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IGF1 Deficiency

IGF1 Deficiency (Mendelian) — Comprehensive Disease Characteristics Report

2026-06-04
Falcon MONDO:0012110 Model: Edison Scientific Literature 27 citations

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)

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

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)

7. Anatomical Structures Affected

7.1 Organ/system level (primary)

7.2 Suggested UBERON terms (mapping suggestions)

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)

Table (click to expand)
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

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)

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.

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