Growth hormone insensitivity with immune dysregulation 1, autosomal recessive

Summary

Growth hormone insensitivity with immune dysregulation 1, autosomal recessive (MONDO:0100211) is a disease caused by STAT5B (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: STAT5B (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 516

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	growth hormone insensitivity with immune dysregulation 1, autosomal recessive
Mondo ID	MONDO:0100211
MeSH	C537871
OMIM	245590
Orphanet	220465
DOID	DOID:0080836
SNOMED CT	724179008
UMLS	C5435698
MedGen	1734133
GARD	0018311
Is cancer (heuristic)	no

Also known as: growth hormone insensitivity due to postreceptor defect · Laron syndrome due to postreceptor defect · Laron syndrome with immunodeficiency · Laron-like syndrome · short stature due to STAT5b deficiency

Data availability: 516 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › growth hormone insensitivity with immune dysregulation 1, autosomal recessive

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

516 retrieved; paginated sample, class counts are floors:

234 likely benign, 225 uncertain significance, 25 pathogenic, 12 conflicting classifications of pathogenicity, 10 benign, 6 benign/likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074067	NM_012448.4(STAT5B):c.121C>T (p.Gln41Ter)	STAT5B	Pathogenic	criteria provided, single submitter
1394582	NM_012448.4(STAT5B):c.2065G>T (p.Glu689Ter)	STAT5B	Pathogenic	criteria provided, single submitter
1408216	NM_012448.4(STAT5B):c.424_427del (p.Leu142fs)	STAT5B	Pathogenic	criteria provided, multiple submitters, no conflicts
1453821	NM_012448.4(STAT5B):c.1009C>T (p.Gln337Ter)	STAT5B	Pathogenic	criteria provided, single submitter
1686232	NM_012448.4(STAT5B):c.1718G>A (p.Trp573Ter)	STAT5B	Pathogenic	criteria provided, single submitter
2003395	NM_012448.4(STAT5B):c.415C>T (p.Gln139Ter)	STAT5B	Pathogenic	criteria provided, single submitter
2018391	NM_012448.4(STAT5B):c.16C>T (p.Gln6Ter)	STAT5B	Pathogenic	criteria provided, single submitter
2119313	NM_012448.4(STAT5B):c.1749del (p.Lys583fs)	STAT5B	Pathogenic	criteria provided, single submitter
2425815	NC_000017.10:g.(?40371710)(40371880_?)del	STAT5B	Pathogenic	criteria provided, single submitter
2739237	NM_012448.4(STAT5B):c.89_90dup (p.Arg31fs)	STAT5B	Pathogenic	criteria provided, single submitter
2840836	NM_012448.4(STAT5B):c.1213_1229del (p.Tyr405fs)	STAT5B	Pathogenic	criteria provided, single submitter
2852676	NM_012448.4(STAT5B):c.303C>A (p.Cys101Ter)	STAT5B	Pathogenic	criteria provided, single submitter
2869095	NM_012448.4(STAT5B):c.1906C>T (p.Gln636Ter)	STAT5B	Pathogenic	criteria provided, single submitter
3384021	NM_012448.4(STAT5B):c.1892G>A (p.Trp631Ter)	STAT5B	Pathogenic	criteria provided, single submitter
3641526	NM_012448.4(STAT5B):c.245del (p.Leu82fs)	STAT5B	Pathogenic	criteria provided, single submitter
4718768	NM_012448.4(STAT5B):c.240_241del (p.Leu82fs)	STAT5B	Pathogenic	criteria provided, single submitter
4804939	NM_012448.4(STAT5B):c.1183G>T (p.Glu395Ter)	STAT5B	Pathogenic	criteria provided, single submitter
492931	NM_012448.4(STAT5B):c.1421A>G (p.Gln474Arg)	STAT5B	Pathogenic	no assertion criteria provided
522611	NM_012448.4(STAT5B):c.530A>C (p.Gln177Pro)	STAT5B	Pathogenic	no assertion criteria provided
5694	NM_012448.4(STAT5B):c.1888G>C (p.Ala630Pro)	STAT5B	Pathogenic	no assertion criteria provided
5695	NM_012448.4(STAT5B):c.1191dup (p.Asn398fs)	STAT5B	Pathogenic	no assertion criteria provided
5697	NM_012448.4(STAT5B):c.454C>T (p.Arg152Ter)	STAT5B	Pathogenic	no assertion criteria provided
5698	NM_012448.4(STAT5B):c.1680+1del	STAT5B	Pathogenic	no assertion criteria provided
579749	NM_012448.4(STAT5B):c.1102dup (p.Gln368fs)	STAT5B	Pathogenic	criteria provided, multiple submitters, no conflicts
840661	NM_012448.4(STAT5B):c.1102del (p.Gln368fs)	STAT5B	Pathogenic	criteria provided, single submitter
3390963	NM_020207.7(ERCC6L2):c.2158_2159dup (p.Pro721fs)	ERCC6L2	Likely pathogenic	criteria provided, single submitter
1066569	NM_012448.4(STAT5B):c.1906+1G>A	STAT5B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2955379	NM_012448.4(STAT5B):c.1681-2A>G	STAT5B	Likely pathogenic	criteria provided, single submitter
3390965	NM_012448.4(STAT5B):c.621G>C (p.Lys207Asn)	STAT5B	Likely pathogenic	criteria provided, single submitter
1122056	NM_012448.4(STAT5B):c.177G>A (p.Gln59=)	STAT5B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
STAT5B	Definitive	Semidominant	growth hormone insensitivity syndrome with immune dysregulation	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAT5B	Orphanet:220465	Laron syndrome with immunodeficiency
STAT5B	Orphanet:520	Acute promyelocytic leukemia
ERCC6L2	Orphanet:319465	Inherited acute myeloid leukemia
ERCC6L2	Orphanet:401764	Pancytopenia-developmental delay syndrome
CAVIN1	Orphanet:228429	Congenital generalized lipodystrophy type 4

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STAT5B	HGNC:11367	ENSG00000173757	P51692	Signal transducer and activator of transcription 5B	gencc,clinvar
ERCC6L2	HGNC:26922	ENSG00000182150	Q5T890	DNA excision repair protein ERCC-6-like 2	clinvar
CAVIN1	HGNC:9688	ENSG00000177469	Q6NZI2	Caveolae-associated protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAT5B	Signal transducer and activator of transcription 5B	Carries out a dual function: signal transduction and activation of transcription.
ERCC6L2	DNA excision repair protein ERCC-6-like 2	Promotes double-strand break (DSB) end-joining and facilitates programmed recombination by controlling how DNA ends are joined in a spatially oriented manner during repair.
CAVIN1	Caveolae-associated protein 1	Plays an important role in caveolae formation and organization.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT5B	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
ERCC6L2	Other/Unknown	no		SNF2_N, Helicase_C-like, DNA/RNA_helicase_DEAH_CS
CAVIN1	Other/Unknown	no		Cavin_fam

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
body of uterus	1
left uterine tube	1
Brodmann (1909) area 23	1
endothelial cell	1
epithelial cell of pancreas	1
popliteal artery	1
right coronary artery	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAT5B	295	ubiquitous	marker	blood, body of uterus, left uterine tube
ERCC6L2	255	ubiquitous	marker	epithelial cell of pancreas, Brodmann (1909) area 23, endothelial cell
CAVIN1	281	ubiquitous	marker	right coronary artery, tendon of biceps brachii, popliteal artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT5B	3,986
ERCC6L2	2,705
CAVIN1	2,304

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAVIN1	Q6NZI2	3
STAT5B	P51692	2
ERCC6L2	Q5T890	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Erythropoietin activates STAT5	1	815.7×	0.009	STAT5B
STAT5 Activation	1	815.7×	0.009	STAT5B
Interleukin-9 signaling	1	634.4×	0.009	STAT5B
FGFR1 mutant receptor activation	1	571.0×	0.009	STAT5B
Interleukin-21 signaling	1	571.0×	0.009	STAT5B
Signaling by KIT in disease	1	571.0×	0.009	STAT5B
FLT3 signaling in disease	1	571.0×	0.009	STAT5B
STAT5 activation downstream of FLT3 ITD mutants	1	571.0×	0.009	STAT5B
Signaling by Leptin	1	519.1×	0.009	STAT5B
Signaling by Erythropoietin	1	519.1×	0.009	STAT5B
Interleukin-2 signaling	1	475.8×	0.009	STAT5B
Prolactin receptor signaling	1	380.7×	0.009	STAT5B
Interleukin-15 signaling	1	380.7×	0.009	STAT5B
Signaling by FLT3 ITD and TKD mutants	1	380.7×	0.009	STAT5B
Signaling by cytosolic FGFR1 fusion mutants	1	317.2×	0.009	STAT5B
Interleukin-2 family signaling	1	317.2×	0.009	STAT5B
Signaling by CSF3 (G-CSF)	1	285.5×	0.009	STAT5B
Signaling by FLT3 fusion proteins	1	285.5×	0.009	STAT5B
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	259.6×	0.010	STAT5B
Growth hormone receptor signaling	1	237.9×	0.010	STAT5B
Inactivation of CSF3 (G-CSF) signaling	1	219.6×	0.010	STAT5B
Signaling by FGFR in disease	1	211.5×	0.010	STAT5B
Interleukin-20 family signaling	1	211.5×	0.010	STAT5B
Downstream signal transduction	1	190.3×	0.010	STAT5B
FLT3 Signaling	1	173.0×	0.011	STAT5B
RNA Polymerase I Transcription Termination	1	163.1×	0.011	CAVIN1
Interleukin-7 signaling	1	158.6×	0.011	STAT5B
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	158.6×	0.011	STAT5B
Signaling by FGFR1 in disease	1	146.4×	0.011	STAT5B
RNA Polymerase I Transcription	1	142.8×	0.011	CAVIN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to interleukin-15	1	2808.7×	0.005	STAT5B
termination of RNA polymerase I transcription	1	1872.4×	0.005	CAVIN1
development of animal secondary female sexual characteristics	1	1872.4×	0.005	STAT5B
development of animal secondary male sexual characteristics	1	1872.4×	0.005	STAT5B
response to interleukin-2	1	1872.4×	0.005	STAT5B
mast cell migration	1	1872.4×	0.005	STAT5B
response to interleukin-4	1	1404.3×	0.005	STAT5B
natural killer cell proliferation	1	1123.5×	0.005	STAT5B
taurine metabolic process	1	936.2×	0.005	STAT5B
erythropoietin-mediated signaling pathway	1	936.2×	0.005	STAT5B
regulation of steroid metabolic process	1	802.5×	0.005	STAT5B
myeloid cell apoptotic process	1	702.2×	0.005	STAT5B
gamma-delta T cell differentiation	1	702.2×	0.005	STAT5B
Peyer’s patch development	1	702.2×	0.005	STAT5B
luteinization	1	624.1×	0.005	STAT5B
transcription initiation at RNA polymerase I promoter	1	624.1×	0.005	CAVIN1
regulation of epithelial cell differentiation	1	624.1×	0.005	STAT5B
negative regulation of myeloid cell apoptotic process	1	624.1×	0.005	STAT5B
positive regulation of gamma-delta T cell differentiation	1	624.1×	0.005	STAT5B
activated T cell proliferation	1	624.1×	0.005	STAT5B
positive regulation of natural killer cell differentiation	1	561.7×	0.005	STAT5B
progesterone metabolic process	1	561.7×	0.005	STAT5B
double-strand break repair via classical nonhomologous end joining	1	561.7×	0.005	ERCC6L2
negative regulation of erythrocyte differentiation	1	510.7×	0.005	STAT5B
growth hormone receptor signaling pathway via JAK-STAT	1	510.7×	0.005	STAT5B
positive regulation of natural killer cell proliferation	1	468.1×	0.005	STAT5B
positive regulation of B cell differentiation	1	374.5×	0.006	STAT5B
rRNA transcription	1	330.4×	0.007	CAVIN1
natural killer cell differentiation	1	295.6×	0.007	STAT5B
positive regulation of cell motility	1	255.3×	0.008	CAVIN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT5B	1	3
ERCC6L2	0	0
CAVIN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN HEXASODIUM	3	STAT5B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
STAT5B	55	Binding:55

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
SURAMIN HEXASODIUM	3	STAT5B

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	STAT5B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ERCC6L2, CAVIN1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ERCC6L2	0	—
CAVIN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.