Congenital Leptin Deficiency

👪

Inheritance

1

Autosomal recessive HP:0000007

Biallelic (homozygous or compound heterozygous) LEP variants are required. The original kindred was highly consanguineous and the affected children were homozygous for a codon 133 frameshift.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:9202122 SUPPORT Human Clinical

"We have examined two severely obese children who are members of the same highly consanguineous pedigree."

The founding report identifies affected children within a single highly consanguineous pedigree, the pattern expected of a recessive trait.

◆

Subtypes

3

Classical hormone deficiency

No secreted hormone, so circulating leptin is low or undetectable. The largest class by far, and the one the disease was originally defined by. Leptin is low or undetectable on both the regular and bioLEP assays, and treatment starts at the standard metreleptin dose of 0.03 mg/kg lean body weight -- the reference point the other two subtypes are measured against.

Show evidence (2 references)

PMID:38470203 SUPPORT Human Clinical

"classical hormone deficiency (21 variants in 128 patients)"

Defines the class and gives its variant and patient counts.

PMID:38470203 SUPPORT Human Clinical

"can receive treatment at a regular metreleptin starting dose of 0.03 mg/kg lean body weight."

Gives the standard metreleptin starting dose for this subtype, which is the baseline the antagonistic subtype departs from.

Biologically inactive hormone

Hormone is secreted and immunoreactive but cannot signal, so a regular ELISA reads normal or high. Diagnosis requires the bioLEP assay alongside the regular one. Takes the same metreleptin starting dose as the classical class. Carries a genotype-phenotype signal worth noting: recurrent or severe infection is significantly more common in this subtype than in classical deficiency (45% vs 16%). That is the one comorbidity reported to differ significantly between subtypes, so the entry-level infection frequency understates the risk for these patients specifically.

Show evidence (3 references)

PMID:38470203 SUPPORT Human Clinical

"biologically inactive hormone (3 variants in 12 patients)"

Defines the class and gives its variant and patient counts.

PMID:38470203 SUPPORT Human Clinical

"the rate of recurrent or severe infections was signicantly higher in patients living with biological inactive leptin compared to patients with classical hormone deficiency (45% vs 16%, P < .05; Table 4)."

Reports the significantly higher infection rate in this subtype relative to classical deficiency. Quoted verbatim including the source's "signicantly" typo, as the snippet must be an exact substring.

PMID:38470203 SUPPORT Human Clinical

"Combined measurements using a regular ELISA and the more recently developed bioLEP ELISA allow for the robust diagnosis of biological inactive leptin."

Gives the two-assay algorithm that identifies this class.

Antagonistic hormone

The mutant hormone antagonises non-variant leptin at the receptor. This is the class that breaks both halves of the usual approach: both assays read normal, so leptin measurement does not identify it at all, and because the variant also antagonises metreleptin, these patients need higher initial doses and variant-tailored tapering rather than the standard regimen.

Show evidence (3 references)

PMID:38470203 SUPPORT Human Clinical

"antagonistic hormone (3 variants in 7 patients)"

Defines the class and gives its variant and patient counts.

PMID:38470203 SUPPORT Human Clinical

"Regular and bioLEP ELISA will measure inconspicuous leptin levels in patients with antagonistic leptin and thus will not help to identify CLD in these patients."

Records that neither assay identifies this class, which is why the diagnosis block cannot present leptin measurement as universally discriminating.

PMID:38470203 SUPPORT Human Clinical

"patients living with antagonistic leptin cannot receive the same dose of metreleptin as patients living with classical hormone deficiency but require higher initial doses and appropriate dose tapering"

Establishes that metreleptin dosing is subtype-dependent, which is why the treatment block cannot assert a uniform response.

⚙

Pathophysiology

5

Absent or Bioinactive Leptin

Biallelic LEP variants remove the circulating leptin signal. The classical lesion is a frameshift or nonsense variant producing no secreted hormone, so serum leptin is low or undetectable despite a greatly expanded fat mass. A second, later-recognised class of missense variants yields a hormone that is secreted and immunoreactive — so measured leptin is normal or high — but biologically inactive or antagonistic at the receptor. Both classes cripple leptin signalling while leaving the assay result normal or high, which is why a normal leptin level does not exclude the diagnosis. "Cripple" rather than "abolish" is deliberate: antagonistic variants trigger no or only little downstream signalling rather than none at all, and p.Gly59Ser retains partial agonist activity.

adipocyte CL:0000136

LEP hgnc:6553

leptin hormone activity GO:0005179 ⇓ LOSS OF FUNCTION

Downstream

Failure of Hypothalamic Leptin Signaling

Show evidence (3 references)

PMID:9202122 SUPPORT Human Clinical

"a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found"

Identifies the founding loss-of-function LEP lesion in the two affected children.

PMID:38470203 SUPPORT Human Clinical

"Recently, variants have been described resulting in secreted mutant forms of the hormone leptin with either biologically inactive or antagonistic properties."

Establishes the second variant class, in which mutant leptin is secreted rather than absent, so the molecular lesion is signal failure rather than simply low hormone concentration.

PMID:26186301 SUPPORT In Vitro

"In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive."

Functional confirmation that a secreted missense LEP product is inactive, supporting bioinactivity as a distinct molecular route to the same disease.

Failure of Hypothalamic Leptin Signaling

Without a functional ligand, leptin receptors on arcuate nucleus neurons are never engaged, so the JAK2/STAT3 cascade downstream of LEPR is not activated. Anorexigenic POMC/CART neurons lose their principal excitatory drive and orexigenic AgRP/NPY neurons lose their principal inhibition. The hypothalamus therefore reports depleted energy stores irrespective of the actual, greatly expanded, adipose mass — the central pathogenic inversion of this disease.

pro-opiomelanocortin neuron of the arcuate nucleus CL:4042033 arcuate AgRP/NPY neuron CL:0000540

leptin-mediated signaling pathway GO:0033210 ↓ DECREASED energy homeostasis GO:0097009 ↓ DECREASED

arcuate nucleus of hypothalamus UBERON:0001932

Downstream

Unopposed Orexigenic Drive

Starvation-Pattern Neuroendocrine Suppression

Impaired T Cell Number and Function

Show evidence (2 references)

PMID:9202122 SUPPORT Human Clinical

"The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans."

The founding report frames the human phenotype as genetic proof that leptin regulates energy balance, which is the signalling failure this node describes.

PMID:22627381 SUPPORT Human Clinical

"Patients are mostly characterized by severe early-onset obesity with severe hyperphagia"

Summarises the clinical consequence of absent hypothalamic leptin signalling across the reported LEP-deficient cohort.

Unopposed Orexigenic Drive

With the satiety limb silent, appetite runs without its physiological brake. Affected children show intense, food-seeking hyperphagia from the first months of life, and energy expenditure is not raised to compensate, so fat mass accumulates rapidly and continuously. This node is the immediate generator of the obesity phenotype and is the arm most visibly and rapidly reversed by leptin replacement.

regulation of appetite GO:0032098 ↓ DECREASED feeding behavior GO:0007631 ↑ INCREASED

Animal models

ob/ob mouse (Lep-deficient) Mouse recapitulates Loss of leptin in the mouse reproduces the hyperphagia and severe obesity that define the human disease, through the orthologous gene.

Downstream

Severe Early-Onset Obesity

Hyperphagia

Show evidence (2 references)

PMID:22627381 SUPPORT INDIRECT Human Clinical

"It results in weight loss, mainly of fat mass, with a major effect on reducing food intake"

Leptin replacement acting principally by reducing food intake supports unopposed appetite drive as the mechanism generating the obesity.

PMID:12393845 SUPPORT INDIRECT Human Clinical

"sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia"

Sustained reversal of appetite and fat mass on leptin supports these as leptin-dependent, and therefore as consequences of the missing signal.

Starvation-Pattern Neuroendocrine Suppression

Leptin is also the permissive signal that tells the hypothalamus there is enough stored energy to run reproduction and full metabolic activity. Read as starvation, the hypothalamus suppresses GnRH-driven gonadotropin secretion, so LH and FSH remain prepubertal and are not pulsatile, and it blunts the thyroid and growth hormone axes. Puberty therefore does not begin, despite obesity — the combination that distinguishes this disease from common obesity, where puberty is typically early.

gonadotropin secretion GO:0032274 ↓ DECREASED

Downstream

Hypogonadotropic Hypogonadism

Delayed Puberty

Show evidence (3 references)

PMID:22343341 SUPPORT Human Clinical

"Initially, the patient had prepubertal basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, low growth hormone and insulin-like growth factor 1 (IGF1) levels and no pulsatile secretion of LH and FSH."

Directly documents suppressed, non-pulsatile gonadotropin secretion plus a blunted GH/IGF1 axis in an untreated leptin-deficient adolescent.

PMID:22343341 SUPPORT Human Clinical

"These data are further proof of the concept that leptin is needed for a timely maturation of the hypothalamic/pituitary/gonadal axis."

States the causal dependence of HPG axis maturation on leptin, which is the mechanism this node asserts.

PMID:12393845 SUPPORT INDIRECT Human Clinical

"Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development."

Reversal of both the thyroid and gonadotropin arms by leptin supports their suppression being caused by the missing signal.

Impaired T Cell Number and Function

Leptin is also an immunomodulatory cytokine acting on lymphocytes, and its absence reduces circulating CD4-positive T cell numbers and impairs T cell proliferation and cytokine release. Clinically this presents as a high rate of childhood infection, which historically accounted for deaths in leptin-deficient kindreds. Like the endocrine arm, it is reversed by leptin replacement, establishing it as a direct consequence of the deficiency rather than a secondary effect of obesity.

CD4-positive, alpha-beta T cell CL:0000624

positive regulation of T cell proliferation GO:0042102 ↓ DECREASED

Downstream

Recurrent Infections

Show evidence (2 references)

PMID:12393845 SUPPORT Human Clinical

"Leptin deficiency was associated with reduced numbers of circulating CD4(+) T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration."

Directly documents the cellular immune defect and its reversal by leptin, supporting both the mechanism and its leptin dependence.

PMID:22627381 SUPPORT Human Clinical

"high rate of infection associated with a deficiency in T cell"

Confirms the clinical infection burden accompanying the T cell defect across reported LEP-deficient patients.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

9

Cardiovascular 1

Hypertension OCCASIONAL HP:0000822

Show evidence (1 reference)

PMID:38470203 SUPPORT Human Clinical

"hypertension (n = 11/103; 11%), hirsutism (n = 2/53 female patients; 4%), sleep apnea (n = 5/103; 5%), and genu valgum (4/103; 4%)."

Systematic denominator placing hypertension at 11% of reported patients.

Endocrine 3

Hypogonadotropic Hypogonadism OCCASIONAL HP:0000044

Show evidence (2 references)

PMID:22343341 SUPPORT Human Clinical

"We describe here the first adolescent with hypogonadotropic hypogonadism due to connatal leptin deficiency."

Directly attributes hypogonadotropic hypogonadism to congenital leptin deficiency in an affected adolescent.

PMID:38470203 SUPPORT Human Clinical

"hypogonadotropic hypogonadism including micropenis, undescended testis, primary amenorrhea, or delayed puberty in 16 of 103 patients [16%; including in all 12 adult patients (100%)]"

Gives both denominators: 16% across a mostly paediatric cohort, but 100% of the adults, which is why the band is OCCASIONAL while the description records it as effectively obligate after pubertal age.

Delayed Puberty OCCASIONAL HP:0000823

Show evidence (1 reference)

PMID:22343341 SUPPORT Human Clinical

"After 76 weeks of therapy, menstruation occurred at the age of 16.3 years."

Menarche only after prolonged leptin substitution, at 16.3 years, documents the delayed pubertal course of the untreated disease.

Hyperinsulinemia OCCASIONAL HP:0000842

Show evidence (2 references)

PMID:12393845 SUPPORT Human Clinical

"sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia"

Identifies hyperinsulinemia as a feature of the untreated state that responds to leptin.

PMID:38470203 SUPPORT Human Clinical

"Of the 103 patients with reported comorbidities, 30 (29%) were reported to have hyperinsulinemia, insulin resistance, and/or (pre) diabetes."

Systematic denominator placing hyperinsulinemia and related dysglycaemia at 29%, which is the OCCASIONAL band.

Immune 1

Recurrent Infections OCCASIONAL HP:0002719

Show evidence (2 references)

PMID:22627381 SUPPORT Human Clinical

"high rate of infection associated with a deficiency in T cell"

Records the increased infection rate and links it to the T cell deficit.

PMID:38470203 SUPPORT Human Clinical

"recurrent and/or severe infections, especially of the respiratory tract (20/103; 19%; Table 4)"

Systematic denominator placing recurrent infection at 19% of reported patients, which is the OCCASIONAL band rather than FREQUENT.

Metabolism 1

Dyslipidemia OCCASIONAL Abnormal circulating lipid concentration HP:0003119

Show evidence (1 reference)

PMID:38470203 SUPPORT Human Clinical

"In total, 22/106 patients (21%) with either reported comorbidities and/or reported triglyceride and cholesterol levels showed evidence of disturbed lipid metabolism"

Places dyslipidemia at 21% of reported patients. Note the denominator is 106 here rather than the 103 used for other comorbidities, because it combines reported dyslipidemia with patients meeting lipid thresholds.

Nervous System 2

Hyperphagia VERY_FREQUENT Polyphagia HP:0002591

Onset: INFANTILE

Show evidence (2 references)

PMID:22627381 SUPPORT Human Clinical

"severe early-onset obesity with severe hyperphagia"

Records severe hyperphagia as a defining feature of LEP-deficient patients.

PMID:26186301 SUPPORT Human Clinical

"a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia"

Documents hyperphagia alongside obesity in siblings with a bioinactive leptin variant.

Developmental Delay OCCASIONAL Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:38470203 SUPPORT Human Clinical

"In addition, in 22/103 patients (21%), a developmental delay was reported."

Systematic denominator placing developmental delay at 21% of reported patients.

Growth 1

Severe Early-Onset Obesity OBLIGATE HP:0001513

Course: PROGRESSIVE Onset: INFANTILE

Sequelae: Hyperinsulinemia

Show evidence (1 reference)

PMID:38470203 SUPPORT Human Clinical

"Biallelic pathogenic leptin gene variants cause severe early-onset obesity usually associated with low or undetectable circulating leptin levels."

States severe early-onset obesity as the defining consequence of biallelic LEP variants.

🧬

Genetic Associations

1

LEP loss of function

Gene: LEP hgnc:6553 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:9202122 SUPPORT Human Clinical

"a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found"

Identifies the causative homozygous LEP frameshift in the founding pedigree.

PMID:22627381 SUPPORT Human Clinical

"Since 1997, less than 20 individuals carrying a LEP gene mutation have been identified."

Quantifies the rarity of causative LEP variants in the reported literature.

PMID:26186301 SUPPORT Human Clinical

"both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin"

Documents a homozygous missense LEP variant producing detectable but inactive hormone, extending the causative allelic spectrum.

💊

Medical Actions

1

Metreleptin

Action: Pharmacotherapy NCIT:C15986

Agent: metreleptin NCIT:C170171

Platform: Protein replacement

Daily subcutaneous recombinant human leptin, which replaces the missing hormone and restores hypothalamic leptin signalling. It is uniquely effective here because the receptor and all downstream circuitry are intact — the defect is the ligand alone. Response spans every arm of the disease: appetite and fat mass fall, thyroid hormone rises, gonadotropin secretion and puberty are induced, and the T cell defect corrects. Dosing is not uniform across subtypes, however. Classical and biologically inactive deficiency take the same starting dose, but antagonistic variants antagonise metreleptin itself at the receptor, so those patients require higher initial doses and variant-tailored tapering.

Mechanism Target:

Failure of Hypothalamic Leptin Signaling — Exogenous leptin supplies the absent ligand for intact hypothalamic leptin receptors, restoring the signal at the point where the disease begins.

Show evidence (1 reference)

PMID:12393845 SUPPORT Human Clinical

"The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency."

Correction of the full multi-system phenotype by replacing the ligand supports the treatment acting at the leptin signalling node.

Unopposed Orexigenic Drive — Restored leptin signalling re-establishes satiety, and reduced food intake is the principal driver of the weight loss observed on therapy.

Show evidence (1 reference)

PMID:22627381 SUPPORT Human Clinical

"It results in weight loss, mainly of fat mass, with a major effect on reducing food intake"

Identifies reduced food intake as the mechanism of the therapeutic weight loss, which is the orexigenic node being corrected.

Impaired T Cell Number and Function — Leptin replacement restores CD4-positive T cell numbers and T cell proliferative and cytokine responses.

Show evidence (1 reference)

PMID:12393845 SUPPORT Human Clinical

"impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration"

Direct evidence that leptin administration reverses the T cell defect.

Starvation-Pattern Neuroendocrine Suppression — Leptin substitution induces pulsatile gonadotropin secretion and permits pubertal progression, and raises thyroid hormone levels.

Show evidence (1 reference)

PMID:22343341 SUPPORT Human Clinical

"After 11 weeks of therapy, basal and stimulated LH and FSH levels rose to pubertal values and nocturnal pulsatility was initiated."

Documents restoration of gonadotropin secretion and pulsatility on leptin, correcting the suppressed neuroendocrine node.

Target Phenotypes: Obesity HP:0001513 Hyperphagia HP:0002591

Show evidence (2 references)

PMID:22627381 SUPPORT Human Clinical

"Therapeutic option (subcutaneous daily injection of leptin) is available for patients with LEP deficiency."

Establishes daily subcutaneous leptin as the available therapy for this specific genotype.

PMID:38470203 SUPPORT Human Clinical

"patients living with antagonistic leptin cannot receive the same dose of metreleptin as patients living with classical hormone deficiency but require higher initial doses and appropriate dose tapering"

Establishes that the dose is subtype-dependent, which is why this entry does not assert a uniform treatment response.

🔬

Diagnosis

1

Circulating leptin measurement with LEP sequencing

Serum leptin is the discriminating first-line test, and it separates this disease from its closest mimic: it is undetectable in LEP mutation carriers but extremely elevated in LEPR (receptor) mutation carriers, whose clinical picture is otherwise similar and who do not respond to leptin replacement. The important caveat is that a normal or high leptin level does not exclude the diagnosis, and it fails in two different ways for the two non-classical subtypes. For biologically inactive leptin, combining a regular ELISA with the bioLEP assay — which measures receptor-binding capacity rather than hormone mass — separates it robustly. For antagonistic leptin, both assays read inconspicuous, so leptin measurement does not identify the disease at all and only sequencing will. LEP sequencing should therefore be considered in any severely obese, hyperphagic child even when circulating leptin is normal and even when the bioLEP assay is also normal.

Show evidence (4 references)

PMID:22627381 SUPPORT Human Clinical

"Measurement of circulating leptin may help for the diagnosis of such obesity: it is undetectable in LEP mutation carriers or extremely elevated in LEPR mutation carriers."

Establishes serum leptin as the diagnostic discriminator between LEP and LEPR deficiency.

PMID:26186301 SUPPORT Human Clinical

"Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin."

Records the caveat that detectable leptin does not exclude the diagnosis, because bioinactive variants are secreted.

PMID:38470203 SUPPORT Human Clinical

"Combined measurements using a regular ELISA and the more recently developed bioLEP ELISA allow for the robust diagnosis of biological inactive leptin."

Gives the two-assay algorithm that identifies the bioinactive subtype.

+ 1 more reference

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

148 patients across 28 distinct homozygous LEP variants in the 2024 systematic classification. The earlier "fewer than 20 individuals" figure is retained below as the 2012 count, because the growth between the two is itself informative rather than merely superseded: most of it is ascertainment of the bioinactive and antagonistic classes, which present with normal or high measured leptin and were therefore missed while a low leptin level was treated as the screening criterion.

Show evidence (2 references)

PMID:38470203 SUPPORT Human Clinical

"A total of 28 distinct homozygous leptin variants were identified in 148 patients."

Current systematic census of reported patients and causative variants.

PMID:22627381 SUPPORT Human Clinical

"Since 1997, less than 20 individuals carrying a LEP gene mutation have been identified."

The 2012 count, retained to show the scale of subsequent ascertainment rather than as the current figure.

🐁

Animal Models

1

ob/ob mouse (Lep-deficient)

The founding model. Extreme obesity in the ob/ob mouse was attributed to mutations in the leptin gene years before any human case was known, and it is what made congenital leptin deficiency a hypothesis worth testing in humans. Its immune phenotype also anticipated the human T cell defect.

Species

Mouse

Genotype

Lep ob/ob

Publication

PMID:9202122

Pathograph links

Unopposed Orexigenic Drive recapitulates fidelity: high observes: organism Loss of leptin in the mouse reproduces the hyperphagia and severe obesity that define the human disease, through the orthologous gene.

Limitations: The mouse phenotype was characterised before the human disease and framed the human expectation rather than being validated against it. The human subtype structure has no murine counterpart: ob/ob is a null, so it models classical hormone deficiency only and says nothing about the bioinactive or antagonistic classes, where the hormone is present but non-functional.

Show evidence (1 reference)

PMID:9202122 SUPPORT Model Organism

"The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure."

Establishes the murine phenotype and its attribution to leptin, the model this node recapitulates.

{ }

Source YAML

click to show

name: Congenital Leptin Deficiency
creation_date: "2026-09-04T02:15:00Z"
category: Metabolic Disorder
description: >-
  Congenital leptin deficiency is a rare autosomal recessive form of severe
  early-onset obesity caused by biallelic pathogenic variants in LEP, the gene
  encoding the adipocyte hormone leptin. Leptin is the afferent limb of the
  adipostat: it is secreted in proportion to fat mass and acts on leptin
  receptors in the hypothalamic arcuate nucleus to activate anorexigenic
  POMC/CART neurons and inhibit orexigenic AgRP/NPY neurons. When leptin is
  absent, or is secreted in a biologically inactive or antagonistic form, the
  hypothalamus reads a state of permanent starvation regardless of adipose
  stores. The result is intense hyperphagia and severe obesity from the first
  months of life, together with the wider starvation-like neuroendocrine
  program: hypogonadotropic hypogonadism with failure of pubertal onset,
  blunted thyroid and growth hormone axes, and impaired T cell number and
  function with recurrent infection. It is distinguished from every other
  monogenic obesity by being pharmacologically correctable — daily recombinant
  leptin (metreleptin) replaces the missing signal and reverses the whole
  phenotype, including the immune and reproductive arms.
disease_term:
  preferred_term: obesity due to congenital leptin deficiency
  term:
    id: MONDO:0013991
    label: obesity due to congenital leptin deficiency
synonyms:
- congenital leptin deficiency
- obesity, morbid, due to leptin deficiency
- leptin deficiency or dysfunction
- obesity, morbid, nonsyndromic 1
- LEPD
parents:
- Obesity Due to MC4R Pathway Disruption
- Inherited Obesity
notes: >-
  Curated as a distinct Disease rather than folded into
  Obesity_Due_to_MC4R_Pathway_Disruption. That entry is an explicitly
  mechanism-based umbrella whose disease_term is the broad MONDO:0011122
  (obesity disorder) and whose pathophysiology is the three generic nodes shared
  by every leptin-melanocortin lesion; its LEP subtype records that this entity
  exists but binds no MONDO term and carries no pathograph. This entry supplies
  the LEP-specific chain, the reproductive and immune arms, and the
  metreleptin mechanism, none of which are properties of the umbrella.

  Deliberately distinct from leptin *receptor* (LEPR) deficiency, which is
  clinically similar but has extremely elevated rather than absent circulating
  leptin and does not respond to leptin replacement. Evidence about LEPR
  patients must not be reused here.
references:
- reference: PMID:9202122
  title: "Congenital leptin deficiency is associated with severe early-onset obesity in humans."
- reference: PMID:12393845
  title: "Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency."
- reference: PMID:38470203
  title: "Classification of Congenital Leptin Deficiency."
- reference: PMID:22627381
  title: "Leptin and leptin receptor-related monogenic obesity."
- reference: PMID:26186301
  title: "Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene."
- reference: PMID:22343341
  title: "Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism."
- reference: PMID:10486419
  title: "Effects of recombinant leptin therapy in a child with congenital leptin deficiency."
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic (homozygous or compound heterozygous) LEP variants are required.
    The original kindred was highly consanguineous and the affected children
    were homozygous for a codon 133 frameshift.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:9202122
    reference_title: "Congenital leptin deficiency is associated with severe early-onset obesity in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have examined two severely obese children who are members of the same highly consanguineous pedigree."
    explanation: >-
      The founding report identifies affected children within a single highly
      consanguineous pedigree, the pattern expected of a recessive trait.
has_subtypes:
- name: Classical
  display_name: Classical hormone deficiency
  description: >-
    No secreted hormone, so circulating leptin is low or undetectable. The
    largest class by far, and the one the disease was originally defined by.
    Leptin is low or undetectable on both the regular and bioLEP assays, and
    treatment starts at the standard metreleptin dose of 0.03 mg/kg lean body
    weight -- the reference point the other two subtypes are measured against.
  evidence:
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "classical hormone deficiency (21 variants in 128 patients)"
    explanation: >-
      Defines the class and gives its variant and patient counts.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can receive treatment at a regular metreleptin starting dose of 0.03 mg/kg lean body weight."
    explanation: >-
      Gives the standard metreleptin starting dose for this subtype, which is
      the baseline the antagonistic subtype departs from.
- name: Bioinactive
  display_name: Biologically inactive hormone
  description: >-
    Hormone is secreted and immunoreactive but cannot signal, so a regular ELISA
    reads normal or high. Diagnosis requires the bioLEP assay alongside the
    regular one. Takes the same metreleptin starting dose as the classical class.

    Carries a genotype-phenotype signal worth noting: recurrent or severe
    infection is significantly more common in this subtype than in classical
    deficiency (45% vs 16%). That is the one comorbidity reported to differ
    significantly between subtypes, so the entry-level infection frequency
    understates the risk for these patients specifically.
  evidence:
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biologically inactive hormone (3 variants in 12 patients)"
    explanation: >-
      Defines the class and gives its variant and patient counts.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the rate of recurrent or severe infections was signicantly higher in patients living with biological inactive leptin compared to patients with classical hormone deficiency (45% vs 16%, P < .05; Table 4)."
    explanation: >-
      Reports the significantly higher infection rate in this subtype relative to
      classical deficiency. Quoted verbatim including the source's "signicantly"
      typo, as the snippet must be an exact substring.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Combined measurements using a regular ELISA and the more recently developed bioLEP ELISA allow for the robust diagnosis of biological inactive leptin."
    explanation: >-
      Gives the two-assay algorithm that identifies this class.
- name: Antagonistic
  display_name: Antagonistic hormone
  description: >-
    The mutant hormone antagonises non-variant leptin at the receptor. This is
    the class that breaks both halves of the usual approach: both assays read
    normal, so leptin measurement does not identify it at all, and because the
    variant also antagonises metreleptin, these patients need higher initial
    doses and variant-tailored tapering rather than the standard regimen.
  evidence:
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "antagonistic hormone (3 variants in 7 patients)"
    explanation: >-
      Defines the class and gives its variant and patient counts.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular and bioLEP ELISA will measure inconspicuous leptin levels in patients with antagonistic leptin and thus will not help to identify CLD in these patients."
    explanation: >-
      Records that neither assay identifies this class, which is why the
      diagnosis block cannot present leptin measurement as universally
      discriminating.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients living with antagonistic leptin cannot receive the same dose of metreleptin as patients living with classical hormone deficiency but require higher initial doses and appropriate dose tapering"
    explanation: >-
      Establishes that metreleptin dosing is subtype-dependent, which is why the
      treatment block cannot assert a uniform response.

pathophysiology:
- name: Absent or Bioinactive Leptin
  biological_scale: MOLECULAR
  description: >-
    Biallelic LEP variants remove the circulating leptin signal. The classical
    lesion is a frameshift or nonsense variant producing no secreted hormone, so
    serum leptin is low or undetectable despite a greatly expanded fat mass.
    A second, later-recognised class of missense variants yields a hormone that
    is secreted and immunoreactive — so measured leptin is normal or high — but
    biologically inactive or antagonistic at the receptor. Both classes cripple
    leptin signalling while leaving the assay result normal or high, which is why
    a normal leptin level does not exclude the diagnosis. "Cripple" rather than
    "abolish" is deliberate: antagonistic variants trigger no or only little
    downstream signalling rather than none at all, and p.Gly59Ser retains partial
    agonist activity.
  gene:
    preferred_term: LEP
    term:
      id: hgnc:6553
      label: LEP
  cell_types:
  - preferred_term: adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  molecular_functions:
  - preferred_term: leptin hormone activity
    term:
      id: GO:0005179
      label: hormone activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:9202122
    reference_title: "Congenital leptin deficiency is associated with severe early-onset obesity in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found"
    explanation: >-
      Identifies the founding loss-of-function LEP lesion in the two affected
      children.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, variants have been described resulting in secreted mutant forms of the hormone leptin with either biologically inactive or antagonistic properties."
    explanation: >-
      Establishes the second variant class, in which mutant leptin is secreted
      rather than absent, so the molecular lesion is signal failure rather than
      simply low hormone concentration.
  - reference: PMID:26186301
    reference_title: "Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive."
    explanation: >-
      Functional confirmation that a secreted missense LEP product is inactive,
      supporting bioinactivity as a distinct molecular route to the same disease.
  downstream:
  - target: Failure of Hypothalamic Leptin Signaling
    causal_link_type: DIRECT
- name: Failure of Hypothalamic Leptin Signaling
  biological_scale: CELLULAR
  description: >-
    Without a functional ligand, leptin receptors on arcuate nucleus neurons
    are never engaged, so the JAK2/STAT3 cascade downstream of LEPR is not
    activated. Anorexigenic POMC/CART neurons lose their principal excitatory
    drive and orexigenic AgRP/NPY neurons lose their principal inhibition. The
    hypothalamus therefore reports depleted energy stores irrespective of the
    actual, greatly expanded, adipose mass — the central pathogenic inversion of
    this disease.
  cell_types:
  - preferred_term: pro-opiomelanocortin neuron of the arcuate nucleus
    term:
      id: CL:4042033
      label: pro-opiomelanocortin neuron
  - preferred_term: arcuate AgRP/NPY neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: arcuate nucleus of hypothalamus
    term:
      id: UBERON:0001932
      label: arcuate nucleus of hypothalamus
  biological_processes:
  - preferred_term: leptin-mediated signaling pathway
    term:
      id: GO:0033210
      label: leptin-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: energy homeostasis
    term:
      id: GO:0097009
      label: energy homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:9202122
    reference_title: "Congenital leptin deficiency is associated with severe early-onset obesity in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans."
    explanation: >-
      The founding report frames the human phenotype as genetic proof that
      leptin regulates energy balance, which is the signalling failure this node
      describes.
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients are mostly characterized by severe early-onset obesity with severe hyperphagia"
    explanation: >-
      Summarises the clinical consequence of absent hypothalamic leptin
      signalling across the reported LEP-deficient cohort.
  downstream:
  - target: Unopposed Orexigenic Drive
    causal_link_type: DIRECT
  - target: Starvation-Pattern Neuroendocrine Suppression
    causal_link_type: DIRECT
  - target: Impaired T Cell Number and Function
    causal_link_type: DIRECT
- name: Unopposed Orexigenic Drive
  biological_scale: ORGANISM
  description: >-
    With the satiety limb silent, appetite runs without its physiological brake.
    Affected children show intense, food-seeking hyperphagia from the first
    months of life, and energy expenditure is not raised to compensate, so fat
    mass accumulates rapidly and continuously. This node is the immediate
    generator of the obesity phenotype and is the arm most visibly and rapidly
    reversed by leptin replacement.
  biological_processes:
  - preferred_term: regulation of appetite
    term:
      id: GO:0032098
      label: regulation of appetite
    modifier: DECREASED
  - preferred_term: feeding behavior
    term:
      id: GO:0007631
      label: feeding behavior
    modifier: INCREASED
  evidence:
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It results in weight loss, mainly of fat mass, with a major effect on reducing food intake"
    explanation: >-
      Leptin replacement acting principally by reducing food intake supports
      unopposed appetite drive as the mechanism generating the obesity.
    directness: INDIRECT
  - reference: PMID:12393845
    reference_title: "Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia"
    explanation: >-
      Sustained reversal of appetite and fat mass on leptin supports these as
      leptin-dependent, and therefore as consequences of the missing signal.
    directness: INDIRECT
  downstream:
  - target: Severe Early-Onset Obesity
    causal_link_type: DIRECT
  - target: Hyperphagia
    causal_link_type: DIRECT
- name: Starvation-Pattern Neuroendocrine Suppression
  biological_scale: ORGANISM
  description: >-
    Leptin is also the permissive signal that tells the hypothalamus there is
    enough stored energy to run reproduction and full metabolic activity. Read
    as starvation, the hypothalamus suppresses GnRH-driven gonadotropin
    secretion, so LH and FSH remain prepubertal and are not pulsatile, and it
    blunts the thyroid and growth hormone axes. Puberty therefore does not
    begin, despite obesity — the combination that distinguishes this disease
    from common obesity, where puberty is typically early.
  biological_processes:
  - preferred_term: gonadotropin secretion
    term:
      id: GO:0032274
      label: gonadotropin secretion
    modifier: DECREASED
  evidence:
  - reference: PMID:22343341
    reference_title: "Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initially, the patient had prepubertal basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, low growth hormone and insulin-like growth factor 1 (IGF1) levels and no pulsatile secretion of LH and FSH."
    explanation: >-
      Directly documents suppressed, non-pulsatile gonadotropin secretion plus a
      blunted GH/IGF1 axis in an untreated leptin-deficient adolescent.
  - reference: PMID:22343341
    reference_title: "Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data are further proof of the concept that leptin is needed for a timely maturation of the hypothalamic/pituitary/gonadal axis."
    explanation: >-
      States the causal dependence of HPG axis maturation on leptin, which is
      the mechanism this node asserts.
  - reference: PMID:12393845
    reference_title: "Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development."
    explanation: >-
      Reversal of both the thyroid and gonadotropin arms by leptin supports
      their suppression being caused by the missing signal.
    directness: INDIRECT
  downstream:
  - target: Hypogonadotropic Hypogonadism
    causal_link_type: DIRECT
  - target: Delayed Puberty
    causal_link_type: DIRECT
- name: Impaired T Cell Number and Function
  biological_scale: CELLULAR
  description: >-
    Leptin is also an immunomodulatory cytokine acting on lymphocytes, and its
    absence reduces circulating CD4-positive T cell numbers and impairs T cell
    proliferation and cytokine release. Clinically this presents as a high rate
    of childhood infection, which historically accounted for deaths in
    leptin-deficient kindreds. Like the endocrine arm, it is reversed by leptin
    replacement, establishing it as a direct consequence of the deficiency
    rather than a secondary effect of obesity.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: positive regulation of T cell proliferation
    term:
      id: GO:0042102
      label: positive regulation of T cell proliferation
    modifier: DECREASED
  evidence:
  - reference: PMID:12393845
    reference_title: "Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leptin deficiency was associated with reduced numbers of circulating CD4(+) T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration."
    explanation: >-
      Directly documents the cellular immune defect and its reversal by leptin,
      supporting both the mechanism and its leptin dependence.
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high rate of infection associated with a deficiency in T cell"
    explanation: >-
      Confirms the clinical infection burden accompanying the T cell defect
      across reported LEP-deficient patients.
  downstream:
  - target: Recurrent Infections
    causal_link_type: DIRECT
phenotypes:
- category: Phenotypic
  name: Severe Early-Onset Obesity
  description: >-
    Rapid weight gain beginning in the first months of life, producing severe
    obesity well outside the range of common childhood obesity.
  sequelae:
  - target: Hyperinsulinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The expanded adipose mass drives insulin resistance and compensatory
      hyperinsulinemia, which is why this is a downstream metabolic consequence
      of the obesity rather than a direct effect of absent leptin signalling.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
    onset:
      onset_category: INFANTILE
    clinical_course: PROGRESSIVE
  frequency: OBLIGATE
  evidence:
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic pathogenic leptin gene variants cause severe early-onset obesity usually associated with low or undetectable circulating leptin levels."
    explanation: >-
      States severe early-onset obesity as the defining consequence of biallelic
      LEP variants.
- category: Phenotypic
  name: Hyperphagia
  description: >-
    Intense, persistent food-seeking behaviour and failure of satiety, present
    from infancy and typically the feature families report first.
  phenotype_term:
    preferred_term: Hyperphagia
    term:
      id: HP:0002591
      label: Polyphagia
    onset:
      onset_category: INFANTILE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe early-onset obesity with severe hyperphagia"
    explanation: >-
      Records severe hyperphagia as a defining feature of LEP-deficient
      patients.
  - reference: PMID:26186301
    reference_title: "Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia"
    explanation: >-
      Documents hyperphagia alongside obesity in siblings with a bioinactive
      leptin variant.
- category: Phenotypic
  name: Hypogonadotropic Hypogonadism
  description: >-
    Failure of the hypothalamic-pituitary-gonadal axis with low, non-pulsatile
    LH and FSH, so secondary sexual development does not begin spontaneously.

    The frequency band understates the clinical reality and needs reading with
    the denominator. In the systematic series it is 16 of 103 patients (16%),
    which is OCCASIONAL — but that cohort is mostly small children in whom the
    phenotype cannot yet be observed. Among the 12 adult patients it was present
    in all 12 (100%). Treat it as effectively obligate in anyone who reaches
    pubertal age, and as unobservable before then.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:22343341
    reference_title: "Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe here the first adolescent with hypogonadotropic hypogonadism due to connatal leptin deficiency."
    explanation: >-
      Directly attributes hypogonadotropic hypogonadism to congenital leptin
      deficiency in an affected adolescent.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypogonadotropic hypogonadism including micropenis, undescended testis, primary amenorrhea, or delayed puberty in 16 of 103 patients [16%; including in all 12 adult patients (100%)]"
    explanation: >-
      Gives both denominators: 16% across a mostly paediatric cohort, but 100%
      of the adults, which is why the band is OCCASIONAL while the description
      records it as effectively obligate after pubertal age.
- category: Phenotypic
  name: Delayed Puberty
  description: >-
    Puberty does not begin at the expected age and is induced only once leptin
    is replaced, in contrast to common obesity where puberty tends to be early.

    Not independent of Hypogonadotropic Hypogonadism above: the systematic series
    counts delayed puberty inside that same 16/103 figure, as one of the signs by
    which the hypogonadism is recognised. Recorded separately because it is the
    presenting complaint, not because it is a second cohort.

    The frequency band therefore carries the same age caveat as its sibling, and
    for the same reason: 16% is the rate across a cohort that is mostly small
    children in whom puberty cannot yet be late, while all 12 adult patients
    showed hypogonadism. Read it as unobservable before pubertal age and
    effectively obligate after, not as a 16% lifetime risk.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:22343341
    reference_title: "Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 76 weeks of therapy, menstruation occurred at the age of 16.3 years."
    explanation: >-
      Menarche only after prolonged leptin substitution, at 16.3 years,
      documents the delayed pubertal course of the untreated disease.
- category: Phenotypic
  name: Recurrent Infections
  description: >-
    Increased childhood infection burden attributable to reduced CD4-positive T
    cell number and impaired T cell function.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high rate of infection associated with a deficiency in T cell"
    explanation: >-
      Records the increased infection rate and links it to the T cell deficit.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent and/or severe infections, especially of the respiratory tract (20/103; 19%; Table 4)"
    explanation: >-
      Systematic denominator placing recurrent infection at 19% of reported
      patients, which is the OCCASIONAL band rather than FREQUENT.
- category: Phenotypic
  name: Hyperinsulinemia
  description: >-
    Elevated circulating insulin accompanying the severe adiposity, and one of
    the metabolic abnormalities that improves on leptin replacement.
  phenotype_term:
    preferred_term: Hyperinsulinemia
    term:
      id: HP:0000842
      label: Hyperinsulinemia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:12393845
    reference_title: "Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia"
    explanation: >-
      Identifies hyperinsulinemia as a feature of the untreated state that
      responds to leptin.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 103 patients with reported comorbidities, 30 (29%) were reported to have hyperinsulinemia, insulin resistance, and/or (pre) diabetes."
    explanation: >-
      Systematic denominator placing hyperinsulinemia and related dysglycaemia
      at 29%, which is the OCCASIONAL band.
- category: Phenotypic
  name: Dyslipidemia
  description: >-
    Abnormal circulating lipids accompanying the severe adiposity, and one of the
    metabolic abnormalities that improves on leptin replacement.
  phenotype_term:
    preferred_term: Dyslipidemia
    term:
      id: HP:0003119
      label: Abnormal circulating lipid concentration
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 22/106 patients (21%) with either reported comorbidities and/or reported triglyceride and cholesterol levels showed evidence of disturbed lipid metabolism"
    explanation: >-
      Places dyslipidemia at 21% of reported patients. Note the denominator is
      106 here rather than the 103 used for other comorbidities, because it
      combines reported dyslipidemia with patients meeting lipid thresholds.
- category: Phenotypic
  name: Hypertension
  description: Raised blood pressure among the obesity-associated comorbidities.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypertension (n = 11/103; 11%), hirsutism (n = 2/53 female patients; 4%), sleep apnea (n = 5/103; 5%), and genu valgum (4/103; 4%)."
    explanation: >-
      Systematic denominator placing hypertension at 11% of reported patients.
- category: Phenotypic
  name: Developmental Delay
  description: >-
    Developmental delay reported in about a fifth of patients. Recorded with a
    caveat the source itself raises: it may reflect the consanguinity common in
    these pedigrees, or immobility from severe early obesity, rather than being a
    direct consequence of absent leptin signalling. It is therefore not linked
    into the pathograph.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, in 22/103 patients (21%), a developmental delay was reported."
    explanation: >-
      Systematic denominator placing developmental delay at 21% of reported
      patients.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    148 patients across 28 distinct homozygous LEP variants in the 2024
    systematic classification. The earlier "fewer than 20 individuals" figure is
    retained below as the 2012 count, because the growth between the two is
    itself informative rather than merely superseded: most of it is ascertainment
    of the bioinactive and antagonistic classes, which present with normal or
    high measured leptin and were therefore missed while a low leptin level was
    treated as the screening criterion.
  evidence:
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 28 distinct homozygous leptin variants were identified in 148 patients."
    explanation: >-
      Current systematic census of reported patients and causative variants.
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since 1997, less than 20 individuals carrying a LEP gene mutation have been identified."
    explanation: >-
      The 2012 count, retained to show the scale of subsequent ascertainment
      rather than as the current figure.
diagnosis:
- name: Circulating leptin measurement with LEP sequencing
  description: >-
    Serum leptin is the discriminating first-line test, and it separates this
    disease from its closest mimic: it is undetectable in LEP mutation carriers
    but extremely elevated in LEPR (receptor) mutation carriers, whose clinical
    picture is otherwise similar and who do not respond to leptin replacement.

    The important caveat is that a normal or high leptin level does not exclude
    the diagnosis, and it fails in two different ways for the two non-classical
    subtypes. For biologically inactive leptin, combining a regular ELISA with
    the bioLEP assay — which measures receptor-binding capacity rather than
    hormone mass — separates it robustly. For antagonistic leptin, both assays
    read inconspicuous, so leptin measurement does not identify the disease at
    all and only sequencing will. LEP sequencing should therefore be considered
    in any severely obese, hyperphagic child even when circulating leptin is
    normal and even when the bioLEP assay is also normal.
  evidence:
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Measurement of circulating leptin may help for the diagnosis of such obesity: it is undetectable in LEP mutation carriers or extremely elevated in LEPR mutation carriers."
    explanation: >-
      Establishes serum leptin as the diagnostic discriminator between LEP and
      LEPR deficiency.
  - reference: PMID:26186301
    reference_title: "Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin."
    explanation: >-
      Records the caveat that detectable leptin does not exclude the diagnosis,
      because bioinactive variants are secreted.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Combined measurements using a regular ELISA and the more recently developed bioLEP ELISA allow for the robust diagnosis of biological inactive leptin."
    explanation: >-
      Gives the two-assay algorithm that identifies the bioinactive subtype.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular and bioLEP ELISA will measure inconspicuous leptin levels in patients with antagonistic leptin and thus will not help to identify CLD in these patients."
    explanation: >-
      Records that neither assay detects the antagonistic subtype, the limit of
      the leptin-measurement strategy.

genetic:
- name: LEP loss of function
  gene_term:
    preferred_term: LEP
    term:
      id: hgnc:6553
      label: LEP
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic LEP variants cause the disease. The founding lesion was a
    homozygous single-guanine deletion in codon 133 producing no secreted
    hormone; later missense variants (for example p.D100Y, p.N103K) are secreted
    but biologically inactive, so circulating leptin is detectable. Fewer than
    20 LEP-mutation carriers had been reported by 2012, and the condition
    remains very rare.
  evidence:
  - reference: PMID:9202122
    reference_title: "Congenital leptin deficiency is associated with severe early-onset obesity in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found"
    explanation: >-
      Identifies the causative homozygous LEP frameshift in the founding
      pedigree.
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since 1997, less than 20 individuals carrying a LEP gene mutation have been identified."
    explanation: >-
      Quantifies the rarity of causative LEP variants in the reported
      literature.
  - reference: PMID:26186301
    reference_title: "Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin"
    explanation: >-
      Documents a homozygous missense LEP variant producing detectable but
      inactive hormone, extending the causative allelic spectrum.
animal_models:
- name: ob/ob mouse (Lep-deficient)
  species: Mouse
  genotype: Lep ob/ob
  publication: PMID:9202122
  description: >-
    The founding model. Extreme obesity in the ob/ob mouse was attributed to
    mutations in the leptin gene years before any human case was known, and it
    is what made congenital leptin deficiency a hypothesis worth testing in
    humans. Its immune phenotype also anticipated the human T cell defect.
  modeled_mechanisms:
  - target: Unopposed Orexigenic Drive
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Loss of leptin in the mouse reproduces the hyperphagia and severe obesity
      that define the human disease, through the orthologous gene.
    limitations: >-
      The mouse phenotype was characterised before the human disease and framed
      the human expectation rather than being validated against it. The human
      subtype structure has no murine counterpart: ob/ob is a null, so it models
      classical hormone deficiency only and says nothing about the bioinactive or
      antagonistic classes, where the hormone is present but non-functional.
    evidence:
    - reference: PMID:9202122
      reference_title: "Congenital leptin deficiency is associated with severe early-onset obesity in humans."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure."
      explanation: >-
        Establishes the murine phenotype and its attribution to leptin, the
        model this node recapitulates.

treatments:
- name: Metreleptin
  description: >-
    Daily subcutaneous recombinant human leptin, which replaces the missing
    hormone and restores hypothalamic leptin signalling. It is uniquely
    effective here because the receptor and all downstream circuitry are intact
    — the defect is the ligand alone. Response spans every arm of the disease:
    appetite and fat mass fall, thyroid hormone rises, gonadotropin secretion
    and puberty are induced, and the T cell defect corrects.

    Dosing is not uniform across subtypes, however. Classical and biologically
    inactive deficiency take the same starting dose, but antagonistic variants
    antagonise metreleptin itself at the receptor, so those patients require
    higher initial doses and variant-tailored tapering.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metreleptin
      term:
        id: NCIT:C170171
        label: Metreleptin
  target_mechanisms:
  - target: Failure of Hypothalamic Leptin Signaling
    description: >-
      Exogenous leptin supplies the absent ligand for intact hypothalamic leptin
      receptors, restoring the signal at the point where the disease begins.
    evidence:
    - reference: PMID:12393845
      reference_title: "Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency."
      explanation: >-
        Correction of the full multi-system phenotype by replacing the ligand
        supports the treatment acting at the leptin signalling node.
  - target: Unopposed Orexigenic Drive
    description: >-
      Restored leptin signalling re-establishes satiety, and reduced food intake
      is the principal driver of the weight loss observed on therapy.
    evidence:
    - reference: PMID:22627381
      reference_title: "Leptin and leptin receptor-related monogenic obesity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It results in weight loss, mainly of fat mass, with a major effect on reducing food intake"
      explanation: >-
        Identifies reduced food intake as the mechanism of the therapeutic
        weight loss, which is the orexigenic node being corrected.
  - target: Impaired T Cell Number and Function
    description: >-
      Leptin replacement restores CD4-positive T cell numbers and T cell
      proliferative and cytokine responses.
    evidence:
    - reference: PMID:12393845
      reference_title: "Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration"
      explanation: >-
        Direct evidence that leptin administration reverses the T cell defect.
  - target: Starvation-Pattern Neuroendocrine Suppression
    description: >-
      Leptin substitution induces pulsatile gonadotropin secretion and permits
      pubertal progression, and raises thyroid hormone levels.
    evidence:
    - reference: PMID:22343341
      reference_title: "Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "After 11 weeks of therapy, basal and stimulated LH and FSH levels rose to pubertal values and nocturnal pulsatility was initiated."
      explanation: >-
        Documents restoration of gonadotropin secretion and pulsatility on
        leptin, correcting the suppressed neuroendocrine node.
  target_phenotypes:
  - preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  - preferred_term: Hyperphagia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:22627381
    reference_title: "Leptin and leptin receptor-related monogenic obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapeutic option (subcutaneous daily injection of leptin) is available for patients with LEP deficiency."
    explanation: >-
      Establishes daily subcutaneous leptin as the available therapy for this
      specific genotype.
  - reference: PMID:38470203
    reference_title: "Classification of Congenital Leptin Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients living with antagonistic leptin cannot receive the same dose of metreleptin as patients living with classical hormone deficiency but require higher initial doses and appropriate dose tapering"
    explanation: >-
      Establishes that the dose is subtype-dependent, which is why this entry
      does not assert a uniform treatment response.

📚

References & Deep Research

References

7

PMID:9202122

Congenital leptin deficiency is associated with severe early-onset obesity in humans.

No top-level findings curated for this source.

PMID:12393845

Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.

No top-level findings curated for this source.

PMID:38470203

Classification of Congenital Leptin Deficiency.

No top-level findings curated for this source.

PMID:22627381

Leptin and leptin receptor-related monogenic obesity.

No top-level findings curated for this source.

PMID:26186301

Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene.

No top-level findings curated for this source.

PMID:22343341

Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism.

No top-level findings curated for this source.

PMID:10486419

Effects of recombinant leptin therapy in a child with congenital leptin deficiency.

No top-level findings curated for this source.

Congenital Leptin Deficiency

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Animal Models

Source YAML

References & Deep Research

References