Prader-Willi syndrome (PWS) was first described in 1956 by Prader, Labhart and Willi [1].

PWS is the most common syndromic cause of obesity, and its prevalence is estimated between 1:10.000 to 1:30.000 and with no predilection for race or sex [1,4,5]. It is characterized by hyperphagia leading to obesity in early childhood, accompanied by short stature and hypogonadism/hypogenitalism due to growth hormone and other endocrine deficiencies, neurodevelopmental or psychiatric disorders, often with behavioral changes [1,5]. Mild craniofacial dysmorphism (dolichocepaly, almond shaped eyes, narrow nasal bridge, thin and downturned upper lip, dental enamel hypoplasia, small hands and feet) and strabismus are common [1,5]. 5Hyperphagia is not present at birth, which is a key distinguishing feature. Generally, the prenatal findings are reduced fetal activity, polyhydramnios (reflecting the inability to coordinate suction and swallowing), pelvic presentation, preterm delivery and small for gesta­tional age and increased head/abdomen circumference ratio [4,5]. At birth, the weight is usually low or, in some cases, in the normal range [1,4]. Another sign that is of massive importance is the severe hypotonia associated with suction and feeding impairment. The combination of these two signs is highly suggestive of PWS in the neonatal period. Until 2 years of age patients present with failure to thrive, feeding difficulties, cryptorchidism, genital hypoplasia (scrotal hypoplasia, hypoplasia of the clitoris and large or small vaginal lips) and developmental delay. At 4-8 years hyperphagia begins with progressive obesity and after 8 years, severe hyperphagia, with food obsession, is universal. To better comprehend the evolution of the weight gain in this syndrome, there are seven distinct nutritional phases which have been identified (Table 1) [6].

Table 1: Summary of nutritional phases in Prader-Willi syndrome, adapted from Miller (2011).

Many other signs/symptoms were identified like obstruc­tive sleep apnea, behavioral disorder, intellectual disability, neurological issues (even epilepsy), increased pain threshold, sel­f-injurious skin lesions, temperature instability, scoliosis, sleep, gastrointestinal and coagulation disorders, vision and dental problems (Table 2) [1,9].

Table 2: An Overview of Common Medical Issues for those with PWS, adapted from Barbara Y. Whitman (2024).

Note: † Feature present in the patient reported in this case.

PWS results from absence of paternal gene expression on chromosome 15q11.2-q13.9. The most common genetic cause is a 5-6 Mb deletion (65%-75% of cases) [9]. Maternal uniparental disomy accounts for 20%-30%, and imprinting defects for 1%-3% [1,5].

There is no cure for PWS. Management focuses on diet, exercise, growth hormone therapy, and behavioral/cognitive interventions to maximize patient abilities [1]. Symptomatic treatments address scoliosis, gastrointestinal, coagulation, or sleep disorders to improve quality of life.

In addition to GH, new therapies targeting obesity and hyperphagia show promise, including oxytocin (appetite control), non-acetylated ghrelin analogs (reduce hyperphagia), and glucagon-like peptide analogs (weight management) [2].

In early 2025, the FDA approved Soleno (Vykat™ XR, diazoxide choline) for PWS patients aged 4 and above, the first drug targeting hyperphagia, the syndrome’s hallmark [7].

A full-term male was delivered by caesarean section due to pelvic presentation, with Apgar scores of 6/7/8 and weight of 2900g. The pregnancy was uneventful and there is no history of consanguinity. Immediately after birth, the newborn (NB) exhibited respiratory depression with bradypnea and severe hypotonia, requiring positive pressure ventilation with recovery at 20 minutes. On day 1 of life, due to hypoglycemia was admitted to the Neonatal Intensive Care Unit (NICU). He presented dysmorphism features (retrognathia, high forehead and high palate), generalized and severe hypotonia, hyporeactivity, with nearly absent Moro reflex (worse at the right side) and bilateral cryptorchidism. Blood analysis revealed elevated CK (18541 U/L), LDH (1961 U/L), AST (477 U/L), and ALT (103 U/L). Other metabolic parameters and thyroid function were normal. Clavicular X-ray was also normal, and testicular ultrasound showing intra-abdominal testes. Brain MRI and echocardiography didn’t show any alterations. Because of facial dysmorphism and severe hypotonia, a Microarray-based Comparative Genomic Hybridization (aCGH) was requested and revealed uniparental disomy of chromosome 15. Genetic testing for Prader-Willi syndrome with Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) confirmed the diagnosis. Physiotherapy was started on D5. CK levels showed a downward trend, with subsequent normalization at D10 (182 U/L). Oxygen support via nasal cannula was required until D15. Despite persistent hypotonia with the need of nasogastric tube for alimentation, NB showed progressive improvement in feeding skills, achieving full oral autonomy at D23. During hospitalization, ophthalmology and otorhinolaryngology examinations were performed and none revealed changes. The NB was discharged on D29, oriented towards consultations of neuropediatrics, rehabilitation, endocrinology, neonatology, pediatric surgery and clinical genetics. Physical therapy and speech therapy were instituted soon after discharge. Endocrinology follow up aims evaluating potential need for growth hormone (GH) therapy.Neurodevelopment milestones have been reached later than expected for the age, however he evolved very favorably. At two months he was able to fix and follow. Social smile occurred by three months, cephalic control and vocalizations by 5 months. By 7 months, he cannot sit without support or fix the lower limbs, but his posture is increasingly correct and upright. He is able to grasp objects, transfer and take to mouth. The neurologic exam exhibits an axial hypotonia, without alterations of the cranial nerves, reasonable appendicular muscle strength, without alterations of the osteotendinous reflexes and with cutaneous plantar reflexes in flexion.Food diversification with vegetables soup and fruit started at 6 months. The somatometry is adequate, 3-15^th percentile of weight and length and 15-50^th of head circumference. He maintains multidisciplinary follow-up. The family was counselled in the genetic consultation, with low recurrence risk for future pregnancies. (See table 2-characteristics of this case are marked with a symbol, considering the age).

Although the clinical characteristics of PWS are well described, early diagnosis can still be challenging, as illustrated by this case.When analyzing pregnancy, the fetus did not present most of the manifestations of the PWS in this stage of life, such as reduced fetal activity, polyhydramnios (reflecting the inability to coordinate suction and swallowing), small for gestational age and increased head/abdomen circumference ratio. However, it was in pelvic presentation, a possible manifestation in PWS, and for this reason a cesarean section was performed. His birth weight was appropriate for gestational age, and, although it can occur in PWS, the most common is a low birth weight [1,5,7].One of the most relevant factors in the evaluation of this newborn was the severe hypotonia and the fact that it had a very high CK at birth. These findings could be compatible with some neurological disorders, namely myopathies. However, the elevated values of CK, the discreet dysmorphology with cryptorchidism put us on the trail of a possible central cause, a genetic syndrome [3,8,10]. Creatine kinase (CK) level is typically either normal or mildly elevated (2–5 times the normal range) in congenital myopathies. There is some suggestion that more moderately elevated levels can be seen in central core disease as well as asymptomatic carriers of the ryanodine receptor mutation in CCD [3,8,10]. Not disregarding the possibility of a peripheral cause for the hypotonia, given the substantial increase in CK, this was so serious that, combined with the slight dysmorphology, led us to request a genetic study, which ended up confirming the suspected syndromic diagnosis. The fact that CK values ??decreased over time, having normalized in days, helped to reduce the suspicion of myopathy or other neurological diseases that are also associated with increased CK in NB and was assumed to be most likely due to the normal birthing process.As previously mentioned, there are 3 genetic forms that can justify PWS [1,5]. The array-CGH revealed a uniparental disomy on chromosome 15, already in favor of PWS. In any case, the MS-MLPA study for this syndrome left no doubt of the diagnosis.

After assuming PWS, the patient was managed by a multidisciplinary team. It is worth noting that he required ventilatory support and nasogastric tube for nutrition as expected in PWS cases. He achieved full oral autonomy at D23 and since then he has been feeding and thriving normally. The most common feature thing in PWS is having difficulty feeding and failure to thrive until the second year of life [1,6]. The authors think that this case is a great example of an early achievement of weight gain, not as expected in PWS, probably linked to the commitment of a multidisciplinary team associated with good parent support. 

Despite ongoing physiotherapy and speech therapy, developmental delays persist, particularly in motor control. He has axial hypotonia and cannot sit without support. Even so, the other areas of neurodevelopment are almost in a normal range. Despites a relatively short follow-up period and obviously expecting additional symptoms/signs of PWS over time, our patient has shown a notable developmental progress. Multidisciplinary follow-up of these patients is essential in order to impose appropriate and timely guidance and so that preventive actions to minimize symptoms and suffering of patients and families. Given that parents are young and wish to have more children, genetic counseling becomes even more relevant.With this case the authors intend to highlight the phenotypic variability of early-onset PWS and emphasize the importance of genetic testing in NB with unexplained hypotonia, even in the presence of atypical biochemical and clinical findings. Ongoing studies to identify potential therapies, improving the quality of life of patients and their families in the future are promising [2,7].

1.        Butler MG, Miller JL, Forster JL. Prader-Willi syndrome: Clinical genetics, diagnosis and treatment approaches: An update. Curr Pediatr Rev. 2019; 15: 207-244.

2.        Mahmoud R, Kimonis V, Butler MG. Clinical trials in Prader-Willi syndrome: A review. Int J Mol Sci. 2023; 24: 2150.

3.        Zhang H, Chang M, Chen D, Yang J, Zhang Y, Sun J, et al. Congenital myopathies: Pathophysiological mechanisms and promising therapies. J Transl Med. 2024; 22: 815.

4.        Passonea CBG, Maestri C, Aquino MM, Ribeiro M. Prader Willi syndrome: What is the general pediatrician supposed to do?. A review. Rev Paul Pediatr. 2018; 36: 345-352.

5.        Angulo MA, Butler MG, Cataletto ME. Prader-Willi syndrome: A review of clinical, genetic, and endocrine findings. J Endocrinol Invest. 2015; 38: 1249-1263.

6.        Miller JL, Lynn CH, Driscoll DC, Goldstone AP, June-Anne G, Kimonis V, et al. Nutritional phases in Prader-Willi syndrome. Am J Med Genet A. 2011; 155: 1040-1049.

7.        Sneha SK. US FDA approves first treatment for rare genetic disorder Prader-Willi Syndrome. Reuters. 2025.

8.        Cassandrini D, Trovato R, Rubegni A, Lenzi S, Fiorillo C, Baldacci J, et al. Congenital myopathies: Clinical phenotypes and new diagnostic tools. Ital J Pediatr. 2017; 43: 101.

9.        Whitman BY. Prader-Willi syndrome: The more we know, the less we know. Mo Med. 2024; 121: 235-241.

10.     Laugel V, Cossee M, Matis J, de Saint-Martin A, Echaniz-Laguna A, Mandel JL, et al. Diagnostic approach to neonatal hypotonia: Retrospective study on 144 neonates. Eur J Pediatr. 2008; 167: 517-523.