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Obesity due to leptin receptor gene deficiency(LEPRD)

MedGen UID:
767139
Concept ID:
C3554225
Disease or Syndrome
Synonym: Leptin receptor deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): LEPR (1p31.3)
 
Monarch Initiative: MONDO:0013992
OMIM®: 614963
Orphanet: ORPHA179494

Definition

Leptin receptor deficiency is characterized by severe early-onset obesity, major hyperphagia, hypogonadotropic hypogonadism, and neuroendocrine/metabolic dysfunction (summary by Dehghani et al., 2018). [from OMIM]

Additional description

From MedlinePlus Genetics
Leptin receptor deficiency is a condition that causes severe obesity beginning in the first few months of life. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight. The extreme hunger leads to chronic excessive eating (hyperphagia) and obesity. Beginning in early childhood, affected individuals develop abnormal eating behaviors such as fighting with other children over food, hoarding food, and eating in secret.

People with leptin receptor deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development. Affected individuals experience delayed puberty or do not go through puberty, and they may be unable to conceive children (infertile).  https://medlineplus.gov/genetics/condition/leptin-receptor-deficiency

Clinical features

From HPO
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Polyphagia
MedGen UID:
9369
Concept ID:
C0020505
Finding
A neurological anomaly with gross overeating associated with an abnormally strong desire or need to eat.
Emotional lability
MedGen UID:
39319
Concept ID:
C0085633
Mental or Behavioral Dysfunction
Unstable emotional experiences and frequent mood changes; emotions that are easily aroused, intense, and/or disproportionate to events and circumstances.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Abnormal hypothalamus morphology
MedGen UID:
866745
Concept ID:
C4021095
Anatomical Abnormality
Any structural anomaly of the hypothalamus.
Abnormal eating behavior
MedGen UID:
867596
Concept ID:
C4021982
Mental or Behavioral Dysfunction
Abnormal eating habits involve excessive or insufficient consumption of food, or any other abnormal pattern of food consumption.
Recurrent upper respiratory tract infections
MedGen UID:
154380
Concept ID:
C0581381
Disease or Syndrome
An increased susceptibility to upper respiratory tract infections as manifested by a history of recurrent upper respiratory tract infections (running ears - otitis, sinusitis, pharyngitis, tonsillitis).
Immune dysregulation
MedGen UID:
335001
Concept ID:
C1844666
Finding
Altered immune function characterized by lymphoid proliferation, immune activation, and excessive autoreactivity often leading to autoimmune/inflammatory complications.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Delayed puberty
MedGen UID:
46203
Concept ID:
C0034012
Pathologic Function
Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Reduced function of the gonads (testes in males or ovaries in females) associated with excess pituitary gonadotropin secretion and resulting in delayed sexual development and growth delay.
Pituitary hypothyroidism
MedGen UID:
777086
Concept ID:
C3665349
Disease or Syndrome
A type of hypothyroidism that results from a defect in thyroid-stimulating hormone secretion.
Decreased response to growth hormone stimulation test
MedGen UID:
1784655
Concept ID:
C5539399
Finding
Insufficient responses to growth hormone (GH) provocation tests. GH deficiency is defined as a serum peak GH concentration less than 10 ng/mL on provocation with a combination of at least two separate stimulation tests.

Term Hierarchy

Follow this link to review classifications for Obesity due to leptin receptor gene deficiency in Orphanet.

Professional guidelines

PubMed

Chan JL, Oral EA
Endocr Pract 2010 Mar-Apr;16(2):310-23. doi: 10.4158/EP09154.RA. PMID: 20061300
Bell-Anderson KS, Bryson JM
Treat Endocrinol 2004;3(1):11-8. doi: 10.2165/00024677-200403010-00002. PMID: 15743109
Kumar A, Inverso NA, Still CD
Curr Gastroenterol Rep 2000 Aug;2(4):337-44. doi: 10.1007/s11894-000-0029-5. PMID: 10981034

Recent clinical studies

Etiology

Zhou B, Liu C, Xu L, Yuan Y, Zhao J, Zhao W, Chen Y, Qiu J, Meng M, Zheng Y, Wang D, Gao X, Li X, Zhao Q, Wei X, Wu D, Zhang H, Hu C, Zhuo X, Zheng M, Wang H, Lu Y, Ma X
Hepatology 2021 Jan;73(1):91-103. Epub 2020 Oct 25 doi: 10.1002/hep.31220. PMID: 32150756
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
von Schnurbein J, Manzoor J, Brandt S, Denzer F, Kohlsdorf K, Fischer-Posovszky P, Weißenberger M, Frank-Podlech S, Mahmood S, Wabitsch M
Obes Facts 2019;12(4):460-475. Epub 2019 Jul 29 doi: 10.1159/000501319. PMID: 31357197Free PMC Article
Unger RH
Annu Rev Med 2002;53:319-36. doi: 10.1146/annurev.med.53.082901.104057. PMID: 11818477
Maffeis C
Eur J Pediatr 2000 Sep;159 Suppl 1:S35-44. doi: 10.1007/pl00014361. PMID: 11011954

Diagnosis

Mazen IH, El-Gammal MA, Elaidy AA, Anwar GM, Ashaat EA, Abdel-Ghafar SF, Abdel-Hamid MS
Mol Genet Genomics 2023 Jul;298(4):919-929. Epub 2023 May 4 doi: 10.1007/s00438-023-02025-1. PMID: 37140700
Evans MC, Lord RA, Anderson GM
Int J Mol Sci 2021 Aug 26;22(17) doi: 10.3390/ijms22179210. PMID: 34502119Free PMC Article
Dubern B, Clement K
Biochimie 2012 Oct;94(10):2111-5. Epub 2012 May 22 doi: 10.1016/j.biochi.2012.05.010. PMID: 22627381
Gautron L, Elmquist JK
J Clin Invest 2011 Jun;121(6):2087-93. Epub 2011 Jun 1 doi: 10.1172/JCI45888. PMID: 21633176Free PMC Article
Santini F, Maffei M, Pelosini C, Salvetti G, Scartabelli G, Pinchera A
Adv Clin Chem 2009;48:95-109. PMID: 19803416

Therapy

Yeo GSH, Chao DHM, Siegert AM, Koerperich ZM, Ericson MD, Simonds SE, Larson CM, Luquet S, Clarke I, Sharma S, Clément K, Cowley MA, Haskell-Luevano C, Van Der Ploeg L, Adan RAH
Mol Metab 2021 Jun;48:101206. Epub 2021 Mar 6 doi: 10.1016/j.molmet.2021.101206. PMID: 33684608Free PMC Article
Klein AB, Nicolaisen TS, Ørtenblad N, Gejl KD, Jensen R, Fritzen AM, Larsen EL, Karstoft K, Poulsen HE, Morville T, Sahl RE, Helge JW, Lund J, Falk S, Lyngbæk M, Ellingsgaard H, Pedersen BK, Lu W, Finan B, Jørgensen SB, Seeley RJ, Kleinert M, Kiens B, Richter EA, Clemmensen C
Nat Commun 2021 Feb 15;12(1):1041. doi: 10.1038/s41467-021-21309-x. PMID: 33589633Free PMC Article
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Wasim M, Awan FR, Najam SS, Khan AR, Khan HN
Biochem Genet 2016 Oct;54(5):565-72. Epub 2016 Jun 16 doi: 10.1007/s10528-016-9751-z. PMID: 27313173
Farooqi IS
Front Horm Res 2008;36:1-11. doi: 10.1159/000115333. PMID: 18230891

Prognosis

Boro H, Bundela V, Mannar V, Nagendra L, Jain V, Jain B, Kumar S, Agstam S
Pediatr Endocrinol Diabetes Metab 2023;29(2):118-123. doi: 10.5114/pedm.2023.129344. PMID: 37728464Free PMC Article
Kanti V, Puder L, Jahnke I, Krabusch PM, Kottner J, Vogt A, Richter C, Andruck A, Lechner L, Poitou C, Krude H, Gottesdiener K, Clément K, Farooqi IS, Wiegand S, Kühnen P, Blume-Peytavi U
Skin Pharmacol Physiol 2021;34(6):307-316. Epub 2021 May 31 doi: 10.1159/000516282. PMID: 34058738
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Baxter J, Armijo PR, Flores L, Krause C, Samreen S, Tanner T
Obes Surg 2019 Dec;29(12):4077-4083. doi: 10.1007/s11695-019-04200-z. PMID: 31641982
Sinha MK, Caro JF
Vitam Horm 1998;54:1-30. doi: 10.1016/s0083-6729(08)60919-x. PMID: 9529971

Clinical prediction guides

Klein AB, Nicolaisen TS, Ørtenblad N, Gejl KD, Jensen R, Fritzen AM, Larsen EL, Karstoft K, Poulsen HE, Morville T, Sahl RE, Helge JW, Lund J, Falk S, Lyngbæk M, Ellingsgaard H, Pedersen BK, Lu W, Finan B, Jørgensen SB, Seeley RJ, Kleinert M, Kiens B, Richter EA, Clemmensen C
Nat Commun 2021 Feb 15;12(1):1041. doi: 10.1038/s41467-021-21309-x. PMID: 33589633Free PMC Article
Santos JL, Cortés VA
Obes Rev 2021 Jan;22(1):e13114. Epub 2020 Aug 2 doi: 10.1111/obr.13114. PMID: 33030294
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Blüher S, Shah S, Mantzoros CS
J Investig Med 2009 Oct;57(7):784-8. doi: 10.2310/JIM.0b013e3181b9163d. PMID: 19730134Free PMC Article
Farooqi IS, O'Rahilly S
Recent Prog Horm Res 2004;59:409-24. doi: 10.1210/rp.59.1.409. PMID: 14749512

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