In this report, we present the genetic findings pertaining to a 2-month-old female patient diagnosed with PWS via Chromosome Microarray Analysis (CMA) and methylation-specific Multiplex Ligation Probe Amplification (MLPA). CMA revealed a 5,040 kbp single copy deletion of 15q11.2q13.1 on chromosome 15, consistent with PWS or AS. Further methylation-specific MLPA confirmed the 15q deletion via copy number analysis and revealed an abnormal paternal methylation pattern and intact maternally contributed PWS:AS critical region. AS was excluded based on the confirmation of the loss of the paternal allele, and the patient was diagnosed with PWS secondary to a presumed de novo deletion in the Prader-Willi Critical Region (PWCR), supported by a comprehensive family history.

CMA is considered a first-line genetic study in identifying potential chromosomal deletions and duplications spanning the entire genome, including deletions in the 15q11-q13 region specific to PWS and AS [9]. Outside the PWCR, CMA can detect other pathogenic copy number variants (CNVs), thereby potentially aiding in the diagnosis of coexisting genetic abnormalities that may influence phenotype [9]. Alternatively, Fluorescence in Situ Hybridization (FISH) enables the direct visualization of chromosomal abnormalities via fluorescently labeled DNA probes [10]. While CMA and FISH can effectively detect deletions typical of PWS, cases of PWS arising from maternal Uniparental Disomy (UPD) or imprinting defects do not involve structural CNVs and therefore evade diagnosis via these methods. Importantly, CMA and FISH are unable to distinguish between PWS and AS in most cases without further testing of parental samples [1].

Methylation-specific MLPA is a definitive diagnostic tool for PWS and AS, as well as for detecting cases of UDP and other non-CNV etiologies [11]. Aberrant methylation patterns characteristic of PWS or AS are identified via this method, allowing for a sensitive and specific analysis [12]. The absence of paternal gene expression (i.e., contribution) at the PWCR is diagnostic for PWS, encompassing the key genetic mechanisms of the disease, including deletions, UPD, and imprinting defects [1].

Deletion breakpoints in PWS are used to subclassify the disease and aid in genotype–phenotype correlations [2]. Type 1 and Type 2 deletions share the distal breakpoint BP3 and break off proximally at BP1 and BP2, respectively [1]. The patient here was found to have a loss of MKRN3 distal to BP1 and HERC2 proximal to BP2, with no further loss of gene outside of the BP2–BP3 region, thus qualifying the deletion as Type 2. Phenotypically, the patient lacked certain characteristic facial features of PWS, such as narrowing of the temples, strabismus, and a thin upper lip [13]. A different case of PWS involving the BP2–BP3 region, as well as the more distal APBA2 and CHRNA7 genes near BP4 and BP5, was also characterized by a lack of the typical facial features of PWS, though importantly, macrocephaly was noted, even prior to initiating growth hormone therapy [2]. Additionally, frontal bossing and large hands and feet were observed, perhaps suggesting that certain pertinent genes upstream of BP3 are responsible for the discrepancy in dysmorphic features [2]. Proximal to BP2, the non-imprinted genes NIPA1, NIPA2, and CYFIP1 were spared in the present, normocephalic case of PWS. At least two reported cases of PWS involving the loss of BP1–BP2 have noted the atypical finding of microcephaly [1,2], thereby implicating the loss of NIPA1, NIPA2, and CYFIP1, or some combination thereof, in the development of this particular clinical feature. Further laboratory investigations into the genetic mechanisms driving the spectrum of PWS presentation should reveal clearer insights into the genotype–phenotype relationship.

This case highlights an unusual presentation of PWS where the initial presentation of hypotonia and markedly elevated CK could have led the physician astray if not for thorough genetic testing and diagnostic acumen. Importantly, PWS is not typically associated with CK levels above the normal range for healthy newborns, though one rare case of elevated CK of unknown origin has been reported [5,14]. In the absence of any congenital muscular disorder, it is well established that the elevated CK could be attributed to perinatal trauma arising from the elective cesarean section [15]. It has been suggested that a serum CK in the range of 805.8 ± 465.2 U/L is consistent with such a scenario [6]. The identification of atypical presentations of PWS with concomitant birth trauma is critical for early diagnosis and intervention, particularly with respect to ruling out adjacent neuromuscular disorders.

In this case, the abnormal creatine kinase level adds a unique dimension to the spectrum of PWS presentations, underscoring the role of laboratory investigation in resolving a complex neurodevelopmental and neuromuscular differential diagnosis.