| 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 (pqac-00000001, pqac-00000006) | 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** (pqac-00000000, pqac-00000001) | (pqac-00000000, pqac-00000001, pqac-00000006) |
| **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 (pqac-00000002) | Genetic causes mentioned include **GHR**, **STAT5B**, **IGF1**, and **ALS/IGFALS**; can overlap with “GH insensitivity” and “Laron syndrome” terminology (pqac-00000002, pqac-00000007) | (pqac-00000002, pqac-00000007) |
| **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 (pqac-00000014) | 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 (pqac-00000014) | (pqac-00000014) |
| **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 (pqac-00000011) | 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 (pqac-00000011, pqac-00000015) | (pqac-00000011, pqac-00000015) |
| **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** (pqac-00000002) | 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 (pqac-00000007, pqac-00000002) | (pqac-00000002, pqac-00000007) |
| **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 (pqac-00000003, pqac-00000005) | 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 (pqac-00000003, pqac-00000005) | (pqac-00000003, pqac-00000005) |
| **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 (pqac-00000015) | 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 (pqac-00000015) | (pqac-00000015) |
| **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 (pqac-00000017, pqac-00000020) | 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 (pqac-00000016, pqac-00000017) | (pqac-00000016, pqac-00000017, pqac-00000020) |


*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.*