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Obesity due to congenital leptin deficiency

Synonym(s) -
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Childhood
  • E66.8
MeSH -
MedDRA -


Disease definition

Congenital leptin deficiency is a form of monogenic obesity characterised by severe early-onset obesity and marked hyperphagia.


It has been described in less than 30 patients.

Clinical description

Patients with congenital leptin deficiency are severely hyperphagic from early infancy and, although birthweight is normal, they rapidly become obese during early childhood. An increased susceptibility to infections has also been reported in these infants and appears to be associated with reduced numbers of circulating CD4+ T cells, and impaired T cell proliferation and cytokine release. Other features of the disorder include hyperinsulinaemia, advanced bone age, hypothalamic hypothyroidism and hypogonadotropic hypogonadism leading to a failure to undergo puberty.


Leptin is an adipocyte-derived hormone that plays an important role in energy balance and appetite suppression. Whilst the majority of obese patients display hyperleptinaemia, patients with congenital leptin deficiency have undetectable levels of leptin in the serum. This absence of serum leptin is caused by homozygous frameshift or missense mutations in the ob gene (7q31.3) and is inherited as an autosomal recessive trait. However, a similar phenotype has been observed in three individuals from one consanguineous family who carried homozygous mutations in the gene encoding the leptin receptor (LEPR, 1p31).

Diagnostic methods

Family history, severe hyperphagia and early-onset obesity may lead to suspicion of a monogenic obesity syndrome. The diagnosis of congenital leptin deficiency can be confirmed by analysis of serum leptin levels or identification of mutations in the ob gene.

Management and treatment

Congenital leptin deficiency can be successfully treated with daily subcutaneous injections of recombinant human leptin, resulting in sustained positive effects on weight loss, reducing appetite, appropriate pubertal development and hyperinsulinaemia.


As a result, the prognosis for patients undergoing treatment appears to be excellent. However, misdiagnosed patients are at risk of developing the complications normally associated with severe obesity (in particular type 2 diabetes), with the prognosis being hampered further by an increased rate of mortality due to childhood infection.

Expert reviewer(s)

  • Pr Sebastiano FILETTI

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