IGF1 Deficiency

Mendelian MONDO:0012110 Pathograph 14 Show in embeddings browser growth hormone insensitivity syndrome hereditary disease

Growth delay due to insulin-like growth factor 1 (IGF1) deficiency is an autosomal recessive disorder caused by biallelic loss-of-function variants in IGF1. Bioinactive or absent IGF-1 fails to activate the type 1 IGF receptor (IGF1R), impairing IGF1R-driven growth signaling during fetal and postnatal development. Affected individuals present with severe intrauterine and postnatal growth restriction, microcephaly, sensorineural deafness, and intellectual disability. It is one cause within the broader clinical category of severe primary IGF-1 deficiency (SPIGFD), which is treated with recombinant human IGF-1 (mecasermin).

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1
Inheritance
3
Pathophys.
8
Phenotypes
14
Pathograph
1
Genes
3
Medical Actions
1
Trials
1
Deep Research
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:23392101 SUPPORT Human Clinical
"Only three homozygous and two families with heterozygous mutations of the IGF1 gene have been described"
The severe disorder follows biallelic (autosomal recessive) inheritance; heterozygotes show a milder gene-dose phenotype.
⚙

Pathophysiology

3
IGF1 Loss of Function
Biallelic pathogenic variants in IGF1 (deletions, frameshifts, or missense changes) abolish or severely reduce the amount or bioactivity of circulating insulin-like growth factor 1. IGF-1 is produced predominantly by hepatocytes under growth hormone control and is the principal effector of the GH-IGF1 growth axis. Loss-of-function variants reduce immunoreactive and bioactive IGF-1, and some missense variants additionally impair the peptide's ability to bind and activate its receptor.
Hepatocyte (principal IGF-1 source) CL:0000182
IGF1 hgnc:5464
Regulation of growth GO:0040008 ↓ DECREASED
Downstream
Impaired IGF1R Growth Signaling Reduced IGF-1 amount or bioactivity fails to engage the type 1 IGF receptor, lowering downstream receptor tyrosine kinase signaling.
Show evidence (2 references)
PMID:23392101 SUPPORT Human Clinical
"Molecular defects of the insulin-like growth factor 1 gene (IGF1) are rare in the human."
Establishes biallelic IGF1 defects as the rare molecular cause of this disorder.
PMID:36546343 SUPPORT In Vitro
"The mutant IGF1 protein had a significantly reduced activity on in vitro bioassays."
Functional bioassay confirms that a homozygous IGF1 missense variant reduces IGF-1 bioactivity, supporting loss of function as the mechanism.
Impaired IGF1R Growth Signaling
IGF-1 normally binds and activates the type 1 IGF receptor (IGF1R), a receptor tyrosine kinase that drives somatic growth and neurodevelopment. In IGF1 deficiency, the loss of bioactive ligand reduces IGF1R autophosphorylation and downstream signal transduction. Missense IGF1 variants have been shown to hamper IGF1R interaction and reduce receptor phosphorylation, while frank loss-of-function alleles remove the ligand entirely.
Insulin-like growth factor receptor signaling pathway GO:0048009 ↓ DECREASED Cell surface receptor tyrosine kinase signaling GO:0007169 ↓ DECREASED
Downstream
Impaired Somatic and Neural Growth Reduced IGF1R signaling compromises pre- and postnatal somatic growth, brain growth, and cochlear development.
Insulin resistance Altered IGF-1 ligand-receptor signaling can perturb insulin-pathway crosstalk and produce insulin resistance in some cases.
Show evidence (2 references)
PMID:36546343 SUPPORT Computational
"In silico analyses indicated the pathogenic potential of the variant with electrostatic variations with the potential of hampering the interaction with the IGF1R"
Demonstrates that a pathogenic IGF1 variant impairs interaction with IGF1R, reducing receptor activation.
PMID:23392101 SUPPORT Human Clinical
"IGF-1 plays a key role in pre- and postnatal growth and development in human."
Confirms the central role of IGF-1/IGF1R signaling in human pre- and postnatal growth, which is lost in IGF1 deficiency.
Impaired Somatic and Neural Growth
Deficient IGF1R signaling during the fetal and postnatal period impairs cellular proliferation and tissue growth across multiple organ systems. Reduced growth signaling produces intrauterine and postnatal growth restriction, deficient brain growth (microcephaly and developmental delay), and abnormal cochlear development leading to sensorineural deafness. Mouse models with disruption of Igf1 or Igf1r recapitulate severe prenatal growth restriction, underscoring the essential growth-promoting role of this axis.
Neuron CL:0000540
Regulation of growth GO:0040008 ↓ DECREASED
Downstream
Intrauterine growth restriction Reduced fetal IGF-1 signaling impairs prenatal growth.
Postnatal growth failure Reduced IGF-1 signaling impairs postnatal somatic growth.
Short stature Severe primary IGF-1 deficiency manifests as marked short stature.
Microcephaly Impaired brain growth manifests as microcephaly.
Sensorineural hearing impairment Impaired IGF-1-dependent cochlear development produces sensorineural hearing impairment.
Intellectual disability Impaired IGF-1-dependent neurodevelopment can produce intellectual disability.
Global developmental delay Impaired fetal and postnatal neural growth delays developmental milestones.
Show evidence (2 references)
PMID:23392101 SUPPORT Human Clinical
"resulting in a variable degree of intrauterine and postnatal growth retardation, microcephaly, developmental delay and deafness"
Directly links IGF1 deficiency to the core multisystem growth and neurodevelopmental phenotype.
PMID:38952118 SUPPORT Human Clinical
"The clinical features of bi-allelic IGF1 defects are well established, i.e., severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness."
Summarizes the established multisystem phenotype resulting from impaired IGF1-driven growth.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for IGF1 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Ear 1
Sensorineural hearing impairment FREQUENT Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:38952118 SUPPORT Human Clinical
"The clinical features of bi-allelic IGF1 defects are well established, i.e., severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness."
Lists sensorineural deafness among the established features of biallelic IGF1 defects.
Head and Neck 1
Microcephaly VERY_FREQUENT Microcephaly HP:0000252
Show evidence (1 reference)
PMID:23392101 SUPPORT Human Clinical
"resulting in a variable degree of intrauterine and postnatal growth retardation, microcephaly, developmental delay and deafness"
Lists microcephaly among the core features of biallelic IGF1 mutations.
Metabolism 1
Insulin resistance OCCASIONAL Insulin resistance HP:0000855
Show evidence (1 reference)
PMID:36546343 SUPPORT Human Clinical
"This study describes a 12.6-year-old girl presenting with severe short stature and insulin resistance"
Documents insulin resistance in a patient with a homozygous IGF1 missense variant.
Nervous System 2
Intellectual disability FREQUENT Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:36546343 SUPPORT Human Clinical
"Phenotype can be heterogenous with varying degrees of neurosensory deafness, cognitive defects, glucose metabolism impairment and short stature."
Documents cognitive defects as part of the heterogeneous IGF1-mutation phenotype.
Global developmental delay FREQUENT Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:23392101 SUPPORT Human Clinical
"resulting in a variable degree of intrauterine and postnatal growth retardation, microcephaly, developmental delay and deafness"
Lists developmental delay among the core features of biallelic IGF1 mutations.
Growth 3
Intrauterine growth restriction VERY_FREQUENT Intrauterine growth retardation HP:0001511
Show evidence (1 reference)
PMID:23392101 SUPPORT Human Clinical
"resulting in a variable degree of intrauterine and postnatal growth retardation, microcephaly, developmental delay and deafness"
Lists intrauterine growth retardation among the core features of IGF1 mutations.
Postnatal growth failure VERY_FREQUENT Postnatal growth retardation HP:0008897
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:23392101 SUPPORT Human Clinical
"resulting in a variable degree of intrauterine and postnatal growth retardation, microcephaly, developmental delay and deafness"
Lists postnatal growth retardation among the core features of IGF1 mutations.
Short stature VERY_FREQUENT Short stature HP:0004322
Show evidence (1 reference)
PMID:37805563 SUPPORT Human Clinical
"Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature"
Defines short stature as a characterizing feature of SPIGFD, the clinical category that includes IGF1 deficiency.
🧬

Genetic Associations

1
IGF1 pathogenic variants (Causative biallelic loss-of-function variants)
Gene: IGF1 hgnc:5464 relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:23392101 SUPPORT Human Clinical
"Molecular defects of the insulin-like growth factor 1 gene (IGF1) are rare in the human."
Establishes IGF1 as the causative gene for this disorder.
💊

Medical Actions

3
Recombinant Human IGF-1 (Mecasermin)
Action: Pharmacotherapy NCIT:C15986
Agent: mecasermin NCIT:C2262
Recombinant human IGF-1 (rhIGF-1; mecasermin, Increlex) provides exogenous IGF-1 to replace the deficient or bioinactive endogenous peptide and is the only disease-specific therapy for severe primary IGF-1 deficiency (SPIGFD). It improves growth velocity, especially in the first years of treatment. Hypoglycemia is a common adverse effect, requiring administration with food and blood glucose monitoring.
Mechanism Target:
BYPASSES IGF1 Loss of Function — Mecasermin supplies exogenous recombinant IGF-1, bypassing the deficient or bioinactive endogenous peptide to restore downstream IGF1R growth signaling.
Show evidence (1 reference)
PMID:19707272 SUPPORT Human Clinical
"The only treatment is recombinant IGF-1 (mecasermin)"
Recombinant IGF-1 replacement directly addresses the IGF1 loss-of-function node by providing the missing peptide.
Show evidence (4 references)
PMID:19707272 SUPPORT Human Clinical
"The only treatment is recombinant IGF-1 (mecasermin)"
Establishes recombinant IGF-1 (mecasermin) as the disease-specific replacement therapy for IGF-1 deficiency.
PMID:39529965 SUPPORT Human Clinical
"The study showed that treatment with rhIGF-1 positively affects growth rate, especially in the first years of treatment."
Real-world cohort showing growth benefit of mecasermin in severe primary IGF-1 deficiency.
PMID:39529965 SUPPORT Human Clinical
"Side effects occurred in 50% of patients, with 40% of patients treated with rhIGF-1 experiencing hypoglycemia during treatment."
Documents hypoglycemia as the principal adverse effect requiring monitoring during mecasermin therapy.
+ 1 more reference
Growth Hormone Therapy
Action: human growth hormone replacement therapy MAXO:0000780
Recombinant human growth hormone (rhGH) has limited, variable benefit in biallelic IGF1 deficiency because the defect lies downstream of GH; growth responses are typically poor to modest. rhGH may be more useful in IGF1 haploinsufficiency, where some residual IGF-1 production remains.
Show evidence (1 reference)
PMID:23392101 PARTIAL Human Clinical
"Data on GH treatment in these children are limited, showing a poor to modest growth response."
Documents the limited efficacy of GH therapy in IGF1/IGF1R defects, where the lesion is downstream of GH.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling for affected families addresses the autosomal recessive recurrence risk and carrier status, particularly relevant given reports of consanguinity in homozygous cases.
Show evidence (1 reference)
PMID:23392101 SUPPORT Human Clinical
"Only three homozygous and two families with heterozygous mutations of the IGF1 gene have been described"
The recessive inheritance and familial clustering underpin the value of genetic counseling for at-risk families.
🔬

Clinical Trials

1
NCT00903110 RECRUITING
European Increlex Growth Forum Database (Eu-IGFD) Registry: a global patient registry monitoring the long-term safety and effectiveness of recombinant human IGF-1 (mecasermin/Increlex) in children and adolescents with severe primary IGF-1 deficiency.
Target Phenotypes: Short stature HP:0004322
Show evidence (1 reference)
PMID:35250870 SUPPORT Human Clinical
"Pubertal growth outcomes were extracted from the European Increlex® Growth Forum Database (Eu-IGFD) Registry (NCT00903110)."
Identifies the Eu-IGFD registry (NCT00903110) as the real-world data source for rhIGF-1 outcomes in SPIGFD.
{ }

Source YAML

click to show 
name: IGF1 Deficiency
creation_date: "2026-06-04T12:00:00Z"
category: Mendelian
description: >-
  Growth delay due to insulin-like growth factor 1 (IGF1) deficiency is an
  autosomal recessive disorder caused by biallelic loss-of-function variants in
  IGF1. Bioinactive or absent IGF-1 fails to activate the type 1 IGF receptor
  (IGF1R), impairing IGF1R-driven growth signaling during fetal and postnatal
  development. Affected individuals present with severe intrauterine and
  postnatal growth restriction, microcephaly, sensorineural deafness, and
  intellectual disability. It is one cause within the broader clinical category
  of severe primary IGF-1 deficiency (SPIGFD), which is treated with recombinant
  human IGF-1 (mecasermin).
disease_term:
  preferred_term: IGF1 deficiency
  term:
    id: MONDO:0012110
    label: growth delay due to insulin-like growth factor type 1 deficiency
parents:
- growth hormone insensitivity syndrome
- hereditary disease
pathophysiology:
- name: IGF1 Loss of Function
  description: >
    Biallelic pathogenic variants in IGF1 (deletions, frameshifts, or missense
    changes) abolish or severely reduce the amount or bioactivity of circulating
    insulin-like growth factor 1. IGF-1 is produced predominantly by hepatocytes
    under growth hormone control and is the principal effector of the GH-IGF1
    growth axis. Loss-of-function variants reduce immunoreactive and bioactive
    IGF-1, and some missense variants additionally impair the peptide's ability
    to bind and activate its receptor.
  gene:
    preferred_term: IGF1
    term:
      id: hgnc:5464
      label: IGF1
  biological_processes:
  - preferred_term: Regulation of growth
    term:
      id: GO:0040008
      label: regulation of growth
    modifier: DECREASED
  cell_types:
  - preferred_term: Hepatocyte (principal IGF-1 source)
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular defects of the insulin-like growth factor 1 gene (IGF1) are rare
      in the human.
    explanation: >-
      Establishes biallelic IGF1 defects as the rare molecular cause of this
      disorder.
  - reference: PMID:36546343
    reference_title: "Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of the Phenotype and Implications for Insulin Resistance."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant IGF1 protein had a significantly reduced activity on in vitro
      bioassays.
    explanation: >-
      Functional bioassay confirms that a homozygous IGF1 missense variant
      reduces IGF-1 bioactivity, supporting loss of function as the mechanism.
  downstream:
  - target: Impaired IGF1R Growth Signaling
    description: >-
      Reduced IGF-1 amount or bioactivity fails to engage the type 1 IGF
      receptor, lowering downstream receptor tyrosine kinase signaling.
- name: Impaired IGF1R Growth Signaling
  description: >
    IGF-1 normally binds and activates the type 1 IGF receptor (IGF1R), a
    receptor tyrosine kinase that drives somatic growth and neurodevelopment.
    In IGF1 deficiency, the loss of bioactive ligand reduces IGF1R
    autophosphorylation and downstream signal transduction. Missense IGF1
    variants have been shown to hamper IGF1R interaction and reduce receptor
    phosphorylation, while frank loss-of-function alleles remove the ligand
    entirely.
  biological_processes:
  - preferred_term: Insulin-like growth factor receptor signaling pathway
    term:
      id: GO:0048009
      label: insulin-like growth factor receptor signaling pathway
    modifier: DECREASED
  - preferred_term: Cell surface receptor tyrosine kinase signaling
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:36546343
    reference_title: "Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of the Phenotype and Implications for Insulin Resistance."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      In silico analyses indicated the pathogenic potential of the variant with
      electrostatic variations with the potential of hampering the interaction
      with the IGF1R
    explanation: >-
      Demonstrates that a pathogenic IGF1 variant impairs interaction with
      IGF1R, reducing receptor activation.
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IGF-1 plays a key role in pre- and postnatal growth and development in
      human.
    explanation: >-
      Confirms the central role of IGF-1/IGF1R signaling in human pre- and
      postnatal growth, which is lost in IGF1 deficiency.
  downstream:
  - target: Impaired Somatic and Neural Growth
    description: >-
      Reduced IGF1R signaling compromises pre- and postnatal somatic growth,
      brain growth, and cochlear development.
  - target: Insulin resistance
    description: >-
      Altered IGF-1 ligand-receptor signaling can perturb insulin-pathway
      crosstalk and produce insulin resistance in some cases.
- name: Impaired Somatic and Neural Growth
  description: >
    Deficient IGF1R signaling during the fetal and postnatal period impairs
    cellular proliferation and tissue growth across multiple organ systems.
    Reduced growth signaling produces intrauterine and postnatal growth
    restriction, deficient brain growth (microcephaly and developmental delay),
    and abnormal cochlear development leading to sensorineural deafness. Mouse
    models with disruption of Igf1 or Igf1r recapitulate severe prenatal growth
    restriction, underscoring the essential growth-promoting role of this axis.
  biological_processes:
  - preferred_term: Regulation of growth
    term:
      id: GO:0040008
      label: regulation of growth
    modifier: DECREASED
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in a variable degree of intrauterine and postnatal growth
      retardation, microcephaly, developmental delay and deafness
    explanation: >-
      Directly links IGF1 deficiency to the core multisystem growth and
      neurodevelopmental phenotype.
  - reference: PMID:38952118
    reference_title: "IGF1 Haploinsufficiency: Phenotype and Response to Growth Hormone Treatment in 9 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features of bi-allelic IGF1 defects are well established,
      i.e., severe growth failure and microcephaly, delayed psychomotor
      development, and sensorineural deafness.
    explanation: >-
      Summarizes the established multisystem phenotype resulting from impaired
      IGF1-driven growth.
  downstream:
  - target: Intrauterine growth restriction
    description: >-
      Reduced fetal IGF-1 signaling impairs prenatal growth.
  - target: Postnatal growth failure
    description: >-
      Reduced IGF-1 signaling impairs postnatal somatic growth.
  - target: Short stature
    description: >-
      Severe primary IGF-1 deficiency manifests as marked short stature.
  - target: Microcephaly
    description: >-
      Impaired brain growth manifests as microcephaly.
  - target: Sensorineural hearing impairment
    description: >-
      Impaired IGF-1-dependent cochlear development produces sensorineural
      hearing impairment.
  - target: Intellectual disability
    description: >-
      Impaired IGF-1-dependent neurodevelopment can produce intellectual
      disability.
  - target: Global developmental delay
    description: >-
      Impaired fetal and postnatal neural growth delays developmental
      milestones.
phenotypes:
- category: Phenotypic abnormality
  name: Intrauterine growth restriction
  description: >-
    Severe prenatal growth failure is a consistent feature, with reported birth
    length and head circumference markedly below the mean.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in a variable degree of intrauterine and postnatal growth
      retardation, microcephaly, developmental delay and deafness
    explanation: >-
      Lists intrauterine growth retardation among the core features of IGF1
      mutations.
- category: Phenotypic abnormality
  name: Postnatal growth failure
  description: >-
    Marked postnatal growth failure with severe short stature; reported
    postnatal height SDS values fall far below normal range.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in a variable degree of intrauterine and postnatal growth
      retardation, microcephaly, developmental delay and deafness
    explanation: >-
      Lists postnatal growth retardation among the core features of IGF1
      mutations.
- category: Phenotypic abnormality
  name: Short stature
  description: >-
    Severe short stature, a defining feature of severe primary IGF-1 deficiency
    (SPIGFD), the broader clinical category encompassing IGF1 deficiency.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37805563
    reference_title: "Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is
      a rare growth disorder characterized by short stature
    explanation: >-
      Defines short stature as a characterizing feature of SPIGFD, the clinical
      category that includes IGF1 deficiency.
- category: Phenotypic abnormality
  name: Microcephaly
  description: >-
    Severe microcephaly reflecting impaired prenatal and postnatal brain growth;
    reported head circumference SDS values are markedly reduced.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in a variable degree of intrauterine and postnatal growth
      retardation, microcephaly, developmental delay and deafness
    explanation: >-
      Lists microcephaly among the core features of biallelic IGF1 mutations.
- category: Phenotypic abnormality
  name: Sensorineural hearing impairment
  description: >-
    Sensorineural deafness is a characteristic feature, reflecting the role of
    IGF-1 signaling in cochlear development.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  frequency: FREQUENT
  evidence:
  - reference: PMID:38952118
    reference_title: "IGF1 Haploinsufficiency: Phenotype and Response to Growth Hormone Treatment in 9 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features of bi-allelic IGF1 defects are well established,
      i.e., severe growth failure and microcephaly, delayed psychomotor
      development, and sensorineural deafness.
    explanation: >-
      Lists sensorineural deafness among the established features of biallelic
      IGF1 defects.
- category: Phenotypic abnormality
  name: Intellectual disability
  description: >-
    Cognitive impairment and developmental delay reflecting impaired
    IGF-1-dependent brain development. Phenotype severity is variable.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:36546343
    reference_title: "Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of the Phenotype and Implications for Insulin Resistance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotype can be heterogenous with varying degrees of neurosensory
      deafness, cognitive defects, glucose metabolism impairment and short
      stature.
    explanation: >-
      Documents cognitive defects as part of the heterogeneous IGF1-mutation
      phenotype.
- category: Phenotypic abnormality
  name: Global developmental delay
  description: >-
    Delayed psychomotor and developmental milestones are repeatedly described in
    affected individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      resulting in a variable degree of intrauterine and postnatal growth
      retardation, microcephaly, developmental delay and deafness
    explanation: >-
      Lists developmental delay among the core features of biallelic IGF1
      mutations.
- category: Laboratory abnormality
  name: Insulin resistance
  description: >-
    Some IGF1-mutation cases display insulin resistance, hypothesized to arise
    from altered insulin receptor signaling by mutant IGF-1. This is a variable,
    not obligate, feature.
  phenotype_term:
    preferred_term: Insulin resistance
    term:
      id: HP:0000855
      label: Insulin resistance
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36546343
    reference_title: "Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of the Phenotype and Implications for Insulin Resistance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study describes a 12.6-year-old girl presenting with severe short
      stature and insulin resistance
    explanation: >-
      Documents insulin resistance in a patient with a homozygous IGF1 missense
      variant.
genetic:
- name: IGF1 pathogenic variants
  gene_term:
    preferred_term: IGF1
    term:
      id: hgnc:5464
      label: IGF1
  association: Causative biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular defects of the insulin-like growth factor 1 gene (IGF1) are rare
      in the human.
    explanation: >-
      Establishes IGF1 as the causative gene for this disorder.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:23392101
      reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Only three homozygous and two families with heterozygous mutations of
        the IGF1 gene have been described
      explanation: >-
        Homozygous (biallelic) IGF1 mutations cause the severe recessive
        phenotype; heterozygotes are more mildly affected.
  variants:
  - name: Biallelic IGF1 loss-of-function variants
    description: >
      Reported disease-causing IGF1 variants include exon deletions, frameshift
      variants producing premature stop codons, and missense variants that
      reduce receptor binding and bioactivity. A homozygous missense variant
      (c.247A>T; p.Ser83Cys) was shown to severely reduce IGF-1 bioactivity.
    gene:
      preferred_term: IGF1
      term:
        id: hgnc:5464
        label: IGF1
    clinical_significance: PATHOGENIC
    type: loss_of_function_variant
    evidence:
    - reference: PMID:36546343
      reference_title: "Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of the Phenotype and Implications for Insulin Resistance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        WES revealed a novel homozygous IGF1 missense variant (c.247A>T),
        causing a change of serine 83 for cysteine
      explanation: >-
        Identifies a specific homozygous pathogenic IGF1 missense variant in an
        affected individual.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only three homozygous and two families with heterozygous mutations of the
      IGF1 gene have been described
    explanation: >-
      The severe disorder follows biallelic (autosomal recessive) inheritance;
      heterozygotes show a milder gene-dose phenotype.
treatments:
- name: Recombinant Human IGF-1 (Mecasermin)
  description: >-
    Recombinant human IGF-1 (rhIGF-1; mecasermin, Increlex) provides exogenous
    IGF-1 to replace the deficient or bioinactive endogenous peptide and is the
    only disease-specific therapy for severe primary IGF-1 deficiency (SPIGFD).
    It improves growth velocity, especially in the first years of treatment.
    Hypoglycemia is a common adverse effect, requiring administration with food
    and blood glucose monitoring.
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: IGF1 Loss of Function
    treatment_effect: BYPASSES
    description: >-
      Mecasermin supplies exogenous recombinant IGF-1, bypassing the deficient
      or bioinactive endogenous peptide to restore downstream IGF1R growth
      signaling.
    evidence:
    - reference: PMID:19707272
      reference_title: "Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The only treatment is recombinant IGF-1 (mecasermin)
      explanation: >-
        Recombinant IGF-1 replacement directly addresses the IGF1 loss-of-function
        node by providing the missing peptide.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mecasermin
      term:
        id: NCIT:C2262
        label: Mecasermin
  evidence:
  - reference: PMID:19707272
    reference_title: "Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The only treatment is recombinant IGF-1 (mecasermin)
    explanation: >-
      Establishes recombinant IGF-1 (mecasermin) as the disease-specific
      replacement therapy for IGF-1 deficiency.
  - reference: PMID:39529965
    reference_title: "Clinical characteristics and treatment efficacy in patients with primary severe IGF-1 deficiency treated with recombinant IGF-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study showed that treatment with rhIGF-1 positively affects growth
      rate, especially in the first years of treatment.
    explanation: >-
      Real-world cohort showing growth benefit of mecasermin in severe primary
      IGF-1 deficiency.
  - reference: PMID:39529965
    reference_title: "Clinical characteristics and treatment efficacy in patients with primary severe IGF-1 deficiency treated with recombinant IGF-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Side effects occurred in 50% of patients, with 40% of patients treated
      with rhIGF-1 experiencing hypoglycemia during treatment.
    explanation: >-
      Documents hypoglycemia as the principal adverse effect requiring
      monitoring during mecasermin therapy.
  - reference: PMID:35250870
    reference_title: "Pubertal Timing and Growth Dynamics in Children With Severe Primary IGF-1 Deficiency: Results From the European Increlex(R) Growth Forum Database Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children and adolescents treated with rhIGF-1 for SPIGFD with growth
      failure experienced an increase in height SDS in prepubertal years
      compared with baseline.
    explanation: >-
      Registry data supporting sustained height gain with rhIGF-1 treatment.
- name: Growth Hormone Therapy
  description: >-
    Recombinant human growth hormone (rhGH) has limited, variable benefit in
    biallelic IGF1 deficiency because the defect lies downstream of GH; growth
    responses are typically poor to modest. rhGH may be more useful in IGF1
    haploinsufficiency, where some residual IGF-1 production remains.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: human growth hormone replacement therapy
    term:
      id: MAXO:0000780
      label: human growth hormone replacement therapy
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Data on GH treatment in these children are limited, showing a poor to
      modest growth response.
    explanation: >-
      Documents the limited efficacy of GH therapy in IGF1/IGF1R defects, where
      the lesion is downstream of GH.
- name: Genetic Counseling
  description: >-
    Genetic counseling for affected families addresses the autosomal recessive
    recurrence risk and carrier status, particularly relevant given reports of
    consanguinity in homozygous cases.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23392101
    reference_title: "Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only three homozygous and two families with heterozygous mutations of the
      IGF1 gene have been described
    explanation: >-
      The recessive inheritance and familial clustering underpin the value of
      genetic counseling for at-risk families.
clinical_trials:
- name: NCT00903110
  status: RECRUITING
  description: >-
    European Increlex Growth Forum Database (Eu-IGFD) Registry: a global patient
    registry monitoring the long-term safety and effectiveness of recombinant
    human IGF-1 (mecasermin/Increlex) in children and adolescents with severe
    primary IGF-1 deficiency.
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:35250870
    reference_title: "Pubertal Timing and Growth Dynamics in Children With Severe Primary IGF-1 Deficiency: Results From the European Increlex(R) Growth Forum Database Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pubertal growth outcomes were extracted from the European Increlex® Growth
      Forum Database (Eu-IGFD) Registry (NCT00903110).
    explanation: >-
      Identifies the Eu-IGFD registry (NCT00903110) as the real-world data
      source for rhIGF-1 outcomes in SPIGFD.
notes: >-
  IGF1 deficiency sits within the broader clinical category of severe primary
  IGF-1 deficiency (SPIGFD), which also includes growth hormone receptor (GHR)
  defects (Laron syndrome) and other GH-IGF axis gene defects. No GeneReviews
  chapter specific to IGF1 deficiency was found (searched 2026-06).
datasets: []
📚

References & Deep Research

Deep Research

1
Falcon ▸
IGF1 Deficiency (Mendelian) — Comprehensive Disease Characteristics Report
Edison Scientific Literature 27 citations 2026-06-04T10:47:07.167843

IGF1 Deficiency (Mendelian) — Comprehensive Disease Characteristics Report

Target disease: IGF1 Deficiency (Mendelian; most classically due to biallelic loss-of-function variants in IGF1) (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2)

Scope note (terminology): In the recent clinical literature, “IGF1 deficiency” (IGF1 gene defects) is closely related to—yet not identical with—severe primary IGF-1 deficiency (SPIGFD)/severe primary IGF-I deficiency and growth hormone insensitivity (GHI)/Laron syndrome (which are defined clinically by low IGF-I despite normal/high GH and can be caused by several GH–IGF axis genes) (backeljauw2023challengesinthe pages 1-3, cappa2009profileofmecasermin pages 1-2, denaite2024clinicalcharacteristicsand pages 1-2). This report therefore covers (1) biallelic IGF1 loss-of-function as a Mendelian disease and (2) the broader, treatment-relevant SPIGFD umbrella as used in registries and practice.

Executive Summary

Biallelic (autosomal-recessive) IGF1 loss-of-function is a very rare cause of extreme pre- and postnatal growth failure, severe microcephaly, and variable neurodevelopmental impairment and sensorineural deafness, with biochemical findings that can include very low/undetectable IGF-I but can also be assay-dependent and paradoxical in some variants (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2). In practice, many patients are identified and treated under the clinical category SPIGFD, defined by severe short stature and low IGF-I with normal/elevated GH; the only disease-specific replacement therapy currently emphasized is recombinant human IGF-1 (rhIGF-1; mecasermin, Increlex®) (backeljauw2023challengesinthe pages 1-3, denaite2024clinicalcharacteristicsand pages 1-2). Recent (2023–2024) developments include a multi-stakeholder consensus-style perspective highlighting diagnostic inequities and access barriers (backeljauw2023challengesinthe pages 1-3, backeljauw2023challengesinthe pages 5-7), a 2024 real-world retrospective mecasermin outcomes report (denaite2024clinicalcharacteristicsand pages 1-2), and a 2024 LC–MS clinical laboratory study showing that heterozygous IGF1 variants can cause systematic under-quantification of total IGF-1 and misclassification against reference ranges if not accounted for (motorykin2024detectionrateof pages 6-8, motorykin2024detectionrateof pages 1-2).

1. Disease Information

1.1 Concise disease overview

Mendelian IGF1 deficiency is classically caused by biallelic IGF1 loss-of-function and presents with a constellation of severe prenatal growth restriction (IUGR), marked postnatal growth failure, microcephaly, and often neurodevelopmental delay and sensorineural hearing loss (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2).

SPIGFD is a related clinical/endocrine entity defined by severe short stature and low IGF-I in the setting of normal/elevated GH, and includes Laron syndrome (GHR defects) and other GH–IGF axis causes (backeljauw2023challengesinthe pages 1-3).

1.2 Key identifiers

Not fully retrievable in this run: OMIM/Orphanet/ICD/MeSH/MONDO identifiers were not available from the retrieved full-text sources and the current toolset did not include direct OMIM/Orphanet lookups.

Trial/registry identifier (highly relevant): The major real‑world data source for rhIGF‑1 (mecasermin) is the Eu‑IGFD registry / Increlex® Growth Forum Database, registered at ClinicalTrials.gov NCT00903110 (Global patient registry; first posted 2008; still active per record versioning) (NCT00903110 chunk 3).

1.3 Synonyms / alternative names (current usage)

  • IGF1 deficiency; congenital IGF1 deficiency (gene defects) (walenkamp2013molecularigf1and pages 1-2)
  • Primary IGF‑1 deficiency; IGF‑1 deficiency (IGFD) (cappa2009profileofmecasermin pages 2-3)
  • Severe primary IGF‑1 deficiency (SPIGFD) / severe primary insulin‑like growth factor‑I deficiency (backeljauw2023challengesinthe pages 1-3)
  • Growth hormone insensitivity (GHI); Laron syndrome (best characterized SPIGFD subtype) (cappa2009profileofmecasermin pages 1-2, backeljauw2023challengesinthe pages 1-3)

1.4 Source type

Evidence in this report is primarily aggregated disease-level resources (registry analyses and reviews) plus human case reports/case series for biallelic IGF1 defects and single-center retrospective cohorts for mecasermin treatment (walenkamp2013molecularigf1and pages 2-4, denaite2024clinicalcharacteristicsand pages 1-2, bang2022pubertaltimingand pages 1-2, backeljauw2023challengesinthe pages 1-3).

2. Etiology

2.1 Primary causal factors

Genetic (Mendelian): Biallelic IGF1 pathogenic variants are a very rare cause of growth failure; one review noted that “Only three homozygous and two families with heterozygous mutations of the IGF1 gene have been described” (as of 2013) (walenkamp2013molecularigf1and pages 1-2). A 2023 report reiterates that IGF1 mutations are “extremely rare causes” of pre- and post-natal growth retardation and can include hearing, cognition, and glucose metabolism phenotypes (giacomozzi2023novelinsulinlikegrowth pages 1-2).

Broader SPIGFD umbrella: SPIGFD can result from defects across the GH–IGF axis (e.g., GHR, STAT5B, IGF1, ALS/IGFALS) (backeljauw2023challengesinthe pages 1-3, cappa2009profileofmecasermin pages 2-3).

2.2 Risk factors

For Mendelian IGF1 deficiency, the principal risk factor is parental carrier status for pathogenic IGF1 alleles; reported homozygous cases often come from consanguineous families (walenkamp2013molecularigf1and pages 2-4, cappa2009profileofmecasermin pages 1-2).

2.3 Protective factors / gene–environment interactions

No robust protective environmental factors were identified in the retrieved sources. A key practical “protective” factor against misdiagnosis is appropriate assay interpretation, including attention to IGF‑1 variants that confound measurement (see Diagnostics) (motorykin2024detectionrateof pages 6-8, motorykin2024detectionrateof pages 1-2).

3. Phenotypes

3.1 Core clinical phenotypes (biallelic IGF1 loss-of-function)

Growth and cranial growth (quantitative): Reported homozygous IGF1-defect cases show extreme deviations. A review summarizing published patients reports approximate ranges: - Birth weight: ~ −2.4 to −4.0 SDS - Birth length: ~ −3.7 to −6.5 SDS - Birth head circumference: ~ −2.5 to −7.5 SDS - Postnatal height: ~ −4.9 to −8.5 SDS - Postnatal head circumference: ~ −4.0 to −8.0 SDS (walenkamp2013molecularigf1and pages 2-4)

Neurodevelopment/sensory: Developmental delay and sensorineural deafness are repeatedly described as key features (walenkamp2013molecularigf1and pages 1-2, giacomozzi2023novelinsulinlikegrowth pages 1-2).

Metabolic: Some cases show insulin sensitivity abnormalities; a 2023 report highlights a phenotype including insulin resistance in a homozygous IGF1 missense variant case and hypothesizes altered insulin receptor signaling (giacomozzi2023novelinsulinlikegrowth pages 1-2).

3.2 SPIGFD phenotype beyond height

A multi-stakeholder 2023 perspective highlights that SPIGFD affects more than stature, listing non-growth features that may include hypoglycemia, dyslipidemia, insulin resistance, delayed puberty, hearing impairment, and immunodeficiency (contextualized as key clinical characteristics and care burden) (backeljauw2023challengesinthe pages 7-8).

3.3 Suggested HPO terms (non-exhaustive; ontology mapping suggestions)

The following are suggested mappings based on the phenotype descriptions above (not directly asserted by the cited papers as HPO IDs): - Short stature (HP:0004322) - Intrauterine growth restriction (HP:0001511) - Postnatal growth failure (HP:0008897) - Microcephaly (HP:0000252) - Global developmental delay (HP:0001263) - Sensorineural hearing impairment (HP:0000407) - Hypoglycemia (HP:0001943) - Insulin resistance (HP:0000855)

3.4 Quality of life impact

The 2023 multi-stakeholder perspective emphasizes “considerable impact on the physical health and quality of life for patients” and underscores unmet needs beyond height (backeljauw2023challengesinthe pages 1-3).

4. Genetic / Molecular Information

4.1 Causal genes

  • IGF1 (Mendelian biallelic loss-of-function; primary disease gene) (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2)
  • SPIGFD (broader) includes GHR, STAT5B, IGF1, IGFALS/ALS among others (backeljauw2023challengesinthe pages 1-3, cappa2009profileofmecasermin pages 2-3).

4.2 Pathogenic variant classes and examples

Biallelic IGF1 defects include deletions/frameshifts leading to truncation or absent functional peptide and missense variants that reduce IGF1R binding/signaling (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2). A 2013 review lists examples including exon deletions and missense variants (e.g., Val→Met; Arg→Gln) and frameshift variants (walenkamp2013molecularigf1and pages 2-4).

Functional consequences: Severe reduction in receptor binding has been measured for some mutants (e.g., up to ~90-fold reduced binding in one reported mutant) and diminished IGF1R phosphorylation/signaling (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2).

4.3 Inheritance

Biallelic IGF1 loss-of-function is autosomal recessive, with gene-dose effects described in heterozygous relatives (milder growth impacts) (walenkamp2013molecularigf1and pages 2-4).

4.4 Epigenetics / chromosomal abnormalities

No IGF1-deficiency-specific epigenetic mechanisms or recurrent chromosomal abnormalities were identified in the retrieved evidence.

5. Environmental Information

No specific toxins, lifestyle factors, or infectious triggers were identified as causal for the Mendelian form in the retrieved evidence; SPIGFD is primarily a genetic/endocrine disorder (backeljauw2023challengesinthe pages 1-3).

6. Mechanism / Pathophysiology

6.1 Causal chain (core model)

1) Upstream trigger: Pathogenic variants in IGF1 (or other GH–IGF axis genes in SPIGFD) reduce the amount or bioactivity of IGF‑1 (walenkamp2013molecularigf1and pages 2-4, backeljauw2023challengesinthe pages 1-3). 2) Molecular consequence: Reduced IGF‑1 bioactivity leads to reduced IGF1R activation (receptor binding and phosphorylation defects have been measured for multiple IGF‑1 mutants) (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2). 3) Cellular/tissue consequence: Impaired IGF1 signaling compromises fetal and postnatal somatic growth and brain development; animal models strongly support prenatal requirement for IGF‑1/IGF1R (IGF1 null mice ~65% birth weight; IGF1R null ~55% and perinatal lethality) (walenkamp2013molecularigf1and pages 1-2). 4) Clinical phenotype: IUGR → severe short stature; microcephaly; neurodevelopmental deficits; sensorineural deafness; possible metabolic complications (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2).

6.2 Pathways (suggested mapping)

Based on the GH–IGF axis and IGF1R signaling described in the sources, the primary downstream pathways likely involve PI3K–AKT and MAPK signaling downstream of IGF1R (not explicitly detailed in the retrieved excerpts). The direct mechanistic evidence in this run is primarily at the level of IGF1R binding/phosphorylation defects (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2).

6.3 Suggested GO and Cell Ontology terms (mapping suggestions)

  • GO Biological Process (suggested): regulation of growth (GO:0040008); insulin-like growth factor receptor signaling pathway (GO:0048009)
  • CL (suggested): hepatocyte (CL:0000182) as a major source of circulating IGF-I (backeljauw2023challengesinthe pages 1-3)

7. Anatomical Structures Affected

7.1 Organ/system level (primary)

  • Endocrine growth axis (pituitary–liver–peripheral tissue IGF production): liver highlighted as the main producer of circulating IGF-I (backeljauw2023challengesinthe pages 1-3).
  • Brain / neurodevelopmental system: neurodevelopmental delay and microcephaly are central features (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2).
  • Auditory system: sensorineural hearing loss is repeatedly described (walenkamp2013molecularigf1and pages 1-2, giacomozzi2023novelinsulinlikegrowth pages 1-2).

7.2 Suggested UBERON terms (mapping suggestions)

  • Liver (UBERON:0002107)
  • Brain (UBERON:0000955)
  • Inner ear (UBERON:0001849)

8. Temporal Development (Natural History)

8.1 Onset

Typically prenatal/congenital, with IUGR evident at birth and severe postnatal growth failure thereafter (giacomozzi2023novelinsulinlikegrowth pages 1-2, walenkamp2013molecularigf1and pages 2-4).

8.2 Progression/course

Growth failure is chronic and persistent. Puberty in SPIGFD is described as delayed in untreated patients; registry-treated patients show delayed pubertal timing but maintained pubertal height SDS gain (bang2022pubertaltimingand pages 1-2).

9. Inheritance and Population

9.1 Epidemiology (SPIGFD)

The 2023 multi-stakeholder perspective cites that in the EU about ~2 per 10,000 have “primary IGF‑I deficiencies (PIGFD)” and that SPIGFD is a smaller subset; in one French cohort ~0.8–1.2% of children referred for slow statural growth were diagnosed with SPIGFD (backeljauw2023challengesinthe pages 1-3).

9.2 Variant frequency / laboratory cohort statistic relevant to diagnosis

A 2024 clinical LC–MS study screening 243,808 patients detected IGF‑1 variants in 1,099 patients (0.45%) (motorykin2024detectionrateof pages 1-2). This is not disease prevalence, but it is a clinically important statistic for interpretation of IGF‑1 testing.

10. Diagnostics

10.1 Clinical/biochemical criteria for SPIGFD

The 2023 multi-stakeholder perspective provides the commonly used definition (quoted from its abstract): “Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH).” (published Oct 2023; https://doi.org/10.1186/s13023-023-02928-7) (backeljauw2023challengesinthe pages 1-3).

A 2024 real-world cohort used a slightly different operational definition: height < −3.0 SD and IGF‑1 below the 2.5th percentile (or < −2 SD), with stimulated GH peak ≥10 ng/mL; and used an IGF‑1 generation test with <50% IGF‑1 rise to confirm severe PIGFD (published Oct 28 2024; https://doi.org/10.3389/fped.2024.1461163) (denaite2024clinicalcharacteristicsand pages 1-2).

10.2 IGF‑1 generation test

A 2009 review describes use of an IGF‑1 generation test (short rhGH course) as a supportive functional test for GH insensitivity/primary IGF‑1 deficiency, with controversies around cutoffs and assay variability (cappa2009profileofmecasermin pages 2-3).

10.3 Genetic testing

A 2023 perspective describes common first-line sequencing of GHR and other GH–IGF axis genes, while also emphasizing that genetic testing is limited by access/cost in many regions and that a genetic diagnosis may not be required for rhIGF‑1 treatment eligibility in some jurisdictions (backeljauw2023challengesinthe pages 5-7).

10.4 Assay pitfalls and recent diagnostic development (2024 LC–MS variant study)

Motorykin et al. (Oct 2024; https://doi.org/10.1515/cclm-2023-0709) show that heterozygous IGF‑1 variants are frequent enough in clinical testing to matter for interpretation. In 243,808 patients, variants were found in 0.45% (motorykin2024detectionrateof pages 1-2). Critically, the study reports that in LC‑MS reports for heterozygous variants, the measured concentration may account for only the wild-type peptide; the authors note that for heterozygous individuals “only half of the total IGF‑1 is quantified” (motorykin2024detectionrateof pages 6-8, motorykin2024detectionrateof pages 1-2). They estimate 280/1,086 (25.8%) variant-positive patients could be miscategorized as outside the reference range if variant contribution is ignored (motorykin2024detectionrateof pages 6-8).

Implication: Apparent “low IGF‑1” in a patient with a heterozygous IGF1 variant may reflect measurement underestimation, potentially confounding evaluation for IGF‑1 deficiency or GH axis disorders (motorykin2024detectionrateof pages 6-8, motorykin2024detectionrateof pages 1-2).

10.5 Differential diagnosis (high level)

Within short stature workups, SPIGFD may be confused with other syndromic short stature conditions; the 2023 perspective notes misdiagnosis with syndromes such as Noonan (backeljauw2023challengesinthe pages 7-8).

11. Outcome / Prognosis

Long-term outcomes vary by genotype, residual signaling, and treatment timing. Registry data suggest improved height SDS with rhIGF‑1 treatment across childhood and puberty (bang2022pubertaltimingand pages 1-2). Earlier initiation is associated with better first-year growth response (backeljauw2023challengesinthe pages 5-7).

12. Treatment

12.1 Standard disease-directed therapy: recombinant human IGF‑1 (mecasermin)

The 2023 perspective states that “Recombinant human IGF‑1 (rhIGF‑1) is currently the only effective therapy for SPIGFD” (https://doi.org/10.1186/s13023-023-02928-7; Oct 2023) (backeljauw2023challengesinthe pages 1-3).

Real-world implementation / registries: Long-term safety and effectiveness are monitored via the Eu‑IGFD Registry (ClinicalTrials.gov NCT00903110) (NCT00903110 chunk 3).

Growth outcomes (registry and cohorts): - Registry-derived first-year height velocity ~7.3 cm/year (95% CI 6.8–7.7; n=81) in treatment-naïve prepubertal patients; earlier initiation predicted better response (Oct 2023 perspective summarizing registry data) (backeljauw2023challengesinthe pages 5-7). - Puberty/growth dynamics from the Eu‑IGFD registry (Frontiers in Endocrinology, Feb 2022; https://doi.org/10.3389/fendo.2022.812568): among those reaching end of puberty, mean height SDS increased from −3.7 to −2.6 (boys) and −3.1 to −2.3 (girls) (bang2022pubertaltimingand pages 1-2). - Single-center 2024 retrospective cohort (Frontiers in Pediatrics; Oct 28 2024): mean change in height SDS from start to end of treatment 0.76 ± 0.64, with hypoglycemia reported in 40% (denaite2024clinicalcharacteristicsand pages 1-2).

Adverse events (hypoglycemia emphasized): - 2024 cohort: “Side effects occurred in 50% of patients, with 40% of patients treated with rhIGF‑1 experiencing hypoglycemia” (denaite2024clinicalcharacteristicsand pages 1-2). - 2023 perspective reports aggregated hypoglycemia AE frequencies: 49% in clinical trials vs 28% in post-marketing data (backeljauw2023challengesinthe pages 7-8).

MAXO terms (suggested mapping): recombinant human insulin-like growth factor 1 therapy; blood glucose monitoring.

12.2 Growth hormone (rhGH)

In biallelic IGF1 deficiency, rhGH responses are variable and depend on the molecular defect; classical cases may show limited response, while some partial functional defects may benefit (giacomozzi2023novelinsulinlikegrowth pages 1-2). A 2013 review notes limited GH treatment data with poor-to-modest response, but also describes catch-up growth with high-dose GH in one report (0.4 mg/kg/week) (walenkamp2013molecularigf1and pages 2-4, walenkamp2013molecularigf1and pages 1-2).

13. Prevention

Primary prevention is not established for Mendelian IGF1 deficiency. Practical prevention focuses on: - Genetic counseling for at-risk families (autosomal recessive inheritance) (walenkamp2013molecularigf1and pages 2-4). - Early detection and early treatment initiation in SPIGFD to optimize growth response (earlier initiation predictor) (backeljauw2023challengesinthe pages 5-7).

14. Other Species / Natural Disease

No naturally occurring veterinary syndrome was identified in the retrieved evidence. However, comparative biology is central to the pathway: - IGF1 knockout mice have ~65% of normal birth weight and most die soon after birth; IGF1R knockout mice have ~55% of normal birth weight and die within hours (walenkamp2013molecularigf1and pages 1-2).

15. Model Organisms

Mouse genetic models (IGF1−/−; IGF1R−/−) demonstrate the critical prenatal role of IGF signaling and recapitulate severe growth restriction and perinatal lethality in the most severe disruptions (walenkamp2013molecularigf1and pages 1-2). These models strongly support causality but may overrepresent lethality compared with human hypomorphic alleles.

Key Concepts and Definitions (with 2023–2024 emphasis)

Disease entity / label Scope / relationship Key diagnostic criteria / definition Key notes Sources
IGF1 deficiency Broad Mendelian disorder caused by pathogenic IGF1 variants; typically refers to biallelic loss-of-function with severe prenatal and postnatal growth failure No single universal cutoff in the extracted sources; human cases are characterized by very low/undetectable or assay-variable IGF-1, often normal-to-elevated GH, with severe growth failure, microcephaly, developmental delay, and deafness (walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2) Reported pathogenic mechanisms include truncating deletions/frameshifts and missense variants that reduce IGF1R binding/signaling; reported variants include exon 4–5 deletion, Val92Met, Arg84Gln, Asn74Argfs*9, Ser83Glnfs*13 (walenkamp2013molecularigf1and pages 1-2, walenkamp2013molecularigf1and pages 2-4) (walenkamp2013molecularigf1and pages 1-2, walenkamp2013molecularigf1and pages 2-4, giacomozzi2023novelinsulinlikegrowth pages 1-2)
Primary IGF-1 deficiency (PIGFD/IGFD) Umbrella clinical/endocrine category for disorders with inadequate IGF-1 production/action despite adequate GH; includes congenital/Mendelian GH insensitivity states and related axis defects Typical pattern: low IGF-1 with normal or high GH; older review notes FDA/EMEA indications centered on severe short stature and low IGF-1 with normal/elevated GH (cappa2009profileofmecasermin pages 2-3) Genetic causes mentioned include GHR, STAT5B, IGF1, and ALS/IGFALS; can overlap with “GH insensitivity” and “Laron syndrome” terminology (cappa2009profileofmecasermin pages 2-3, cappa2009profileofmecasermin pages 1-2) (cappa2009profileofmecasermin pages 2-3, cappa2009profileofmecasermin pages 1-2)
Severe primary IGF-1 deficiency (SPIGFD) Narrower treatment-relevant subset of primary IGF-1 deficiency used in modern care frameworks and registries Short stature SDS ≤ -3.0, IGF-I SDS ≤ -3.0, and normal or elevated GH; this is the definition used in the 2023 international multi-stakeholder perspective (backeljauw2023challengesinthe pages 1-3) Best-characterized form is Laron syndrome due to GHR defects; SPIGFD is a subset of primary IGF-1 deficiencies and diagnosis/treatment access remain challenging (backeljauw2023challengesinthe pages 1-3) (backeljauw2023challengesinthe pages 1-3)
PSIGFD / severe primary IGF-1 deficiency (single-center 2024 study definition) Operational clinical definition used in a 2024 retrospective mecasermin cohort Height < -3.0 SD for age/sex, IGF-1 below the 2.5th percentile or < -2 SD, and normal GH with GH peak ≥10 ng/mL on stimulation; IGF-1 generation test after 4-day rhGH with <50% rise in IGF-1 used to confirm SPIGFD (denaite2024clinicalcharacteristicsand pages 1-2) Illustrates real-world variation from the stricter IGF-I SDS ≤ -3.0 definition used elsewhere; useful for understanding why eligibility/diagnosis may differ across centers or jurisdictions (denaite2024clinicalcharacteristicsand pages 1-2, backeljauw2023challengesinthe pages 5-7) (denaite2024clinicalcharacteristicsand pages 1-2, backeljauw2023challengesinthe pages 5-7)
Growth hormone insensitivity (GHI) / Laron syndrome Syndromic/etiologic subset within primary IGF-1 deficiency; classic Mendelian GH resistance state Clinical pattern of low IGF-1 despite normal/high GH; older review cites FDA/EMEA treatment indications of height SDS ≤ -3, basal IGF-1 SDS ≤ -3, and normal/elevated GH (cappa2009profileofmecasermin pages 2-3) Most commonly due to GHR mutations; older review states >250 reported GHR defects and notes consanguinity in many families; mecasermin is the only specific replacement therapy discussed (cappa2009profileofmecasermin pages 1-2, cappa2009profileofmecasermin pages 2-3) (cappa2009profileofmecasermin pages 2-3, cappa2009profileofmecasermin pages 1-2)
IGF1 haploinsufficiency Heterozygous IGF1 loss; related but usually milder than classic biallelic IGF1 deficiency Not defined by fixed biochemical cutoffs in the extracted evidence; phenotype includes prenatal/postnatal growth failure, microcephaly, feeding difficulties, low/low-normal serum IGF-I with relatively preserved IGFBP-3 (punt2025igf1haploinsufficiencyphenotype pages 2-3, punt2025igf1haploinsufficiencyphenotype pages 1-1) Reported molecular lesions include whole/partial gene deletions and a frameshift (c.243_246dupCAGC; p.Ser83Glnfs*13); important differential within monogenic short stature rather than classic SPIGFD (punt2025igf1haploinsufficiencyphenotype pages 2-3, punt2025igf1haploinsufficiencyphenotype pages 1-1) (punt2025igf1haploinsufficiencyphenotype pages 2-3, punt2025igf1haploinsufficiencyphenotype pages 1-1)
Diagnostic variability across regions / assays Cross-cutting issue affecting classification of SPIGFD/PSIGFD US-style threshold cited as basal IGF-I SDS ≤ -3.0, while EU criteria may use <2.5th percentile; assay recommendations exist but uptake is limited, creating inter-assay and inter-region variability (backeljauw2023challengesinthe pages 5-7) IGF-I generation test may support diagnosis but is often inconclusive in non-classic cases; lack of normative IGF-I SDS/percentile data complicates biochemical diagnosis (backeljauw2023challengesinthe pages 5-7) (backeljauw2023challengesinthe pages 5-7)
IGF-1 LC-MS variant/assay interpretation issue Laboratory interpretation issue relevant to diagnosing apparent low IGF-1 in some patients Not a disease definition, but clinically important because heterozygous IGF1 variants can cause reported LC-MS IGF-1 to represent only the wild-type peptide, effectively underestimating total circulating IGF-1 (motorykin2024detectionrateof pages 1-2, motorykin2024detectionrateof pages 8-9) In 243,808 patients, variants were detected in 1,099 (0.45%); 25.8% of variant-positive patients could be miscategorized relative to the reference range if variant contribution is ignored (motorykin2024detectionrateof pages 6-8, motorykin2024detectionrateof pages 1-2) (motorykin2024detectionrateof pages 6-8, motorykin2024detectionrateof pages 1-2, motorykin2024detectionrateof pages 8-9)

Table: This table compares the main disease labels used around Mendelian IGF1 deficiency and severe primary IGF-1 deficiency, emphasizing how definitions and cutoffs vary across sources. It is useful for reconciling nomenclature, eligibility criteria, and assay-related diagnostic caveats.

Recent Developments and Latest Research (prioritizing 2023–2024)

1) International multi-stakeholder perspective (Oct 2023): formalizes current SPIGFD definition and highlights diagnostic variability, inequitable access to therapy, and the need to characterize disease burden beyond height (https://doi.org/10.1186/s13023-023-02928-7) (backeljauw2023challengesinthe pages 1-3, backeljauw2023challengesinthe pages 5-7). 2) Novel homozygous IGF1 missense variant with insulin resistance (Dec 2023): expands phenotypic spectrum, highlights bioassays and in silico receptor interaction hypotheses (https://doi.org/10.1210/clinem/dgac738) (giacomozzi2023novelinsulinlikegrowth pages 1-2). 3) LC–MS diagnostic confounding by IGF‑1 variants (Oct 2024): large cohort shows variant detection rate 0.45% and quantification pitfalls that can shift z-scores and reference-range categorization (https://doi.org/10.1515/cclm-2023-0709) (motorykin2024detectionrateof pages 6-8, motorykin2024detectionrateof pages 1-2). 4) Real-world mecasermin cohort outcomes (Oct 2024): documents growth gains and frequent hypoglycemia, reinforcing the need for monitoring (https://doi.org/10.3389/fped.2024.1461163) (denaite2024clinicalcharacteristicsand pages 1-2).

Current Applications / Real-world Implementation

  • rhIGF‑1 (mecasermin; Increlex®) is used clinically for SPIGFD and is monitored through the global registry NCT00903110 (NCT00903110 chunk 3).
  • Clinical implementation requires nutrition timing and glucose monitoring due to hypoglycemia risk, consistent across recent cohort and consensus-style discussions (denaite2024clinicalcharacteristicsand pages 1-2, backeljauw2023challengesinthe pages 7-8).
  • Modern diagnostics increasingly use next-generation sequencing and LC–MS-based IGF‑1 quantification, but the 2024 LC–MS variant paper indicates interpretation must explicitly account for variant peptides to avoid misclassification (motorykin2024detectionrateof pages 6-8, motorykin2024detectionrateof pages 1-2).

Figure/Table Evidence from Retrieved Visual Content

Baseline cohort characteristics for a 2024 mecasermin-treated PSIGFD cohort are summarized in the paper’s Table 1 (cropped extraction) (denaite2024clinicalcharacteristicsand media c5b349d8).

Evidence Gaps / Limitations in this run

  • Direct OMIM/Orphanet/MeSH/ICD/MONDO identifiers for “IGF1 deficiency” were not extractable with the current retrieval set and tools.
  • A key registry safety paper focused on hypoglycemia risk factors (Bang et al.; Eu‑IGFD registry; DOI:10.1210/clinem/dgad479; PMID cited in trial record) was referenced but not retrievable as full text in this run; therefore, hypoglycemia risk-factor modeling results are not included (NCT00903110 chunk 3).

URLs and Publication Dates (examples of primary/authoritative sources used)

  • Backeljauw et al. Orphanet J Rare Dis — Oct 2023 — https://doi.org/10.1186/s13023-023-02928-7 (backeljauw2023challengesinthe pages 1-3)
  • Giacomozzi et al. J Clin Endocrinol Metab — Dec 2023 — https://doi.org/10.1210/clinem/dgac738 (giacomozzi2023novelinsulinlikegrowth pages 1-2)
  • Motorykin et al. Clin Chem Lab Med — Oct 2024 — https://doi.org/10.1515/cclm-2023-0709 (motorykin2024detectionrateof pages 1-2)
  • Denaite & Navardauskaite Front Pediatr — Oct 28 2024 — https://doi.org/10.3389/fped.2024.1461163 (denaite2024clinicalcharacteristicsand pages 1-2)
  • Bang et al. Front Endocrinol — Feb 2022 — https://doi.org/10.3389/fendo.2022.812568 (bang2022pubertaltimingand pages 1-2)
  • ClinicalTrials.gov registry: NCT00903110 (first posted 2008; record updated through 2026 versioning) — https://clinicaltrials.gov/study/NCT00903110 (registry record excerpt) (NCT00903110 chunk 3)

References

  1. (walenkamp2013molecularigf1and pages 2-4): M.J.E. Walenkamp, M. Losekoot, and J.M. Wit. Molecular igf-1 and igf-1 receptor defects: from genetics to clinical management. Endocrine development, 24:128-37, Feb 2013. URL: https://doi.org/10.1159/000342841, doi:10.1159/000342841. This article has 81 citations.

  2. (giacomozzi2023novelinsulinlikegrowth pages 1-2): Claudio Giacomozzi, Ayelen Martin, María Celia Fernández, Mariana Gutiérrez, Maria Iascone, Horacio M Domené, Fernando P Dominici, Ignacio Bergadá, Biagio Cangiano, Luca Persani, and Patricia A Pennisi. Novel insulin-like growth factor 1 gene mutation: broadening of the phenotype and implications for insulin resistance. The Journal of clinical endocrinology and metabolism, 108:1355-1369, Dec 2023. URL: https://doi.org/10.1210/clinem/dgac738, doi:10.1210/clinem/dgac738. This article has 10 citations.

  3. (backeljauw2023challengesinthe pages 1-3): Philippe F. Backeljauw, Mary Andrews, Peter Bang, Leo Dalle Molle, Cheri L. Deal, Jamie Harvey, Shirley Langham, Elżbieta Petriczko, Michel Polak, Helen L. Storr, and Mehul T. Dattani. Challenges in the care of individuals with severe primary insulin-like growth factor-i deficiency (spigfd): an international, multi-stakeholder perspective. Orphanet Journal of Rare Diseases, Oct 2023. URL: https://doi.org/10.1186/s13023-023-02928-7, doi:10.1186/s13023-023-02928-7. This article has 9 citations and is from a peer-reviewed journal.

  4. (cappa2009profileofmecasermin pages 1-2): Cappa, Danilo Fintini, and Claudia Brufani. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary igf-1 deficiency. Therapeutics and Clinical Risk Management, 5:553-559, Jul 2009. URL: https://doi.org/10.2147/tcrm.s6178, doi:10.2147/tcrm.s6178. This article has 68 citations and is from a peer-reviewed journal.

  5. (denaite2024clinicalcharacteristicsand pages 1-2): Dovile Denaite and Ruta Navardauskaite. Clinical characteristics and treatment efficacy in patients with primary severe igf-1 deficiency treated with recombinant igf-1. Frontiers in Pediatrics, Oct 2024. URL: https://doi.org/10.3389/fped.2024.1461163, doi:10.3389/fped.2024.1461163. This article has 2 citations.

  6. (backeljauw2023challengesinthe pages 5-7): Philippe F. Backeljauw, Mary Andrews, Peter Bang, Leo Dalle Molle, Cheri L. Deal, Jamie Harvey, Shirley Langham, Elżbieta Petriczko, Michel Polak, Helen L. Storr, and Mehul T. Dattani. Challenges in the care of individuals with severe primary insulin-like growth factor-i deficiency (spigfd): an international, multi-stakeholder perspective. Orphanet Journal of Rare Diseases, Oct 2023. URL: https://doi.org/10.1186/s13023-023-02928-7, doi:10.1186/s13023-023-02928-7. This article has 9 citations and is from a peer-reviewed journal.

  7. (motorykin2024detectionrateof pages 6-8): Ievgen Motorykin, Jianying Mu, Bradley S. Miller, Allison Li, Nigel J. Clarke, Michael J. McPhaul, and Zengru Wu. Detection rate of igf-1 variants and their implication to protein binding: study of over 240,000 patients. Clinical Chemistry and Laboratory Medicine (CCLM), 62:484-492, Oct 2024. URL: https://doi.org/10.1515/cclm-2023-0709, doi:10.1515/cclm-2023-0709. This article has 6 citations.

  8. (motorykin2024detectionrateof pages 1-2): Ievgen Motorykin, Jianying Mu, Bradley S. Miller, Allison Li, Nigel J. Clarke, Michael J. McPhaul, and Zengru Wu. Detection rate of igf-1 variants and their implication to protein binding: study of over 240,000 patients. Clinical Chemistry and Laboratory Medicine (CCLM), 62:484-492, Oct 2024. URL: https://doi.org/10.1515/cclm-2023-0709, doi:10.1515/cclm-2023-0709. This article has 6 citations.

  9. (NCT00903110 chunk 3): Global Patient Registry to Monitor Long-term Safety and Effectiveness of Increlex® in Children and Adolescents With Severe Primary Insulin-like Growth Factor-1 Deficiency (SPIGFD).. Esteve Pharmaceuticals, S.A.. 2008. ClinicalTrials.gov Identifier: NCT00903110

  10. (walenkamp2013molecularigf1and pages 1-2): M.J.E. Walenkamp, M. Losekoot, and J.M. Wit. Molecular igf-1 and igf-1 receptor defects: from genetics to clinical management. Endocrine development, 24:128-37, Feb 2013. URL: https://doi.org/10.1159/000342841, doi:10.1159/000342841. This article has 81 citations.

  11. (cappa2009profileofmecasermin pages 2-3): Cappa, Danilo Fintini, and Claudia Brufani. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary igf-1 deficiency. Therapeutics and Clinical Risk Management, 5:553-559, Jul 2009. URL: https://doi.org/10.2147/tcrm.s6178, doi:10.2147/tcrm.s6178. This article has 68 citations and is from a peer-reviewed journal.

  12. (bang2022pubertaltimingand pages 1-2): Peter Bang, Michel Polak, Valérie Perrot, Caroline Sert, Haris Shaikh, and Joachim Woelfle. Pubertal timing and growth dynamics in children with severe primary igf-1 deficiency: results from the european increlex® growth forum database registry. Frontiers in Endocrinology, Feb 2022. URL: https://doi.org/10.3389/fendo.2022.812568, doi:10.3389/fendo.2022.812568. This article has 9 citations.

  13. (backeljauw2023challengesinthe pages 7-8): Philippe F. Backeljauw, Mary Andrews, Peter Bang, Leo Dalle Molle, Cheri L. Deal, Jamie Harvey, Shirley Langham, Elżbieta Petriczko, Michel Polak, Helen L. Storr, and Mehul T. Dattani. Challenges in the care of individuals with severe primary insulin-like growth factor-i deficiency (spigfd): an international, multi-stakeholder perspective. Orphanet Journal of Rare Diseases, Oct 2023. URL: https://doi.org/10.1186/s13023-023-02928-7, doi:10.1186/s13023-023-02928-7. This article has 9 citations and is from a peer-reviewed journal.

  14. (punt2025igf1haploinsufficiencyphenotype pages 2-3): Lauren D. Punt, Daniëlle C.M. van der Kaay, Petra A. van Setten, Kirsten de Groote, Anne R. Kruijsen, Gianni Bocca, Sonja A. de Munnik, Judith S. Renes, Christiaan de Bruin, Monique Losekoot, Hermine A. van Duyvenvoorde, Jan M. Wit, and Sjoerd D. Joustra. Igf1 haploinsufficiency: phenotype and response to growth hormone treatment in 9 patients. Jun 2025. URL: https://doi.org/10.1159/000540053, doi:10.1159/000540053. This article has 2 citations and is from a peer-reviewed journal.

  15. (punt2025igf1haploinsufficiencyphenotype pages 1-1): Lauren D. Punt, Daniëlle C.M. van der Kaay, Petra A. van Setten, Kirsten de Groote, Anne R. Kruijsen, Gianni Bocca, Sonja A. de Munnik, Judith S. Renes, Christiaan de Bruin, Monique Losekoot, Hermine A. van Duyvenvoorde, Jan M. Wit, and Sjoerd D. Joustra. Igf1 haploinsufficiency: phenotype and response to growth hormone treatment in 9 patients. Jun 2025. URL: https://doi.org/10.1159/000540053, doi:10.1159/000540053. This article has 2 citations and is from a peer-reviewed journal.

  16. (motorykin2024detectionrateof pages 8-9): Ievgen Motorykin, Jianying Mu, Bradley S. Miller, Allison Li, Nigel J. Clarke, Michael J. McPhaul, and Zengru Wu. Detection rate of igf-1 variants and their implication to protein binding: study of over 240,000 patients. Clinical Chemistry and Laboratory Medicine (CCLM), 62:484-492, Oct 2024. URL: https://doi.org/10.1515/cclm-2023-0709, doi:10.1515/cclm-2023-0709. This article has 6 citations.

  17. (denaite2024clinicalcharacteristicsand media c5b349d8): Dovile Denaite and Ruta Navardauskaite. Clinical characteristics and treatment efficacy in patients with primary severe igf-1 deficiency treated with recombinant igf-1. Frontiers in Pediatrics, Oct 2024. URL: https://doi.org/10.3389/fped.2024.1461163, doi:10.3389/fped.2024.1461163. This article has 2 citations.

Artifacts