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Obesity due to congenital leptin deficiency(LEPD)

MedGen UID:: 767138
•Concept ID:: C3554224
•: Disease or Syndrome

Synonyms:	Leptin Deficiency; Leptin deficiency or dysfunction
SNOMED CT:	Congenital leptin deficiency (700150001); Obesity due to congenital leptin deficiency (700150001)
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). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	LEP (7q32.1)

Monarch Initiative:	MONDO:0013991
OMIM®:	614962
Orphanet:	ORPHA66628

Definition

Leptin deficiency or dysfunction (LEPD) is characterized by severe early-onset obesity, hyperphagia, hypogonadotropic hypogonadism, and neuroendocrine/metabolic dysfunction (Ozata et al., 1999). [from OMIM]

Additional description

From MedlinePlus Genetics
Congenital leptin 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. Without treatment, the extreme hunger continues and 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 congenital leptin deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development. Without treatment, affected individuals experience delayed puberty or do not go through puberty, and may be unable to conceive children (infertile). https://medlineplus.gov/genetics/condition/congenital-leptin-deficiency

Clinical features

From HPO

Primary amenorrhea

MedGen UID:: 115918
•Concept ID:: C0232939
•: Disease or Syndrome

Abnormally late or absent menarche in a female with normal secondary sexual characteristics.

See: Feature record | Search on this feature

Decreased testicular size

MedGen UID:: 66027
•Concept ID:: C0241355
•: Finding

Reduced volume of the testicle (the male gonad).

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Micropenis

MedGen UID:: 1633603
•Concept ID:: C4551492
•: Congenital Abnormality

Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.

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Obesity

MedGen UID:: 18127
•Concept ID:: C0028754
•: Disease or Syndrome

Accumulation of substantial excess body fat.

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Polyphagia

MedGen UID:: 9369
•Concept ID:: C0020505
•: Finding

A neurological anomaly with gross overeating associated with an abnormally strong desire or need to eat.

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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).

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Recurrent pneumonia

MedGen UID:: 195802
•Concept ID:: C0694550
•: Disease or Syndrome

An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.

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Recurrent ear infections

MedGen UID:: 473277
•Concept ID:: C0743360
•: Finding

Increased susceptibility to ear infections, as manifested by recurrent episodes of ear infections.

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Hypogonadism

MedGen UID:: 5711
•Concept ID:: C0020619
•: Disease or Syndrome

A decreased functionality of the gonad.

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Decreased serum leptin

MedGen UID:: 373413
•Concept ID:: C1837802
•: Finding

A decreased concentration of leptin in the blood.

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Gynecomastia

MedGen UID:: 6694
•Concept ID:: C0018418
•: Disease or Syndrome

Abnormal development of large mammary glands in males resulting in breast enlargement.

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Show all Hide all

Abnormality of the breast
- Gynecomastia
Abnormality of the endocrine system
- Decreased serum leptin
- Hypogonadism
Abnormality of the genitourinary system
Abnormality of the immune system
- Recurrent ear infections
Abnormality of the nervous system
- Polyphagia
Abnormality of the respiratory system
- Recurrent pneumonia
- Recurrent upper respiratory tract infections
Growth abnormality
- Obesity

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVMonogenic Non-Syndromic Obesity, Autosomal Recessive
- CROGVObesity due to congenital leptin deficiency
- CROGVObesity due to leptin receptor gene deficiency
- CROGVObesity due to pro-opiomelanocortin deficiency
- CROGVObesity due to prohormone convertase I deficiency

Growth abnormality
- Abnormality of body weight
  - Increased body weight
    - Obesity
      - Inherited obesity
        Hereditary non-syndromic obesity
        Obesity due to congenital leptin deficiency

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

Professional guidelines

PubMed

Diagnosis and treatment of lipodystrophy: a step-by-step approach.

Araújo-Vilar D, Santini F
J Endocrinol Invest 2019 Jan;42(1):61-73. Epub 2018 Apr 27 doi: 10.1007/s40618-018-0887-z. PMID: 29704234 Free PMC Article

Leptin treatment: facts and expectations.

Paz-Filho G, Mastronardi CA, Licinio J
Metabolism 2015 Jan;64(1):146-56. Epub 2014 Aug 3 doi: 10.1016/j.metabol.2014.07.014. PMID: 25156686

Clinical classification and treatment of congenital and acquired lipodystrophy.

Chan JL, Oral EA
Endocr Pract 2010 Mar-Apr;16(2):310-23. doi: 10.4158/EP09154.RA. PMID: 20061300

See all (4)

Recent clinical studies

Etiology

High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor.

Saeed S, Khanam R, Janjua QM, Manzoor J, Ning L, Hanook S, Canouil M, Ali M, Ayesha H, Khan WI, Farooqi IS, Yeo GSH, O'Rahilly S, Bonnefond A, Butt TA, Arslan M, Froguel P
Cell Rep Med 2023 Sep 19;4(9):101187. Epub 2023 Sep 1 doi: 10.1016/j.xcrm.2023.101187. PMID: 37659411 Free PMC Article

Monogenic leptin deficiency in early childhood obesity.

ElSaeed G, Mousa N, El-Mougy F, Hafez M, Khodeera S, Alhelbawy M, Fouda E, Elsheikh S, ElKaffas R, Eldeeb S, Elsharkawy M
Pediatr Obes 2020 Jan;15(1):e12574. Epub 2019 Sep 4 doi: 10.1111/ijpo.12574. PMID: 31483094

Leptin Is Not Essential for Obesity-Associated Hypertension.

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: 31357197 Free PMC Article

Lipodystrophy: Syndrome of severe insulin resistance.

Bindlish S, Presswala LS, Schwartz F
Postgrad Med 2015 Jun;127(5):511-6. Epub 2015 Feb 17 doi: 10.1080/00325481.2015.1015927. PMID: 25690482

From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century.

Blüher M, Mantzoros CS
Metabolism 2015 Jan;64(1):131-45. Epub 2014 Oct 23 doi: 10.1016/j.metabol.2014.10.016. PMID: 25497344

See all (30)

Diagnosis

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Altarejos JY, Pangilinan J, Podgrabinska S, Akinci B, Foss-Freitas M, Neidert AH, Ray Y, Zheng W, Kim S, Kamat V, Huang M, Min S, Mastaitis J, Dominguez-Gutierrez G, Kim JH, Stevis P, Huang T, Zambrowicz B, Olson WC, Godin S, Bradley E, Gewitz AD, Baker M, Hench R, Davenport MS, Chenevert TL, DiPaola F, Yancopoulos GD, Murphy AJ, Herman GA, Musser BJ, Dansky H, Harp J, Gromada J, Sleeman MW, Oral EA, Olenchock BA
Sci Transl Med 2023 Nov 22;15(723):eadd4897. doi: 10.1126/scitranslmed.add4897. PMID: 37992152

Congenital leptin and leptin receptor deficiencies in nine new families: identification of six novel variants and review of literature.

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

Monogenic leptin deficiency in early childhood obesity.

Diagnosis and treatment of lipodystrophy: a step-by-step approach.

Araújo-Vilar D, Santini F
J Endocrinol Invest 2019 Jan;42(1):61-73. Epub 2018 Apr 27 doi: 10.1007/s40618-018-0887-z. PMID: 29704234 Free PMC Article

Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals.

Moon HS, Dalamaga M, Kim SY, Polyzos SA, Hamnvik OP, Magkos F, Paruthi J, Mantzoros CS
Endocr Rev 2013 Jun;34(3):377-412. Epub 2013 Mar 8 doi: 10.1210/er.2012-1053. PMID: 23475416 Free PMC Article

See all (28)

Therapy

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Leptin Is Not Essential for Obesity-Associated Hypertension.

Diagnosis and treatment of lipodystrophy: a step-by-step approach.

Araújo-Vilar D, Santini F
J Endocrinol Invest 2019 Jan;42(1):61-73. Epub 2018 Apr 27 doi: 10.1007/s40618-018-0887-z. PMID: 29704234 Free PMC Article

Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity.

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

Leptin treatment: facts and expectations.

Paz-Filho G, Mastronardi CA, Licinio J
Metabolism 2015 Jan;64(1):146-56. Epub 2014 Aug 3 doi: 10.1016/j.metabol.2014.07.014. PMID: 25156686

See all (42)

Prognosis

Prevalence estimates of putatively pathogenic leptin variants in the gnomAD database.

Rajcsanyi LS, Zheng Y, Fischer-Posovszky P, Wabitsch M, Hebebrand J, Hinney A
PLoS One 2022;17(9):e0266642. Epub 2022 Sep 19 doi: 10.1371/journal.pone.0266642. PMID: 36121795 Free PMC Article

Morbidly obese pregnant woman with congenital leptin deficiency: Follow-up and obstetric outcome.

Cagliyan E, Ozmen S, Timur HT, Ozgozen ME, Semiz GG
J Obstet Gynaecol Res 2022 Nov;48(11):2964-2967. Epub 2022 Jul 31 doi: 10.1111/jog.15379. PMID: 35909242

Early-onset severe obesity due to complete deletion of the leptin gene in a boy.

Ozsu E, Ceylaner S, Onay H
J Pediatr Endocrinol Metab 2017 Oct 26;30(11):1227-1230. doi: 10.1515/jpem-2017-0063. PMID: 29040067

From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century.

Blüher M, Mantzoros CS
Metabolism 2015 Jan;64(1):131-45. Epub 2014 Oct 23 doi: 10.1016/j.metabol.2014.10.016. PMID: 25497344

Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O'Rahilly S
N Engl J Med 2007 Jan 18;356(3):237-47. doi: 10.1056/NEJMoa063988. PMID: 17229951 Free PMC Article

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