-Dr. Sai Lavanya Patnala, Intern, Apollo Medical College, Hyderabad


A new study led by researchers from McMaster University has shown that, while relatively rare in the general population, there are a large number of varied, genetic syndromes associated with obesity. [1]

Genetic influences on the determination of human fat mass are profound and powerful, a statement that does not conflict with the obvious influence of environmental factors that drive recent changes in the prevalence of obesity. [2]

Recent reviews on obesity have reported 20 to 30 syndromes, but in the first systematic review on obesity syndromes, investigators from McMaster and the University of British Columbia had catalogued 79 syndromes with obesity that have been described in literature.

Of the 79 syndromes, 19 have been genetically solved to the point where, a lab test could confirm a doctor’s suspicions. Another 11 have been partially clarified, and 27 have been mapped to a chromosomal region. For the remaining 22 syndromes, neither the gene(s) nor the chromosomal location(s) have yet been identified yet. [1]

Hence, it is important to learn about these syndromes, their manifestations and incidence, in order to clinically correlate and understand their prognosis.

A 1680 painting by Juan Carreño de Miranda of Eugenia Martínez Vallejo, a girl presumed to have had PWS[4]


Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic condition due to paternal loss of imprinted genes on chromosome 15 and is characterized by a range of mental and physical findings that can be life-threatening. It affects an estimated 350,000–400,000 people worldwide.

Approximately 70% of individuals with PWS have a non-inherited (i.e., de novo) deletion in the paternally derived chromosome 15q11-q13 region. The remaining PWS individuals (about 25%) result from maternal disomy 15 (i.e., both chromosome 15s from the mother and no paternal chromosome 15), genomic imprinting defects due to microdeletions or epimutations of the imprinting center located in the 15q11-q13 region in less than 3% of cases, or chromosome 15 translocations or rearrangements.

The cardinal features of PWS include:

  • infantile hypotonia
  • feeding difficulties due to a poor suck
  • hypogonadism and hypogenitalism in both males and females
  • Hyperphagia
  • onset of obesity in early childhood
  • short stature due to growth hormone deficiency
  • small hands and feet
  • mild intellectual disability (average IQ of 65)
  • behavioral problems including skin picking, temper tantrums, stubbornness and a particular facial appearance
  • Facial findings include a small upturned nose, narrow bifrontal diameter with almond-shaped eyes, down-turned corners of the mouth with sticky salivary secretions and generally lighter skin, hair and eye color than other family members.[3]


Angelman syndrome is a complex genetic disorder which results from the loss of function of a gene called UBE3A that primarily affects the nervous system. It is known to affect an estimated 1 in 12,000 to 20,000 people. The life expectancy of people with this condition appears to be nearly normal. [5]

Characteristic features of this condition include:

  • delayed development
  • intellectual disability
  • severe speech impairment
  • problems with movement and balance (ataxia)
  • recurrent seizures (epilepsy)
  • a small head size (microcephaly)
  • Delayed development becomes noticeable by the age of 6 to 12 months
  • Children with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements
  • Hyperactivity and a short attention span are common
  • Most affected children also have difficulty sleeping and need less sleep than usual
  • unusually fair skin with light-colored hair
  • an abnormal side-to-side curvature of the spine (scoliosis)[5]
  • Older children with Angelman syndrome tend to have large appetites, which may lead to obesity[6]


Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome.[8]

This syndrome does not usually cause the high appetite seen in people with Prader-Willi syndrome. Schaaf-Yang syndrome is caused by a mutation in the MAGEL2 gene on chromosome 15. [9]

SYS should be suspected in individuals with the following clinical and suggestive laboratory findings.

Clinical findings:

  • Generalized hypotonia of infancy
  • Respiratory distress in infancy
  • Infant feeding difficulties with failure to thrive
  • Hyperphagia with subsequent obesity in childhood or adolescence
  • Mild-to-profound developmental delay or intellectual disability
  • Autism spectrum disorder or autistic features
  • Nonspecific dysmorphic facial features, including a pointed chin, frontal bossing, and low-set ears
  • Short stature
  • Joint contractures of variable severity, ranging from mild contractures of the distal phalanges of the hands to severe arthrogryposis multiplex congenita
  • Endocrinopathy, including:
    • Hypopituitarism
    • Growth hormone deficiency
    • Hypogonadism and/or undervirilization in males

Laboratory findings:

  • Normal methylation analysis of the 15q11.2 region (Prader-Willi/Angelman syndrome locus)
  • Any of the following hormonal or metabolic findings [McCarthy et al 2018b]:
    • Low IGF-1 levels despite normal weight and adequate nutrition
    • Elevated glucose levels on oral glucose tolerance testing (OGTT)
    • Elevated fasting ghrelin levels[8]


Chitayat-Hall syndrome, initially described in 1990, is a rare condition caused by pathogenic variants in MAGEL2 and shares a common aetiology with Schaaf-Yang syndrome.[11]

Clinical features include:

  • early feeding difficulties followed by excessive weight gain in some patient
  • ntellectual disability, early feeding difficulties
  • followed by excessive weight gain in some patients,
  • hypotonia, and contractures ranging in severity
  • from distal arthrogryposis to severe arthrogryp-
  • osis multiplex congenita
  • ntellectual disability, early feeding difficulties
  • followed by excessive weight gain in some patients,
  • hypotonia, and contractures ranging in severity
  • from distal arthrogryposis to severe arthrogryp-
  • osis multiplex congenita
  • intellectual disability
  • hypotonia
  • contractures ranging in severity from distal arthrogryposis to severe arthrogryposis multiplex congenita
  • hypopituitarism including growth hormone (GH) deficiency
  • mental retardation
  • facial anomalies[11]


Clinical syndromes causing obesity are quite rare. The most commonly known syndromes include Prader Willi syndrome, Angelman syndrome, Schaaf Yang syndrome and Chitayat Hall syndrome. Understanding these syndromes will not only improve the lives of those affected, but will also help us understand the genetic basis of obesity.


  1. McMaster University. “Rare genetic forms of obesity more numerous, diverse than previously thought: Obesity rates in North America have risen dramatically over the past 3 decades.” ScienceDaily. ScienceDaily, 27 March 2017.
  2. Stephen O’Rahilly, I. Sadaf Farooqi, Giles S. H. Yeo, Benjamin G. Challis, Minireview: Human Obesity—Lessons from Monogenic Disorders, Endocrinology, Volume 144, Issue 9, 1 September 2003, Pages 3757–3764,
  3. Butler MG. Prader-Willi Syndrome: Obesity due to Genomic Imprinting. Curr Genomics. 2011 May;12(3):204-15. doi: 10.2174/138920211795677877. PMID: 22043168; PMCID: PMC3137005.

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