Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.
BACKGROUND
A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined.


METHODS
We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives.


RESULTS
Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency.


CONCLUSIONS
The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.
Farooqi
I Sadaf
IS
Cambridge Institute for Medical Research, University Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom. isf20@cam.ac.uk
Wangensteen
Teresia
T
Collins
Stephan
S
Kimber
Wendy
W
Matarese
Giuseppe
G
Keogh
Julia M
JM
Lank
Emma
E
Bottomley
Bill
B
Lopez-Fernandez
Judith
J
Ferraz-Amaro
Ivan
I
Dattani
Mehul T
MT
Ercan
Oya
O
Myhre
Anne Grethe
AG
Retterstol
Lars
L
Stanhope
Richard
R
Edge
Julie A
JA
McKenzie
Sheila
S
Lessan
Nader
N
Ghodsi
Maryam
M
De Rosa
Veronica
V
Perna
Francesco
F
Fontana
Silvia
S
Barroso
Inês
I
Undlien
Dag E
DE
O'Rahilly
Stephen
S
D000328:Adult; D017668:Age of Onset; D001481:Basal Metabolism; D001823:Body Composition; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D005838:Genotype; D006801:Humans; D006963:Hyperphagia / Q000097:blood / Q000150:complications / Q000235:genetics; D007006:Hypogonadism / Q000097:blood / Q000150:complications / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000150:complications / Q000235:genetics; D020738:Leptin / Q000097:blood; D018655:Lymphocyte Count; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics*; D054411:Receptors, Leptin
C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin