Autosomal recessive STAT5B deficiency is a post-receptor form of growth hormone insensitivity combined with a primary immune dysregulation disorder. Biallelic loss-of-function variants in STAT5B remove the transcription factor that the GH receptor-JAK2 complex uses to induce IGF1, so patients have normal or elevated GH with very low IGF-1, IGFBP-3 and acid-labile subunit, severe postnatal growth failure that phenocopies Laron syndrome, and no growth response to recombinant GH. Because STAT5B also carries IL-2 receptor signalling in lymphocytes, the same lesion depletes FOXP3+ regulatory T cells and impairs NK cell maturation and cytotoxicity. The immune arm presents as severe eczema, autoimmunity, hypergammaglobulinemia and elevated IgE, T-cell lymphopenia, recurrent and opportunistic infections, and chronic pulmonary disease that can progress through lymphocytic interstitial pneumonia to fatal pulmonary fibrosis. Hyperprolactinemia is a recurrent endocrine finding whose mechanism is unresolved. Recombinant IGF-1 is the growth therapy, with a smaller response than in GH receptor defects; no single therapy corrects both growth and immunity.
Ask a research question about STAT5B Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: STAT5B Deficiency
creation_date: "2026-09-24T16:22:46Z"
category: Mendelian
description: >-
Autosomal recessive STAT5B deficiency is a post-receptor form of growth
hormone insensitivity combined with a primary immune dysregulation disorder.
Biallelic loss-of-function variants in STAT5B remove the transcription factor
that the GH receptor-JAK2 complex uses to induce IGF1, so patients have
normal or elevated GH with very low IGF-1, IGFBP-3 and acid-labile subunit,
severe postnatal growth failure that phenocopies Laron syndrome, and no growth
response to recombinant GH. Because STAT5B also carries IL-2 receptor
signalling in lymphocytes, the same lesion depletes FOXP3+ regulatory T cells
and impairs NK cell maturation and cytotoxicity. The immune arm presents as
severe eczema, autoimmunity, hypergammaglobulinemia and elevated IgE, T-cell
lymphopenia, recurrent and opportunistic infections, and chronic pulmonary
disease that can progress through lymphocytic interstitial pneumonia to fatal
pulmonary fibrosis. Hyperprolactinemia is a recurrent endocrine finding whose
mechanism is unresolved. Recombinant IGF-1 is the growth therapy, with a
smaller response than in GH receptor defects; no single therapy corrects both
growth and immunity.
disease_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
synonyms:
- STAT5B deficiency, autosomal recessive
- growth hormone insensitivity with immunodeficiency
- short stature due to STAT5b deficiency
- growth hormone insensitivity due to postreceptor defect
- Laron syndrome with immunodeficiency
parents:
- Growth Hormone Insensitivity Syndrome
notes: >-
This entry is the dedicated home for the autosomal recessive STAT5B arm of
growth hormone insensitivity syndrome. The Growth_Hormone_Insensitivity_Syndrome
entry carries a STAT5B Deficiency subtype scoped to what distinguishes it
from the GHR, IGFALS, IGF1 and IGF1R arms, and names this concept
(MONDO:0100211) as the intended home for the immunologic detail; the two are
meant to be read together. Heterozygous dominant-negative STAT5B variants
(growth hormone insensitivity with immune dysregulation 2, autosomal
dominant; OMIM 604260) are a separate MONDO concept with milder growth
failure, eczema and elevated IgE but without the severe immune and pulmonary
disease, and are deliberately not merged here. Somatic activating STAT5B
variants in T-cell and myeloid neoplasms are unrelated to this germline
loss-of-function disease. Hematopoietic stem cell transplantation has been
proposed for the T-cell defect in reviews, but no outcome data were found, so
it is not recorded as a treatment.
inheritance:
- name: Autosomal Recessive
description: >-
Homozygous loss-of-function STAT5B variants, usually in consanguineous
families. Heterozygous carriers of these recessive alleles are of normal
height and without immune or pulmonary disease, which distinguishes this
disorder from the dominant-negative heterozygous form.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:17389811
reference_title: "Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This is the first STAT5b defect to be identified in siblings, further supporting the autosomal recessive mode of transmission of STAT5b deficiency."
explanation: >-
Affected siblings with a homozygous STAT5B variant and heterozygous
parents of normal height support recessive transmission.
- 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
quote_role: BACKGROUND
snippet: "One copy of wild-type (WT) STAT5B allele appears to be sufficient for normality as heterozygous relatives of affected patients are of normal height and without immunological or pulmonary complications"
explanation: >-
Heterozygous relatives of recessive patients are unaffected, so the
classic loss-of-function alleles act recessively. The sentence summarises
earlier reports in the introduction of the dominant-negative study.
genetic:
- name: STAT5B
gene_term:
preferred_term: STAT5B
term:
id: hgnc:11367
label: STAT5B
association: Causative biallelic loss-of-function variants
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
Reported recessive alleles include SH2-domain missense variants (p.Ala630Pro,
p.Phe646Ser), a nonsense variant at codon 152, and several frameshifts
(for example p.Gln368fs, p.Leu142fs and p.Asp485Thrfs), all predicted or
shown to abolish transcriptional activity.
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
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"
explanation: >-
Establishes biallelic STAT5B mutation as the cause of this Laron-like
growth hormone 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
quote_role: BACKGROUND
snippet: "Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications."
explanation: >-
Restates the recessive STAT5B disease as severe GHIS with immune and
pulmonary complications, in contrast to the dominant-negative form the
paper reports.
- reference: PMID:33122102
reference_title: "Human growth disorders associated with impaired GH action: Defects in STAT5B and JAK2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Only AR STAT5B defects, however, confer additional characteristics of immune dysfunction which can manifest as chronic, potentially fatal, pulmonary disease."
explanation: >-
Separates the recessive loss-of-function disease curated here, which
carries the immune and pulmonary arm, from the dominant-negative form.
pathophysiology:
- name: Biallelic STAT5B Loss of Function
biological_scale: MOLECULAR
description: >-
Recessive STAT5B variants abolish the transcription factor. Missense changes
in the SH2 domain cause misfolding and aggregation (p.Ala630Pro) or prevent
transcription despite phosphorylation (p.Phe646Ser); nonsense and
frameshift alleles truncate the protein before the SH2 and transactivation
domains, often leaving no detectable protein. The highly similar STAT5A does
not compensate in humans.
genetic_context:
gene:
preferred_term: STAT5B
term:
id: hgnc:11367
label: STAT5B
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
molecular_functions:
- preferred_term: STAT5B DNA-binding transcription factor activity
term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
modifier: DECREASED
evidence:
- reference: PMID:16303763
reference_title: "Aberrant folding of a mutant Stat5b causes growth hormone insensitivity and proteasomal dysfunction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our results are compatible with a model in which Stat5bA630P is an inactive transcription factor by virtue of its aberrant folding and diminished solubility triggered by a misfolded SH2 domain."
explanation: >-
The first reported missense allele yields an inactive, misfolded
transcription factor.
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This novel mutation determined a complete absence of protein expression."
explanation: >-
A homozygous nonsense allele removes STAT5B protein entirely in the
patient.
- reference: PMID:22419735
reference_title: "A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The phosphorylated p.Phe646Ser, however, could not drive transcription."
explanation: >-
A second SH2 missense allele is phosphorylated but transcriptionally
inactive, confirming loss of the transcription factor function.
- 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
quote_role: BACKGROUND
snippet: "All seven recessively inherited inactivating STAT5B mutations characterized to date lack functional SH2 and downstream TAD domains, and often the entire protein is immunologically undetectable"
explanation: >-
Summarises the recessive allele series as inactivating, with loss of the
SH2 and transactivation domains.
downstream:
- target: Defective GH Receptor-STAT5B Signaling
description: >-
Without functional STAT5B, GH receptor-JAK2 activation cannot drive the
STAT5B transcriptional program in GH target cells.
- target: Defective IL-2 Receptor-STAT5B Signaling in Lymphocytes
description: >-
STAT5B is also the principal transducer of IL-2 signalling in T and NK
cells, so the same lesion disables the lymphocyte arm.
- target: Disrupted Prolactin Negative Feedback
description: >-
Loss of STAT5B is proposed to disrupt negative feedback on prolactin
production; the mechanism is not established.
- name: Defective GH Receptor-STAT5B Signaling
biological_scale: CELLULAR
description: >-
GH binding to the GH receptor activates JAK2, which recruits and
phosphorylates STAT5B. In STAT5B deficiency this signal cannot induce IGF1
transcription, and STAT5A activation does not restore it. The defect is
downstream of an intact receptor, so exogenous GH does not correct it.
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
biological_processes:
- preferred_term: growth hormone receptor signaling pathway via JAK-STAT
term:
id: GO:0060397
label: growth hormone receptor signaling pathway via JAK-STAT
modifier: DECREASED
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "the loss of functional STAT5B correlated to loss of GH-induced IGF1 expression"
explanation: >-
In patient dermal fibroblasts loss of STAT5B abolished GH-induced IGF1
expression, linking the lesion to the signalling defect.
- reference: PMID:21396575
reference_title: "STAT5b deficiency: lessons from STAT5b gene mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Growth hormone (GH) regulates insulin-like growth factor (IGF)-I production primarily through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5b signaling cascade."
explanation: >-
Places STAT5B as the main transducer between the GH receptor and IGF-I
production.
downstream:
- target: Impaired GH-Induced IGF-1 Production
description: >-
GH receptor signalling without STAT5B fails to induce IGF1 and the
GH-dependent components of the circulating IGF ternary complex.
- name: Impaired GH-Induced IGF-1 Production
biological_scale: ORGANISM
description: >-
Circulating IGF-1, IGFBP-3 and acid-labile subunit are all very low and do
not rise with GH treatment, while GH secretion is normal or elevated. This
is the growth hormone insensitivity state, and its severity tracks the
postnatal growth failure. Birth size is normal, consistent with a
postnatal, GH-dependent defect.
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Serum IGF-I, IGFBP-3 and ALS concentrations in all cases were abnormally low (Table 1), and remained low after GH treatment in an IGF-I generation test"
explanation: >-
IGF-I, IGFBP-3 and ALS are low in every reported patient and unresponsive
to GH, defining the GH-insensitive IGF deficiency.
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Some of the subjects underwent growth hormone therapy (1yr to 4yr), but growth response was uniformly poor"
explanation: >-
Recombinant GH does not rescue growth, as expected for a defect
downstream of the GH receptor.
- reference: PMID:16787985
reference_title: "Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Extremely low levels of IGF-I (-6.9 SDS), IGF-binding protein-3 (-12 SDS), and acid-labile subunit (-7.5 SDS) were found."
explanation: >-
Quantifies the deficiency of all three GH-dependent ternary complex
components in a homozygous patient.
downstream:
- target: Decreased Circulating IGF-1
description: Low hepatic IGF1 output lowers serum IGF-1.
- target: Decreased Circulating Acid-Labile Subunit
description: The GH-dependent acid-labile subunit is also not induced.
- target: Elevated Circulating Growth Hormone
description: >-
Stimulated GH is often elevated, the expected pituitary response when
GH action is blocked downstream of its receptor.
- target: Postnatal Growth Failure
description: IGF-1 deficiency drives the severe postnatal growth failure.
- target: Delayed Puberty
description: Low circulating IGF-I contributes to delayed puberty.
- target: Delayed Skeletal Maturation
description: Bone age is considerably delayed with IGF deficiency.
- name: Defective IL-2 Receptor-STAT5B Signaling in Lymphocytes
biological_scale: CELLULAR
description: >-
IL-2 and related common gamma-chain cytokines signal through STAT5B to
induce CD25 (IL-2 receptor alpha) and FOXP3. Patient T cells show impaired
IL-2 signalling and proliferation and reduced CD25 induction, while other
IL-2 responses are preserved, so the defect is selective. Reduced CD25 on
conventional T cells is also proposed to contribute to infection
susceptibility.
biological_processes:
- preferred_term: interleukin-2-mediated signaling pathway
term:
id: GO:0038110
label: interleukin-2-mediated signaling pathway
modifier: DECREASED
evidence:
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In vitro T-cell proliferation and interleukin 2 signaling were impaired."
explanation: >-
Patient T cells tested in vitro show defective IL-2 signalling and
proliferation.
- reference: PMID:16920911
reference_title: "Cutting edge: Decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Expression of CD25, a component of the high-affinity IL-2R, was also reduced in response to IL-2 or after in vitro propagation."
explanation: >-
STAT5B-deficient T cells fail to upregulate the high-affinity IL-2
receptor chain in response to IL-2.
- reference: PMID:23773921
reference_title: "Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Upon knocking down STAT5A or STAT5B in human primary T cells, we found differentially regulated expression of FOXP3 and IL-2R in STAT5B knockdown T cells"
explanation: >-
STAT5B knockdown in primary human T cells alters FOXP3 and IL-2 receptor
expression, showing a STAT5B-specific role that STAT5A does not cover.
downstream:
- target: Regulatory T Cell Deficiency and Dysfunction
description: >-
IL-2-STAT5B signalling is required for accumulation of functional FOXP3+
regulatory T cells.
- target: NK Cell Maturation and Cytotoxicity Defect
description: >-
IL-2 and IL-15 signalling through STAT5B supports NK cell terminal
maturation and cytolytic function.
- target: T-Cell Lymphopenia
description: >-
Impaired cytokine-driven T-cell proliferation and homeostasis lower T-cell
numbers.
- target: Recurrent Respiratory Infections
description: >-
Decreased CD25 on T cells is proposed to contribute to increased
susceptibility to infection.
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: "The increased susceptibility to opportunistic infections could also be related to decreased CD25 on all T cells, as has been reported in humans with severe CD25 deficiency"
explanation: >-
Proposes, by analogy with CD25 deficiency, that reduced CD25 on T cells
contributes to infection susceptibility.
- name: Regulatory T Cell Deficiency and Dysfunction
biological_scale: CELLULAR
description: >-
CD4+CD25high regulatory T cells are reduced in number, express low FOXP3,
and are impaired in suppressing conventional T-cell proliferation. Loss of
Treg control of T-cell homeostasis is the proposed driver of autoimmunity
and of lymphocyte accumulation in extra-lymphoid tissues such as the lung.
cell_types:
- preferred_term: CD4-positive, CD25-positive, alpha-beta regulatory T cell
term:
id: CL:0000792
label: CD4-positive, CD25-positive, alpha-beta regulatory T cell
biological_processes:
- preferred_term: regulatory T cell differentiation
term:
id: GO:0045066
label: regulatory T cell differentiation
modifier: DECREASED
evidence:
- reference: PMID:16920911
reference_title: "Cutting edge: Decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A patient homozygous for a missense A630P STAT5b mutation displayed immune dysregulation and decreased numbers of CD4+ CD25(high) T cells."
explanation: >-
Documents reduced regulatory T-cell numbers with immune dysregulation in
a homozygous patient.
- reference: PMID:16920911
reference_title: "Cutting edge: Decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "STAT5b(A630P/A630P) CD4+ CD25(high) T cells had low expression of forkhead box P3 and an impaired ability to suppress the proliferation of or to kill CD4+ CD25- T cells."
explanation: >-
The residual regulatory T cells have low FOXP3 and poor suppressive
function.
- reference: PMID:16920911
reference_title: "Cutting edge: Decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These results indicate that STAT5b propagates an important IL-2-mediated signal for the in vivo accumulation of functional regulatory T cells."
explanation: >-
Links the IL-2-STAT5B signalling defect to the regulatory T-cell
deficiency.
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CD4+ and CD25+ regulatory T cells were significantly diminished"
explanation: >-
An independent patient with a nonsense allele also has diminished
regulatory T cells.
- reference: PMID:23773921
reference_title: "Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Functional ex vivo studies in homozygous STAT5B-deficient patients showed reduced FOXP3 expression with impaired regulatory function of STAT5B-null Treg cells, also of increased memory phenotype."
explanation: >-
Ex vivo patient Treg cells confirm reduced FOXP3 and impaired
suppressive function.
downstream:
- target: Loss of Peripheral Immune Tolerance
description: >-
Reduced and dysfunctional regulatory T cells fail to restrain effector
lymphocytes.
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
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: >-
Proposes the regulatory T-cell defect as the cause of lymphocyte
accumulation in extra-lymphoid tissues.
- target: Decreased Regulatory T Cell Proportion
description: The Treg defect is measured as a reduced Treg fraction.
- name: Loss of Peripheral Immune Tolerance
biological_scale: ORGANISM
description: >-
Without adequate regulatory T-cell control, chronically activated T cells
and hyperactive B cells produce autoantibodies, hypergammaglobulinemia,
elevated IgE and atopy, and lymphocytes infiltrate extra-lymphoid tissues,
most consequentially the lung. The immune phenotype is variable even between
siblings with the same variant.
evidence:
- reference: PMID:33090292
reference_title: "Developmental Adaptive Immune Defects Associated with STAT5B Deficiency in Three Young Siblings."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All three siblings demonstrated consistent B cell hyperactivity including elevated IgE levels and autoantibody production, associated with diagnoses of atopy and autoimmunity."
explanation: >-
Serial immunophenotyping in three young siblings shows B-cell
hyperactivity, autoantibodies, atopy and autoimmunity.
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "T cells presented a chronically hyperactivated phenotype."
explanation: >-
Chronic T-cell hyperactivation is the effector side of failed tolerance.
downstream:
- target: Autoimmunity
description: Failed tolerance permits autoantibody production and autoimmune disease.
- target: Eczema
description: Immune dysregulation manifests in skin as severe eczema.
- target: Lymphocytic Interstitial Pneumonia
description: >-
Lymphocytes accumulate in the lung interstitium, producing lymphocytic
interstitial pneumonia.
- target: Chronic Lung Disease
description: >-
Lymphocytic lung infiltration underlies the chronic pulmonary disease.
- target: Hypergammaglobulinemia
description: B-cell hyperactivity raises circulating immunoglobulin.
- target: Increased Circulating IgE
description: B-cell hyperactivity includes elevated IgE with atopy.
- name: NK Cell Maturation and Cytotoxicity Defect
biological_scale: CELLULAR
description: >-
STAT5B-deficient NK cells are reduced in number, stall before terminal
maturation, express less perforin and CD16, and form lytic synapses poorly,
so their cytolytic capacity is low. IL-2 stimulation partly restores
granule convergence and killing in vitro. Stat5b knockout mice show the
same NK defect.
cell_types:
- preferred_term: natural killer cell
term:
id: CL:0000623
label: natural killer cell
biological_processes:
- preferred_term: natural killer cell mediated cytotoxicity
term:
id: GO:0042267
label: natural killer cell mediated cytotoxicity
modifier: DECREASED
- preferred_term: natural killer cell differentiation
term:
id: GO:0001779
label: natural killer cell differentiation
modifier: DECREASED
evidence:
- reference: PMID:31600547
reference_title: "Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Furthermore, human STAT5b-deficient NK cells had low cytolytic capacity, and fixed-cell microscopy showed poor convergence of lytic granules."
explanation: >-
Patient NK cells have low cytolytic capacity with defective lytic
synapse formation.
- reference: PMID:31600547
reference_title: "Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We observed low NK cell numbers and impaired NK cell maturation, suggesting that STAT5b is involved in terminal NK cell maturation in Stat5b-/- mice."
explanation: >-
The Stat5b knockout mouse reproduces the NK number and maturation defect.
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "very low numbers of natural killer (18/mm3) and gammadelta T (5/mm3) cells"
explanation: >-
A patient with complete STAT5B absence has very low NK counts.
downstream:
- target: Reduced NK Cell Count
description: Impaired NK maturation lowers circulating NK cell counts.
- target: Recurrent Respiratory Infections
description: >-
Deficient NK cytotoxicity weakens early defence against viral and other
infections.
- target: Herpetic Keratitis
description: >-
Impaired NK and T-cell antiviral function permits recurrent herpesvirus
infection.
- name: Disrupted Prolactin Negative Feedback
biological_scale: ORGANISM
description: >-
Serum prolactin is elevated in most patients in whom it was measured,
without macroprolactin or pituitary tumor. The leading explanation is loss
of a STAT5B-dependent negative feedback loop on prolactin production, but
this has not been demonstrated.
biological_processes:
- preferred_term: negative regulation of prolactin secretion
term:
id: GO:1902721
label: negative regulation of prolactin secretion
modifier: DECREASED
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: "It is likely that the STAT5B mutations disrupted the negative feedback loop for PRL production, although the mechanisms involved remain to be clarified."
explanation: >-
States the feedback-loss hypothesis for hyperprolactinemia and that it
is unproven.
downstream:
- target: Hyperprolactinemia
description: Loss of feedback raises circulating prolactin.
phenotypes:
- category: Growth
name: Postnatal Growth Failure
description: >-
Severe postnatal growth failure with normal birth size, indistinguishable
from classic Laron syndrome; height SDS at first report ranged from about
-3 to -9.9.
phenotype_term:
preferred_term: Postnatal growth retardation
term:
id: HP:0008897
label: Postnatal growth retardation
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Postnatal growth failure was significant and consistent with the degree of IGF deficiency. Growth profiles were indistinguishable from those with GHI (or Laron) syndrome"
explanation: >-
Postnatal growth failure is the defining growth phenotype and tracks the
IGF deficiency.
- reference: PMID:37586336
reference_title: "Recombinant Human Insulin-Like Growth Factor-1 Treatment of Severe Growth Failure in Three Siblings with STAT5B Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Patients with homozygous recessive mutations in STAT5B have severe progressive postnatal growth failure and insulin-like growth factor-I (IGF-I) deficiency associated with immunodeficiency and increased risk of autoimmune and pulmonary conditions."
explanation: >-
Restates severe progressive postnatal growth failure as the core feature.
- category: Laboratory
name: Decreased Circulating IGF-1
description: >-
Serum IGF-1 and IGFBP-3 are markedly low in every reported patient and do
not rise in an IGF-I generation test.
frequency: OBLIGATE
diagnostic: true
phenotype_term:
preferred_term: Decreased circulating insulin-like growth factor 1 concentration
term:
id: HP:0030353
label: Decreased circulating serum insulin-like growth factor 1 concentration
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Unlike the endocrine profiles that showed an absolute association between STAT5B mutations and IGF deficiency"
explanation: >-
IGF deficiency is present in all recessive patients, supporting an
obligate frequency.
- reference: PMID:22419735
reference_title: "A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD."
explanation: >-
Low IGF-I and IGFBP-3 with normal GH stimulation in a patient with the
p.Phe646Ser allele.
- category: Laboratory
name: Decreased Circulating Acid-Labile Subunit
description: Serum acid-labile subunit is markedly low.
phenotype_term:
preferred_term: Decreased circulating acid-labile subunit concentration
term:
id: HP:0045046
label: Decreased circulating insulin-like growth factor-binding protein acid labile subunit concentration
evidence:
- reference: PMID:16787985
reference_title: "Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Extremely low levels of IGF-I (-6.9 SDS), IGF-binding protein-3 (-12 SDS), and acid-labile subunit (-7.5 SDS) were found."
explanation: Documents markedly reduced acid-labile subunit.
- category: Laboratory
name: Elevated Circulating Growth Hormone
description: >-
Basal GH is normal and stimulated GH is frequently elevated, the
biochemical signature of GH insensitivity rather than GH deficiency.
phenotype_term:
preferred_term: Elevated circulating growth hormone concentration
term:
id: HP:0000845
label: Elevated circulating growth hormone concentration
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Basal GH levels were normal, and when stimulated, GH concentrations were frequently elevated."
explanation: Stimulated GH is often elevated across reported patients.
- category: Endocrine
name: Hyperprolactinemia
description: >-
Serum prolactin is abnormally high whenever measured in the early series,
not explained by macroprolactin or a pituitary tumor; it is an endocrine
clue to the diagnosis.
phenotype_term:
preferred_term: Hyperprolactinemia
term:
id: HP:0000870
label: Increased circulating prolactin concentration
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Interestingly, serum prolactin levels, when recorded, were abnormally high (Table 1)."
explanation: Hyperprolactinemia is a recurrent finding across patients.
- reference: PMID:16787985
reference_title: "Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We show for the first time that immunological or pulmonary problems or elevated GH secretion are not obligatory signs of STAT5b deficiency, whereas hyperprolactinemia appears to be part of the syndrome."
explanation: >-
Identifies hyperprolactinemia as part of the syndrome even in a patient
without immune or pulmonary disease.
- reference: PMID:20538865
reference_title: "A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both siblings had laboratory findings compatible with GHI associated with hyperprolactinemia."
explanation: Hyperprolactinemia accompanies GHI in two affected brothers.
- category: Endocrine
name: Delayed Puberty
description: Puberty is consistently delayed.
phenotype_term:
preferred_term: Delayed puberty
term:
id: HP:0000823
label: Delayed puberty
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Puberty was also consistently delayed (Table 1), reflecting the low levels of circulating IGF-I (Table 1) and a state of chronic illness"
explanation: >-
Delayed puberty is consistent across patients and attributed to low IGF-I
and chronic illness.
- category: Skeletal
name: Delayed Skeletal Maturation
description: Bone age is considerably delayed.
phenotype_term:
preferred_term: Delayed skeletal maturation
term:
id: HP:0002750
label: Delayed skeletal maturation
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Bone age, when measured, was considerably delayed"
explanation: Delayed bone age is reported where measured.
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "persistently low growth rate, severely delayed bone age, and postnatal growth failure resulting from growth hormone resistance"
explanation: Severely delayed bone age in a patient with a nonsense allele.
- category: Craniofacial
name: Frontal Bossing
description: >-
Mild Laron-like facial features, including a prominent forehead, are seen
in some patients.
phenotype_term:
preferred_term: Prominent forehead
term:
id: HP:0002007
label: Frontal bossing
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Mild facial dysmorphic features, such as a prominent forehead, depressed nasal bridge and high-pitched voice, were noted for some of the STAT5B deficient subjects"
explanation: A prominent forehead is among the mild dysmorphic features.
- category: Craniofacial
name: Depressed Nasal Bridge
description: A depressed nasal bridge is noted in some patients.
phenotype_term:
preferred_term: Depressed nasal bridge
term:
id: HP:0005280
label: Depressed nasal bridge
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Mild facial dysmorphic features, such as a prominent forehead, depressed nasal bridge and high-pitched voice, were noted for some of the STAT5B deficient subjects"
explanation: A depressed nasal bridge is among the mild dysmorphic features.
- category: Otolaryngologic
name: High-Pitched Voice
description: A high-pitched voice, as in classic Laron syndrome, is noted in some patients.
phenotype_term:
preferred_term: High-pitched voice
term:
id: HP:0001620
label: Abnormally high-pitched voice
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Mild facial dysmorphic features, such as a prominent forehead, depressed nasal bridge and high-pitched voice, were noted for some of the STAT5B deficient subjects"
explanation: A high-pitched voice is among the mild Laron-like features.
- category: Dermatologic
name: Eczema
description: >-
Severe, often generalized eczema from infancy is one of the most
consistent immune-arm features.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: 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
quote_role: REVIEW_SYNTHESIS
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: Severe eczema was present in 8 of 10 reported patients.
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "suffered generalized eczema and recurrent infections of the skin and respiratory tract since birth"
explanation: Generalized eczema from birth in a patient with complete protein absence.
- category: Respiratory
name: Chronic Lung Disease
description: >-
Chronic pulmonary disease beginning as early as the first year of life,
the main cause of mortality. Two reported patients with residual or
atypical alleles lacked severe lung disease.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Chronic lung disease
term:
id: HP:0006528
label: Chronic lung disease
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
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: Chronic pulmonary disease was present in 8 of 10 reported patients.
- reference: PMID:21396575
reference_title: "STAT5b deficiency: lessons from STAT5b gene mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Unlike GHIS due to GHR mutations, patients carrying STAT5b mutations also presented with chronic pulmonary disease and evidence of perturbations of T-cell homeostasis."
explanation: >-
Chronic pulmonary disease distinguishes STAT5B deficiency from GHR
deficiency.
- category: Respiratory
name: Lymphocytic Interstitial Pneumonia
description: >-
Lymphocytic (lymphoid) interstitial pneumonia develops in childhood in
most patients with lung disease and can progress to pulmonary fibrosis and
respiratory insufficiency.
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
quote_role: REVIEW_SYNTHESIS
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: LIP and lung fibrosis are confirmed in the pulmonary cases.
- reference: PMID:33090292
reference_title: "Developmental Adaptive Immune Defects Associated with STAT5B Deficiency in Three Young Siblings."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "STAT5B deficient patients experience frequent respiratory infections in infancy and typically develop lymphocytic interstitial pneumonia (LIP) during childhood resulting in fatal respiratory insufficiency before the age of 30"
explanation: >-
Summarises the typical pulmonary course from infantile infections to LIP
and fatal respiratory insufficiency.
sequelae:
- target: Pulmonary Fibrosis
description: LIP can progress to fibrosis and respiratory failure.
- category: Respiratory
name: Pulmonary Fibrosis
description: >-
Progressive pulmonary fibrosis with respiratory failure caused the deaths
of three early patients, including the first reported case; one patient
underwent lung transplantation.
phenotype_term:
preferred_term: Pulmonary fibrosis
term:
id: HP:0002206
label: Pulmonary fibrosis
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "three of the patients, including the first described case of STAT5B deficiency (carrying p.Ala630Pro)(47), succumbed and died as consequences of progressive pulmonary fibrosis and respiratory failure"
explanation: Progressive pulmonary fibrosis is the fatal outcome in several patients.
- category: Immunologic
name: T-Cell Lymphopenia
description: Moderate T-cell lymphopenia with CD4+ and CD8+ counts often below normal.
phenotype_term:
preferred_term: T-cell lymphopenia
term:
id: HP:0005403
label: Decreased total T cell count
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "hypergammaglobulinemia and T-cell lymphopenia were common observations, with both CD4+ and CD8+ T-cells often below normal ranges"
explanation: T-cell lymphopenia is a common finding.
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The main immunologic findings were moderate T-cell lymphopenia (1274/mm3), normal CD4/CD8 ratio"
explanation: Moderate T-cell lymphopenia in a patient with complete protein absence.
- category: Immunologic
name: Decreased Regulatory T Cell Proportion
description: CD4+CD25high FOXP3+ regulatory T cells are reduced.
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
quote_role: REVIEW_SYNTHESIS
snippet: "In particular, a subset of CD4+ cells, the CD4+CD25high cells or T regulatory cells (Treg), is significantly diminished."
explanation: Regulatory T cells are significantly diminished across patients.
- category: Immunologic
name: Reduced NK Cell Count
description: Circulating NK cells are reduced.
phenotype_term:
preferred_term: Reduced natural killer cell count
term:
id: HP:0040218
label: Reduced total natural killer cell count
evidence:
- reference: PMID:20538865
reference_title: "A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed."
explanation: Reduced NK cells in two affected brothers.
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "very low numbers of natural killer (18/mm3) and gammadelta T (5/mm3) cells"
explanation: Very low NK counts in a further patient.
- category: Immunologic
name: Reduced Gamma-Delta T Cells
description: >-
Very few circulating gamma-delta T cells, reported in a single patient
homozygous for a nonsense allele that abolished STAT5B protein expression.
phenotype_term:
preferred_term: Reduced gamma-delta T cells
term:
id: HP:0500271
label: Decreased gamma-delta T cell proportion
notes: >-
The source reports an absolute count (5/mm3 against 1274/mm3 total T
cells), not a proportion. HPO has no absolute-count gamma-delta term
(OLS search of hp for "gamma-delta" returns only the proportion terms
HP:0500269-HP:0500271), so the proportion term is bound; the count
corresponds to well under 1% of T cells.
evidence:
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "very low numbers of natural killer (18/mm3) and gammadelta T (5/mm3) cells"
explanation: Single-patient report of very low gamma-delta T cell numbers.
- category: Immunologic
name: Hypergammaglobulinemia
description: >-
Hypergammaglobulinemia is common, although some patients have normal
immunoglobulins.
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
quote_role: REVIEW_SYNTHESIS
snippet: "hypergammaglobulinemia and T-cell lymphopenia were common observations, with both CD4+ and CD8+ T-cells often below normal ranges"
explanation: Hypergammaglobulinemia is a common finding.
- reference: PMID:36265659
reference_title: "Atypical STAT5B deficiency, severe short stature and mild immunodeficiency associated with a novel homozygous STAT5B Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "an immune profile notable for hypergammaglobulinaemia and elevated B lymphocytes, and lack of pulmonary disease"
explanation: Hypergammaglobulinemia even in an atypical patient without lung disease.
- category: Immunologic
name: Increased Circulating IgE
description: Elevated IgE with atopy, documented from early childhood.
phenotype_term:
preferred_term: Increased circulating IgE concentration
term:
id: HP:0003212
label: Increased circulating IgE concentration
evidence:
- reference: PMID:33090292
reference_title: "Developmental Adaptive Immune Defects Associated with STAT5B Deficiency in Three Young Siblings."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All three siblings demonstrated consistent B cell hyperactivity including elevated IgE levels and autoantibody production, associated with diagnoses of atopy and autoimmunity."
explanation: Elevated IgE in all three young siblings.
- category: Immunologic
name: Autoimmunity
description: >-
Autoantibody production and autoimmune disease are prominent; reported
manifestations include autoimmune thyroiditis, juvenile idiopathic
arthritis and immune thrombocytopenic purpura.
phenotype_term:
preferred_term: Autoimmunity
term:
id: HP:0002960
label: Autoimmunity
evidence:
- reference: PMID:33090292
reference_title: "Developmental Adaptive Immune Defects Associated with STAT5B Deficiency in Three Young Siblings."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All three siblings demonstrated consistent B cell hyperactivity including elevated IgE levels and autoantibody production, associated with diagnoses of atopy and autoimmunity."
explanation: Autoantibodies and autoimmune diagnoses in all three siblings.
sequelae:
- target: Autoimmune Thyroiditis
description: Thyroid-directed autoimmunity.
- target: Juvenile Idiopathic Arthritis
description: Joint-directed autoimmunity.
- target: Immune Thrombocytopenia
description: Platelet-directed autoimmunity.
- category: Endocrine
name: Autoimmune Thyroiditis
description: Autoimmune thyroiditis reported in a patient with the p.Phe646Ser allele.
phenotype_term:
preferred_term: Autoimmune thyroiditis
term:
id: HP:0100646
label: Thyroiditis
evidence:
- reference: PMID:22419735
reference_title: "A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis."
explanation: Autoimmune thyroiditis in a homozygous patient.
- category: Musculoskeletal
name: Juvenile Idiopathic Arthritis
description: Juvenile idiopathic arthritis reported in one of two affected sisters.
phenotype_term:
preferred_term: Juvenile idiopathic arthritis
term:
id: HP:0005681
label: Juvenile rheumatoid arthritis
evidence:
- reference: PMID:17389811
reference_title: "Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "siblings 2 and 1 presented with, respectively, a diagnosis of juvenile idiopathic arthritis and recurrent pulmonary infections"
explanation: Juvenile idiopathic arthritis in an affected sibling.
- category: Hematologic
name: Immune Thrombocytopenia
description: Thrombocytopenic purpura reported in affected brothers.
phenotype_term:
preferred_term: Immune thrombocytopenic purpura
term:
id: HP:0001973
label: Autoimmune thrombocytopenia
evidence:
- reference: PMID:20538865
reference_title: "A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura"
explanation: Thrombocytopenic purpura accompanies GHI and lung disease in two brothers.
- category: Immunologic
name: Recurrent Respiratory Infections
description: >-
Recurrent respiratory infections from infancy, often preceding chronic
lung disease.
phenotype_term:
preferred_term: Recurrent respiratory infections
term:
id: HP:0002205
label: Recurrent respiratory infections
evidence:
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "suffered generalized eczema and recurrent infections of the skin and respiratory tract since birth"
explanation: Recurrent respiratory infections from birth.
- reference: PMID:17389811
reference_title: "Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "siblings 2 and 1 presented with, respectively, a diagnosis of juvenile idiopathic arthritis and recurrent pulmonary infections"
explanation: Recurrent pulmonary infections in an affected sibling.
- category: Ophthalmologic
name: Herpetic Keratitis
description: Recurrent herpetic keratitis, an opportunistic viral infection.
phenotype_term:
preferred_term: Herpetic keratitis
term:
id: HP:0000491
label: Keratitis
evidence:
- reference: PMID:17030597
reference_title: "Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She also suffered severe chronic lung disease and multiple episodes of herpetic keratitis."
explanation: Multiple episodes of herpetic keratitis in a patient with complete protein absence.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
About ten homozygous patients carrying seven STAT5B mutations had been
reported by 2015-2016; further families have been described since.
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported."
explanation: Counts reported cases at the time of the review.
- reference: PMID:25753012
reference_title: "Long-term follow-up of STAT5B deficiency in three argentinian patients: clinical and immunological features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There are currently ten published cases of STAT5B deficiency, four of which are Argentinians."
explanation: Independent count of ten published cases.
treatments:
- name: Recombinant Human IGF-1 (Mecasermin)
description: >-
Recombinant IGF-1 bypasses the GH receptor-STAT5B defect and is the
growth-directed therapy. In three siblings it raised height velocity over
the first three years, but the response was smaller than in other forms of
severe primary IGF-I deficiency, and hypoglycemia limited dosing in one
child. An earlier report found no meaningful response in a chronically ill
patient. It does not address the immune defect.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: mecasermin
term:
id: CHEBI:749581
label: mecasermin
target_mechanisms:
- target: Impaired GH-Induced IGF-1 Production
treatment_effect: BYPASSES
description: >-
Exogenous IGF-1 replaces the hormone that GH can no longer induce.
evidence:
- reference: PMID:37586336
reference_title: "Recombinant Human Insulin-Like Growth Factor-1 Treatment of Severe Growth Failure in Three Siblings with STAT5B Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "With rhIGF-1 therapy, HVs increased to 5.2-6.0, 4.8-7.1, and 5.5-7.4 cm/year, respectively, in the first 3 years of treatment"
explanation: Height velocity rose on rhIGF-1 in all three siblings.
evidence:
- reference: PMID:37586336
reference_title: "Recombinant Human Insulin-Like Growth Factor-1 Treatment of Severe Growth Failure in Three Siblings with STAT5B Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The response to rhIGF-1 therapy is less than observed with rhIGF-1 therapy for patients previously described with severe primary IGF-I deficiency, including patients with documented defects in the growth hormone receptor, but may still provide patients with STAT5B deficiency with an opportunity to prevent worsening growth failure."
explanation: >-
rhIGF-1 is beneficial but less effective than in GH receptor defects.
- reference: PMID:37586336
reference_title: "Recombinant Human Insulin-Like Growth Factor-1 Treatment of Severe Growth Failure in Three Siblings with STAT5B Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "P3 also experienced hypoglycemia that limited our ability to maintain target rhIGF-1 dosing."
explanation: Hypoglycemia is a dose-limiting adverse effect.
- reference: PMID:20538865
reference_title: "A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy)"
explanation: >-
One treated patient showed no significant growth response, which the
authors attributed possibly to chronic illness.
- name: Corticosteroids for Pulmonary Disease
description: >-
Systemic corticosteroids, with oxygen, temporarily stabilize worsening lung
function in lymphocytic interstitial pneumonia but do not halt progression.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: corticosteroid
term:
id: CHEBI:50858
label: corticosteroid
target_mechanisms:
- target: Loss of Peripheral Immune Tolerance
treatment_effect: INHIBITS
description: >-
Corticosteroids suppress the lymphocytic inflammation driving the lung
disease.
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Corticosteroid and oxygen treatments temporarily stabilize worsening pulmonary functions"
explanation: Corticosteroids give temporary stabilization of lung function.
- name: Lung Transplantation
description: >-
Lung transplantation has been performed for end-stage pulmonary disease in
one reported patient, relieving the oxygen requirement; long-term outcome
is unknown.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Lung transplantation
term:
id: NCIT:C15274
label: Lung Transplantation
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Only one of the patients has undergone a lung transplantation at age 17.5 years that appeared to have successful alleviated impaired pulmonary function and the requirement for oxygen"
explanation: Single-patient experience with lung transplantation.
animal_models:
- name: Stat5b knockout mouse
species: Mouse
genotype: Stat5b(-/-)
publication: PMID:9207075
description: >-
Targeted Stat5b disruption produces dwarfism with elevated GH and low
IGF-I resembling Laron-type GH resistance, loss of male-pattern growth and
liver gene expression, and a marked NK cell proliferation and cytotoxicity
defect.
modeled_mechanisms:
- target: Impaired GH-Induced IGF-1 Production
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: >-
Knockout mice are GH-resistant with elevated GH and low IGF-I.
limitations: >-
The growth defect is largely confined to males (loss of sexually
dimorphic growth), and IGF-I falls only partially, because mouse Stat5a
partially compensates; in humans STAT5A does not compensate and IGF
deficiency is profound in both sexes.
divergences:
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >-
Mouse Stat5a partly substitutes for Stat5b in GH signalling, so the
knockout under-represents the human IGF-I deficiency and spares
females, whereas human STAT5A cannot substitute.
evidence:
- reference: PMID:9207075
reference_title: "Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Indeed, the dwarfism, elevated plasma GH, low plasma insulin-like growth factor I, and development of obesity seen in STAT5b-/- mice are all characteristics of Laron-type dwarfism"
explanation: The knockout reproduces the GH-resistant IGF-I deficiency.
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: REVIEW_SYNTHESIS
snippet: "suggested that, in mice, Stat5a can partially compensate for loss of Stat5b"
explanation: Explains why the mouse growth phenotype is milder than the human one.
- target: NK Cell Maturation and Cytotoxicity Defect
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: >-
Stat5b-deficient mice have fewer, poorly responsive NK cells with
greatly diminished cytolytic activity.
evidence:
- reference: PMID:9841920
reference_title: "Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These data indicate an essential nonredundant role for Stat5b for potent NK cell-mediated proliferation and cytolytic activity."
explanation: The knockout has the NK defect later found in patients.
evidence:
- reference: PMID:9207075
reference_title: "Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Although these responses are similar to those observed in GH-deficient Little mice, STAT5b-/- mice are not GH-deficient, suggesting that they may be GH pulse-resistant."
explanation: The knockout is GH-resistant rather than GH-deficient, like the human disease.
discussions:
- discussion_id: stat5a_compensation_growth
kind: HUMAN_MODEL_MISMATCH
attaches_to:
- pathophysiology#Impaired GH-Induced IGF-1 Production
- animal_models#Mouse
prompt: >-
Why does mouse Stat5a partly substitute for Stat5b in growth-hormone
signalling when human STAT5A apparently does not?
rationale: >-
The Stat5b knockout mouse is GH-resistant with low IGF-I, but its growth
defect is largely confined to males and the IGF-I fall is partial, which
the mouse literature attributes to partial compensation by Stat5a. In
patients IGF deficiency is profound in both sexes, and in patient dermal
fibroblasts endogenous STAT5A did not restore GH-induced IGF1 expression.
The mouse therefore under-models the growth arm of the disease, and the
paralog-redundancy difference that would explain this is not established
in human hepatocytes, the cells that produce circulating IGF-I.
evidence:
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: REVIEW_SYNTHESIS
snippet: "suggested that, in mice, Stat5a can partially compensate for loss of Stat5b"
explanation: States the mouse-side compensation that blunts the knockout's growth phenotype.
- reference: PMID:26703237
reference_title: "STAT5B deficiency: Impacts on human growth and immunity."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: REVIEW_SYNTHESIS
snippet: "which was not restored by activation of endogenous STAT5A"
explanation: >-
In patient fibroblasts STAT5A did not rescue GH-induced IGF1 expression,
the human-side counterpart of the mismatch; fibroblasts are not the
hepatocytes that produce circulating IGF-I.
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.
Create: STAT5B_Deficiency · 2026-09-24T17:03:24Z · View source
New entry for autosomal recessive STAT5B deficiency (MONDO:0100211), the dedicated home named by the STAT5B Deficiency subtype in Growth_Hormone_Insensitivity_Syndrome, which was left unedited. Curated both arms from primary case reports and reviews: the GH-IGF1 arm (GH receptor-STAT5B signalling failure, low IGF-1/IGFBP-3/ALS with normal or high GH, poor response to rhGH, mecasermin therapy with a smaller response than in GHR defects and dose-limiting hypoglycemia) and the immune arm (IL-2-STAT5B signalling failure, regulatory T-cell loss with low FOXP3, NK maturation and cytotoxicity defect, autoimmunity, eczema, hypergammaglobulinemia and IgE, T lymphopenia, recurrent infections and herpetic keratitis, lymphocytic interstitial pneumonia progressing to pulmonary fibrosis) plus hyperprolactinemia recorded as an unproven feedback-loss mechanism. Stat5b knockout mouse linked with a species-mismatch divergence (Stat5a compensation). The heterozygous dominant-negative form (GHIDR2) is mentioned in notes and not merged. Deep research: OpenScientist run completed (exit 0); preflight-dr PASS; its leads PMID:33122102 and PMID:23773921 were fetched and quoted; its suggested HP:0040163 and HP:0008291 were flagged by its own term validation as naming other concepts and were not used. HP:0030353 is bound with the label in cache/hp/terms.csv, which differs from the current OLS label (no 'serum'). An IUIS 2022 table snippet (PMID:35748970) was dropped because 'just validate' refreshes that cache file to an abstract-only version. Validation: validate, validate-terms, count-verified-snippets (78/78), entity refs, causal targets, duplicate keys, enum values and validate-disorders all pass; 22 of 24 phenotypes causally connected (the two facial features are not).
Disease: STAT5B Deficiency (Growth Hormone Insensitivity with Immunodeficiency) MONDO ID: MONDO:0100211 · OMIM: 245590 (phenotype) / 604260 (gene) · Orphanet: ORPHA:181399 · Gene: STAT5B (HGNC:11367; chr17q21.2; NCBI Gene 6777; UniProt P51692) Category:* Mendelian, autosomal recessive
STAT5B deficiency is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function (LOF) mutations in STAT5B, the transcription factor that couples two otherwise distinct receptor systems to their nuclear output. On the endocrine side, STAT5B is the non-redundant signal transducer downstream of the growth hormone receptor (GHR)–JAK2 axis that drives transcription of IGF1, IGFBP3, and IGFALS. On the immune side, STAT5B relays IL-2-family cytokine signals that maintain FOXP3⁺ regulatory T-cell (Treg) homeostasis and normal T/NK-cell biology. Because a single molecular lesion disables both arms, affected patients present with a striking dual phenotype: growth hormone insensitivity (GHI) with severe IGF-I deficiency and postnatal growth failure, plus a primary immunodeficiency/"Tregopathy" featuring autoimmunity, atopy/eczema, recurrent (often viral/herpetic) infections, and potentially fatal lymphocytic interstitial lung disease. This immune component is the defining feature that distinguishes STAT5B deficiency from GHR-mutation (Laron) syndrome, in which growth failure occurs without immune disease.
The two branches of the phenotype are mechanistically largely independent downstream of the shared STAT5B node — IGF-I deficiency drives the growth failure, while Treg failure drives the immune dysregulation. This has a direct therapeutic consequence: recombinant human IGF-1 (rhIGF-1, mecasermin) bypasses the GH-signaling block and partially rescues linear growth, but it does not correct the immunodeficiency, and no single therapy currently addresses both. Prognosis is therefore largely determined by the pulmonary/immune complications, with chronic interstitial lung disease being the principal cause of morbidity and mortality. The closely related paralog STAT5A (>95% amino-acid identity) cannot compensate for loss of STAT5B, explaining the non-redundancy in humans.
This report synthesizes 11 confirmed findings drawn from 45 reviewed papers across all 15 requested sections. Evidence spans human clinical case series (the disorder is documented in roughly a dozen classic homozygous patients as of the mid-2010s, plus additional and "atypical" cases since), in vitro functional studies of variant protein folding and signaling, and the Stat5b-null mouse model, which faithfully recapitulates the Laron-type growth phenotype and the loss of GH-dependent sexual dimorphism.
Overview. STAT5B deficiency is a monogenic growth hormone insensitivity syndrome combined with a primary immunodeficiency. Patients exhibit severe postnatal growth failure with markedly low IGF-I despite normal or elevated GH (i.e., GH insensitivity), together with immune dysfunction that can manifest as chronic, potentially fatal pulmonary disease. It was first defined by the identification of a homozygous STAT5B mutation (p.A630P, SH2 domain) in a female with GHI, immune dysfunction, and severe pulmonary disease [PMID: 21396575].
"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." — PMID: 26703237
Key identifiers. MONDO:0100211; OMIM 245590 (growth hormone insensitivity with immunodeficiency); OMIM 604260 (STAT5B gene); Orphanet ORPHA:181399; MeSH concepts relate to "Laron Syndrome"/"growth hormone insensitivity." The gene STAT5B* is HGNC:11367 on chromosome 17q21.2.
Synonyms / alternative names. Growth hormone insensitivity with immunodeficiency; GHI due to STAT5B deficiency; STAT5b growth hormone insensitivity syndrome (GHIS); autosomal recessive growth hormone insensitivity with immune dysregulation.
Information source. Disease-level knowledge here is derived predominantly from aggregated individual patient case reports and small case series (given ultra-rarity), supplemented by in vitro functional studies and the mouse knockout, rather than from EHR-scale or population registries.
Primary cause — genetic. The disease is caused by biallelic (homozygous or compound-heterozygous) inactivating mutations in STAT5B. The critical role of STAT5B in IGF-I production became evident when homozygous, autosomal recessive STAT5B mutations were found in children with severe postnatal growth failure, GHIS, and marked IGF-I deficiency [PMID: 21396575].
"the critical importance of STAT5b in IGF-I production became evident with the identification of homozygous, autosomal recessive STAT5b mutations in patients who presented with severe postnatal growth failure, growth hormone insensitivity syndrome (GHIS) and marked IGF-I deficiency" — PMID: 21396575
Genetic risk factors. The causal variants are the STAT5B LOF alleles themselves (nonsense, frameshift, SH2-domain missense; see Section 4). Consanguinity is a major risk context: most classic patients are born to consanguineous unions, consistent with recessive inheritance of rare alleles. Modifier effect: the specific variant class modifies immune/pulmonary expressivity — some expressed-LOF variants give an "atypical," immunologically milder phenotype [PMID: 36265659].
Environmental risk / protective factors. No established environmental cause, protective diet, exposure, or lifestyle factor exists for this Mendelian disorder. Environmental exposures (e.g., infectious agents) act as triggers of complications (see Section 5) rather than causes of disease.
Gene–environment interactions. The principal gene–environment interplay is that the underlying immunodeficiency renders patients susceptible to environmental pathogens (viral/herpetic and respiratory infections), which precipitate the chronic lung disease that dominates prognosis. This is a downstream consequence of the genotype rather than a classical GxE susceptibility modifier.
STAT5B deficiency spans two phenotypic domains. Onset is congenital-to-early-childhood; growth failure is essentially fully penetrant in complete biallelic LOF, while the immune/pulmonary features are variably expressed.
| Phenotype | Type | Onset / severity / frequency | Suggested HPO term |
|---|---|---|---|
| Severe postnatal short stature (height typically −4 to −6 SDS) | Physical/clinical sign | Postnatal, severe, near-complete penetrance | HP:0004322 (Short stature) / HP:0008897 (Postnatal growth retardation) |
| IGF-I deficiency (low serum IGF-I) | Laboratory abnormality | Congenital/childhood, consistent | HP:0040163 (Decreased circulating IGF-1) |
| Growth hormone insensitivity (normal/high GH, failed IGF-I generation) | Laboratory abnormality | Childhood, consistent | HP:0008291 (Growth hormone resistance) |
| Eczema / atopic dermatitis | Clinical sign | From birth in severe cases | HP:0000964 (Eczema) / HP:0001047 (Atopic dermatitis) |
| Recurrent infections (skin, respiratory) | Clinical sign | From birth, severe | HP:0002719 (Recurrent infections) |
| Chronic/lymphocytic interstitial lung disease | Clinical sign/manifestation | Childhood, severe, potentially fatal | HP:0006515 (Interstitial pulmonary abnormality) / HP:0002205 (Recurrent respiratory infections) |
| Herpetic keratitis / recurrent herpes-varicella | Clinical sign | Recurrent, reflects NK/T defect | HP:0100648 / HP:0002205 |
| Autoimmunity (thyroiditis, cytopenias/thrombocytopenia, juvenile idiopathic arthritis) | Clinical sign | Variable | HP:0002960 (Autoimmunity) |
| Elevated IgE | Laboratory abnormality | Variable | HP:0003212 (Increased IgE level) |
| T-cell lymphopenia; low NK and γδ T cells; reduced Tregs | Laboratory abnormality | Consistent in severe cases | HP:0005403 (Decreased T cells) |
| Hyperprolactinemia | Laboratory abnormality | Reported | HP:0000870 (Increased circulating prolactin) |
Representative quantitative immunophenotype from a complete-LOF patient (homozygous nonsense, codon 152): moderate T-cell lymphopenia (1274/mm³), very low NK (18/mm³) and γδ T cells (5/mm³), chronically hyperactivated T cells, impaired IL-2 signaling, diminished CD4⁺CD25⁺ Tregs [PMID: 17030597].
"The main immunologic findings were moderate T-cell lymphopenia (1274/mm3), normal CD4/CD8 ratio, and very low numbers of natural killer (18/mm3) and gammadelta T (5/mm3) cells." — PMID: 17030597
"generalized eczema and recurrent infections of the skin and respiratory tract since birth. She also suffered severe chronic lung disease and multiple episodes of herpetic keratitis" — PMID: 17030597
Quality of life impact. Combined burden is substantial: severe short stature (psychosocial and functional impact), chronic lung disease (respiratory limitation, hospitalizations, mortality risk), recurrent infections, atopic disease, and autoimmune complications. No disease-specific EQ-5D/SF-36 instrument data are available given ultra-rarity.
Causal gene. STAT5B (HGNC:11367; OMIM 604260; chr17q21.2; NCBI Gene 6777; UniProt P51692). STAT5B lies adjacent to its paralog STAT5A, with which it shares >95% amino-acid identity; STAT5A cannot* compensate for loss of STAT5B [PMID: 26703237].
Pathogenic variant spectrum. Reported biallelic LOF variants include:
| Variant | Type | Consequence |
|---|---|---|
| p.Arg152* (codon 152, exon 5) | Nonsense | Complete absence of protein [PMID: 17030597] |
| p.Trp631* | Nonsense | Loss of function; treated siblings [PMID: 37586336] |
| p.Gln368Profs*9 | Frameshift | LOF |
| p.Asp485Thrfs*29 | Frameshift (expressed) | Atypical, milder immune phenotype [PMID: 36265659] |
| p.A630P (SH2 domain) | Missense | Misfolding/aggregation → inactive TF [PMID: 23160480] |
| p.F646S (SH2 domain) | Missense | LOF |
| p.K632N (heterozygous) | Missense | Inactivating; partial GHI, mild immune [PMID: 31902742] |
As of 2016, 7 homozygous inactivating mutations were reported across 10 patients; the number has grown since [PMID: 26703237].
Functional consequences. Most are loss of function. SH2-domain missense variants act by protein misfolding, aggregation, and diminished solubility, abolishing GH-induced tyrosine phosphorylation, dimerization, and nuclear translocation [PMID: 23160480].
"STAT5b(A630P) was found to be an inactive transcription factor based on its aberrant folding, diminished solubility, and propensity for aggregation triggered by its misfolded SH2 domain" — PMID: 23160480
Genotype–phenotype correlation. Classic complete biallelic LOF → severe growth failure + immunodeficiency + pulmonary disease. Some expressed LOF variants (e.g., p.Asp485Thrfs29) produce severe short stature with only mild immunodeficiency and no pulmonary disease ("atypical STAT5B deficiency") [PMID: 36265659]. Heterozygous inactivating/dominant-negative variants (e.g., p.K632N) cause milder partial* GHI [PMID: 31902742].
"expressed loss-of-function STAT5B variants may alleviate severe immune and pulmonary issues normally associated with STAT5B deficiency" — PMID: 36265659
Allele frequency / origin. Causal alleles are ultra-rare/private, enriched in consanguineous families; germline in origin. (Note: somatic activating STAT5B mutations cause lymphoproliferative disease but do not affect growth — see Section 11.) Modifier genes / epigenetics / chromosomal abnormalities: none specifically established for classic STAT5B deficiency; a mosaic 17q21–25 duplication is a distinct GHI mimic affecting NF-κB/STAT5 signaling [PMID: 26670721].
Branch A — Growth (endocrine): 3A. GH binds GHR → JAK2 activates, but STAT5B cannot relay the signal → failure to transactivate IGF1, IGFBP3, IGFALS [PMID: 33122102]. (demonstrated) 4A. → IGF-I deficiency (low IGF-I, IGFBP-3, ALS) → severe postnatal growth failure / GH insensitivity [PMID: 21396575, 26703237]. (demonstrated)
Branch B — Immunity: 3B. IL-2/IL-7/IL-15 and other cytokine receptors → JAK → STAT5B signaling is lost [PMID: 33122102]. (demonstrated) 4B. → reduced FOXP3⁺ CD4⁺CD25⁺ Treg numbers and impaired suppressive function; disturbed T/NK homeostasis [PMID: 23773921, 17030597]. (demonstrated) 5B. → loss of peripheral tolerance + immunodeficiency → autoimmunity, atopy/eczema, recurrent (viral/herpetic) infections, and lymphocytic interstitial pneumonitis / chronic lung disease [PMID: 23773921, 17030597]. (demonstrated / clinically observed)
Branch C — Neuroendocrine (inferred/observed): 3C. Loss of STAT5B negative feedback on prolactin/somatostatin → hyperprolactinemia [PMID: 17287404]; mouse data show reduced hypothalamic somatostatin mRNA [PMID: 15796771].
"GH promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-JAK2-signal transducer and activator of transcription (STAT)-5B signaling pathway" — PMID: 33122102
"Only AR STAT5B defects, however, confer additional characteristics of immune dysfunction which can manifest as chronic, potentially fatal, pulmonary disease" — PMID: 33122102
"Functional ex vivo studies in homozygous STAT5B-deficient patients showed reduced FOXP3 expression with impaired regulatory function of STAT5B-null Treg cells, also of increased memory phenotype." — PMID: 23773921
biallelic STAT5B LOF
│
(absent / misfolded, aggregated STAT5B)
│
┌───────────────────┴────────────────────┐
GH → GHR → JAK2 IL-2/IL-7/IL-15 → JAK
│ (STAT5B cannot phosphorylate/translocate to nucleus)
▼ ▼
↓ IGF1/IGFBP3/IGFALS transcription ↓ FOXP3+ Treg number & function
│ │
▼ ▼
IGF-I DEFICIENCY LOSS OF TOLERANCE + IMMUNODEFICIENCY
│ │
▼ ▼
SEVERE GROWTH FAILURE autoimmunity · eczema/atopy · recurrent/viral
(GH insensitivity) infections · interstitial lung disease
│
rhIGF-1 rescues ── partial ──► (does NOT rescue immune branch)
Upstream vs downstream. STAT5B loss is the single upstream node; IGF-I deficiency (growth) and Treg failure (immunity) are parallel downstream endpoints. Their independence explains why rhIGF-1 rescues growth but not immunity.
Suggested ontology terms. Biological processes: GO:0007259 (JAK-STAT signaling), GO:0060397 (GH receptor signaling via JAK-STAT), GO:0060333 (cytokine-mediated signaling), GO:0002456 (T-cell mediated immunity), GO:0043069 (regulation of programmed cell death / tolerance). Cell types: CL:0000792 (CD4⁺CD25⁺ Treg), CL:0000623 (NK cell), CL:0000798 (γδ T cell), CL:0000182 (hepatocyte), CL:0000138 (chondrocyte). Subcellular: GO:0005634 (nucleus). Chemical entities: CHEBI IGF-1 / prolactin / somatostatin.
"The cellular abundance of somatostatin mRNA in STAT5b-deficient mice was significantly reduced in the periventricular nucleus" — PMID: 15796771
"To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported." — PMID: 26703237
Biochemical signature of GH insensitivity: - Severe short stature (height typically −4 to −6 SDS) - Markedly low serum IGF-I (< −2.5 SDS) and IGFBP-3 (< −3 SDS); low ALS - Normal-to-elevated basal/stimulated GH - Failed IGF-I generation test (no IGF-I rise after rhGH)
Representative GHI-cohort values: mean height SDS −4.1 ± 0.95, IGF-1 SDS −2.8 ± 1.4, IGFBP3 SDS −3.0 ± 2.1, basal/peak GH 11.9 / 32.9 µg/L [PMID: 29500309].
"basal and stimulated growth hormone levels were very high, IGF-1 was low, and the inadequate response to the IGF generation test was consistent with growth hormone insensitivity" — PMID: 41099230
Immune workup (distinguishes from Laron/GHR disease): T-cell subsets (moderate T lymphopenia), low NK and γδ T cells, Treg quantification (low CD4⁺CD25⁺FOXP3⁺), IgE, autoantibodies, and prolactin (often elevated) [PMID: 17030597, 17287404]. Chest imaging/HRCT for interstitial lung disease.
"Prolactin secretion was increased by sixfold." — PMID: 17287404
Genetic testing. Confirmation is molecular: single-gene STAT5B sequencing, GH/IGF-axis gene panels, or WES/WGS. Upfront genomic sequencing is increasingly advocated for primary atopic/immune-dysregulation presentations [PMID: 39381601].
Differential diagnosis of GHI: GHR defects (Laron syndrome — no immune disease); IGFALS and IGF1 defects; IGF1R haploinsufficiency (relatively high IGF-I); STAT3 gain-of-function (partial GHI + autoimmunity) [PMID: 29378236]; IKBKB/NF-κB pathway defects; PGM1-CDG [PMID: 41099230] and Fanconi anemia [PMID: 28502327] (Laron mimics); rasopathies (Noonan/NS-LAH). The key discriminator for STAT5B deficiency is GHI + immune dysfunction (± hyperprolactinemia).
Screening. Cascade genetic testing of at-risk relatives in consanguineous families; carrier testing once the familial variant is known.
"can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease" — PMID: 26703237
Growth therapy — rhIGF-1 (mecasermin / Increlex; NCIT-suggested: recombinant human IGF-1). Because the defect lies downstream of GHR, exogenous GH is ineffective; rhIGF-1 bypasses the block. In three siblings with homozygous STAT5B p.Trp631, rhIGF-1 (40 µg/kg/dose BID escalating to 110–120 µg/kg/dose SQ BID) raised height velocity from ~3.0 cm/yr baseline to 4.8–7.4 cm/yr in the first 3 years, then declined (3.8–4.7 cm/yr), i.e., incomplete catch-up* [PMID: 37586336].
"With rhIGF-1 therapy, HVs increased to 5.2-6.0, 4.8-7.1, and 5.5-7.4 cm/year, respectively, in the first 3 years of treatment, before they decreased to 4.7, 3.8, and 4.3" — PMID: 37586336
Broader Laron/GHI cohorts confirm rhIGF-1 raises height velocity durably (e.g., 3.4→6.5 cm/yr in year 1, sustained over years) though many patients do not reach normal adult height [PMID: 39657622]. Mecasermin rinfabate (rhIGF-1/rhIGFBP-3 complex) is an alternative formulation developed for GHIS [PMID: 15777106]. Dosing is limited by hypoglycemia risk; glucose monitoring is required.
Critical limitation. rhIGF-1 does not correct the immunodeficiency; no single treatment improves both growth and immune disease [PMID: 21396575].
"At present, no single treatment(s) is available to improve both poor statural growth and immune deficiency." — PMID: 21396575
Immune/supportive management: infection prophylaxis and prompt treatment, management of interstitial lung disease, immunomodulation for autoimmune complications, and management of atopy. Hematopoietic stem cell transplantation (HSCT) has been considered for the immune component (curative-intent for the Tregopathy), given parallels with other Tregopathies [PMID: 30527062].
Advanced/experimental: No approved gene or cell therapy specific to STAT5B deficiency; conceptually, the Tregopathy framework raises cell/gene-therapy possibilities for the immune arm [PMID: 30527062]. NCIT-suggested intervention terms: recombinant IGF-1 therapy; hematopoietic stem cell transplantation; supportive/anti-infective therapy.
Mouse Stat5b knockout is the principal model. Gene disruption causes loss of male-characteristic body-growth rates and male-specific liver gene expression, dwarfism, elevated plasma GH, low plasma IGF-I, and obesity — all features of Laron-type dwarfism [PMID: 9207075]. The mice are GH-pulse-resistant, not GH-deficient; STAT5b is tyrosine-phosphorylated by intermittent (male-pattern) GH pulses in liver [PMID: 10752065]. STAT5b-deficient mice also show reduced hypothalamic periventricular somatostatin mRNA [PMID: 15796771].
"the dwarfism, elevated plasma GH, low plasma insulin-like growth factor I, and development of obesity seen in STAT5b-/- mice are all characteristics of Laron-type dwarfism, a human GH-resistance disease generally associated with a defective GH receptor" — PMID: 9207075
"STAT5b is tyrosine phosphorylated in male but not female rats in response to GH pulses" — PMID: 10752065
Model types: mammalian (mouse knockout; rat for GH-pulse phosphorylation studies); in vitro/cellular systems (fibroblasts, primary human T cells with STAT5B knockdown [PMID: 23773921]) for the immune arm. Genetic model types available: knockout (documented); conditional/tissue-specific approaches feasible.
Phenotype recapitulation: The mouse faithfully recapitulates the growth/GH-resistance phenotype and sexual-dimorphism loss. Limitations: the human immune/pulmonary phenotype is less completely modeled, and paralog redundancy differs between species (STAT5A/STAT5B compensation differs), so the mouse under-represents the human immunodeficiency. Human T-cell knockdown studies are needed to model the immune arm.
Resources: MGI (mouse Stat5b), IMSR/IMPC for strain availability.
STAT5B deficiency is best understood as a single-node, two-output signaling failure. STAT5B sits at the convergence of the GHR–JAK2 growth axis and the IL-2-family immune axis. Its loss simultaneously (1) uncouples GH from hepatic IGF-I production, producing GH insensitivity and severe growth failure, and (2) uncouples IL-2-family cytokines from FOXP3⁺ Treg maintenance, producing a Tregopathy with autoimmunity, atopy, infection susceptibility, and interstitial lung disease. These two outputs are mechanistically independent downstream of STAT5B, which is the central clinical insight: it predicts (correctly) that rhIGF-1 — acting below the block — rescues growth while leaving the immune deficit untouched, and it frames HSCT (replacing the hematopoietic compartment) as the rational strategy for the immune arm. Genotype tunes the balance: complete biallelic LOF yields the full dual syndrome, whereas expressed hypomorphic/atypical LOF can retain enough immune signaling to spare the lungs. The mouse knockout validates the growth arm decisively but under-models the immune arm, reflecting species differences in STAT5A/STAT5B redundancy.
A further axis of classification places STAT5B LOF among the "program switchers" — inborn errors of immunity that convert immunodeficiency into autoimmunity — and among primary atopic disorders and Tregopathies [PMID: 27803128, 30527062]. This contrasts sharply with somatic activating STAT5B mutations, which cause clonal lymphoproliferative/neoplastic disease (e.g., LGL leukemia) without impairing linear growth, underscoring that it is germline biallelic loss of function, not gain of function, that produces the growth-plus-immunodeficiency syndrome [PMID: 33122102].
| PMID | Title (abbrev.) | Supports |
|---|---|---|
| 26703237 | STAT5B deficiency: impacts on growth and immunity | Dual phenotype; rarity; STAT5A non-compensation |
| 21396575 | Lessons from STAT5b gene mutations | AR inheritance; IGF-I role; no dual therapy |
| 33122102 | GH action disorders: STAT5B & JAK2 | Upstream axis; immune branch unique to AR LOF; GOF contrast |
| 23773921 | STAT5B vs STAT5A in CD4⁺ T cells | Treg/FOXP3 defect; STAT5B non-redundancy |
| 17030597 | Immunodeficiency in STAT5b mutation | Quantitative immunophenotype; eczema/infections |
| 17287404 | GH secretion & immunity in STAT5b patient | Hyperprolactinemia |
| 23160480 | STAT5b folding/activity | SH2 misfolding/aggregation mechanism |
| 36265659 | Atypical STAT5B deficiency | Genotype–phenotype: expressed LOF spares lungs |
| 31902742 | Heterozygous STAT5B variant | Partial GHI from heterozygous inactivating variant |
| 37586336 | rhIGF-1 in 3 STAT5B siblings | rhIGF-1 efficacy and waning |
| 39657622 | 22-yr IGF-1 in Laron syndrome | Long-term rhIGF-1 growth benefit context |
| 9207075 | Stat5b required for sexual dimorphism | Mouse KO recapitulates Laron growth phenotype |
| 10752065 | GH pulse-activated STAT5 | GH-pulse activation mechanism |
| 15796771 | Hypothalamic STAT5b/somatostatin | Neuroendocrine involvement (mouse) |
| 29500309 | Pseudoexon GHR mutation cohort | GHI biochemical signature values |
| 41099230 | PGM1-CDG misdiagnosed as Laron | IGF-I generation test; differential |
| 30527062 | Tregopathies review | Classification; treatment framework |
| 27803128 | STAT program switchers | Autoimmune/allergic + infection spectrum |
Contrasting/supporting nuance: [PMID: 27803128] and [PMID: 33122102] together frame the germline-LOF (growth + immunodeficiency) versus somatic-GOF (immune neoplasia, no growth effect) dichotomy.
"Somatic activating STAT5B and JAK2 mutations are associated with a plethora of immune abnormalities but appear not to impact human linear growth." — PMID: 33122102
"STAT5B LOF and STAT3 GOF mutations are both associated with disorders characterized by autoimmune or allergic manifestations, together with increased risk of infections." — PMID: 27803128
Report compiled from 11 confirmed findings across 5 investigation iterations and 45 reviewed publications. Evidence types: human clinical case series/reports, in vitro functional studies, and the Stat5b-null mouse model.
Checked with linkml-reference-validator 0.3.0rc1.
| Outcome | Count |
|---|---|
| References checked | 23 |
| Resolved | 23 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 20 |
| Quoted claims found in source | 20 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 23 |
| On topic | 15 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 32 |
| Resolved | 30 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 2 |
| Terms whose name was checked | 22 |
| Terms named correctly | 7 |
| Terms named as a different term | 4 |
| Terms whose name is worth a second look | 11 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0040163 (1 mention) - the report calls it "Decreased circulating IGF-1"; HP calls it Abnormal pelvis bone morphologyHP:0008291 (1 mention) - the report calls it "Growth hormone resistance"; HP calls it Pituitary corticotropic cell adenomaGO:0005634 (3 mentions) - the report calls it "nucleus", "Subcellular: defective cytoplasm→nucleus"; GO calls it nucleusCL:0000792 (2 mentions) - the report calls it "CD4⁺CD25⁺ Treg"; CL calls it CD4-positive, CD25-positive, alpha-beta regulatory T cellThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0003212 (1 mention) - the report calls it "Increased IgE level"; HP calls it Increased circulating IgE concentration, and lists "Increased circulating IgE level" among its other namesHP:0005403 (1 mention) - the report calls it "Decreased T cells"; HP calls it Decreased total T cell count, and lists "Decrease in T cell count" among its other namesHP:0000870 (1 mention) - the report calls it "Increased circulating prolactin"; HP calls it Increased circulating prolactin concentrationGO:0007259 (1 mention) - the report calls it "JAK-STAT signaling"; GO calls it cell surface receptor signaling pathway via JAK-STAT, and lists "JAK-STAT signal transduction" among its other namesGO:0060397 (1 mention) - the report calls it "GH receptor signaling via JAK-STAT"; GO calls it growth hormone receptor signaling pathway via JAK-STATGO:0060333 (1 mention) - the report calls it "cytokine-mediated signaling"; GO calls it type II interferon-mediated signaling pathway, and lists "type II IFN-mediated signaling pathway" among its other namesGO:0043069 (1 mention) - the report calls it "regulation of programmed cell death / tolerance"; GO calls it negative regulation of programmed cell death, and lists "downregulation of programmed cell death" among its other namesCL:0000623 (2 mentions) - the report calls it "NK cell"; CL calls it natural killer cell, and lists "NK cell" among its other namesCL:0000798 (2 mentions) - the report calls it "γδ T cell"; CL calls it gamma-delta T cell, and lists "gd T cell" among its other namesUBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other namesUBERON:0002405 (1 mention) - the report calls it "Immune system / lymphoid tissue"; UBERON calls it immune systemThe report gives these identifiers more than one name of its own:
GO:0005634 - called "nucleus", "Subcellular: defective cytoplasm→nucleus"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.