Severe hypotonia is consistently observed at birth and during the neonatal period (Fig. 1)¹²⁾. PWS should thus be considered in all cases of neonatal hypotonia. Neonatologists appear to be on the frontline of early diagnosis including PWS in the differential diagnosis of severe neonatal hypotonia¹³⁾. The first stage of PWS, occurring in infancy, is characterized by lethargy, marked hypotonia, global developmental delay, and small genitalia with frequent cryptorchidism¹⁴⁾. Although poor weight gain is typically noted on standard infant growth charts, studies have documented excessive body fat in infants with PWS by skinfold measurements¹⁵⁾, dual energy-x-ray absorptiometry, and doubly labeled water¹⁶⁾. Conversely, lean body mass measurements are decreased in PWS infants, correlating with a 30% lower energy expenditure as compared to healthy individuals¹⁶⁾.

Patients with PWS have characteristic dysmorphic features including a narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, and thin upper lip with a down-turned mouth (Fig. 2). These patients very commonly have shorter total hand size, narrow palms with hypoplastic hypothenar bulges, and short feet with short toes. Fair hair and hypopigmentation of the eyes and skin relative to other family members are frequently observed in patients with deletion-type PWS; these features are less commonly observed in patients with uniparental disomy.

Gross motor and language milestones are delayed. Early milestones are reached on average at double the normal age (e.g., sitting at 12 months, walking at 24 months, and words at 2 years). Cognitive disability is evident by school age. Most patients with PWS are mildly mentally retarded (mean intelligence quotient (IQ): 60-70 score), with approximately 40% having borderline mental retardation or low-normal intelligence and approximately 20% having moderate retardation17-¹⁹⁾. Impaired physical function in PWS patients during childhood is most often related to body composition abnormalities and hypotonia, rather than to linear growth deficits.

Obesity typically begins between 1 and 4 years of age. During later childhood, a seemingly insatiable appetite (hyperphagia) begins. This hyperphagia is hypothalamic in origin, caused by a lack of sense of satiety20, ²¹⁾. Food seeking is common, and if intake is not controlled externally, central obesity results from these behaviors combined with a low metabolic rate and decreased activity level (that result in a decreased total caloric requirement). Body composition studies demonstrated both increased body fat and reduced muscle mass in patients with PWS from infancy to adulthood.

Individuals with PWS have sleep-disordered breathing, including central and obstructive sleep apnea, abnormal arousal, abnormal circadian rhythms in rapid eye movement (REM) sleep, reduced REM latency, and abnormal response to hypercapnia as well as excessive daytime sleepiness²²⁾. Obesity can worsen the sleep disorder.

A characteristic behavioral pattern begins in early childhood in 70-90% of affected individuals. It is typified by temper tantrums, stubbornness, controlling and manipulative behavior, compulsive-like behaviors (repeated organizing, writing, collecting, and need to finish 1 thing before moving to the next), and difficulty with changes in routine¹⁷⁾. Autism spectrum disorder, attention deficit/hyperactivity symptoms, and insistence on sameness are common and of early onset23, ²⁴⁾.

The 15q11.2-q13 region is highly complex and contains a number of imprinted and non-imprinted genes (Fig. 3). The majority of patients with deletions have 1 of 2 common proximal breakpoints (BP1 and BP2) and a common distal breakpoint (BP3)34-³⁶⁾. The paternally expressed genes are located in the more centromeric part of the region. These are MKRN3; MAGEL2; NDN; C15orf2; SNURF-SNRPN (typically referred to as SNRPN); and the C/D box small nucleolar RNA (snoRNA) genes SNORD107 (previously HBII-436), SNORD64 (previously HBII-13), SNORD108 (previously HBII-437), SNORD109A (previously HBII-438A), SNORD116 (previously HBII-85), SNORD115 (previously HBII-52), and SNORD109B (previously HBII-438B). SNORD115 and SNORD116 are present as multicopy gene clusters, whereas the other snoRNA genes are single-copy genes. In contrast to other C/D box snoRNAs, which are usually involved in the modification of ribosomal RNAs, these snoRNAs do not have a region complementary to ribosomal RNA and might be involved in the modification of mRNAs, probably by modulating alternative splicing37-³⁹⁾. Paternal-only expression of MKRN3, NDN, and SNRPN is regulated by parent-of-origin-specific DNA methylation of the promoter regions of each gene. Whereas the active paternal allele is unmethylated, the inactive maternal allele is methylated.

The most complex gene in the 15q11-q13 region is SNRPN. The original gene, found to consist of 10 exons, encodes 2 different proteins. Exons 1-3 encode SNURF, a small polypeptide of unknown function⁴⁰⁾, while exons 4-10 encode SmN, a spliceosomal protein involved in mRNA splicing in the brain⁴¹⁾. Many 5' and 3' exons of SNRPN have been identified. These exons have 2 peculiar features: They do not have any protein coding potential, and they occur in many different splice forms of the primary transcript³³⁾. According to recent reports, the SNORD116 locus is probably a major gene contributing to the PWS phenotype42-⁴⁴⁾. It is likely, however, that 1 or more additional genes in the region also contribute to the phenotype.

On June 20, 2000, the US Food and Drug Administration approved the use of GH in children with genetically confirmed PWS and the evidence of growth failure⁵³⁾. GH deficiency has been well documented in PWS by GH response testing with decreased GH response, relatively low IGF-1 levels, and abnormal body composition with high fat mass and low lean body mass. Numerous beneficial effects of GH therapy have been documented, including improvement in linear growth, physical appearance, functional muscle mass, and infant neurodevelopment. However, GH therapy does not appear to enhance the development of scoliosis, and it anecdotally modulates behavior in some patients52-⁵⁴⁾. Treatment of adult PWS patients with GH is under investigation and appears to be promising⁵⁵⁾. Currently, the recommended dose of GH is 24 U/m² per week (1.0 mg/(m² · day) for patients over 2 years of age. Korean insurance covers patients diagnosed with PWS by clinical symptoms and genetic testing; Genotropin (somatotropin (rDNA origin) for injection, Pfizer) is used for treatment. The optional dose of GH covered by Korean insurance is 0.035 mg/(kg · day) or 1 mg/(m² · day) (but less than 2.7 mg/day). Treatment is covered from over 2 years of age, until the bone age is 14-15 years in girls and 15-16 years in boys. Once a female's height reaches 150 cm or a male's height reaches 160 cm, insurance coverage is no longer provided in Korea. Then, after a GH stimulation test, if the patient has GH deficiency, the patient can continue GH treatment with the adult dosage (2 U/day), which is covered by insurance.

Although GH therapy in PWS has various beneficial effects, body composition and physical function (muscle strength and agility) remain abnormal even after 4 years of GH therapy, with high doses given the last 2 years⁵⁶⁾. These persistent manifestations of the syndrome might reflect non-GH-related abnormalities intrinsic to PWS and/or the late initiation of GH therapy following a critical period of adipose and muscle development during infancy¹⁴⁾. Therefore, it is important to evaluate the effects of early GH therapy on the physical findings and neurodevelopment of infants and toddlers with PWS.

In 1 study including similar-aged children with PWS who had received or not received long-term GH therapy, the strongest evidence to date showed that GH therapy, when started early in life, beneficially and significantly altered the natural history of PWS by reducing body fat and improving muscle strength physical function, and lipid profiles without adverse effects⁵⁷⁾. Thus, physicians and families can favorably weigh the sustained long-term value of GH treatment in infantile patients with PWS. Some experts advise that GH treatment should be started at a low dose such as 0.25-0.30 mg/(m² · day) or 0.009-0.012 mg/(kg · day) and increased during the first weeks and months to reach the standard replacement GH dose of approximately 1.0 mg/(m² · day) or 0.035 mg/(kg · day) with the monitoring of clinical effects, such as sleep apnea and increase in the level of IGF-I, particularly if there is a clinical suspicion of overtreatment (edema, worsening or new development of snoring, headache, and/or acromegalic clinical features)⁵¹⁾. In recent years, the diagnosis of PWS during infancy has increased. At the Samsung Medical Center, there are nearly 180 patients with PWS, and 86 patients were diagnosed during infancy. Although children younger than 2 years of age are not covered by health insurance in Korea, GH therapy has been started in infants after obtaining informed consent from their parents in recent years. Their growth curve and development relative to chronologic age have improved with GH therapy. There have been no severe side effects. However, a long-term follow-up of the patients treated with GH may be needed.

In a randomized, controlled trial, administration of GH to infants and toddlers with PWS normalized height, increased accrual of lean body mass, and reduced the percent body fat after 1 year of treatment. The 2-year data showed that the accumulation of excess body fat was delayed and reduced but not prevented, similar to an earlier study reporting a body fat SDS of +3 after 2.5 years of GH treatment⁶⁰⁾. The age at independent walking was younger than typical for the syndrome, 23.3±4.8 months in this study and 24.1 months in a previous study⁶¹⁾. Subjectively, the GH-treated infants and toddlers were reported to be more alert and energetic by their families. An increased rate of language and cognitive development in the treated group was noted. It is unclear whether these results are solely from the known effects of GH therapy on muscle tone. However, the concomitant increase in head growth suggests that a central nervous system effect may also play a role¹⁴⁾. In 1 study, IGF-I levels increased rapidly during GH treatment from below the normal range to the high-normal range⁶²⁾. IGF-I receptors have been localized in several areas of the human brain, indicating that IGF-I may have a neuroregulatory role in the central nervous system⁶³⁾. Theoretically, IGF-I may directly influence the central nervous system or GH might induce local IGF-I expression in brain tissue, thereby improving psychomotor development⁶²⁾. Another possible explanation for the improvement in mental development during GH treatment might be that because of the improved motor development, children are able to sit, stand, and walk independently, enabling them to explore and interact with the environment, resulting in subsequent improvement in mental development⁶²⁾.

In another study, after 1 year of GH treatment, there was a significant improvement in both mental and motor development in PWS infants and toddlers compared to randomized controls⁶²⁾. Head circumference increased from low-normal to normal during GH treatment. Children with an initially lower motor developmental age improved more than children with a higher initial motor developmental age, indicating that early treatment with GH might be beneficial. In the general population, there is evidence that intelligence tends to be higher in subjects with a greater head circumference, and brain growth during infancy and early childhood appears to be more important than that during fetal life in determining cognitive function⁶⁴⁾.

Children with PWS are at risk of developing sleep-disordered breathing secondary to both deficient autonomic sleep control and upper airway obstruction. It has been suggested that GH exacerbates preexisting gas-exchange deficiencies in 3 ways: by stimulating adenotonsillar hypertrophy⁶⁵⁾, increasing the basal metabolic rate with a resultant rise in oxygen demand⁶⁶⁾, and normalizing previously decreased hydration with an augmentation of the volume load⁶⁷⁾. A causal relationship between GH and sudden death has not been demonstrated, although important concerns over safety have been raised. Concerns over possible worsening of obstruction are justified in the obese group, and patients with PWS require careful dietary, ENT, and respiratory evaluation before starting treatment with GH. Selected cases may benefit from noninvasive ventilatory support.