or feeding problems during infancy. There was no formal cognitive assessment during childhood or adolescence, and no apparent behavioral manifestations. At the age of 37, PWS was diagnosed after a visit for nightly sweats and a normocytic normochromic anemia. Our patient had a history of intrauterine hypoxia, a weak cry at birth, and poor spirit. Although no special feeding was required, there was no weight gain for the first month after birth. The patient’s weight, height and head circumference at each stage of growth were below or equal to the average growth standard for same age and sex [
24]. The patient’s birth weight was in the 50th centile of the PWS neonatal percentiles may be a further feature supporting the suspicion of neonatal PWS [
25]. He is currently 10 months old, unable to roll over and sit alone, and his deciduous teeth have not erupted. Examination of hypotonia, simian crease, exceptional facial features. Our patient did not show the typical clinical features of PWS, partly because the mosaic deletion rescued part of the clinical phenotype, and partly because the patient was still young and some clinical manifestations were not yet apparent. A retrospective study [
9] of 90 patients with PWS confirmed by genetic testing found that 15 of the 90 molecularly diagnosed patients did not meet the clinical diagnostic criteria, suggesting that the existing clinical diagnostic criteria may be too exclusionary and suggesting that the clinical diagnostic criteria should be modified to raise diagnostic suspicion at a lower threshold to ensure that all appropriate individuals are tested. This is consistent with the cases we reported and emphasizes the important role of diagnostic tests in confirming the diagnosis of clinically atypical cases.
At present, there is no clear conclusion on the relationship between the proportion of chimerism and the specific phenotypic characteristics of PWS patients. The phenotype might also vary according to the degree of mosaicism in different tissues. A study [
26] reported four cases with chimeric deletions of chromosome 15, either with atypical features of PWS or with typical features of PWS, but with undetectable deletions in cytogenetics. Detection using fluorescent in situ hybridization (four commercially available probes) revealed peripheral blood leukocyte deletions ranging from 14 to 60%. The authors suggest that the percentage of cells missing in other tissues may be high in this case. Without knowing the proportion of missing cells in other tissue types and determining more accurately the size of the missing cells, it is not possible to determine the association between genotype and phenotype. To clarify the relationship between clinical symptom typicality and the level of methylated cells, it is necessary to investigate the tissues directly involved in the disease and to quantitatively analyze patients with atypical PWS, and additional studies are needed.
In summary, we report one patient with atypical PWS due to a mosaic deletion in the region 15q11.2-q13 of paternal origin and suggests that the diagnosis of PWS should not be excluded clinically in the case of incomplete PWS phenotypes. The data collected by a combination of the conventional cytogenetic tools, and molecular genetic methods thus enable identification of atypical and complex disease mechanisms. This provides yet another novel insight into the understanding of a mosaicism imprinting disorder.