Prader-Willi Syndrome

Overview

Plain-Language Overview

Prader-Willi Syndrome is a rare genetic disorder that affects many parts of the body. It is present from birth and causes a variety of symptoms including weak muscle tone, poor growth, and delayed development. Children with this condition often have an insatiable appetite which can lead to obesity if not managed carefully. People with Prader-Willi Syndrome may also experience learning difficulties and behavioral problems. The condition requires lifelong care and support to manage its effects.

Clinical Definition

Prader-Willi Syndrome is a complex neurodevelopmental disorder caused by the loss of function of paternally expressed genes on chromosome 15q11-q13, most commonly due to a paternal deletion, maternal uniparental disomy, or imprinting defects. It is characterized by neonatal hypotonia, feeding difficulties in infancy, followed by hyperphagia and obesity in early childhood. Patients exhibit distinctive facial features, short stature, hypogonadism, and cognitive impairment. Behavioral problems such as temper outbursts, obsessive-compulsive tendencies, and skin picking are common. Endocrine abnormalities include growth hormone deficiency and hypothalamic dysfunction. Diagnosis is confirmed by molecular genetic testing. Management is multidisciplinary, focusing on controlling weight, hormone replacement, and supportive therapies. The syndrome has a prevalence of approximately 1 in 10,000 to 30,000 live births. Early diagnosis and intervention improve outcomes and quality of life.

Inciting Event

The inciting event is a genetic mutation or deletion affecting paternal genes on chromosome 15.
No environmental or infectious triggers are involved.

Latency Period

none

Diagnostic Delay

Early hypotonia and feeding difficulties may be mistaken for other neonatal conditions, delaying diagnosis.
Lack of awareness of the syndrome's characteristic features can contribute to delayed recognition.
Variable presentation and subtle early signs may postpone genetic testing.

Clinical Presentation

Signs & Symptoms

Neonatal hypotonia with poor feeding and weak cry.
Development of hyperphagia leading to severe obesity in early childhood.
Intellectual disability and developmental delays are common.
Behavioral problems including temper tantrums and obsessive-compulsive features.
Hypogonadism with delayed or incomplete puberty.

History of Present Illness

Newborns present with hypotonia and poor feeding leading to failure to thrive.
In early childhood, there is the onset of hyperphagia causing rapid weight gain and obesity.
Developmental delays, intellectual disability, and behavioral problems such as temper tantrums and compulsivity are common.
Patients often have hypogonadism with delayed or incomplete puberty.

Past Medical History

History of neonatal hypotonia and feeding difficulties.
Previous episodes of obesity-related complications such as type 2 diabetes or sleep apnea may be present.
Growth hormone deficiency may have been documented.

Family History

Most cases are sporadic, but rare familial cases can occur due to imprinting defects.
No consistent family history of similar symptoms is typical due to the genetic mechanism involving paternal gene loss.
Genetic counseling is recommended for families with known imprinting center defects.

Physical Exam Findings

Hypotonia with decreased muscle tone is commonly observed in infants.
Characteristic facial features include almond-shaped eyes, a narrow forehead, and a thin upper lip.
Short stature and small hands and feet are typical physical findings.
Mild scoliosis may be present on spinal examination.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of Prader-Willi Syndrome requires clinical features including neonatal hypotonia with poor suck, followed by excessive eating and obesity in early childhood, characteristic facial features, hypogonadism, and developmental delays. Confirmation is achieved through molecular genetic testing demonstrating loss of paternal gene expression in the 15q11-q13 region via deletion, uniparental disomy, or imprinting defects.

Pathophysiology

Key Mechanisms

Prader-Willi syndrome results from the loss of expression of paternally inherited genes on chromosome 15q11-q13, primarily due to paternal deletion, maternal uniparental disomy, or imprinting defects.
The absence of these genes leads to hypothalamic dysfunction, causing impaired regulation of appetite, growth hormone deficiency, and abnormal temperature regulation.
Hypothalamic dysfunction also results in hypogonadism and developmental delays.

Involvement	Details
Organs	Hypothalamus is the primary organ affected in Prader-Willi syndrome, leading to endocrine and appetite dysregulation.
Organs	Pituitary gland dysfunction results in growth hormone deficiency and hypogonadism in affected individuals.
Tissues	Adipose tissue is increased in Prader-Willi syndrome due to hyperphagia and decreased energy expenditure.
Cells	Hypothalamic neurons are critical in Prader-Willi syndrome due to their role in appetite regulation and endocrine function.
Chemical Mediators	Ghrelin levels are elevated in Prader-Willi syndrome, contributing to hyperphagia and obesity.

Treatment

Pharmacological Treatments

Growth hormone
- Mechanism: Stimulates growth and improves body composition by increasing muscle mass and decreasing fat mass
- Side effects: edema, joint pain, insulin resistance
Psychotropic medications
- Mechanism: Used to manage behavioral problems such as irritability and obsessive-compulsive behaviors
- Side effects: sedation, weight gain, metabolic syndrome

Non-pharmacological Treatments

Strict dietary management to control hyperphagia and prevent obesity.
Regular physical therapy to improve muscle tone and motor development.
Behavioral interventions to address compulsive behaviors and improve social skills.
Early developmental support and special education to enhance cognitive function.

Prevention

Pharmacological Prevention

Recombinant growth hormone therapy to improve growth, body composition, and muscle tone.
Management of hypothyroidism with levothyroxine if present.
Use of psychotropic medications for behavioral and psychiatric symptoms as needed.

Non-pharmacological Prevention

Strict dietary control and supervision to prevent obesity.
Early physical and occupational therapy to improve muscle tone and motor skills.
Behavioral interventions to manage hyperphagia and psychiatric symptoms.
Regular monitoring for sleep apnea and use of CPAP if indicated.

Outcome & Complications

Complications

Severe obesity leading to cardiovascular disease.
Respiratory failure due to sleep apnea and hypoventilation.
Metabolic syndrome with type 2 diabetes and dyslipidemia.
Psychiatric disorders including mood and psychotic disorders.

Short-term Sequelae	Long-term Sequelae
Feeding difficulties and failure to thrive in infancy. Early onset of obesity due to hyperphagia. Sleep disturbances including obstructive sleep apnea.	Severe obesity with associated cardiovascular and metabolic complications. Persistent intellectual disability and behavioral problems. Hypogonadism causing infertility and delayed sexual development. Scoliosis and orthopedic complications from musculoskeletal abnormalities.

Differential Diagnoses

Prader-Willi Syndrome versus Angelman Syndrome

Prader-Willi Syndrome	Angelman Syndrome
Mild to moderate intellectual disability with initial hypotonia progressing to hyperphagia and obesity.	Presence of severe intellectual disability with a happy, excitable demeanor and frequent laughing episodes.
Characteristic hypogonadism and small hands and feet.	Characteristic microcephaly and ataxic gait.
Presence of hyperphagia leading to obesity.	Absence of hyperphagia and obesity.

Prader-Willi Syndrome versus Bardet-Biedl Syndrome

Prader-Willi Syndrome	Bardet-Biedl Syndrome
Neonatal hypotonia with feeding difficulties followed by hyperphagia.	Presence of retinitis pigmentosa causing progressive vision loss.
Characteristic hypogonadism and small hands and feet.	Postaxial polydactyly and renal abnormalities.
Absence of polydactyly and retinal degeneration.	Obesity with normal or delayed puberty but no characteristic hypotonia.

Prader-Willi Syndrome versus Down Syndrome

Prader-Willi Syndrome	Down Syndrome
Neonatal hypotonia with early feeding difficulties followed by hyperphagia and obesity.	Characteristic facial features including upslanting palpebral fissures and single palmar crease.
Characteristic hypogonadism and small hands and feet.	Associated with congenital heart defects such as atrioventricular septal defect.
Distinctive genetic cause involving paternal deletion or maternal uniparental disomy of chromosome 15.	Hypotonia present but no hyperphagia or obesity in infancy.