Growth Hormone Insensitivity Syndrome

Mendelian MONDO:0015892 Pathograph 19 Show in embeddings browser hereditary disease

Growth hormone insensitivity syndrome (GHIS) is a group of Mendelian growth disorders defined by severe postnatal short stature with normal or elevated growth hormone (GH) concentrations that fail to generate a normal increase in insulin-like growth factor 1 (IGF-1) and fail to respond to exogenous GH. The shared lesion is interruption of the GH-IGF1 axis at, or downstream of, the GH receptor. The molecular causes form a continuum: GH receptor loss of function (classic Laron syndrome, GHR), post-receptor signaling defects (STAT5B; the paralog STAT5A is implicated but not yet proven in humans), acid-labile subunit deficiency (IGFALS), IGF-1 deficiency (IGF1), and IGF-1 resistance (IGF1R). This entry models the root entity (MONDO:0015892) with its molecular-cause subtypes; the IGF1-deficiency subtype is curated in detail separately (MONDO:0012110, kb/disorders/IGF1_Deficiency.yaml) and cross-referenced here rather than duplicated.

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2
Inheritance
6
Pathophys.
11
Phenotypes
1
Gaps
19
Pathograph
6
Genes
3
Medical Actions
7
Subtypes
1
Trials
1
Deep Research
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Inheritance

2
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:23502138 SUPPORT Human Clinical
"Mutations identified have been predominantly recessive."
GH-IGF axis defects causing GHIS are predominantly autosomal recessive.
Autosomal Dominant HP:0000006
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29844444 SUPPORT Human Clinical
"We now report the first germline heterozygous STAT5B variants with dominant-negative effects, identified by targeted and whole-exome sequencing (WES), in short-statured subjects from three unrelated families."
Dominant-negative heterozygous STAT5B (and GHR) variants produce autosomal-dominant GHIS.
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Subtypes

7
Classic Laron Syndrome (GHR deficiency) MONDO:0009877
GHR hgnc:4263 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GHR (hgnc:4263). hgnc:4263 is a gene from the HUGO Gene Nomenclature Committee.
Classic primary growth hormone insensitivity caused by biallelic loss-of-function variants in the GH receptor (GHR; OMIM 262500, MONDO:0009877). The prototype of GHIS: severe postnatal short stature with high GH, very low IGF-1 and IGFBP-3, and (for extracellular-domain defects) low/absent GH-binding protein. Rare autosomal-dominant cases arise from dominant-negative GHR variants. Cognition is typically normal. Lifelong low IGF-1 confers a striking protection from cancer and type 2 diabetes.
Show evidence (1 reference)
PMID:33029712 SUPPORT Human Clinical
"Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency."
Establishes GHR loss of function as the classic molecular cause of GHIS (Laron syndrome).
STAT5B Deficiency, Autosomal Recessive (post-receptor signaling defect) MONDO:0100211
STAT5B hgnc:11367 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in STAT5B (hgnc:11367). hgnc:11367 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Post-receptor GH signaling defect caused by biallelic loss-of-function STAT5B variants (OMIM 245590; MONDO:0100211). It phenocopies classic GHI but adds a distinctive, potentially fatal primary immunodeficiency: reduced regulatory T-cell number and function, modest T-cell lymphopenia, hypergammaglobulinemia, severe eczema, and chronic pulmonary disease that can progress to lymphocytic interstitial pneumonia and fatal fibrosis. This subtype - not the whole GHIS entry - is one of the two entities IUIS lists in its 2022 inborn-errors-of-immunity classification, Table 2 section 9 (Other Defects), the other being the dominant-negative form curated as the separate STAT5B Dominant-Negative subtype below. The immunologic detail is curated in kb/disorders/STAT5B_Deficiency.yaml, which is bound to the same MONDO:0100211 concept; the content here is scoped to what a GHIS reader needs to distinguish this subtype from the GHR/IGFALS/IGF1/IGF1R arms.
Show evidence (4 references)
PMID:35748970 SUPPORT Other
"STAT5b deficiency STAT5B AR 245590"
The IUIS 2022 Table 2 section 9 row listing autosomal recessive STAT5b deficiency as a combined immunodeficiency with syndromic features.
PMID:35748970 SUPPORT Other
"Growth-hormone insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity"
The IUIS clinical column for recessive STAT5b deficiency, pairing the GH insensitivity with the immunologic and pulmonary manifestations.
PMID:26703237 SUPPORT Human Clinical
"The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron..."
STAT5B loss of function is an established post-receptor cause of GHIS that phenocopies Laron syndrome.
+ 1 more reference
STAT5B Dominant-Negative Deficiency, Autosomal Dominant MONDO:0100219
STAT5B hgnc:11367 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in STAT5B (hgnc:11367). hgnc:11367 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Heterozygous germline STAT5B missense variants that act dominant-negatively on the wild-type protein (OMIM 604260; MONDO:0100219). Postnatal growth impairment is significant but GH insensitivity is mild, and the severe immune and pulmonary disease of the recessive form is absent - eczema and elevated IgE are the immune features. Curated as a subtype row distinct from the recessive form above because MONDO, OMIM and the IUIS 2022 classification all keep the two apart, and because the severe immunodeficiency and chronic pulmonary disease that define the recessive arm are reported absent here.
Show evidence (3 references)
PMID:29844444 SUPPORT Human Clinical
"We now report the first germline heterozygous STAT5B variants with dominant-negative effects, identified by targeted and whole-exome sequencing (WES), in short-statured subjects from three unrelated families."
Establishes heterozygous dominant-negative STAT5B variants as a distinct autosomal dominant cause of GH insensitivity.
PMID:29844444 SUPPORT Human Clinical
"Altogether, we demonstrate that specific heterozygous STAT5B germline mutations exert dominant-negative effects resulting in STAT5B deficiency clinically characterized by significant postnatal growth impairment, mild GH insensitivity, eczema, and elevated IgE."
Source of this subtype's clinical scope: significant postnatal growth impairment with only mild GH insensitivity, eczema and elevated IgE.
PMID:35748970 SUPPORT Other
"eczema (no immune defects compared to AR STAT5 deficiency)"
The IUIS 2022 clinical column for the dominant-negative row, supporting the milder immune phenotype of the heterozygous form.
STAT5A Deficiency (candidate post-receptor defect)
STAT5A hgnc:11366 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in STAT5A (hgnc:11366). hgnc:11366 is a gene from the HUGO Gene Nomenclature Committee.
Proposed post-receptor node based on the close STAT5B paralog STAT5A, which shares >95% amino acid identity yet cannot compensate for loss of STAT5B. Human disease-causing STAT5A variants had not been identified as of the key reviews, so this subtype is a mechanistically motivated candidate rather than an established human disease; see the knowledge-gap discussion. Included for completeness of the post-receptor signaling arm (prior project discussion in monarch-initiative/dismech issue 1411, PR 1424).
Show evidence (1 reference)
PMID:26703237 SUPPORT Human Clinical
"Of note, the closely related STAT5A, which shares >95% amino acid identity with STAT5B, could not compensate for loss of functional STAT5B."
Supports STAT5A as a non-redundant component of GH signaling, motivating it as a candidate post-receptor node, while noting it is not (yet) an established human disease gene.
Acid-Labile Subunit (ALS) Deficiency MONDO:0014420
IGFALS hgnc:5468 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in IGFALS (hgnc:5468). hgnc:5468 is a gene from the HUGO Gene Nomenclature Committee.
Deficiency of the acid-labile subunit from biallelic IGFALS variants. ALS stabilizes the circulating IGF-1/IGFBP-3 ternary complex; its loss lowers total IGF-1 with comparatively mild short stature (often with delayed puberty) and a tendency to insulin insensitivity, distinguishing it from the severe growth failure of GHR/STAT5B/IGF1 defects.
Show evidence (3 references)
PMID:39060265 SUPPORT Human Clinical
"Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency characterized by growth hormone resistance with or without delayed puberty."
Establishes biallelic IGFALS loss of function as a cause of acid-labile subunit deficiency, a GH-resistance (GHIS) subtype, with characteristic short stature and variable delayed puberty.
PMID:39060265 SUPPORT Human Clinical
"He showed short stature consistent with ALS deficiency."
Documents short stature in a patient with biallelic IGFALS variants (acid-labile subunit deficiency).
PMID:23502138 SUPPORT Human Clinical
"Other phenotypic features - immune deficiency for STAT5B defects and insulin insensitivity for IGFALS defects - are of note."
Highlights the IGFALS-specific feature (insulin insensitivity) that differentiates ALS deficiency from other GHIS subtypes.
Growth Delay due to IGF-1 Deficiency (IGF1) MONDO:0012110
IGF1 hgnc:5464 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in IGF1 (hgnc:5464). hgnc:5464 is a gene from the HUGO Gene Nomenclature Committee.
Growth delay due to IGF-1 deficiency from biallelic IGF1 variants (MONDO:0012110). Unlike GHR/STAT5B defects, the lesion is the ligand itself, causing intrauterine plus postnatal growth failure, microcephaly, sensorineural deafness, and intellectual disability. Curated in detail in kb/disorders/IGF1_Deficiency.yaml and cross-referenced here rather than duplicated.
Show evidence (1 reference)
PMID:33029712 SUPPORT Human Clinical
"Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I."
Places IGF1 (and STAT5B, IGFALS) defects within the GHIS molecular spectrum as causes of IGF-I deficiency/reduced bioavailability.
IGF-1 Resistance (IGF1R defect) MONDO:0010038
IGF1R hgnc:5465 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in IGF1R (hgnc:5465). hgnc:5465 is a gene from the HUGO Gene Nomenclature Committee.
Growth delay due to IGF-1 resistance from heterozygous IGF1R defects. End organs are insensitive to IGF-1, so birth size is small (IUGR) and postnatal growth fails despite normal or elevated IGF-1 - the biochemical inverse of the IGF-1-deficiency subtypes. Because the defect is the receptor, exogenous IGF-1 (mecasermin) is largely ineffective.
Show evidence (2 references)
PMID:23502138 SUPPORT Human Clinical
"Clinical conditions of IGF-I resistance due to mutations in the IGF-I receptor (IGFIR) similarly lead to IUGR and postnatal growth retardation."
Establishes IGF1R defects as the IGF-1-resistance arm of GHIS, causing IUGR and postnatal growth retardation.
PMID:33029712 SUPPORT Human Clinical
"Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides."
Explains the mechanism of the IGF1R subtype (receptor-level resistance to IGF-I and IGF-II).
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Discussions and Knowledge Gaps

1
Are biallelic (or dominant-negative) STAT5A variants a genuine human cause of growth hormone insensitivity, given that STAT5A cannot compensate for STAT5B loss but no disease-causing human STAT5A variants have yet been identified?
KNOWLEDGE GAP OPEN knowledge_gap_stat5a_human_ghi
Attached to
pathophysiology#GH-IGF1 Axis Disruption
STAT5A shares >95% identity with STAT5B and is activated by the same GHR-JAK2 cascade, yet the two paralogs are non-redundant. STAT5A is therefore a mechanistically plausible post-receptor GHIS node, but as of the key reviews human disease-causing STAT5A variants had not been reported, so the STAT5A subtype is included as a candidate pending human genetic confirmation. Targeted/exome sequencing of STAT5A in GHIS patients lacking GHR/STAT5B/IGFALS/IGF1/IGF1R variants, with functional testing of candidate variants for IGF1 transcriptional output, would resolve the gap.
Show evidence (1 reference)
PMID:26703237 SUPPORT Human Clinical
"Human mutations in STAT5A, as noted above, have yet to be identified."
Confirms that human disease-causing STAT5A variants were not established, defining the knowledge gap.
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Pathophysiology

6
GH-IGF1 Axis Disruption
Growth hormone binds the homodimeric GH receptor (GHR), activating the receptor-associated kinase JAK2, which phosphorylates STAT5B; phosphorylated STAT5B dimerizes, translocates to the nucleus, and drives hepatic transcription of IGF1, IGFBP3, and IGFALS. In GHIS this cascade is interrupted at the receptor (GHR loss of function in Laron syndrome) or post-receptor (STAT5B; candidate STAT5A), producing GH insensitivity - low IGF-1 despite normal or elevated GH.
Hepatocyte (principal IGF-1 source) CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (principal IGF-1 source), annotated with hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
GHR hgnc:4263 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GHR (hgnc:4263). hgnc:4263 is a gene from the HUGO Gene Nomenclature Committee.
STAT5B hgnc:11367 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT5B (hgnc:11367). hgnc:11367 is a gene from the HUGO Gene Nomenclature Committee. STAT5A hgnc:11366 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT5A (hgnc:11366). hgnc:11366 is a gene from the HUGO Gene Nomenclature Committee.
Growth hormone receptor signaling pathway GO:0060396 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Growth hormone receptor signaling pathway (GO:0060396). GO:0060396 is a biological process from the Gene Ontology. GHR-JAK2-STAT5B signal transduction GO:0007259 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased GHR-JAK2-STAT5B signal transduction, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology.
growth hormone receptor activity GO:0004903 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased growth hormone receptor activity (GO:0004903). GO:0004903 is a molecular function from the Gene Ontology.
Downstream
Reduced IGF-1 Production and Action Interrupted GH signaling (or, in downstream subtypes, ALS/IGF1/IGF1R defects) reduces circulating IGF-1 amount, stability, or action.
Show evidence (2 references)
PMID:26703237 SUPPORT Human Clinical
"The binding of GH to cell surface homo-dimeric GHR(18) activates the associated JAK2, which initiates signaling cascades including four STAT pathways (STAT1, STAT3, STAT5A and STAT5B), the MAPK (mitogen-activated protein kinase) and the PI3K (phosphoinositide-3 kinase) pathways."
Describes the GHR-JAK2-STAT5 signaling cascade whose interruption defines GHIS.
PMID:29844444 SUPPORT Human Clinical
"Patients diagnosed with growth hormone insensitivity syndrome (GHIS) share common clinical characteristics of impaired postnatal growth due to low or undetectable serum IGF1 concentrations despite normal or elevated growth hormone (GH) concentrations"
States the unifying biochemical signature of GHIS (low IGF-1 with normal/high GH) that results from axis disruption.
Reduced IGF-1 Production and Action
Reduced GH signaling (GHR/STAT5B), reduced IGF-1 stability (IGFALS), absent ligand (IGF1), or receptor resistance (IGF1R) all converge on deficient IGF-1 action at target tissues. The ternary IGF-1/IGFBP-3/ALS complex that normally stabilizes serum IGF-1 is depleted in the production/transport defects.
IGFALS hgnc:5468 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IGFALS (hgnc:5468). hgnc:5468 is a gene from the HUGO Gene Nomenclature Committee. IGF1 hgnc:5464 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IGF1 (hgnc:5464). hgnc:5464 is a gene from the HUGO Gene Nomenclature Committee. IGF1R hgnc:5465 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IGF1R (hgnc:5465). hgnc:5465 is a gene from the HUGO Gene Nomenclature Committee.
Insulin-like growth factor receptor signaling pathway GO:0048009 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Insulin-like growth factor receptor signaling pathway (GO:0048009). GO:0048009 is a biological process from the Gene Ontology.
Downstream
Impaired Linear Growth Deficient IGF-1 action impairs growth-plate chondrocyte proliferation.
Loss of IGF-1 Negative Feedback on GH Secretion Low IGF-1 removes negative feedback on pituitary GH secretion, raising GH.
Show evidence (1 reference)
PMID:23502138 SUPPORT Human Clinical
"Defects in the GH-IGF-I axis, including mutations in the GHR, STAT5B and IGFALS genes, lead to postnatal IGF deficiency and GH insensitivity. Patients are of normal birth size but present with severe postnatal growth failure, despite normal or elevated levels of GH."
Confirms that convergent axis defects produce postnatal IGF deficiency and GH insensitivity with normal birth size.
Impaired Linear Growth
Deficient IGF-1 action at the epiphyseal growth plate reduces chondrocyte proliferation and longitudinal bone growth, producing severe postnatal growth failure and short stature with delayed bone age. Birth size is near-normal because prenatal growth is only partly GH-dependent.
Growth-plate chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Growth-plate chondrocyte, annotated with chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Regulation of growth GO:0040008 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Regulation of growth (GO:0040008). GO:0040008 is a biological process from the Gene Ontology.
Downstream
Short stature Impaired linear growth manifests as severe short stature.
Postnatal growth retardation Reduced IGF-1 action produces postnatal growth failure.
Show evidence (1 reference)
PMID:21525302 SUPPORT Human Clinical
"GH insensitivity (GHI) presents in childhood as growth failure and in its severe form is associated with dysmorphic and metabolic abnormalities."
Links the GHIS axis defect to its central clinical output - childhood growth failure.
Loss of IGF-1 Negative Feedback on GH Secretion
IGF-1 normally restrains pituitary GH secretion. In the IGF-1-deficiency subtypes (GHR, STAT5B, IGF1, IGFALS) the loss of this feedback causes GH hypersecretion, generating the paradoxical "high GH, low IGF-1" biochemical signature. In the IGF1R-resistance subtype IGF-1 is normal or elevated instead.
Growth hormone secretion GO:0030252 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Growth hormone secretion (GO:0030252). GO:0030252 is a biological process from the Gene Ontology.
Downstream
Elevated circulating growth hormone Loss of IGF-1 feedback raises circulating GH.
Show evidence (1 reference)
PMID:8334752 SUPPORT Human Clinical
"The boy and the girl showed very short stature (-6.8 and -6.1 SDS), high GH (79 and 147 IU/I), low plasma IGF-I (0.12 and 0.18 U/ml) and undetectable GH-binding protein."
Documents the high-GH/low-IGF-1 signature (with absent GHBP) in Laron syndrome patients.
Reduced Pro-Aging Signaling and Metabolic Protection
A distinctive downstream consequence of lifelong severe GHR/IGF-1 deficiency (best characterized in the GHR-deficiency Ecuadorian cohort): reduced pro-aging GH-IGF-1 signaling is associated with enhanced insulin sensitivity and marked protection from cancer and type 2 diabetes. This protective metabolic phenotype is specific to the IGF-1-deficiency arm and is not a feature of IGF1R resistance.
Reduced (pro-aging) IGF-1 receptor signaling GO:0048009 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Reduced (pro-aging) IGF-1 receptor signaling, annotated with insulin-like growth factor receptor signaling pathway (GO:0048009). GO:0048009 is a biological process from the Gene Ontology. Enhanced insulin receptor signaling (insulin sensitivity) GO:0008286 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Enhanced insulin receptor signaling (insulin sensitivity), annotated with insulin receptor signaling pathway (GO:0008286). GO:0008286 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:21325617 SUPPORT Human Clinical
"The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects."
Documents the cancer- and diabetes-protective phenotype of severe GHR/ IGF-1 deficiency.
PMID:21325617 SUPPORT Human Clinical
"indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects."
Links the protective phenotype to enhanced insulin sensitivity in GHR deficiency.
STAT5B-Dependent Regulatory T-Cell Failure
The STAT5B-specific immune arm, and the reason IUIS lists STAT5b deficiency as an inborn error of immunity. STAT5B is not confined to the GH receptor cascade: it also transduces interleukin receptor signals, including IL-2, and drives FOXP3 expression in regulatory T cells. Loss of STAT5B therefore reduces CD4+CD25high Treg number and FOXP3 expression independently of the growth axis, permitting lymphocyte accumulation in extra-lymphoid tissue and opportunistic infection. This node is parallel to, not downstream of, GH-IGF1 axis disruption - which is why the GHR, IGFALS, IGF1, and IGF1R subtypes share the growth phenotype without the immune one.
CD4+CD25high regulatory T cell CL:0000815 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4+CD25high regulatory T cell, annotated with regulatory T cell (CL:0000815). CL:0000815 is a cell type from the Cell Ontology.
STAT5B hgnc:11367 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT5B (hgnc:11367). hgnc:11367 is a gene from the HUGO Gene Nomenclature Committee.
interleukin-2-mediated signaling pathway GO:0038110 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interleukin-2-mediated signaling pathway (GO:0038110). GO:0038110 is a biological process from the Gene Ontology. regulatory T cell differentiation GO:0045066 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulatory T cell differentiation (GO:0045066). GO:0045066 is a biological process from the Gene Ontology.
Downstream
Decreased Regulatory T-Cell Proportion
Primary Immunodeficiency
Lymphocytic Interstitial Pneumonia
Hypergammaglobulinemia
Show evidence (3 references)
PMID:26703237 SUPPORT Human Clinical
"The forkhead-box family of transcription factor, FOXP3, shown to be regulated by STAT5 (51,52), is highly expressed in Treg, but was significantly reduced in STAT5B deficient Treg"
Identifies the STAT5B-FOXP3 link as the molecular basis of the Treg defect.
PMID:26703237 SUPPORT Human Clinical
"Altogether, the reduced CD25high and FOXP3 expression associated with homozygous STAT5B mutations appears likely to have contributed to the novel immunodeficiency observed in these patients."
The review's own causal attribution of the immunodeficiency to reduced CD25high/FOXP3 expression.
PMID:26703237 SUPPORT Human Clinical
"the modular src-homology 2 (SH2) domain permits STAT5B to bind phosphorylated tyrosines, including those on activated receptors such as the GH receptor (GHR) or interleukin (IL) receptors"
Supports the dual-pathway role of STAT5B that makes the immune arm parallel to rather than downstream of the growth arm.
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Pathograph

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

11
Blood 2
Decreased Regulatory T-Cell Proportion HP:0020113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased regulatory T cell proportion (HP:0020113). HP:0020113 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26703237 SUPPORT Human Clinical
"In particular, a subset of CD4+ cells, the CD4+CD25high cells or T regulatory cells (Treg), is significantly diminished."
Directly documents the reduced regulatory T-cell compartment in STAT5B deficiency.
PMID:35748970 SUPPORT Other
"Modestly decreased, reduced Treg number and function"
The IUIS T-cell column for recessive STAT5b deficiency records both the modest T-cell decrease and the reduced Treg number and function.
Hypergammaglobulinemia Increased circulating immunoglobulin concentration HP:0010702 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergammaglobulinemia, annotated with Increased circulating immunoglobulin concentration (HP:0010702). HP:0010702 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26703237 SUPPORT Human Clinical
"Nevertheless, hypergammaglobulinemia and T-cell lymphopenia were common observations, with both CD4+ and CD8+ T-cells often below normal ranges"
Documents hypergammaglobulinemia together with T-cell lymphopenia as the common laboratory pattern in STAT5B deficiency.
Endocrine 2
Decreased circulating IGF-1 VERY_FREQUENT Decreased circulating serum insulin-like growth factor 1 concentration HP:0030353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating IGF-1 concentration, annotated with Decreased circulating serum insulin-like growth factor 1 concentration (HP:0030353). HP:0030353 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29844444 SUPPORT Human Clinical
"Patients diagnosed with growth hormone insensitivity syndrome (GHIS) share common clinical characteristics of impaired postnatal growth due to low or undetectable serum IGF1 concentrations despite normal or elevated growth hormone (GH) concentrations"
Low or undetectable serum IGF-1 is a shared clinical characteristic of GHIS.
Elevated circulating growth hormone FREQUENT Elevated circulating growth hormone concentration HP:0000845 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating growth hormone concentration (HP:0000845). HP:0000845 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8334752 SUPPORT Human Clinical
"The boy and the girl showed very short stature (-6.8 and -6.1 SDS), high GH (79 and 147 IU/I), low plasma IGF-I (0.12 and 0.18 U/ml) and undetectable GH-binding protein."
Documents elevated GH with low IGF-1 in Laron syndrome.
Immune 3
Primary Immunodeficiency HP:0002721 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary immunodeficiency, annotated with Immunodeficiency (HP:0002721). HP:0002721 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26703237 SUPPORT Human Clinical
"STAT5B deficient patients, unlike patients deficient in GHR, can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease."
Establishes primary immunodeficiency as a STAT5B-subtype-specific feature absent from the other GHIS arms.
PMID:26703237 SUPPORT Human Clinical
"Unlike the endocrine profiles that showed an absolute association between STAT5B mutations and IGF deficiency, the abnormalities in the immunological profile, where evaluated, was variable, even between siblings who carried the same homozygous STAT5B mutation"
Documents the variability of the immune phenotype, which is why the binding is to the general immunodeficiency term.
Severe eczema Eczematoid dermatitis HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe eczema, annotated with Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26703237 SUPPORT Human Clinical
"Shared symptoms in 8 of the 10 patients include severe eczema, chronic pulmonary disease manifesting as early as the first year of life"
Documents severe eczema among the shared immune-dysfunction symptoms of the recessive STAT5B-deficient patients.
Eczema with elevated IgE Eczematoid dermatitis HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eczema with elevated IgE, annotated with Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29844444 SUPPORT Human Clinical
"Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems."
Documents eczema with elevated IgE in dominant-negative STAT5B deficiency.
Metabolism 1
Hypoglycemia OCCASIONAL HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
The available abstract evidence (PMID:8334752) records hypoglycemic blood-glucose values in patients who were on recombinant human IGF-1 (rhIGF-1) therapy, so it documents on-treatment hypoglycemia. Untreated, disease-intrinsic fasting/ketotic hypoglycemia is clinically recognized in the IGF-1-deficiency subtypes of GHIS but is not directly captured in the cited abstract.
Show evidence (1 reference)
PMID:8334752 SUPPORT Human Clinical
"Daily assessment of blood sugar showed asymptomatic low values (< 2.8 mM/I) in 11/730 and 22/730 measurements in the boy and the girl, respectively."
Documents hypoglycemic blood-glucose values in Laron syndrome patients; note these were recorded during rhIGF-1 therapy, so this evidences hypoglycemia susceptibility in GHIS rather than a purely untreated disease-intrinsic measurement.
Respiratory 1
Lymphocytic Interstitial Pneumonia HP:0006527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphocytic interstitial pneumonia (HP:0006527). HP:0006527 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26703237 SUPPORT Human Clinical
"Shared symptoms in 8 of the 10 patients include severe eczema, chronic pulmonary disease manifesting as early as the first year of life"
Quantifies the chronic pulmonary disease and eczema burden in the reported STAT5B-deficient cohort.
PMID:35748970 SUPPORT Other
"Growth-hormone insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity"
IUIS records lymphocytic interstitial pneumonitis in the clinical column for recessive STAT5b deficiency.
Growth 2
Short stature VERY_FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33029712 SUPPORT Human Clinical
"Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency."
Severe postnatal growth failure (short stature) is the core feature of GHIS.
Postnatal growth retardation VERY_FREQUENT HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897), qualified as course progressive. HP:0008897 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:23502138 SUPPORT Human Clinical
"Patients are of normal birth size but present with severe postnatal growth failure, despite normal or elevated levels of GH."
Documents normal birth size with severe postnatal growth failure in GH-IGF axis defects.
🧬

Genetic Associations

6
GHR pathogenic variants (Laron syndrome) (Causative loss-of-function variants)
Gene: GHR hgnc:4263 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GHR (hgnc:4263). hgnc:4263 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:33029712 SUPPORT Human Clinical
"Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency."
Establishes GHR as the classic causative gene for GHIS.
STAT5B biallelic loss-of-function variants (Causative biallelic loss-of-function variants (GHI with immune dysregulation))
Gene: STAT5B hgnc:11367 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT5B (hgnc:11367). hgnc:11367 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:26703237 SUPPORT Human Clinical
"The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron..."
Establishes homozygous, autosomal recessive STAT5B loss of function as a cause of GH insensitivity.
STAT5B dominant-negative heterozygous variants (Causative heterozygous dominant-negative variants (milder GHI))
Gene: STAT5B hgnc:11367 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT5B (hgnc:11367). hgnc:11367 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29844444 SUPPORT Human Clinical
"We now report the first germline heterozygous STAT5B variants with dominant-negative effects, identified by targeted and whole-exome sequencing (WES), in short-statured subjects from three unrelated families."
Documents dominant-negative STAT5B variants as a cause of GHIS, in addition to the recessive form.
IGFALS pathogenic variants (ALS deficiency) (Causative biallelic loss-of-function variants)
Gene: IGFALS hgnc:5468 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IGFALS (hgnc:5468). hgnc:5468 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive inheritance
Show evidence (2 references)
PMID:39060265 SUPPORT Human Clinical
"Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency characterized by growth hormone resistance with or without delayed puberty."
Establishes biallelic (loss-of-function) IGFALS variants as causative of ALS deficiency, a GH-resistance subtype of GHIS.
PMID:39060265 SUPPORT Human Clinical
"He showed short stature consistent with ALS deficiency."
Documents a patient with biallelic IGFALS variants and short stature (ALS deficiency).
IGF1R pathogenic variants (IGF-1 resistance) (Causative; heterozygous defects causing IGF-1 resistance)
Gene: IGF1R hgnc:5465 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IGF1R (hgnc:5465). hgnc:5465 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:18515143 SUPPORT Human Clinical
"the recent identification of human IGF1 and IGF1 receptor (IGF1R) mutations, as well as information obtained from transgenic animals, points to a strong genetic component being of pivotal importance in the development of growth retardation."
Establishes IGF1R mutations as a genetic cause of growth retardation (IGF-1 resistance).
IGF1 pathogenic variants (IGF-1 deficiency) (Causative homozygous variants causing IGF-1 deficiency)
Gene: IGF1 hgnc:5464 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IGF1 (hgnc:5464). hgnc:5464 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:23502138 SUPPORT REVIEW SYNTHESIS Human Clinical
"The importance of IGF-I for both in utero as well as postnatal human growth is highlighted by rare human homozygous IGF1 mutations, which are characterized by intrauterine growth retardation (IUGR), microcephaly, mental retardation and severe postnatal growth failure."
Establishes homozygous IGF1 loss-of-function variants as a cause of intrauterine and postnatal growth failure within the GH-IGF-I axis.
💊

Medical Actions

3
Recombinant Human IGF-1 (Mecasermin)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: mecasermin NCIT:C2262 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses mecasermin (NCIT:C2262). NCIT:C2262 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Recombinant human IGF-1 (rhIGF-1; mecasermin, Increlex) is the mainstay disease-specific therapy for the IGF-1-deficiency subtypes of GHIS (GHR, STAT5B, IGF1, IGFALS). By directly supplying IGF-1 it bypasses the receptor/ signaling block; GH itself is ineffective because the defect is GH resistance. The IGF1R-resistance subtype responds poorly because the defect is the receptor. Dose with meals - hypoglycemia is the principal adverse effect.
Mechanism Target:
BYPASSES Reduced IGF-1 Production and Action — Mecasermin supplies exogenous IGF-1, bypassing the upstream GH-receptor/ signaling block to restore IGF-1 action.
Show evidence (1 reference)
PMID:8334752 SUPPORT Human Clinical
"During the first 6 months of treatment, height velocity increased to 7.8 and 8.4 cm/year without any clinical evidence of side-effects."
rhIGF-1 restores growth-plate signaling and increases height velocity in Laron syndrome, bypassing the receptor defect.
Show evidence (2 references)
PMID:40626687 SUPPORT Human Clinical
"treatment in children and adolescents with severe growth failure due to severe primary IGF-I deficiency (SPIGFD)"
Real-world registry establishes rhIGF-1 (mecasermin) as the treatment for severe primary IGF-I deficiency, the regulatory category covering GHIS subtypes.
PMID:8334752 SUPPORT Human Clinical
"During the first 6 months of treatment, height velocity increased to 7.8 and 8.4 cm/year without any clinical evidence of side-effects."
Early trial demonstrating the growth-promoting efficacy of rhIGF-1 in Laron syndrome.
Growth Hormone Therapy (ineffective)
Action: human growth hormone replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is human growth hormone replacement therapy, annotated with Hormone Replacement Therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Platform: Protein replacement
Recombinant human GH is ineffective in the primary GHIS subtypes because the lesion is at or downstream of the GH receptor; failure of IGF-1 to rise on GH stimulation is in fact the diagnostic confirmatory test.
Show evidence (1 reference)
PMID:33029712 SUPPORT Human Clinical
"Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency."
Indirect/mechanistic evidence: because GHIS is GH insensitivity at or below the receptor, GH therapy is not expected to correct the downstream IGF-1 deficiency. The snippet establishes the mechanism rather than directly experimentally refuting GH therapy.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling addresses the (predominantly) autosomal recessive recurrence risk and is especially relevant in the consanguineous/founder populations where GHR and other axis defects cluster.
Show evidence (1 reference)
PMID:23502138 SUPPORT Human Clinical
"Mutations identified have been predominantly recessive."
Predominantly recessive inheritance underpins the value of genetic counseling for at-risk families.
🔬

Clinical Trials

1
NCT00903110 RECRUITING
Global Increlex Growth Forum Database (IGFD) Registry: a real-world registry monitoring the effectiveness and safety of recombinant human IGF-1 (mecasermin/Increlex) in children and adolescents with severe growth failure due to severe primary IGF-I deficiency (SPIGFD), the regulatory category that covers GHIS subtypes.
Target Phenotypes: Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40626687 SUPPORT Human Clinical
"treatment in children and adolescents with severe growth failure due to severe primary IGF-I deficiency (SPIGFD)"
Identifies the IGFD registry (NCT00903110) as the real-world data source for rhIGF-1 outcomes in SPIGFD/GHIS.
{ }

Source YAML

click to show 
name: Growth Hormone Insensitivity Syndrome
creation_date: "2026-06-30T12:00:00Z"
category: Mendelian
description: >-
  Growth hormone insensitivity syndrome (GHIS) is a group of Mendelian growth
  disorders defined by severe postnatal short stature with normal or elevated
  growth hormone (GH) concentrations that fail to generate a normal increase in
  insulin-like growth factor 1 (IGF-1) and fail to respond to exogenous GH. The
  shared lesion is interruption of the GH-IGF1 axis at, or downstream of, the GH
  receptor. The molecular causes form a continuum: GH receptor loss of function
  (classic Laron syndrome, GHR), post-receptor signaling defects (STAT5B; the
  paralog STAT5A is implicated but not yet proven in humans), acid-labile subunit
  deficiency (IGFALS), IGF-1 deficiency (IGF1), and IGF-1 resistance (IGF1R).
  This entry models the root entity (MONDO:0015892) with its molecular-cause
  subtypes; the IGF1-deficiency subtype is curated in detail separately
  (MONDO:0012110, kb/disorders/IGF1_Deficiency.yaml) and cross-referenced here
  rather than duplicated.
disease_term:
  preferred_term: growth hormone insensitivity syndrome
  term:
    id: MONDO:0015892
    label: growth hormone insensitivity syndrome
parents:
- hereditary disease
has_subtypes:
- name: Laron Syndrome
  display_name: Classic Laron Syndrome (GHR deficiency)
  description: >-
    Classic primary growth hormone insensitivity caused by biallelic
    loss-of-function variants in the GH receptor (GHR; OMIM 262500,
    MONDO:0009877). The prototype of GHIS: severe postnatal short stature with
    high GH, very low IGF-1 and IGFBP-3, and (for extracellular-domain defects)
    low/absent GH-binding protein. Rare autosomal-dominant cases arise from
    dominant-negative GHR variants. Cognition is typically normal. Lifelong low
    IGF-1 confers a striking protection from cancer and type 2 diabetes.
  subtype_term:
    preferred_term: Laron syndrome
    term:
      id: MONDO:0009877
      label: Laron syndrome
  genes:
  - preferred_term: GHR
    term:
      id: hgnc:4263
      label: GHR
  evidence:
  - reference: PMID:33029712
    reference_title: "Genetic causes of growth hormone insensitivity beyond GHR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth hormone insensitivity (GHI) syndrome, first described in 1966, is
      classically associated with monogenic defects in the GH receptor (GHR)
      gene which result in severe post-natal growth failure as consequences of
      insulin-like growth factor I (IGF-I) deficiency.
    explanation: >-
      Establishes GHR loss of function as the classic molecular cause of GHIS
      (Laron syndrome).
- name: STAT5B Deficiency
  display_name: STAT5B Deficiency, Autosomal Recessive (post-receptor signaling defect)
  description: >-
    Post-receptor GH signaling defect caused by biallelic loss-of-function
    STAT5B variants (OMIM 245590; MONDO:0100211). It phenocopies classic GHI but
    adds a distinctive, potentially fatal primary immunodeficiency: reduced
    regulatory T-cell number and function, modest T-cell lymphopenia,
    hypergammaglobulinemia, severe eczema, and chronic pulmonary disease that
    can progress to lymphocytic interstitial pneumonia and fatal fibrosis. This
    subtype - not the whole GHIS entry - is one of the two entities IUIS lists in
    its 2022 inborn-errors-of-immunity classification, Table 2 section 9 (Other
    Defects), the other being the dominant-negative form curated as the separate
    STAT5B Dominant-Negative subtype below. The immunologic detail is curated in
    kb/disorders/STAT5B_Deficiency.yaml, which is bound to the same
    MONDO:0100211 concept; the content here is scoped to what a GHIS reader
    needs to distinguish this subtype from the GHR/IGFALS/IGF1/IGF1R arms.
  subtype_term:
    preferred_term: growth hormone insensitivity with immune dysregulation 1, autosomal recessive
    term:
      id: MONDO:0100211
      label: growth hormone insensitivity with immune dysregulation 1, autosomal recessive
  genes:
  - preferred_term: STAT5B
    term:
      id: hgnc:11367
      label: STAT5B
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "STAT5b deficiency STAT5B AR 245590"
    explanation: >-
      The IUIS 2022 Table 2 section 9 row listing autosomal recessive STAT5b
      deficiency as a combined immunodeficiency with syndromic features.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Growth-hormone insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity"
    explanation: >-
      The IUIS clinical column for recessive STAT5b deficiency, pairing the GH
      insensitivity with the immunologic and pulmonary manifestations.
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The critical importance of STAT5B in human IGF-I production was confirmed
      with the identification of the first homozygous, autosomal recessive,
      STAT5B mutation in a young female patient who phenotypically resembled
      patients with classical growth hormone insensitivity (GHI) syndrome (Laron
      syndrome) due to mutations in the GHR gene, presenting with severe
      postnatal growth failure and marked IGF-I deficiency.
    explanation: >-
      STAT5B loss of function is an established post-receptor cause of GHIS that
      phenocopies Laron syndrome.
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAT5B deficient patients, unlike patients deficient in GHR, can also
      present with a novel, potentially fatal, primary immunodeficiency, which
      can manifest as chronic pulmonary disease.
    explanation: >-
      Distinguishes STAT5B deficiency from GHR deficiency by its associated
      immunodeficiency and lung disease.
- name: STAT5B Dominant-Negative
  display_name: STAT5B Dominant-Negative Deficiency, Autosomal Dominant
  description: >-
    Heterozygous germline STAT5B missense variants that act dominant-negatively
    on the wild-type protein (OMIM 604260; MONDO:0100219). Postnatal growth
    impairment is significant but GH insensitivity is mild, and the severe immune
    and pulmonary disease of the recessive form is absent - eczema and elevated
    IgE are the immune features. Curated as a subtype row distinct from the
    recessive form above because MONDO, OMIM and the IUIS 2022 classification all
    keep the two apart, and because the severe immunodeficiency and chronic
    pulmonary disease that define the recessive arm are reported absent here.
  subtype_term:
    preferred_term: growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant
    term:
      id: MONDO:0100219
      label: growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant
  genes:
  - preferred_term: STAT5B
    term:
      id: hgnc:11367
      label: STAT5B
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29844444
    reference_title: Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now report the first germline heterozygous STAT5B variants with
      dominant-negative effects, identified by targeted and whole-exome
      sequencing (WES), in short-statured subjects from three unrelated families.
    explanation: >-
      Establishes heterozygous dominant-negative STAT5B variants as a distinct
      autosomal dominant cause of GH insensitivity.
  - reference: PMID:29844444
    reference_title: Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Altogether, we demonstrate that specific heterozygous STAT5B germline
      mutations exert dominant-negative effects resulting in STAT5B deficiency
      clinically characterized by significant postnatal growth impairment, mild
      GH insensitivity, eczema, and elevated IgE.
    explanation: >-
      Source of this subtype's clinical scope: significant postnatal growth
      impairment with only mild GH insensitivity, eczema and elevated IgE.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "eczema (no immune defects compared to AR STAT5 deficiency)"
    explanation: >-
      The IUIS 2022 clinical column for the dominant-negative row, supporting the
      milder immune phenotype of the heterozygous form.
- name: STAT5A Deficiency
  display_name: STAT5A Deficiency (candidate post-receptor defect)
  description: >-
    Proposed post-receptor node based on the close STAT5B paralog STAT5A, which
    shares >95% amino acid identity yet cannot compensate for loss of STAT5B.
    Human disease-causing STAT5A variants had not been identified as of the key
    reviews, so this subtype is a mechanistically motivated candidate rather
    than an established human disease; see the knowledge-gap discussion. Included
    for completeness of the post-receptor signaling arm (prior project discussion
    in monarch-initiative/dismech issue 1411, PR 1424).
  genes:
  - preferred_term: STAT5A
    term:
      id: hgnc:11366
      label: STAT5A
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, the closely related STAT5A, which shares >95% amino acid identity
      with STAT5B, could not compensate for loss of functional STAT5B.
    explanation: >-
      Supports STAT5A as a non-redundant component of GH signaling, motivating
      it as a candidate post-receptor node, while noting it is not (yet) an
      established human disease gene.
- name: IGFALS Deficiency
  display_name: Acid-Labile Subunit (ALS) Deficiency
  description: >-
    Deficiency of the acid-labile subunit from biallelic IGFALS variants. ALS
    stabilizes the circulating IGF-1/IGFBP-3 ternary complex; its loss lowers
    total IGF-1 with comparatively mild short stature (often with delayed
    puberty) and a tendency to insulin insensitivity, distinguishing it from the
    severe growth failure of GHR/STAT5B/IGF1 defects.
  subtype_term:
    preferred_term: acid-labile subunit deficiency
    term:
      id: MONDO:0014420
      label: short stature due to primary acid-labile subunit deficiency
  genes:
  - preferred_term: IGFALS
    term:
      id: hgnc:5468
      label: IGFALS
  evidence:
  - reference: PMID:39060265
    reference_title: "Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency
      characterized by growth hormone resistance with or without delayed
      puberty.
    explanation: >-
      Establishes biallelic IGFALS loss of function as a cause of acid-labile
      subunit deficiency, a GH-resistance (GHIS) subtype, with characteristic
      short stature and variable delayed puberty.
  - reference: PMID:39060265
    reference_title: "Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He showed short stature consistent with ALS deficiency.
    explanation: >-
      Documents short stature in a patient with biallelic IGFALS variants
      (acid-labile subunit deficiency).
  - reference: PMID:23502138
    reference_title: "IGF-I in human growth: lessons from defects in the GH-IGF-I axis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other phenotypic features - immune deficiency for STAT5B defects and
      insulin insensitivity for IGFALS defects - are of note.
    explanation: >-
      Highlights the IGFALS-specific feature (insulin insensitivity) that
      differentiates ALS deficiency from other GHIS subtypes.
- name: IGF1 Deficiency
  display_name: Growth Delay due to IGF-1 Deficiency (IGF1)
  description: >-
    Growth delay due to IGF-1 deficiency from biallelic IGF1 variants
    (MONDO:0012110). Unlike GHR/STAT5B defects, the lesion is the ligand itself,
    causing intrauterine plus postnatal growth failure, microcephaly,
    sensorineural deafness, and intellectual disability. Curated in detail in
    kb/disorders/IGF1_Deficiency.yaml and cross-referenced here rather than
    duplicated.
  subtype_term:
    preferred_term: growth delay due to IGF-1 deficiency
    term:
      id: MONDO:0012110
      label: growth delay due to insulin-like growth factor type 1 deficiency
  genes:
  - preferred_term: IGF1
    term:
      id: hgnc:5464
      label: IGF1
  evidence:
  - reference: PMID:33029712
    reference_title: "Genetic causes of growth hormone insensitivity beyond GHR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production,
      while defects in IGFALS and PAPPA2, disrupt transport and release of
      circulating IGF-I, respectively, affecting bioavailability of the
      growth-promoting IGF-I.
    explanation: >-
      Places IGF1 (and STAT5B, IGFALS) defects within the GHIS molecular
      spectrum as causes of IGF-I deficiency/reduced bioavailability.
- name: IGF1 Resistance
  display_name: IGF-1 Resistance (IGF1R defect)
  description: >-
    Growth delay due to IGF-1 resistance from heterozygous IGF1R defects. End
    organs are insensitive to IGF-1, so birth size is small (IUGR) and postnatal
    growth fails despite normal or elevated IGF-1 - the biochemical inverse of
    the IGF-1-deficiency subtypes. Because the defect is the receptor, exogenous
    IGF-1 (mecasermin) is largely ineffective.
  subtype_term:
    preferred_term: IGF-1 resistance
    term:
      id: MONDO:0010038
      label: growth delay due to insulin-like growth factor I resistance
  genes:
  - preferred_term: IGF1R
    term:
      id: hgnc:5465
      label: IGF1R
  evidence:
  - reference: PMID:23502138
    reference_title: "IGF-I in human growth: lessons from defects in the GH-IGF-I axis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical conditions of IGF-I resistance due to mutations in the IGF-I
      receptor (IGFIR) similarly lead to IUGR and postnatal growth retardation.
    explanation: >-
      Establishes IGF1R defects as the IGF-1-resistance arm of GHIS, causing
      IUGR and postnatal growth retardation.
  - reference: PMID:33029712
    reference_title: "Genetic causes of growth hormone insensitivity beyond GHR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not
      only IGF-I actions, but actions of the related IGF-II peptides.
    explanation: >-
      Explains the mechanism of the IGF1R subtype (receptor-level resistance to
      IGF-I and IGF-II).
pathophysiology:
- name: GH-IGF1 Axis Disruption
  description: >-
    Growth hormone binds the homodimeric GH receptor (GHR), activating the
    receptor-associated kinase JAK2, which phosphorylates STAT5B; phosphorylated
    STAT5B dimerizes, translocates to the nucleus, and drives hepatic
    transcription of IGF1, IGFBP3, and IGFALS. In GHIS this cascade is
    interrupted at the receptor (GHR loss of function in Laron syndrome) or
    post-receptor (STAT5B; candidate STAT5A), producing GH insensitivity - low
    IGF-1 despite normal or elevated GH.
  genes:
  - preferred_term: STAT5B
    term:
      id: hgnc:11367
      label: STAT5B
  - preferred_term: STAT5A
    term:
      id: hgnc:11366
      label: STAT5A
  gene:
    preferred_term: GHR
    term:
      id: hgnc:4263
      label: GHR
  molecular_functions:
  - preferred_term: growth hormone receptor activity
    term:
      id: GO:0004903
      label: growth hormone receptor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: Growth hormone receptor signaling pathway
    term:
      id: GO:0060396
      label: growth hormone receptor signaling pathway
    modifier: DECREASED
  - preferred_term: GHR-JAK2-STAT5B signal transduction
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  cell_types:
  - preferred_term: Hepatocyte (principal IGF-1 source)
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The binding of GH to cell surface homo-dimeric GHR(18) activates the
      associated JAK2, which initiates signaling cascades including four STAT
      pathways (STAT1, STAT3, STAT5A and STAT5B), the MAPK (mitogen-activated
      protein kinase) and the PI3K (phosphoinositide-3 kinase) pathways.
    explanation: >-
      Describes the GHR-JAK2-STAT5 signaling cascade whose interruption defines
      GHIS.
  - reference: PMID:29844444
    reference_title: "Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients diagnosed with growth hormone insensitivity syndrome (GHIS) share
      common clinical characteristics of impaired postnatal growth due to low or
      undetectable serum IGF1 concentrations despite normal or elevated growth
      hormone (GH) concentrations
    explanation: >-
      States the unifying biochemical signature of GHIS (low IGF-1 with
      normal/high GH) that results from axis disruption.
  downstream:
  - target: Reduced IGF-1 Production and Action
    description: >-
      Interrupted GH signaling (or, in downstream subtypes, ALS/IGF1/IGF1R
      defects) reduces circulating IGF-1 amount, stability, or action.
- name: Reduced IGF-1 Production and Action
  description: >-
    Reduced GH signaling (GHR/STAT5B), reduced IGF-1 stability (IGFALS), absent
    ligand (IGF1), or receptor resistance (IGF1R) all converge on deficient
    IGF-1 action at target tissues. The ternary IGF-1/IGFBP-3/ALS complex that
    normally stabilizes serum IGF-1 is depleted in the production/transport
    defects.
  genes:
  - preferred_term: IGFALS
    term:
      id: hgnc:5468
      label: IGFALS
  - preferred_term: IGF1
    term:
      id: hgnc:5464
      label: IGF1
  - preferred_term: IGF1R
    term:
      id: hgnc:5465
      label: IGF1R
  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
  evidence:
  - reference: PMID:23502138
    reference_title: "IGF-I in human growth: lessons from defects in the GH-IGF-I axis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Defects in the GH-IGF-I axis, including mutations in the GHR, STAT5B and
      IGFALS genes, lead to postnatal IGF deficiency and GH insensitivity.
      Patients are of normal birth size but present with severe postnatal growth
      failure, despite normal or elevated levels of GH.
    explanation: >-
      Confirms that convergent axis defects produce postnatal IGF deficiency and
      GH insensitivity with normal birth size.
  downstream:
  - target: Impaired Linear Growth
    description: Deficient IGF-1 action impairs growth-plate chondrocyte proliferation.
  - target: Loss of IGF-1 Negative Feedback on GH Secretion
    description: >-
      Low IGF-1 removes negative feedback on pituitary GH secretion, raising GH.
- name: Impaired Linear Growth
  description: >-
    Deficient IGF-1 action at the epiphyseal growth plate reduces chondrocyte
    proliferation and longitudinal bone growth, producing severe postnatal
    growth failure and short stature with delayed bone age. Birth size is
    near-normal because prenatal growth is only partly GH-dependent.
  biological_processes:
  - preferred_term: Regulation of growth
    term:
      id: GO:0040008
      label: regulation of growth
    modifier: DECREASED
  cell_types:
  - preferred_term: Growth-plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:21525302
    reference_title: "Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GH insensitivity (GHI) presents in childhood as growth failure and in its
      severe form is associated with dysmorphic and metabolic abnormalities.
    explanation: >-
      Links the GHIS axis defect to its central clinical output - childhood
      growth failure.
  downstream:
  - target: Short stature
    description: Impaired linear growth manifests as severe short stature.
  - target: Postnatal growth retardation
    description: Reduced IGF-1 action produces postnatal growth failure.
- name: Loss of IGF-1 Negative Feedback on GH Secretion
  description: >-
    IGF-1 normally restrains pituitary GH secretion. In the IGF-1-deficiency
    subtypes (GHR, STAT5B, IGF1, IGFALS) the loss of this feedback causes GH
    hypersecretion, generating the paradoxical "high GH, low IGF-1" biochemical
    signature. In the IGF1R-resistance subtype IGF-1 is normal or elevated
    instead.
  biological_processes:
  - preferred_term: Growth hormone secretion
    term:
      id: GO:0030252
      label: growth hormone secretion
    modifier: INCREASED
  evidence:
  - reference: PMID:8334752
    reference_title: "Effects of 17 months treatment using recombinant insulin-like growth factor-I in two children with growth hormone insensitivity (Laron) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The boy and the girl showed very short stature (-6.8 and -6.1 SDS), high
      GH (79 and 147 IU/I), low plasma IGF-I (0.12 and 0.18 U/ml) and
      undetectable GH-binding protein.
    explanation: >-
      Documents the high-GH/low-IGF-1 signature (with absent GHBP) in Laron
      syndrome patients.
  downstream:
  - target: Elevated circulating growth hormone
    description: Loss of IGF-1 feedback raises circulating GH.
- name: Reduced Pro-Aging Signaling and Metabolic Protection
  description: >-
    A distinctive downstream consequence of lifelong severe GHR/IGF-1 deficiency
    (best characterized in the GHR-deficiency Ecuadorian cohort): reduced
    pro-aging GH-IGF-1 signaling is associated with enhanced insulin sensitivity
    and marked protection from cancer and type 2 diabetes. This protective
    metabolic phenotype is specific to the IGF-1-deficiency arm and is not a
    feature of IGF1R resistance.
  biological_processes:
  - preferred_term: Reduced (pro-aging) IGF-1 receptor signaling
    term:
      id: GO:0048009
      label: insulin-like growth factor receptor signaling pathway
    modifier: DECREASED
  - preferred_term: Enhanced insulin receptor signaling (insulin sensitivity)
    term:
      id: GO:0008286
      label: insulin receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:21325617
    reference_title: "Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals with GHR deficiency exhibited only one nonlethal
      malignancy and no cases of diabetes, in contrast to a prevalence of 17%
      for cancer and 5% for diabetes in control subjects.
    explanation: >-
      Documents the cancer- and diabetes-protective phenotype of severe GHR/
      IGF-1 deficiency.
  - reference: PMID:21325617
    reference_title: "Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      indicating higher insulin sensitivity, which could explain the absence of
      diabetes in these subjects.
    explanation: >-
      Links the protective phenotype to enhanced insulin sensitivity in GHR
      deficiency.
- name: STAT5B-Dependent Regulatory T-Cell Failure
  description: >-
    The STAT5B-specific immune arm, and the reason IUIS lists STAT5b
    deficiency as an inborn error of immunity. STAT5B is not confined to the
    GH receptor cascade: it also transduces interleukin receptor signals,
    including IL-2, and drives FOXP3 expression in regulatory T cells. Loss of
    STAT5B therefore reduces CD4+CD25high Treg number and FOXP3 expression
    independently of the growth axis, permitting lymphocyte accumulation in
    extra-lymphoid tissue and opportunistic infection. This node is parallel
    to, not downstream of, GH-IGF1 axis disruption - which is why the GHR,
    IGFALS, IGF1, and IGF1R subtypes share the growth phenotype without the
    immune one.
  gene:
    preferred_term: STAT5B
    term:
      id: hgnc:11367
      label: STAT5B
  biological_processes:
  - preferred_term: interleukin-2-mediated signaling pathway
    term:
      id: GO:0038110
      label: interleukin-2-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: regulatory T cell differentiation
    term:
      id: GO:0045066
      label: regulatory T cell differentiation
    modifier: DECREASED
  cell_types:
  - preferred_term: CD4+CD25high regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The forkhead-box family of transcription factor, FOXP3, shown to be
      regulated by STAT5 (51,52), is highly expressed in Treg, but was
      significantly reduced in STAT5B deficient Treg
    explanation: >-
      Identifies the STAT5B-FOXP3 link as the molecular basis of the Treg
      defect.
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Altogether, the reduced CD25high and FOXP3 expression associated with
      homozygous STAT5B mutations appears likely to have contributed to the
      novel immunodeficiency observed in these patients.
    explanation: >-
      The review's own causal attribution of the immunodeficiency to reduced
      CD25high/FOXP3 expression.
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the modular src-homology 2 (SH2) domain permits STAT5B to bind
      phosphorylated tyrosines, including those on activated receptors such as
      the GH receptor (GHR) or interleukin (IL) receptors
    explanation: >-
      Supports the dual-pathway role of STAT5B that makes the immune arm
      parallel to rather than downstream of the growth arm.
  downstream:
  - target: Decreased Regulatory T-Cell Proportion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26703237
      reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In particular, a subset of CD4+ cells, the CD4+CD25high cells or T
        regulatory cells (Treg), is significantly diminished.
      explanation: >-
        The reduced Treg compartment is the direct readout of this node.
  - target: Primary Immunodeficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26703237
      reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Perturbations of Tregs, which are essential for the propagation and
        homeostasis of T-cell populations (49), most likely lead to an abnormal
        accumulation and proliferation of lymphocytes in extra-lymphoid
        tissues.
      explanation: >-
        Connects the Treg defect to the broader immune dysregulation, with the
        authors' own hedge preserved.
  - target: Lymphocytic Interstitial Pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26703237
      reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        confirmed lung fibrosis and/or lymphoid interstitial pneumonia (LIP), a
        condition of unknown etiology that is rare in children and often
        associated with autoimmune disease
      explanation: >-
        The pulmonary endpoint is recognized but its etiology is stated to be
        unknown, so the edge is left indirect.
  - target: Hypergammaglobulinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26703237
      reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Nevertheless, hypergammaglobulinemia and T-cell lymphopenia were common
        observations, with both CD4+ and CD8+ T-cells often below normal ranges
      explanation: >-
        Records hypergammaglobulinemia as a common laboratory consequence,
        without an established mechanism.
phenotypes:
- category: Phenotypic abnormality
  name: Short stature
  description: >-
    Severe postnatal short stature (often -4 to -10 SDS in the GHR/STAT5B/IGF1
    subtypes) is the defining feature of GHIS across all molecular causes.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33029712
    reference_title: "Genetic causes of growth hormone insensitivity beyond GHR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth hormone insensitivity (GHI) syndrome, first described in 1966, is
      classically associated with monogenic defects in the GH receptor (GHR)
      gene which result in severe post-natal growth failure as consequences of
      insulin-like growth factor I (IGF-I) deficiency.
    explanation: >-
      Severe postnatal growth failure (short stature) is the core feature of
      GHIS.
- category: Phenotypic abnormality
  name: Postnatal growth retardation
  description: >-
    Birth size is near-normal followed by severe postnatal growth failure - a
    hallmark distinguishing GHIS from primary IGF1 deficiency (which adds
    prenatal growth restriction).
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23502138
    reference_title: "IGF-I in human growth: lessons from defects in the GH-IGF-I axis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients are of normal birth size but present with severe postnatal growth
      failure, despite normal or elevated levels of GH.
    explanation: >-
      Documents normal birth size with severe postnatal growth failure in GH-IGF
      axis defects.
- category: Laboratory abnormality
  name: Decreased circulating IGF-1
  description: >-
    Low or undetectable serum IGF-1 that fails to rise on GH stimulation (the
    IGF-1 generation test) is the central biochemical signature of GHIS, present
    in the GHR/STAT5B/IGFALS/IGF1 subtypes; in the IGF1R-resistance subtype
    IGF-1 is instead normal or elevated.
  phenotype_term:
    preferred_term: Decreased circulating IGF-1 concentration
    term:
      id: HP:0030353
      label: Decreased circulating serum insulin-like growth factor 1 concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29844444
    reference_title: "Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients diagnosed with growth hormone insensitivity syndrome (GHIS) share
      common clinical characteristics of impaired postnatal growth due to low or
      undetectable serum IGF1 concentrations despite normal or elevated growth
      hormone (GH) concentrations
    explanation: >-
      Low or undetectable serum IGF-1 is a shared clinical characteristic of
      GHIS.
- category: Laboratory abnormality
  name: Elevated circulating growth hormone
  description: >-
    Normal or elevated basal GH, reflecting loss of IGF-1 negative feedback, in
    the face of low IGF-1 - the paradoxical signature that defines GH
    insensitivity and distinguishes it from GH deficiency.
  phenotype_term:
    preferred_term: Elevated circulating growth hormone concentration
    term:
      id: HP:0000845
      label: Elevated circulating growth hormone concentration
  frequency: FREQUENT
  evidence:
  - reference: PMID:8334752
    reference_title: "Effects of 17 months treatment using recombinant insulin-like growth factor-I in two children with growth hormone insensitivity (Laron) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The boy and the girl showed very short stature (-6.8 and -6.1 SDS), high
      GH (79 and 147 IU/I), low plasma IGF-I (0.12 and 0.18 U/ml) and
      undetectable GH-binding protein.
    explanation: >-
      Documents elevated GH with low IGF-1 in Laron syndrome.
- category: Laboratory abnormality
  name: Hypoglycemia
  description: >-
    Fasting/ketotic hypoglycemia, prominent in infancy, reflects impaired
    counter-regulation and enhanced insulin sensitivity in the IGF-1-deficiency
    subtypes.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  frequency: OCCASIONAL
  notes: >-
    The available abstract evidence (PMID:8334752) records hypoglycemic
    blood-glucose values in patients who were on recombinant human IGF-1
    (rhIGF-1) therapy, so it documents on-treatment hypoglycemia. Untreated,
    disease-intrinsic fasting/ketotic hypoglycemia is clinically recognized in
    the IGF-1-deficiency subtypes of GHIS but is not directly captured in the
    cited abstract.
  evidence:
  - reference: PMID:8334752
    reference_title: "Effects of 17 months treatment using recombinant insulin-like growth factor-I in two children with growth hormone insensitivity (Laron) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Daily assessment of blood sugar showed asymptomatic low values (< 2.8
      mM/I) in 11/730 and 22/730 measurements in the boy and the girl,
      respectively.
    explanation: >-
      Documents hypoglycemic blood-glucose values in Laron syndrome patients;
      note these were recorded during rhIGF-1 therapy, so this evidences
      hypoglycemia susceptibility in GHIS rather than a purely untreated
      disease-intrinsic measurement.
- category: Phenotypic abnormality
  name: Primary Immunodeficiency
  subtype: STAT5B Deficiency
  description: >-
    Subtype-specific to STAT5B deficiency: a primary, potentially fatal
    immunodeficiency with chronic pulmonary disease and autoimmunity,
    reflecting STAT5B's role downstream of the IL-2 receptor in regulatory
    T-cell homeostasis. Not a feature of the GHR/IGFALS/IGF1/IGF1R subtypes.
    The severity label matters here: the immunologic profile is variable even
    between siblings carrying the same homozygous variant, and the T-cell
    lymphopenia is modest rather than the profound T-cell loss of a severe
    combined immunodeficiency - so this is bound to the general
    immunodeficiency term rather than to "Severe T-cell immunodeficiency"
    (HP:0005352), which the cited sources do not support.
  phenotype_term:
    preferred_term: Primary immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAT5B deficient patients, unlike patients deficient in GHR, can also
      present with a novel, potentially fatal, primary immunodeficiency, which
      can manifest as chronic pulmonary disease.
    explanation: >-
      Establishes primary immunodeficiency as a STAT5B-subtype-specific
      feature absent from the other GHIS arms.
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike the endocrine profiles that showed an absolute association between
      STAT5B mutations and IGF deficiency, the abnormalities in the
      immunological profile, where evaluated, was variable, even between
      siblings who carried the same homozygous STAT5B mutation
    explanation: >-
      Documents the variability of the immune phenotype, which is why the
      binding is to the general immunodeficiency term.

- category: Laboratory abnormality
  name: Decreased Regulatory T-Cell Proportion
  subtype: STAT5B Deficiency
  description: >-
    Reduced CD4+CD25high regulatory T cells with diminished FOXP3 expression is
    the specific cellular lesion behind the STAT5B immunodeficiency, and the
    finding IUIS records for this row. It follows from STAT5B's position
    downstream of the IL-2 receptor, and is the mechanistic reason the immune
    phenotype tracks with STAT5B rather than with GH insensitivity as such.
  phenotype_term:
    preferred_term: Decreased regulatory T cell proportion
    term:
      id: HP:0020113
      label: Decreased regulatory T cell proportion
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, a subset of CD4+ cells, the CD4+CD25high cells or T
      regulatory cells (Treg), is significantly diminished.
    explanation: >-
      Directly documents the reduced regulatory T-cell compartment in STAT5B
      deficiency.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Modestly decreased, reduced Treg number and function"
    explanation: >-
      The IUIS T-cell column for recessive STAT5b deficiency records both the
      modest T-cell decrease and the reduced Treg number and function.

- category: Phenotypic abnormality
  name: Lymphocytic Interstitial Pneumonia
  subtype: STAT5B Deficiency
  description: >-
    Chronic pulmonary disease is the manifestation that makes recessive STAT5B
    deficiency potentially fatal. It can begin in the first year of life and
    progress to confirmed lung fibrosis or lymphocytic interstitial pneumonia;
    three of the ten originally reported patients died of progressive
    pulmonary fibrosis and respiratory failure. It is absent from the
    dominant-negative form.
  phenotype_term:
    preferred_term: Lymphocytic interstitial pneumonia
    term:
      id: HP:0006527
      label: Lymphocytic interstitial pneumonia
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shared symptoms in 8 of the 10 patients include severe eczema, chronic
      pulmonary disease manifesting as early as the first year of life
    explanation: >-
      Quantifies the chronic pulmonary disease and eczema burden in the
      reported STAT5B-deficient cohort.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Growth-hormone insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity"
    explanation: >-
      IUIS records lymphocytic interstitial pneumonitis in the clinical column
      for recessive STAT5b deficiency.

- category: Laboratory abnormality
  name: Hypergammaglobulinemia
  subtype: STAT5B Deficiency
  description: >-
    Elevated serum immunoglobulins with T-cell lymphopenia is the recurring
    laboratory pattern in recessive STAT5B deficiency - the inverse of the
    hypogammaglobulinemia seen in antibody-deficiency syndromes, and consistent
    with loss of regulatory T-cell restraint rather than a B-cell production
    defect. IUIS records normal B cells with hypergammaglobulinemia and
    increased IgE.
  phenotype_term:
    preferred_term: Hypergammaglobulinemia
    term:
      id: HP:0010702
      label: Increased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, hypergammaglobulinemia and T-cell lymphopenia were common
      observations, with both CD4+ and CD8+ T-cells often below normal ranges
    explanation: >-
      Documents hypergammaglobulinemia together with T-cell lymphopenia as the
      common laboratory pattern in STAT5B deficiency.
- category: Phenotypic abnormality
  name: Severe eczema
  subtype: STAT5B Deficiency
  description: >-
    Severe eczema is one of the shared immune-dysfunction features of the
    autosomal recessive form, present in 8 of the 10 patients in the reported
    series and distinguishing STAT5B deficiency from the GHR, IGF1, IGF1R and
    IGFALS arms.
  phenotype_term:
    preferred_term: Severe eczema
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shared symptoms in 8 of the 10 patients include severe eczema, chronic
      pulmonary disease manifesting as early as the first year of life
    explanation: >-
      Documents severe eczema among the shared immune-dysfunction symptoms of the
      recessive STAT5B-deficient patients.
- category: Phenotypic abnormality
  name: Eczema with elevated IgE
  subtype: STAT5B Dominant-Negative
  description: >-
    Eczema with elevated IgE is the immune manifestation of the
    dominant-negative form, which lacks the severe immune and pulmonary disease
    of the recessive form.
  phenotype_term:
    preferred_term: Eczema with elevated IgE
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:29844444
    reference_title: "Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report dominant-negative, inactivating STAT5B germline mutations
      in patients with growth failure, eczema, and elevated IgE but without
      severe immune and pulmonary problems.
    explanation: >-
      Documents eczema with elevated IgE in dominant-negative STAT5B deficiency.
genetic:
- name: GHR pathogenic variants (Laron syndrome)
  subtype: Laron Syndrome
  gene_term:
    preferred_term: GHR
    term:
      id: hgnc:4263
      label: GHR
  association: Causative loss-of-function variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:33029712
    reference_title: "Genetic causes of growth hormone insensitivity beyond GHR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth hormone insensitivity (GHI) syndrome, first described in 1966, is
      classically associated with monogenic defects in the GH receptor (GHR)
      gene which result in severe post-natal growth failure as consequences of
      insulin-like growth factor I (IGF-I) deficiency.
    explanation: >-
      Establishes GHR as the classic causative gene for GHIS.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
- name: STAT5B biallelic loss-of-function variants
  subtype: STAT5B Deficiency
  gene_term:
    preferred_term: STAT5B
    term:
      id: hgnc:11367
      label: STAT5B
  association: Causative biallelic loss-of-function variants (GHI with immune dysregulation)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Split from the dominant-negative heterozygous record below because the two
    are separate MONDO concepts (MONDO:0100211 and MONDO:0100219) with different
    inheritance and different immunologic risk, and because `subtype:` is
    single-valued. Detailed immunologic curation of this arm lives in
    kb/disorders/STAT5B_Deficiency.yaml.
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The critical importance of STAT5B in human IGF-I production was confirmed
      with the identification of the first homozygous, autosomal recessive,
      STAT5B mutation in a young female patient who phenotypically resembled
      patients with classical growth hormone insensitivity (GHI) syndrome (Laron
      syndrome) due to mutations in the GHR gene, presenting with severe
      postnatal growth failure and marked IGF-I deficiency.
    explanation: >-
      Establishes homozygous, autosomal recessive STAT5B loss of function as a
      cause of GH insensitivity.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
- name: STAT5B dominant-negative heterozygous variants
  subtype: STAT5B Dominant-Negative
  gene_term:
    preferred_term: STAT5B
    term:
      id: hgnc:11367
      label: STAT5B
  association: Causative heterozygous dominant-negative variants (milder GHI)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:29844444
    reference_title: "Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now report the first germline heterozygous STAT5B variants with
      dominant-negative effects, identified by targeted and whole-exome
      sequencing (WES), in short-statured subjects from three unrelated
      families.
    explanation: >-
      Documents dominant-negative STAT5B variants as a cause of GHIS, in
      addition to the recessive form.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
- name: IGFALS pathogenic variants (ALS deficiency)
  subtype: IGFALS Deficiency
  gene_term:
    preferred_term: IGFALS
    term:
      id: hgnc:5468
      label: IGFALS
  association: Causative biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:39060265
    reference_title: "Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency
      characterized by growth hormone resistance with or without delayed
      puberty.
    explanation: >-
      Establishes biallelic (loss-of-function) IGFALS variants as causative of
      ALS deficiency, a GH-resistance subtype of GHIS.
  - reference: PMID:39060265
    reference_title: "Homozygous 6-bp deletion of IGFALS in a prepubertal boy with short stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He showed short stature consistent with ALS deficiency.
    explanation: >-
      Documents a patient with biallelic IGFALS variants and short stature
      (ALS deficiency).
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
- name: IGF1R pathogenic variants (IGF-1 resistance)
  subtype: IGF1 Resistance
  gene_term:
    preferred_term: IGF1R
    term:
      id: hgnc:5465
      label: IGF1R
  association: Causative; heterozygous defects causing IGF-1 resistance
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:18515143
    reference_title: "IGF signaling defects as causes of growth failure and IUGR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the recent identification of human IGF1 and IGF1 receptor (IGF1R)
      mutations, as well as information obtained from transgenic animals, points
      to a strong genetic component being of pivotal importance in the
      development of growth retardation.
    explanation: >-
      Establishes IGF1R mutations as a genetic cause of growth retardation
      (IGF-1 resistance).
- name: IGF1 pathogenic variants (IGF-1 deficiency)
  subtype: IGF1 Deficiency
  gene_term:
    preferred_term: IGF1
    term:
      id: hgnc:5464
      label: IGF1
  association: Causative homozygous variants causing IGF-1 deficiency
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Recorded here so the IGF1 arm of this umbrella is a declared causal gene and
    not only a gene descriptor on the IGF1 Deficiency subtype row. Detailed
    curation of the disease itself is in kb/disorders/IGF1_Deficiency.yaml
    (MONDO:0012110) and is not duplicated.
  evidence:
  - reference: PMID:23502138
    reference_title: "IGF-I in human growth: lessons from defects in the GH-IGF-I axis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The importance of IGF-I for both in utero as well as postnatal human growth
      is highlighted by rare human homozygous IGF1 mutations, which are
      characterized by intrauterine growth retardation (IUGR), microcephaly,
      mental retardation and severe postnatal growth failure.
    explanation: >-
      Establishes homozygous IGF1 loss-of-function variants as a cause of
      intrauterine and postnatal growth failure within the GH-IGF-I axis.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23502138
    reference_title: "IGF-I in human growth: lessons from defects in the GH-IGF-I axis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations identified have been predominantly recessive.
    explanation: >-
      GH-IGF axis defects causing GHIS are predominantly autosomal recessive.
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29844444
    reference_title: "Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now report the first germline heterozygous STAT5B variants with
      dominant-negative effects, identified by targeted and whole-exome
      sequencing (WES), in short-statured subjects from three unrelated
      families.
    explanation: >-
      Dominant-negative heterozygous STAT5B (and GHR) variants produce
      autosomal-dominant GHIS.
treatments:
- name: Recombinant Human IGF-1 (Mecasermin)
  description: >-
    Recombinant human IGF-1 (rhIGF-1; mecasermin, Increlex) is the mainstay
    disease-specific therapy for the IGF-1-deficiency subtypes of GHIS (GHR,
    STAT5B, IGF1, IGFALS). By directly supplying IGF-1 it bypasses the receptor/
    signaling block; GH itself is ineffective because the defect is GH
    resistance. The IGF1R-resistance subtype responds poorly because the defect
    is the receptor. Dose with meals - hypoglycemia is the principal adverse
    effect.
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: Reduced IGF-1 Production and Action
    treatment_effect: BYPASSES
    description: >-
      Mecasermin supplies exogenous IGF-1, bypassing the upstream GH-receptor/
      signaling block to restore IGF-1 action.
    evidence:
    - reference: PMID:8334752
      reference_title: "Effects of 17 months treatment using recombinant insulin-like growth factor-I in two children with growth hormone insensitivity (Laron) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During the first 6 months of treatment, height velocity increased to
        7.8 and 8.4 cm/year without any clinical evidence of side-effects.
      explanation: >-
        rhIGF-1 restores growth-plate signaling and increases height velocity in
        Laron syndrome, bypassing the receptor defect.
  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:40626687
    reference_title: "Near-Adult Height Outcomes in Patients Treated With rhIGF-1 for Severe Growth Failure: Real-World IGFD Registry Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment in children and adolescents with severe growth failure due to
      severe primary IGF-I deficiency (SPIGFD)
    explanation: >-
      Real-world registry establishes rhIGF-1 (mecasermin) as the treatment for
      severe primary IGF-I deficiency, the regulatory category covering GHIS
      subtypes.
  - reference: PMID:8334752
    reference_title: "Effects of 17 months treatment using recombinant insulin-like growth factor-I in two children with growth hormone insensitivity (Laron) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the first 6 months of treatment, height velocity increased to 7.8
      and 8.4 cm/year without any clinical evidence of side-effects.
    explanation: >-
      Early trial demonstrating the growth-promoting efficacy of rhIGF-1 in
      Laron syndrome.
- name: Growth Hormone Therapy (ineffective)
  description: >-
    Recombinant human GH is ineffective in the primary GHIS subtypes because the
    lesion is at or downstream of the GH receptor; failure of IGF-1 to rise on
    GH stimulation is in fact the diagnostic confirmatory test.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: human growth hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
  evidence:
  - reference: PMID:33029712
    reference_title: "Genetic causes of growth hormone insensitivity beyond GHR."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth hormone insensitivity (GHI) syndrome, first described in 1966, is
      classically associated with monogenic defects in the GH receptor (GHR)
      gene which result in severe post-natal growth failure as consequences of
      insulin-like growth factor I (IGF-I) deficiency.
    explanation: >-
      Indirect/mechanistic evidence: because GHIS is GH insensitivity at or
      below the receptor, GH therapy is not expected to correct the downstream
      IGF-1 deficiency. The snippet establishes the mechanism rather than
      directly experimentally refuting GH therapy.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the (predominantly) autosomal recessive
    recurrence risk and is especially relevant in the consanguineous/founder
    populations where GHR and other axis defects cluster.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23502138
    reference_title: "IGF-I in human growth: lessons from defects in the GH-IGF-I axis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations identified have been predominantly recessive.
    explanation: >-
      Predominantly recessive inheritance underpins the value of genetic
      counseling for at-risk families.
clinical_trials:
- name: NCT00903110
  status: RECRUITING
  description: >-
    Global Increlex Growth Forum Database (IGFD) Registry: a real-world registry
    monitoring the effectiveness and safety of recombinant human IGF-1
    (mecasermin/Increlex) in children and adolescents with severe growth failure
    due to severe primary IGF-I deficiency (SPIGFD), the regulatory category
    that covers GHIS subtypes.
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:40626687
    reference_title: "Near-Adult Height Outcomes in Patients Treated With rhIGF-1 for Severe Growth Failure: Real-World IGFD Registry Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment in children and adolescents with severe growth failure due to
      severe primary IGF-I deficiency (SPIGFD)
    explanation: >-
      Identifies the IGFD registry (NCT00903110) as the real-world data source
      for rhIGF-1 outcomes in SPIGFD/GHIS.
discussions:
- discussion_id: knowledge_gap_stat5a_human_ghi
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#GH-IGF1 Axis Disruption
  prompt: >-
    Are biallelic (or dominant-negative) STAT5A variants a genuine human cause
    of growth hormone insensitivity, given that STAT5A cannot compensate for
    STAT5B loss but no disease-causing human STAT5A variants have yet been
    identified?
  rationale: >-
    STAT5A shares >95% identity with STAT5B and is activated by the same
    GHR-JAK2 cascade, yet the two paralogs are non-redundant. STAT5A is
    therefore a mechanistically plausible post-receptor GHIS node, but as of the
    key reviews human disease-causing STAT5A variants had not been reported, so
    the STAT5A subtype is included as a candidate pending human genetic
    confirmation. Targeted/exome sequencing of STAT5A in GHIS patients lacking
    GHR/STAT5B/IGFALS/IGF1/IGF1R variants, with functional testing of candidate
    variants for IGF1 transcriptional output, would resolve the gap.
  evidence:
  - reference: PMID:26703237
    reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Human mutations in STAT5A, as noted above, have yet to be identified.
    explanation: >-
      Confirms that human disease-causing STAT5A variants were not established,
      defining the knowledge gap.
notes: >-
  Scope: this entry models the GHIS root (MONDO:0015892) with molecular-cause
  subtypes per the MONDO definition (Laron/GHR, STAT5B, IGFALS/ALS, IGF1, IGF1R;
  plus candidate STAT5A). It is a distinct, broader entity from growth delay due
  to IGF-1 deficiency (MONDO:0012110), which is curated separately in
  kb/disorders/IGF1_Deficiency.yaml and itself lists growth hormone
  insensitivity syndrome as a parent; the IGF1 subtype here cross-references that
  entry rather than duplicating its detailed content. STAT5A/STAT5B subtype
  scoping coordinated with prior project discussion in monarch-initiative/dismech
  issue 1411 / PR 1424. No GeneReviews chapter specific to "growth hormone
  insensitivity syndrome" or Laron syndrome was found (PubMed searched 2026-06;
  re-confirmed against the committed index of every PubMed-indexed GeneReviews
  chapter, snapshot 2026-09-10, which holds no chapter for either name).
  PAPPA2 (impaired IGF-1 bioavailability) and IGF2/imprinting defects are part of
  the broader GHI/IGF spectrum but are intentionally out of scope for this root
  entry's requested subtype set.

  IUIS scope: the two STAT5B subtypes - and only those - are the entities listed
  in the IUIS 2022 inborn errors of immunity classification, Table 2 section 9
  (Other Defects), as two rows: "STAT5b deficiency" STAT5B AR 245590, and
  "STAT5b deficiency" STAT5B AD (dominant negative) 604260 (PMID:35748970). This
  entry therefore carries no entry-level iuis_category: GHIS as a whole is a
  growth-disorder root whose GHR, IGFALS, IGF1, and IGF1R arms are not inborn
  errors of immunity, and classifying the root would assert an immunodeficiency
  for all of them. The dedicated entry for the recessive arm now exists -
  kb/disorders/STAT5B_Deficiency.yaml, bound to MONDO:0100211 - and carries the
  immunologic detail and that classification; the STAT5B Deficiency row here is
  scoped to what distinguishes the subtype from the other arms, as the IGF1
  subtype is scoped against kb/disorders/IGF1_Deficiency.yaml. The
  dominant-negative arm (MONDO:0100219) has no dedicated entry and is curated
  here as the STAT5B Dominant-Negative subtype.

  MONDO anchoring of the subtype rows. All MONDO classes bound as
  has_subtypes[].subtype_term here are children of this entry's own
  MONDO:0015892 anchor: MONDO:0009877 Laron syndrome, MONDO:0012110,
  MONDO:0014420 and MONDO:0010038 directly, and MONDO:0100211 / MONDO:0100219
  through the intermediate class MONDO:0100210 growth hormone insensitivity
  syndrome with immune dysregulation. MONDO:0100210 is not bound separately: it
  has three children (MONDO:0100211, MONDO:0100219 and MONDO:1060224 STAT5
  haploinsufficiency, read from its OLS hierarchicalChildren on 2026-09-26), of
  which the two monogenic STAT5B forms are bound as subtype rows and the third is
  discussed below.

  A tension in MONDO:0014420's own text, recorded rather than resolved. Its
  Orphanet-derived definition describes acid-labile subunit deficiency as
  occurring "in the absence of growth hormone (GH) deficiency or GH
  insensitivity", while MONDO classifies it as a child of MONDO:0015892 growth
  hormone insensitivity syndrome. The endocrinology literature this entry cites
  supports the classification rather than the definition: PMID:23502138 states
  that defects in the GH-IGF-I axis "including mutations in the GHR, STAT5B and
  IGFALS genes, lead to postnatal IGF deficiency and GH insensitivity", and
  PMID:39060265 describes biallelic IGFALS variants as causing "growth hormone
  resistance with or without delayed puberty". The definition appears to be using
  "GH insensitivity" in the narrow receptor/post-receptor sense, in which ALS
  deficiency indeed does not qualify. The binding is kept; the discrepancy is
  noted so a later curator does not read it as a mis-parented term.

  STAT5A has no MONDO class of its own. Searched ols:mondo (synonym-inclusive)
  for "STAT5A", "STAT5", "STAT5A deficiency" and "signal transducer and activator
  of transcription 5A" on 2026-09-26. The only hit naming STAT5A is
  MONDO:1060224 STAT5 haploinsufficiency, defined as "haploinsufficient levels of
  STAT5 protein due to reduced copy number or expression of the STAT5A and/or
  STAT5B genes" - a joint copy-number condition with no RO:0004003 causal gene
  asserted, rather than a STAT5A-specific monogenic disease. It therefore does not
  anchor the candidate STAT5A subtype and is not bound. No `genetic:` record is
  created for STAT5A either: the row remains a mechanistically motivated
  candidate, and a causal gene-disease record would assert more than the evidence
  supports.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-4-8[1m] 21 citations 2026-06-30T08:46:50.776104

1. Disease Information

Overview. Growth Hormone Insensitivity Syndrome (Laron syndrome) is an autosomal recessive disorder of severe postnatal growth failure caused by the inability to generate insulin-like growth factor-1 (IGF-1) in response to growth hormone (GH). The defining biochemical hallmark is high or normal circulating GH with low serum IGF-1 that fails to rise on GH stimulation — i.e., the pituitary is intact but peripheral tissues are "deaf" to GH. It was first described by the Israeli pediatric endocrinologist Zvi Laron in 1966 in a series of consanguineous Yemenite Jewish families.

Key identifiers: - OMIM: #262500 (Laron syndrome / GH insensitivity, classic GHR-deficiency form); related loci/forms: GHR gene 600946; STAT5B GHI with immune dysregulation #245590 (GHISID1); IGFALS deficiency (ACLSD) #615961; IGF1 deficiency #608747; IGF1R resistance #270450. - MONDO: MONDO:0008638 (Laron syndrome). - Orphanet: ORPHA:633 (Growth hormone insensitivity syndrome / Laron syndrome). - ICD-10: E34.3 (Short stature due to endocrine disorder); ICD-11: 5A60.1 (Growth hormone insensitivity). - MeSH: D046150 "Laron Syndrome." - UMLS/SNOMED CT:* Laron-type dwarfism (e.g., SNOMED 237689005).

Synonyms / alternative names: Laron-type dwarfism; primary growth hormone insensitivity (GHI); growth hormone receptor deficiency (GHRD); Laron-type pituitary dwarfism; severe primary IGF-1 deficiency (SPIGFD — the regulatory/therapeutic term used in the mecasermin label); somatomedin deficiency.

Data derivation. The knowledge is aggregated from disease-level resources (OMIM, Orphanet, GeneReviews) and from a small number of deeply phenotyped cohorts of individual patients — principally the Israeli cohort (assembled by Zvi Laron from 1958; ~64 patients by 2009) and the southern Ecuadorian cohort (~100 individuals, studied by Jaime Guevara-Aguirre). It is not primarily an EHR-derived entity given its rarity.

Sources: OMIM #262500; OMIM *600946 GHR; MedlinePlus: Laron syndrome; NORD: Growth Hormone Insensitivity.

2. Etiology

Primary cause (genetic). Classic Laron syndrome results from biallelic (homozygous or compound heterozygous) loss-of-function mutations in GHR (growth hormone receptor gene, 5p13–p12). Over 70–100 distinct GHR mutations have been catalogued — deletions, nonsense, missense, and splice-site variants — predominantly affecting the extracellular hormone-binding domain, abolishing GH binding or receptor dimerization. Post-receptor and downstream defects (STAT5B, etc.) cause clinically overlapping GHI.

"Laron syndrome is caused by homozygous or compound heterozygous mutation in the growth hormone receptor gene (GHR; 600946)… Over 70 mutations of the GHR gene have been identified including deletions, missense and nonsense point mutations and splice site mutations." — OMIM #262500.

Genetic risk factors. - Causal variants: biallelic GHR LoF (most common). The canonical Ecuadorian founder allele is E180splice (exon 6 splice mutation, c.594A>G); the Israeli/Mediterranean cohorts carry other recurrent alleles. - Other causal genes (broader GHI spectrum): STAT5B (recessive and dominant-negative forms — GHI with immune dysregulation); IGFALS (acid-labile subunit deficiency — milder); IGF1 (IGF-1 deficiency with intrauterine growth restriction, microcephaly, deafness, intellectual disability); IGF1R (IGF-1 resistance); PAPPA2 (impaired IGF-1 bioavailability). A continuum of genetic, biochemical, and phenotypic severity exists across these genes (PMID:21525302). - Modifier loci: variation in IGFBP3, ALS, and the IGF1R axis modulate residual growth.

Environmental risk factors. No environmental cause — the disorder is monogenic. The dominant non-genetic risk factor is consanguinity / population isolation, which raises homozygosity for the recessive allele. Nutrition and intercurrent illness modify the severity of hypoglycemia and growth, not disease occurrence.

Protective factors. Not applicable to disease causation. Notably, the disease state itself is associated with downstream protection against cancer and type 2 diabetes (see §6/§11) — a "protective phenotype," not a protective factor against the disorder.

Gene–environment interactions. Caloric intake and recurrent fasting interact with the impaired counter-regulatory capacity (low IGF-1, enhanced insulin sensitivity) to provoke fasting/ketotic hypoglycemia, especially in infancy.

Sources: OMIM #262500; Genetic causes of GHI beyond GHR (PMC7979432); Genetic defects in the GH–IGF-I axis (PMC3356141); Continuum of GHI abnormalities, PMID:21525302.

3. Phenotypes

Phenotypes cluster into (a) severe proportionate short stature, (b) characteristic craniofacial/somatic features, (c) metabolic abnormalities, and (d) the biochemical signature.

Phenotype Type Onset Severity / course Frequency Suggested HPO
Severe proportionate short stature (often −4 to −10 SDS; adult height ~95–124 cm) Physical/growth Postnatal (birth length near-normal, then failure) Severe, lifelong Obligate (~100%) HP:0004322 Short stature; HP:0008897 Postnatal growth retardation
Low/undetectable serum IGF-1, unresponsive to GH Lab Congenital Severe, stable ~100% HP:0003575 (GH excess); HP:0008258 (decreased serum IGF-1)
Elevated/normal basal GH Lab Congenital — ~100% HP:0000824-related
Frontal bossing / saddle nose / "doll-like" facies, sparse hair Clinical sign Childhood Stable Frequent HP:0002007 Frontal bossing; HP:0000414 Bulbous nose
Hypoglycemia (fasting/ketotic), neonatal Lab/clinical Neonatal–infancy Episodic, can be severe Frequent HP:0001943 Hypoglycemia; HP:0001998 Neonatal hypoglycemia
Truncal/central obesity, increased body fat, reduced lean mass Physical Childhood→adult Progressive Frequent HP:0001513 Obesity; HP:0003712 (abnormal muscle)
Micropenis / small genitalia, delayed puberty Physical Childhood/adolescence Variable Frequent (males) HP:0000054 Micropenis; HP:0000823 Delayed puberty
High-pitched voice, hypoplastic larynx Sign Childhood Stable Frequent HP:0001620 High-pitched voice
Small hands/feet (acromicria), thin skin, limited elbow extension Physical Childhood Stable Frequent HP:0001167 Abnormal finger morphology; HP:0001238 (acromicria)
Delayed bone age, osteopenia, thin cortical bone Radiologic Childhood Progressive Frequent HP:0002750 Delayed skeletal maturation; HP:0000938 Osteopenia
Reduced muscle strength / hypotonia (infancy), motor delay Sign Infancy Improves with growth Variable HP:0001324 Muscle weakness
Blue sclerae, hip degeneration, sparse/thin hair Sign Variable Stable/progressive Occasional HP:0000592 Blue sclerae
STAT5B subtype only: eczema, pulmonary disease, recurrent infection (immune dysregulation) Clinical Childhood Progressive Subtype-defining HP:0002721 Immunodeficiency; HP:0000964 Eczema

Onset/severity/progression generalities: Birth size is near-normal (IGF-1 prenatally is only partly GH-dependent), with dramatic postnatal growth failure. Short stature is non-progressive but permanent; metabolic features (obesity, insulin sensitivity) evolve over the lifespan.

Quality-of-life impact. Marked short stature affects psychosocial functioning, education/employment, and (structurally) injury risk from falls; obesity and skeletal fragility add morbidity. Cognition is generally normal in classic GHR-deficiency Laron syndrome (in contrast to IGF1-gene defects, which cause intellectual disability and deafness).

Sources: OMIM #262500; Laron syndrome review, In Vivo 2016; Brazilian Laron series, PMC7197995.

4. Genetic / Molecular Information

Causal gene — GHR (HGNC:4263; OMIM *600946; chromosome 5p13–p12). Encodes a 620-aa single-pass transmembrane cytokine-receptor-superfamily protein with an extracellular GH-binding domain (the proteolytically shed portion forms serum GH-binding protein, GHBP), a transmembrane domain, and an intracellular domain coupling to JAK2/STAT5.

Pathogenic variants: - Type/class: the full mutational spectrum — large/partial gene deletions, nonsense, missense (esp. extracellular domain, e.g., disrupting disulfide bonds or dimerization), splice-site (the Ecuadorian E180 splice founder allele), and intronic/pseudoexon variants. Dominant-negative GHR variants in the transmembrane/intracellular region cause milder dominant GHI. - Classification (ACMG/AMP): recurrent founder alleles are classified Pathogenic in ClinVar; many private missense variants are Likely Pathogenic/VUS pending functional data. - Allele frequency: individually ultra-rare in gnomAD; enriched only in founder populations (southern Ecuador, Mediterranean/Middle Eastern consanguineous groups). - Origin: germline, biallelic (recessive). No somatic role. - Functional consequence: loss of function — failure of GH binding, receptor dimerization, or JAK2/STAT5 signal transduction → no IGF-1 transcription. GHBP is low/absent when the defect is in the extracellular domain (a useful biochemical discriminator) but normal/high in transmembrane/intracellular and post-receptor (STAT5B) defects.

Downstream-axis genes (broader GHI): STAT5B (HGNC:11367) — recessive LoF and dominant-negative; IGFALS (HGNC:5466); IGF1 (HGNC:5464); IGF1R (HGNC:5465); PAPPA2 (HGNC:8602). Mechanistic split: IGF-1 deficiency (GHR, STAT5B, IGF1), IGF-1 bioavailability (IGFALS, PAPPA2), IGF-1 resistance (IGF1R).

"Mutations in a number of components along this axis result in GHI and IGF deficiency (STAT5B, IGF1), IGF bioavailability (IGFALS, PAPPA2) or IGF resistance (IGF1R)." — Genetic causes of GHI beyond GHR (PMC7979432).

Modifier genes. Polymorphisms/variants in IGFBP3, IGFALS, and the IGF1R pathway modulate residual linear growth and treatment response.

Epigenetics. No established primary epigenetic mechanism in classic Laron syndrome. Of note, genome-wide profiling of Laron patients identified novel cancer-protection transcriptional/methylation pathways (e.g., differential expression of genes regulating apoptosis, DNA repair, and metabolism) — relevant to the protective phenotype rather than disease causation.

Chromosomal abnormalities. Large multi-exon/whole-GHR deletions occur; otherwise no recurrent aneuploidy or translocation.

Sources: OMIM *600946; GHI beyond GHR (PMC7979432); Dominant-negative STAT5B (PMC5974024); Genome-wide profiling of Laron patients (PMC6627189).

5. Environmental Information

  • Environmental factors: none causal. The disorder is fully penetrant monogenic.
  • Lifestyle factors: diet and fasting interact with the metabolic phenotype (hypoglycemia risk in infancy; obesity in later life), but do not cause or prevent the disorder.
  • Infectious agents: not applicable to classic GHR-deficiency. (In the STAT5B subtype, recurrent infections are a consequence of immune dysregulation, not a trigger.)

Source: MedlinePlus: Laron syndrome.

6. Mechanism / Pathophysiology

Core causal chain (upstream → downstream):

  1. Biallelic GHR loss of function (upstream trigger) → GH cannot bind/signal at target cells (chiefly hepatocytes).
  2. Failure of JAK2–STAT5B signal transduction. Normally, GH binding induces GHR dimerization → JAK2 activation → STAT5B tyrosine phosphorylation, homodimerization, nuclear translocation, and transcription of IGF1, IGFBP3, and IGFALS.

    "Recruited STAT5B is tyrosine phosphorylated by JAK2, homodimerizes, and translocate[s] to the nucleus, where it binds DNA, regulating production of circulating IGF-I, IGFBP-3 and ALS." — PMC7979432.

  3. Hepatic IGF-1 (and IGFBP-3, ALS) production collapses → low circulating IGF-1; the ternary complex (IGF-1/IGFBP-3/ALS) that stabilizes serum IGF-1 is depleted.
  4. Loss of negative feedback — IGF-1 normally restrains pituitary GH secretion; its absence causes GH hypersecretion (the paradoxical "high GH, low IGF-1" signature).
  5. Downstream phenotype: loss of IGF-1–driven chondrocyte proliferation at the growth plate → severe postnatal linear growth failure; reduced anabolic signaling → altered body composition; impaired counter-regulation → hypoglycemia.

Molecular pathways: GH/GHR → JAK2–STAT5B (canonical), with secondary involvement of PI3K–AKT–mTOR and RAS–MAPK downstream of IGF-1/IGF1R. The disorder is fundamentally a JAK-STAT signaling defect (KEGG/Reactome: GH receptor signaling; JAK-STAT pathway; IGF-1 receptor signaling).

Cellular processes: reduced chondrocyte and osteoblast proliferation (growth plate); altered adipocyte and myocyte anabolism (obesity, sarcopenia); in the protective phenotype, reduced pro-aging signaling, increased apoptosis of damaged cells, and reduced oxidative DNA damage.

"Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide… [GHRD subjects had] only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control[s]." — Guevara-Aguirre et al., Sci Transl Med 2011 (PMID:21325617).

Protein dysfunction: loss of function of the GH receptor (or, in subtypes, of STAT5B as a transcription factor). Extracellular-domain mutants fail to bind GH and reduce serum GHBP; transmembrane/intracellular mutants may bind GH but fail to signal.

Metabolic changes: markedly enhanced insulin sensitivity (low IGF-1 → reduced lipolytic/diabetogenic GH-axis output relative to IGF-1 feedback) despite obesity; tendency to fasting hypoglycemia in infancy; reduced IGF-1–mediated lipid handling.

Immune involvement: none in classic GHR deficiency; central to the STAT5B subtype (STAT5B is also required for regulatory T-cell and NK function → eczema, lymphocytic interstitial pneumonitis, autoimmunity, recurrent infection).

Tissue damage mechanisms: primarily developmental/anabolic deficit rather than active tissue destruction; skeletal fragility (osteopenia) is a downstream consequence.

Molecular profiling: transcriptomic/genome-wide profiling of Laron patient cells shows differential regulation of cancer-, apoptosis-, and metabolism-related genes underpinning the cancer-protective phenotype (PMC6627189).

Suggested ontology terms: - GO biological process: GO:0060396 growth hormone receptor signaling pathway; GO:0007259 receptor signaling pathway via JAK-STAT; GO:0048009 IGF receptor signaling pathway; GO:0040007 growth; GO:0035556 intracellular signal transduction. - CL cell types: CL:0000182 hepatocyte; CL:0000138 chondrocyte; CL:0000062 osteoblast; CL:0000136 adipocyte; CL:0000084 T cell (STAT5B subtype). - CHEBI: CHEBI:37845 (somatotropin/GH); IGF-1 (peptide hormone); CHEBI for mecasermin/IGF-1 therapeutic.

Sources: Guevara-Aguirre 2011, PMID:21325617; GHI beyond GHR (PMC7979432); Genome-wide profiling (PMC6627189).

7. Anatomical Structures Affected

  • Organ/system level:
  • Endocrine system (primary) — GH–IGF-1 (somatotropic) axis; pituitary (GH hypersecretion), liver (principal failed IGF-1 source).
  • Musculoskeletal system — growth plate / long bones (UBERON:0006255 growth plate; UBERON:0002481 bone tissue), reduced bone mass, small hands/feet, limited joint extension, hip degeneration.
  • Reproductive — small genitalia/micropenis, delayed puberty.
  • Integumentary — thin skin, sparse hair.
  • Body composition — increased adipose tissue, reduced skeletal muscle.
  • STAT5B subtype: lungs (interstitial disease), immune organs.
  • Tissue/cell level: growth-plate chondrocytes (CL:0000138), osteoblasts (CL:0000062), hepatocytes (CL:0000182), adipocytes (CL:0000136).
  • Subcellular level: plasma membrane (GHR; GO:0005886); cytoplasm/JAK2 docking; nucleus (STAT5B-mediated transcription; GO:0005634).
  • Localization / lateralization: systemic and bilateral/symmetric (a generalized endocrine signaling defect, not focal).

Suggested UBERON terms: UBERON:0006255 (growth plate); UBERON:0002107 (liver); UBERON:0000007 (pituitary gland); UBERON:0002481 (bone tissue); UBERON:0001013 (adipose tissue).

8. Temporal Development

  • Onset: congenital (genetic) with postnatal clinical emergence. Birth length is near-normal; growth failure becomes evident within the first 1–2 years. Neonatal hypoglycemia and micropenis can present in the newborn period.
  • Onset pattern: chronic/insidious for growth; episodic for hypoglycemia.
  • Progression / stages: infancy (hypoglycemia, growth failure, hypotonia) → childhood (established severe short stature, characteristic facies) → adolescence (delayed puberty, eventual spontaneous but delayed sexual maturation) → adulthood (final short stature, central obesity, insulin sensitivity, osteopenia). Short stature is permanent and non-progressive once growth ceases; metabolic features evolve.
  • Course: chronic, lifelong, stable (not relapsing-remitting). No spontaneous remission.
  • Critical window for intervention: early childhood, before growth-plate fusion — rhIGF-1 therapy started young yields the greatest height benefit; benefit falls sharply after puberty/epiphyseal closure.

Sources: OMIM #262500; Near-adult height IGFD registry, PMID:40626687.

9. Inheritance and Population

Epidemiology. - Prevalence: ultra-rare, estimated ~1–9 per 1,000,000. Roughly 350 patients described worldwide (with substantial under-diagnosis likely). - Geographic clustering: two large founder cohorts — southern Ecuador (~100 individuals, the world's largest cluster) and Israel/Mediterranean (~64–69 individuals); additional cases in Brazil, Chile, Mexico, and the broader Middle East. Genetic evidence links several New World/Mediterranean cohorts to a common ancestral (likely Sephardic converso) origin.

Genetic transmission (classic GHR deficiency): - Inheritance: autosomal recessive (dominant GHI exists with dominant-negative GHR or STAT5B variants but is milder). - Penetrance: essentially complete for biallelic LoF. - Expressivity: variable (final height spans roughly −4 to −10 SDS depending on allele/genetic background). - Anticipation: none (not a repeat-expansion disorder). - Germline mosaicism: not a recognized feature. - Founder effects: prominent — the Ecuadorian E180 splice allele and Mediterranean recurrent alleles. - Consanguinity: a major driver of homozygosity and regional clustering. - Carrier frequency: elevated only within founder/consanguineous populations; negligible in the general population.

Demographics: - Affected populations: enriched in southern Ecuadorian, Sephardic/Mediterranean Jewish, Middle Eastern, and other consanguineous communities. - Sex ratio: roughly equal (1:1) — autosomal; males are more clinically conspicuous (micropenis). - Age distribution: diagnosed in infancy/early childhood; cohorts now include long-surviving adults.

Sources: OMIM #262500; MedlinePlus; In Vivo 2016 clinical/molecular review; Zvi Laron / cohort history (Healio).

10. Diagnostics

Biochemical (the cornerstone): - Low serum IGF-1 (often undetectable) with normal or elevated basal GH (LOINC: IGF-1 [e.g., 2484-4]; GH). - Failure of IGF-1 to rise on IGF-1 generation test (GH stimulation) — the functional confirmatory test distinguishing GHI from GH deficiency. - Low IGFBP-3 and low ALS (acid-labile subunit). - Low/absent GHBP (growth hormone–binding protein) — supports an extracellular-domain GHR defect; normal GHBP points to transmembrane/intracellular or post-receptor (STAT5B) causes. - Ancillary: fasting hypoglycemia, low fasting glucose with relatively high insulin sensitivity; elevated cholesterol in some.

Imaging / functional: - Bone-age radiograph (delayed); skeletal survey shows thin cortices, small facial bones. - DXA — osteopenia/low bone mass. - Pituitary MRI typically normal (distinguishes from organic GH deficiency).

Genetic testing (confirmatory): - Single-gene GHR sequencing (first-line when the phenotype/biochemistry is classic) including deletion/duplication analysis (MLPA) for whole/partial-gene deletions. - Targeted GHI/short-stature gene panel (GHR, STAT5B, IGFALS, IGF1, IGF1R, PAPPA2) when GHBP is normal or features (immune dysregulation, microcephaly/deafness) suggest a downstream cause. - WES/WGS for atypical/unsolved cases. - Chromosomal microarray to exclude deletions overlapping GHR.

Clinical criteria (Laron/consensus, simplified): severe short stature (height ≤ −3 SDS) + low IGF-1 + normal/high GH + subnormal IGF-1 response to GH, with supportive low IGFBP-3/ALS/GHBP.

Differential diagnosis: - GH deficiency (low GH and low IGF-1; responds to GH — opposite GH pattern). - Malnutrition / chronic illness / poorly controlled diabetes / hepatic disease (acquired low IGF-1). - GH gene/biologically inactive GH variants. - IGF-1 / IGF1R / IGFALS / PAPPA2 defects (distinguished by panel + GHBP, IGFBP-3/ALS, IGF-1 levels — IGF1R defects show high IGF-1). - Secondary (acquired) GH insensitivity — antibodies, systemic disease.

Screening: no population newborn screening; cascade carrier testing and prenatal/preimplantation genetic testing are offered in known founder families via genetic counseling.

Sources: GHI beyond GHR (PMC7979432); OMIM #262500; Brazilian series, PMC7197995.

11. Outcome / Prognosis

Survival / mortality. Life expectancy is generally near-normal. In the Ecuadorian cohort, lifespan is comparable to unaffected relatives; accidents and alcohol-related deaths (with structural vulnerability to falls) are leading causes — not cancer or cardiovascular disease.

"The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects." — Guevara-Aguirre 2011 (PMID:21325617).

Morbidity / function. Untreated: severe short stature with attendant functional/psychosocial impact; obesity; osteopenia/fractures; hip degeneration. Cognition is normal in classic GHR deficiency. A striking feature is the protective metabolic phenotype — near-absence of type 2 diabetes and very low cancer incidence, attributed to lifelong low IGF-1/reduced pro-aging signaling; some data also suggest cognitive/memory advantages.

Disease course / complications. Hypoglycemia (infancy), obesity-related metabolic features (despite preserved insulin sensitivity), skeletal fragility; for the STAT5B subtype, immune complications (interstitial lung disease, recurrent infection, autoimmunity) can be life-threatening.

Prognostic factors for growth outcome. Age at rhIGF-1 initiation (earlier = better), baseline height SDS, genotype/residual signaling, treatment adherence, and pubertal status.

Sources: Guevara-Aguirre 2011, PMID:21325617; Scientific American summary; USC memory study.

12. Treatment

Pharmacotherapy — the mainstay: recombinant human IGF-1 (rhIGF-1, mecasermin / Increlex). - Mechanism: bypasses the receptor/signaling block by directly supplying IGF-1, restoring growth-plate signaling. GH itself is ineffective (the defect is GH resistance). - Regulatory status: FDA-approved (2005) and EMA-approved for long-term treatment of growth failure in severe primary IGF-1 deficiency (SPIGFD), including Laron syndrome. A combination product (mecasermin rinfabate, IGF-1 + IGFBP-3) was previously available. - Dosing: twice-daily subcutaneous injection, titrated; administer with meals to avoid hypoglycemia.

"Mecasermin, recombinant human IGF-1, is … FDA-approved for the long-term treatment of growth failure in children with severe primary IGF-I deficiency (Laron syndrome)." — NCBI/CADTH review.

  • Efficacy: height velocity rises markedly in the first year (early trials: ~7.8–8.4 cm/yr in the first 6 months, PMID:8334752); real-world IGFD registry data confirm improved near-adult height, though gains are less than in GH-treated GH-deficient children and are blunted by late start (PMID:40626687). A 22-year Saudi cohort confirms long-term height benefit and safety.
  • Adverse events: hypoglycemia (most important — dose with food), lipohypertrophy at injection sites, tonsillar/adenoid hypertrophy, intracranial hypertension, slipped capital femoral epiphysis, and theoretical long-term neoplasia/IGF-1–driven concerns (monitored). In trials, ~83% had ≥1 adverse event.

Supportive / adjunctive care. - Treat/prevent hypoglycemia (frequent feeds in infancy). - Manage obesity and metabolic features; monitor bone health. - Endocrine management of puberty as needed. - STAT5B subtype: management of immune dysregulation/interstitial lung disease (immunomodulation, infection prophylaxis).

Surgical/interventional: none disease-specific (orthopedic/hip management as needed).

Experimental / future: gene-axis–directed approaches and improved IGF-1 formulations are areas of interest; no gene therapy is established. (Search ClinicalTrials.gov for active SPIGFD/mecasermin studies.)

Pharmacogenomics / personalized medicine: genotype (GHR vs downstream gene) and GHBP status guide whether IGF-1 replacement (vs other approaches) is rational; IGF1R-defect patients respond poorly to IGF-1 (resistance, not deficiency).

Suggested MAXO terms: MAXO:0000058-type pharmacotherapy / hormone replacement therapy; MAXO:0000088 dietary intervention (hypoglycemia prevention); MAXO:0000079 genetic counseling; MAXO:0000950 supportive care. (Verify exact MAXO IDs with OAK before curation.) CHEBI/therapeutic agent: mecasermin (recombinant IGF-1) — bind via NCIT (e.g., NCIT mecasermin) if no CHEBI term.

Sources: Mecasermin clinical/pharmacoeconomic reviews (NCBI Bookshelf NBK596664/NBK596662); Early rhIGF-1 trial, PMID:8334752; Near-adult height IGFD registry, PMID:40626687; 22-year Saudi cohort (Karger, 2025); NHS England mecasermin policy.

13. Prevention

  • Primary prevention: not preventable (monogenic). Genetic counseling for at-risk/consanguineous families and known founder communities is the principal preventive measure; carrier and cascade testing identify at-risk couples.
  • Reproductive options: prenatal diagnosis and preimplantation genetic testing (PGT) where the familial variant is known.
  • Secondary prevention (early detection): prompt biochemical workup (IGF-1, GH, GHBP) in infants with early growth failure + hypoglycemia enables early diagnosis and timely rhIGF-1 initiation within the critical growth window.
  • Tertiary prevention (complication prevention): dosing rhIGF-1 with meals to prevent hypoglycemia; metabolic/bone monitoring; for STAT5B subtype, infection prophylaxis and pulmonary surveillance.
  • Immunization / public health / environmental: not applicable (no infectious or environmental etiology).

Sources: MedlinePlus; [GeneReviews/Orphanet genetic-counseling guidance].

14. Other Species / Natural Disease

  • Taxonomy: humans (NCBITaxon:9606). The GHR gene and GH–IGF-1 axis are deeply conserved across vertebrates.
  • Orthologous genes: Ghr in mouse (NCBI Gene 14600), rat, and other mammals; orthologs in zebrafish, chicken, cattle, etc.
  • Naturally occurring / engineered animal disease:
  • Mouse: the GHR-knockout ("Laron mouse," Ghr⁻/⁻) is the canonical model — dwarfism, low IGF-1, high GH, obesity, enhanced insulin sensitivity, reduced cancer, and extended lifespan (one of the longest-lived laboratory mouse lines).
  • Cattle/poultry: GHR variants underlie growth/dwarf phenotypes (e.g., sex-linked dwarfism in chickens maps to GHR; bovine GHR polymorphisms affect stature/milk).
  • Dogs/companion animals: GH-axis growth disorders are recognized in veterinary endocrinology (OMIA catalogues GH/IGF-axis traits across species).
  • Comparative biology: the conserved GH→JAK2/STAT5→IGF-1 cascade means model phenotypes (dwarfism + metabolic protection + longevity) closely mirror human Laron syndrome, making it a leading model for aging and cancer-protection research (the GH/IGF-1 longevity axis).
  • Transmission / zoonosis: none (genetic, non-communicable).

Suggested terms: NCBITaxon:9606 (human), NCBITaxon:10090 (mouse); OMIA for veterinary GHR phenotypes; VBO for affected breeds (e.g., chicken dwarf lines).

Sources: Guevara-Aguirre 2011, PMID:21325617 (links human to long-lived Ghr−/− mouse); comparative GH/IGF-1 longevity literature (e.g., Bartke/Coschigano Ghr-KO studies).

15. Model Organisms

  • Model types: mammalian (mouse, rat), with cellular/in-vitro systems from patient-derived material; zebrafish and cattle/poultry for comparative growth genetics.
  • Flagship genetic model — the GHR-knockout / "Laron mouse" (Ghr⁻/⁻):
  • Types available: global knockout, plus tissue-specific/conditional (e.g., liver-specific Ghr knockout to dissect hepatic IGF-1's role) and humanized/knock-in lines.
  • Phenotype recapitulation (excellent): proportionate dwarfism, very low IGF-1, elevated GH, increased adiposity, enhanced insulin sensitivity, reduced cancer incidence, and markedly extended lifespan — faithfully mirroring the human metabolic/longevity/cancer-protection phenotype.
  • Limitations: murine craniofacial/skeletal proportions and the human-specific psychosocial dimension are not captured; the dramatic murine lifespan extension is more pronounced than the (near-normal) human lifespan, so longevity translation must be made cautiously.
  • Patient-derived in vitro models: Laron-serum and patient-cell assays demonstrated reduced oxidative DNA damage and increased apoptosis of stressed cells, and genome-wide profiling identified candidate cancer-protection pathways (PMC6627189) — key for the protective-phenotype mechanism.
  • Applications: dissecting GH–IGF-1 signaling, aging/longevity biology, cancer chemoprevention, insulin sensitivity/diabetes, and rhIGF-1 pharmacology.
  • Resources/databases: MGI / IMPC / KOMP (mouse Ghr alleles), Alliance of Genome Resources, OMIA (cross-species GHR phenotypes), Cellosaurus (patient cell lines).

Sources: Guevara-Aguirre 2011, PMID:21325617; Genome-wide profiling of Laron patients (PMC6627189); Bartke/Coschigano Ghr-KO longevity literature (MGI).

Summary of Key Curation Anchors (for the dismech entry)

  • MONDO: MONDO:0008638 · OMIM: #262500 · Orphanet: ORPHA:633 · Category: Mendelian (autosomal recessive).
  • Causal gene: GHR (HGNC:4263); broader axis: STAT5B, IGFALS, IGF1, IGF1R, PAPPA2.
  • Central mechanism: biallelic GHR LoF → failed JAK2–STAT5B signaling → hepatic IGF-1 deficiency with loss of GH negative feedback (high GH, low IGF-1) → growth-plate chondrocyte failure → severe postnatal short stature; plus a protective metabolic phenotype (low cancer/diabetes).
  • Biochemical signature for definitions block: low IGF-1 + normal/high GH + subnormal IGF-1-generation response + low IGFBP-3/ALS ± low GHBP.
  • Treatment: rhIGF-1 (mecasermin) replacement (MAXO pharmacotherapy / hormone replacement); GH is ineffective.
  • Landmark evidence PMIDs: 21325617 (cancer/diabetes protection, Sci Transl Med), 8334752 (early rhIGF-1 efficacy), 40626687 (near-adult height registry), 21525302 (GHI continuum), plus STAT5B (PMC5974024) and cancer-protection pathways (PMC6627189).

Sources

Curation caveats for dismech: Per the project SOP, every PMID and snippet above must be re-verified with just fetch-reference and just validate-references before entry — treat this report as leads, not ground truth. In particular, confirm exact HPO/GO/CL/UBERON/MAXO/CHEBI IDs with OAK (runoak ... info), and run the NEC preflight against MONDO:0008638 (causal gene = GHR; OMIM 262500) given the GHI/Laron name-and-synonym overlap with the downstream-gene GHI subtypes. Frequency bands (Frequent/Occasional) are qualitative estimates here and need their own quantitative evidence before being committed with a frequency: value.