IL6ST-Related Stuve-Wiedemann Syndrome

🏷

Classifications

Harrison's Part

ISDS Skeletal Nosology

🔗

Mappings

MONDO

MONDO:0031280 Stuve-Wiedemann syndrome Not Yet Curated

MONDO:0031280 is the parent grouping covering both the LIFR-related (MONDO:0800043) and IL6ST-related (MONDO:0030756) forms. This entry is restricted to the IL6ST disease.

👪

Inheritance

1

Autosomal recessive HP:0000007

Autosomal recessive. All reported individuals carry biallelic IL6ST loss-of-function alleles — homozygous in every published case — segregating in three unrelated families in the delineating series and in one further consanguineous pregnancy.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31914175 SUPPORT Human Clinical

"We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping)."

Establishes biallelic (homozygous) IL6ST loss of function as the genetic basis across the delineating families.

PMID:40835206 SUPPORT Human Clinical

"Bi-allelic loss-of-function variants in either the leukemia inhibitory factor receptor encoding LIFR or the interleukin-6 cytokine family signal transducer encoding IL6ST are causative."

Independent restatement of biallelic inheritance for the IL6ST form, alongside the LIFR form.

?

Discussions and Knowledge Gaps

2

Is the bent-bone phenotype of STWS2 driven by loss of LIF signaling alone, or do the concurrently lost IL-6, IL-11, IL-27 and OSM arms contribute to the skeletal phenotype in a way that the LIFR-null comparison cannot detect?

KNOWLEDGE GAP OPEN stws2_lif_versus_pan_family_skeletal_attribution

Attached to

pathophysiology#Failed LIF-Dependent Skeletal Development

The attribution of the skeletal arm to LIF rests entirely on a phenotype comparison: STWS1 loses only LIF-family input and looks the same. That is an argument from similarity across two tiny case series, and it cannot exclude a contribution from IL-11, which has an established role in bone. Distinguishing them matters because it decides whether a signaling-restoration strategy would need to restore GP130 or could target the LIF axis alone. No IL6ST-null animal model of the skeletal phenotype has been reported alongside a LIFR-null comparison in the same study.

Show evidence (1 reference)

PMID:38133879 SUPPORT Other

"Similarities of patients with loss of LIFR signaling and patients that had complete absence of GP130 suggest that LIF is essential during embryonic development."

The word "suggest" is the authors' own hedge, and marks this as an inference from phenotypic similarity rather than a demonstrated attribution.

Is there any tractable therapeutic strategy for complete GP130 loss, given that hematopoietic-restricted correction cannot reach the skeletal and autonomic compartments?

KNOWLEDGE GAP OPEN stws2_gp130_reconstitution_delivery_gap

Attached to

treatments#

Lentiviral reconstitution of GP130 rescues signaling in patient-derived cells, so the defect is correctable in principle. But the disorder is prenatal and multi-organ, and allogeneic bone marrow transplantation — the approach borrowed from STAT3 hyper-IgE — corrects only the hematopoietic compartment. Whether any delivery route could reach chondrocytes and autonomic neurons early enough is unaddressed in the literature.

Show evidence (1 reference)

PMID:38133879 SUPPORT Other

"this will not be effective in treating the multi-organ manifestations of severe Stüve-Wiedemann syndrome."

States that hematopoietic correction cannot address the multi-organ phenotype, which is the gap this discussion records.

⚙

Pathophysiology

5

Biallelic IL6ST Loss of Function

Biallelic essential loss-of-function IL6ST alleles — nonsense (c.841C>T, p.Arg281*), an intronic splice variant causing exon 13 skipping (c.1699+4A>G), and a further truncating allele (p.Ser375*) — abolish functional cell-surface GP130. The truncating alleles lie in the extracellular domains, so the predicted products are soluble rather than membrane-anchored receptor fragments; the exon-13 skipping allele instead misfolds the membrane-proximal D6 domain, which is where the receptor transmits signal across the membrane.

IL6ST hgnc:6021

Genetic context variant_origin: GERMLINE allelic_hit_role: BIALLELIC_INACTIVATION zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Homozygous germline null alleles of IL6ST (nonsense or essential splice). No compound-heterozygous STWS2 genotype has been reported; every published case arose in a consanguineous or homozygous-by-descent setting.

cytokine receptor activity GO:0004896 ⇓ LOSS OF FUNCTION

Downstream

Pan-IL-6-Family GP130 Signaling Failure

Show evidence (3 references)

PMID:31914175 SUPPORT Human Clinical

"We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping)."

Names the two allele classes in the delineating series and calls them essential (as opposed to cytokine-selective) loss of function.

PMID:38133879 SUPPORT Other

"Loss of exon 13 in the c.1699+4A>G splice variant abrogates folding of GP130 membrane-proximal domain D6 impairing transmembrane signal transmission"

Gives the structural reason the splice allele is a null rather than a hypomorph, which is what places it in the complete-loss class.

PMID:38133879 SUPPORT Other

"These variants affect the extracellular domains of GP130 likely leading to the expression of truncated soluble GP130 variants"

Establishes that the truncating STWS2 alleles remove the receptor from the membrane rather than producing a signaling-competent stump.

Pan-IL-6-Family GP130 Signaling Failure

GP130 is the shared transducer of the whole IL-6 cytokine family, so its complete loss silences every member at once — IL-6, IL-11, IL-27, oncostatin M and LIF have all been shown unresponsive in patient cells. This is the node that separates STWS2 from STWS1: LIFR loss removes only the LIF-receiving chain, leaving IL-6, IL-11 and IL-27 signaling intact. It also separates STWS2 from the IL6ST hyper-IgE and craniosynostosis phenotypes, which are cytokine-selective defects that spare LIF. Lentiviral reconstitution of GP130 in patient cells restores signaling, which is the strongest available evidence that the failure is the direct consequence of the genotype.

interleukin-6-mediated signaling pathway GO:0070102 ⇓ LOSS OF FUNCTION interleukin-11-mediated signaling pathway GO:0038154 ⇓ LOSS OF FUNCTION interleukin-27-mediated signaling pathway GO:0070106 ⇓ LOSS OF FUNCTION oncostatin-M-mediated signaling pathway GO:0038165 ⇓ LOSS OF FUNCTION leukemia inhibitory factor signaling pathway GO:0048861 ⇓ LOSS OF FUNCTION JAK-STAT cascade GO:0007259 ↓ DECREASED

Experimental models

Lentiviral GP130 reconstitution in patient-derived cells PRIMARY CELL CULTURE Restoring GP130 in the patient's own cells reverses the signaling defect, establishing that the loss of IL-6-family responses follows from the IL6ST genotype rather than from a co-segregating variant or a culture artifact.

Downstream

Failed LIF-Dependent Skeletal Development

Autonomic and Respiratory Dysfunction

Loss of IL-6 and IL-11 Dependent Hematopoietic, Epithelial and Hepatic Responses

Show evidence (4 references)

PMID:31914175 SUPPORT In Vitro

"Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF)."

Direct patient-cell readout that all five tested GP130-dependent cytokines fail, which is the defining property of this node.

PMID:31914175 SUPPORT In Vitro

"Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect."

Rescue experiment establishing that the signaling failure is caused by the IL6ST genotype rather than by a co-segregating factor.

PMID:31914175 SUPPORT Other

"The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines."

States why one receptor loss silences a whole cytokine family, which is the premise of this node.

+ 1 more reference

Failed LIF-Dependent Skeletal Development

Absent LIF-family signaling in the developing skeleton produces the bent-bone phenotype. That this arm is LIF-driven rather than IL-6- or IL-11-driven is inferred from the near-identity of the STWS2 and STWS1 skeletal phenotypes: LIFR loss removes only LIF-family input, and reproduces the same bowing, shortening and defective mineralization.

chondrocyte CL:0000138 osteoblast CL:0000062

skeletal system development GO:0001501 ↓ DECREASED chondrocyte differentiation GO:0002062 ↓ DECREASED

Downstream

Bowing of the Long Bones

Short Long Bones

Narrow Thorax

Abnormal Bone Mineralization

Joint Dislocations

Dolichocephaly

Show evidence (3 references)

PMID:31914175 SUPPORT Human Clinical

"This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development."

The authors' own attribution of the pre- and perinatal developmental phenotype to the LIF arm specifically.

PMID:38133879 SUPPORT Other

"Similarities of patients with loss of LIFR signaling and patients that had complete absence of GP130 suggest that LIF is essential during embryonic development."

States the STWS1/STWS2 phenotype-comparison argument this node rests on.

PMID:40835206 SUPPORT Human Clinical

"The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."

Gives the skeletal findings of the most completely described IL6ST case.

Autonomic and Respiratory Dysfunction

As in LIFR-related STWS1, loss of LIF-family signaling in autonomic and sensory neurons produces neonatal dysautonomia, and the neonate presents with lung dysfunction that, combined with the narrow thorax, is the usual proximate cause of perinatal death.

cytokine-mediated signaling pathway GO:0019221 ⇓ LOSS OF FUNCTION

Downstream

Neonatal Respiratory Distress

Abnormal Autonomic Nervous System Physiology

Show evidence (2 references)

PMID:31914175 SUPPORT Human Clinical

"We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal..."

Establishes neonatal lung dysfunction as a defining feature of the delineating series.

PMID:40835206 SUPPORT Human Clinical

"Stüve-Wiedemann syndrome is a rare skeletal dysplasia characterized by severe shortening and bowing of the long bones and by immunological and autonomous dysfunction, usually resulting in early death."

Places autonomic ("autonomous") dysfunction in the defining description of the syndrome, for which both genes are causative.

Loss of IL-6 and IL-11 Dependent Hematopoietic, Epithelial and Hepatic Responses

This node is what "extended" Stuve-Wiedemann syndrome means. IL-11 is required for megakaryocytopoiesis and IL-6 for the hepatic acute-phase response; both are intact in STWS1 and both are lost in STWS2. The resulting congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities and absent acute-phase response are the features that distinguish the IL6ST disorder clinically from the LIFR one, and they are the mechanistic signature of losing the shared transducer rather than one ligand chain.

acute-phase response GO:0006953 ⇓ LOSS OF FUNCTION interleukin-11-mediated signaling pathway GO:0038154 ⇓ LOSS OF FUNCTION

Downstream

Congenital Thrombocytopenia

Eczematoid Dermatitis

Abnormal Renal Morphology

Defective Acute-Phase Response

Show evidence (2 references)

PMID:31914175 SUPPORT Human Clinical

"with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"

Enumerates exactly the extra-skeletal features this node accounts for.

PMID:31914175 SUPPORT Other

"Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling."

Frames the complete-loss genotype against the selective ones, which is why these additional features appear only here.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

12

Immune 1

Eczematoid Dermatitis HP:0000964

Show evidence (1 reference)

PMID:31914175 SUPPORT Human Clinical

"with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"

Lists eczematoid dermatitis among the additional features.

Limbs 1

Bowing of the Long Bones VERY_FREQUENT HP:0006487

Show evidence (1 reference)

PMID:40835206 SUPPORT Human Clinical

"Stüve-Wiedemann syndrome is a rare skeletal dysplasia characterized by severe shortening and bowing of the long bones and by immunological and autonomous dysfunction, usually resulting in early death."

Bowing of the long bones is given as a defining feature.

Musculoskeletal 2

Narrow Thorax Narrow chest HP:0000774

Show evidence (1 reference)

PMID:40835206 SUPPORT Human Clinical

"The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."

Records a narrow upper thorax on postmortem examination.

Joint Dislocations HP:0001373

Show evidence (1 reference)

PMID:40835206 SUPPORT Human Clinical

"The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."

Reports joint dislocations directly.

Nervous System 1

Abnormal Autonomic Nervous System Physiology HP:0012332

Show evidence (1 reference)

PMID:40835206 SUPPORT Human Clinical

"Stüve-Wiedemann syndrome is a rare skeletal dysplasia characterized by severe shortening and bowing of the long bones and by immunological and autonomous dysfunction, usually resulting in early death."

"Autonomous dysfunction" (dysautonomia) is given as a defining feature of the syndrome for which IL6ST is one of the two causative genes.

Respiratory 1

Neonatal Respiratory Distress VERY_FREQUENT HP:0002643

Show evidence (1 reference)

PMID:31914175 SUPPORT Human Clinical

"We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal..."

Neonatal lung dysfunction is named as a defining feature.

Other 6

Short Long Bones VERY_FREQUENT HP:0003026

Show evidence (1 reference)

PMID:40835206 SUPPORT Human Clinical

"We here report on a sixth case that came to attention at 21 weeks of gestation with short and bowed long bones."

Documents shortening together with bowing at 21 weeks of gestation.

Abnormal Bone Mineralization Abnormal bone ossification HP:0011849

Show evidence (1 reference)

PMID:40835206 SUPPORT Human Clinical

"The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."

Reports abnormal bone mineralization directly.

Dolichocephaly HP:0000268

Show evidence (1 reference)

PMID:40835206 SUPPORT Human Clinical

"The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."

Reports dolichocephalus directly.

Congenital Thrombocytopenia HP:0001905

Show evidence (1 reference)

PMID:31914175 SUPPORT Human Clinical

"with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"

Lists congenital thrombocytopenia among the additional features.

Abnormal Renal Morphology HP:0012210

Show evidence (1 reference)

PMID:31914175 SUPPORT Human Clinical

"with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"

Lists renal abnormalities among the additional features.

Defective Acute-Phase Response Decreased circulating C-reactive protein concentration HP:0032437

Show evidence (1 reference)

PMID:31914175 SUPPORT Human Clinical

"with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"

Lists a defective acute-phase response among the additional features. The HP binding is to the C-reactive protein readout, which is the measurable form the defect takes; "defective acute-phase response" itself has no HP term.

🧬

Genetic Associations

1

IL6ST

Gene: IL6ST hgnc:6021 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:31914175 SUPPORT Human Clinical

"We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping)."

Establishes IL6ST as the causal gene for this disorder.

PMID:40835206 SUPPORT Human Clinical

"Prenatal trio exome sequencing revealed the homozygous novel variant p.(Ser375∗) in IL6ST in the fetus."

Adds an independent truncating allele in an independent family.

PMID:38133879 SUPPORT Other

"A patient with craniosynostosis and dental anomalies but no immune dysregulation carried a homozygous missense variant p.R281Q"

Documents the same-codon contrast: a missense at Arg281 gives an IL-11-selective phenotype, whereas the nonsense allele at that codon gives STWS2.

💊

Medical Actions

2

Neonatal Intensive and Supportive Care

Action: Supportive Care NCIT:C15747

There is no disease-modifying therapy. Management is intensive neonatal and supportive care directed at the respiratory failure, the autonomic instability and the feeding difficulties.

Show evidence (1 reference)

PMID:38133879 SUPPORT Other

"The therapeutic implication for patients with pathogenic IL6ST variants depends on the underlying condition ranging from intensive neonatal and supportive care in patients with Stuve-Wiedemann syndrome"

States intensive neonatal and supportive care as the management for the Stuve-Wiedemann end of the IL6ST spectrum.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Autosomal recessive recurrence risk of 25% for the parents of an affected child. All reported cases have been homozygous, so carrier testing of both parents and prenatal or preimplantation testing are the relevant options.

Show evidence (1 reference)

PMID:40835206 SUPPORT Human Clinical

"Prenatal trio exome sequencing revealed the homozygous novel variant p.(Ser375∗) in IL6ST in the fetus."

Demonstrates that prenatal molecular diagnosis of this disorder is achievable, which is what genetic counseling is offering.

📈

Progression

2

Prenatal onset

Age: Second trimester onward

Short and bowed long bones are detectable on ultrasound from the second trimester, and prenatal exome sequencing has established the diagnosis in utero. Intrauterine fetal death has been reported.

Show evidence (2 references)

PMID:40835206 SUPPORT Human Clinical

"We here report on a sixth case that came to attention at 21 weeks of gestation with short and bowed long bones."

Documents prenatal detectability at 21 weeks of gestation.

PMID:40835206 SUPPORT Human Clinical

"The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."

Records intrauterine fetal death as one outcome of this disorder.

Perinatal lethality

Age: Birth to early infancy

Death is usually prenatal or perinatal, driven by the neonatal lung dysfunction and dysautonomia. Survival beyond early childhood has been recorded but is exceptional. Curated here rather than as a `phenotypes` entry because the HPO death terms (HP:0003811 Neonatal death, HP:0001522 Death in infancy) sit in the Mortality/Aging branch rather than under HP:0000118 phenotypic abnormality, so they are outside the PhenotypeTerm dynamic enum.

Show evidence (2 references)

PMID:38133879 SUPPORT Other

"Despite this prediction, complete loss of GP130 has been described in patients with pathognomonic features of Stüve-Wiedemann Syndrome, a lethal neonatal condition characterized by severe skeletal dysplasia and dysautonomia originally associated with loss-of-function mutations in LIFR"

Characterizes the complete-GP130-loss phenotype as a lethal neonatal condition.

PMID:38133879 SUPPORT Other

"In exceptional instances, patients can survive early childhood"

Qualifies the lethality: survival occurs but is exceptional, so this is recorded as the usual rather than the invariable outcome.

📊

Prevalence

1

Worldwide, published-case literature

Cases In Literature Ultra Rare

Six individuals in total: five from three unrelated families in the delineating series (PMID:31914175), plus one further fetus reported as the sixth case (PMID:40835206). No population-based prevalence estimate exists for the IL6ST form; the count is the only quantitative statement the literature supports.

Show evidence (2 references)

PMID:40835206 SUPPORT Human Clinical

"So far, five individuals from three unrelated families were described with IL6ST associated Stüve-Wiedemann syndrome."

States the published case count prior to this report, which adds a sixth.

PMID:40835206 SUPPORT Human Clinical

"We here report on a sixth case that came to attention at 21 weeks of gestation with short and bowed long bones."

Supplies the sixth published individual.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from IL6ST-Related Stuve-Wiedemann Syndrome:

Campomelic dysplasia (SOX9) MONDO:0007251

Overlapping Features The other perinatally lethal bent-bone dysplasia with a narrow thorax and respiratory failure, and the main non-Stuve-Wiedemann differential on a prenatal scan showing bowed femora. Campomelic dysplasia is dominant and de novo, adds Pierre-Robin sequence and 46,XY sex reversal, and lacks the dysautonomia and the hematologic and acute-phase findings.

🧫

Experimental Models

1

Lentiviral GP130 reconstitution in patient-derived cells PRIMARY_CELL_CULTURE

Patient-derived cells carrying a biallelic IL6ST null genotype, transduced with a lentivirus expressing wild-type GP130. This is the isogenic-repair arm of the delineating study and is what upgrades the signaling failure from a correlation with the genotype to a consequence of it.

Organism

human NCBITaxon:9606

Cell source

PATIENT_DERIVED

Publication

PMID:31914175

Pathograph links

Pan-IL-6-Family GP130 Signaling Failure rescues fidelity: high Restoring GP130 in the patient's own cells reverses the signaling defect, establishing that the loss of IL-6-family responses follows from the IL6ST genotype rather than from a co-segregating variant or a culture artifact.

Limitations: A cellular rescue only. It says nothing about whether restoring GP130 in a developing skeleton or autonomic nervous system would rescue the disease phenotype, and the disorder is prenatal and multi-organ — a gap recorded separately as discussions#stws2_gp130_reconstitution_delivery_gap.

Readouts

Cellular response to GP130-dependent cytokines

Direction: RESTORED

Interpretation: The signaling defect measured across IL-6, IL-11, IL-27, OSM and LIF is reversed when GP130 is restored.

Show evidence (1 reference)

PMID:31914175 SUPPORT In Vitro

"Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect."

Reports the rescue directly, in the patient's own cells.

Show evidence (1 reference)

PMID:31914175 SUPPORT In Vitro

"Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect."

Establishes this reconstitution system as informative for the GP130 signaling node, since it manipulates exactly the receptor that node is about.

{ }

Source YAML

click to show

name: IL6ST-Related Stuve-Wiedemann Syndrome
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Stuve-Wiedemann syndrome 2 (STWS2), also called extended Stuve-Wiedemann
  syndrome, is an ultra-rare autosomal recessive bent-bone dysplasia caused by
  biallelic essential loss-of-function variants in IL6ST, which encodes GP130 —
  the shared signal transducer of the entire IL-6 cytokine family. Affected
  fetuses and neonates have severe shortening and bowing of the long bones, a
  narrow thorax, neonatal lung dysfunction and dysautonomia, and death is
  usually prenatal or perinatal.

  STWS2 is the phenocopy that makes the mechanism of Stuve-Wiedemann syndrome
  legible. STWS1 removes LIFR, the ligand-binding chain that pairs with GP130 to
  receive LIF; STWS2 removes GP130 itself, and so abolishes signaling by IL-6,
  IL-11, IL-27, oncostatin M and LIF together. The skeletal and autonomic core
  of the two disorders is nevertheless the same, which is the argument that LIF
  signaling specifically is what the developing skeleton and autonomic nervous
  system depend on: the extra cytokines lost in STWS2 add features rather than
  changing the ones LIFR loss already produces.

  Those extra features are what "extended" names — congenital thrombocytopenia,
  eczematoid dermatitis, renal abnormalities and a defective acute-phase
  response, none of which belong to LIFR-related STWS1. IL6ST is also a striking
  allelic series: the same gene yields recessive and dominant hyper-IgE syndrome
  when a variant spares LIF signaling, and isolated craniosynostosis when it
  spares everything except IL-11. STWS2 is the floor of that series, the class
  in which nothing is spared.
disease_term:
  preferred_term: Stuve-Wiedemann syndrome 2
  term:
    id: MONDO:0030756
    label: Stuve-Wiedemann syndrome 2
parents:
- hereditary disease
- Skeletal Dysplasia
synonyms:
- STWS2
- Stuve-Wiedemann Syndrome 2
- Stuve-Wiedemann syndrome, IL6ST-related
- extended Stuve-Wiedemann syndrome
- extended Stüve-Wiedemann syndrome
- Stüve-Wiedemann syndrome 2
- IL6ST-related Stuve-Wiedemann syndrome
- GP130 deficiency, complete
notes: >-
  NAMING: gene-anchored because "Stuve-Wiedemann syndrome" alone is locus-ambiguous.
  The OMIM/MONDO numbering (STWS2) is kept as a synonym and as the `disease_term`
  label; the entry name carries the gene. Same rule as its LIFR counterpart and as the
  two kyphomelic dysplasia entries in the same ISDS group.

  LUMP/SPLIT: this entry models only IL6ST-related Stuve-Wiedemann syndrome 2
  (MONDO:0030756; OMIM:619751) and is deliberately separate from
  kb/disorders/LIFR-Related_Stuve-Wiedemann_Syndrome.yaml (LIFR; MONDO:0800043;
  OMIM:601559). Three independent authorities split them and dismech follows:
  OMIM assigns distinct phenotype numbers, MONDO mints distinct classes under
  the parent grouping MONDO:0031280, and the ISDS 2023 nosology lists them as
  two rows in group 20 (NOS 20-0020 LIFR, NOS 20-0030 IL6ST). The mechanistic
  reason is that the two are not the same lesion at different severities: LIFR
  loss is ligand-chain-selective, whereas GP130 loss removes the shared
  transducer of ten IL-6-family cytokines, and the clinical difference —
  thrombocytopenia, dermatitis, renal anomalies, absent acute-phase response —
  tracks that difference. Folding them together would present a
  pan-IL-6-family signaling failure and a LIF-selective one as one pathograph.

  The split is NOT made on severity. Both disorders are usually lethal in the
  perinatal period, and the published IL6ST series is too small (six
  individuals) to support a claim that one is uniformly more severe.

  IL6ST is also the gene of autosomal recessive and autosomal dominant hyper-IgE
  syndrome and of an IL-11-selective craniosynostosis phenotype. Those are
  cytokine-selective partial defects and are separate diseases, not subtypes of
  this one; see differential_diagnoses. dismech does not curate them here.

  No dedicated GeneReviews chapter was found for either Stuve-Wiedemann form
  (PubMed searches "IL6ST GeneReviews" and "gp130 deficiency GeneReviews" return
  nothing; "Stuve-Wiedemann syndrome 2 GeneReviews" returns only PMID:40521311,
  which is the prenatal ultrasound series that searched GeneReviews as a
  literature source rather than a chapter — the same hit the LIFR sibling entry
  rules out). Recorded here so the search is not repeated.

  Orphanet has no structured record keyed to the IL6ST form specifically
  (ORPHA:3206 is Stuve-Wiedemann syndrome undifferentiated), so prevalence is
  recorded from the published case literature rather than an Orphanet
  epidemiology class.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0031280
      label: Stuve-Wiedemann syndrome
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0031280 is the parent grouping covering both the LIFR-related
      (MONDO:0800043) and IL6ST-related (MONDO:0030756) forms. This entry is
      restricted to the IL6ST disease.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Mendelian recessive skeletal dysplasia (ISDS bent-bone group). The
      immunologic features — defective acute-phase response, eczematoid
      dermatitis, congenital thrombocytopenia — are curated as mechanism and
      phenotype of the single IL6ST disorder rather than as an additional
      Harrison's Part, because they arise from the same loss of GP130 that
      produces the skeletal phenotype.
  isds_skeletal_category:
  - classification_value: bent_bone_dysplasia
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (11th edition;
      Unger et al., PMID:36779427), group 20 "Bent bones dysplasia group",
      entry NOS 20-0030, listed there as "Stuve-Wiedemann syndrome,
      IL6ST-related" (AR, IL6ST, MIM 619751). The IL6ST form is new in the 2023
      revision; it has no counterpart row in the 2019 revision
      (PMID:31633310), which predates the 2020 gene discovery. The committee
      listing it as its own row rather than as a note on the LIFR row is the
      nosological basis for curating it as a separate dismech entry.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Autosomal recessive. All reported individuals carry biallelic IL6ST
    loss-of-function alleles — homozygous in every published case — segregating
    in three unrelated families in the delineating series and in one further
    consanguineous pregnancy.
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping)."
    explanation: >-
      Establishes biallelic (homozygous) IL6ST loss of function as the genetic
      basis across the delineating families.
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic loss-of-function variants in either the leukemia inhibitory factor receptor encoding LIFR or the interleukin-6 cytokine family signal transducer encoding IL6ST are causative."
    explanation: >-
      Independent restatement of biallelic inheritance for the IL6ST form,
      alongside the LIFR form.
prevalence:
- population: Worldwide, published-case literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Six individuals in total: five from three unrelated families in the
    delineating series (PMID:31914175), plus one further fetus reported as the
    sixth case (PMID:40835206). No population-based prevalence estimate exists
    for the IL6ST form; the count is the only quantitative statement the
    literature supports.
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "So far, five individuals from three unrelated families were described with IL6ST associated Stüve-Wiedemann syndrome."
    explanation: >-
      States the published case count prior to this report, which adds a sixth.
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report on a sixth case that came to attention at 21 weeks of gestation with short and bowed long bones."
    explanation: >-
      Supplies the sixth published individual.
pathophysiology:
- name: Biallelic IL6ST Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic essential loss-of-function IL6ST alleles — nonsense
    (c.841C>T, p.Arg281*), an intronic splice variant causing exon 13 skipping
    (c.1699+4A>G), and a further truncating allele (p.Ser375*) — abolish
    functional cell-surface GP130. The truncating alleles lie in the
    extracellular domains, so the predicted products are soluble rather than
    membrane-anchored receptor fragments; the exon-13 skipping allele instead
    misfolds the membrane-proximal D6 domain, which is where the receptor
    transmits signal across the membrane.
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    allelic_hit_role: BIALLELIC_INACTIVATION
    zygosity: HOMOZYGOUS
    description: >-
      Homozygous germline null alleles of IL6ST (nonsense or essential splice).
      No compound-heterozygous STWS2 genotype has been reported; every published
      case arose in a consanguineous or homozygous-by-descent setting.
  genes:
  - preferred_term: IL6ST
    term:
      id: hgnc:6021
      label: IL6ST
  molecular_functions:
  - preferred_term: cytokine receptor activity
    term:
      id: GO:0004896
      label: cytokine receptor activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping)."
    explanation: >-
      Names the two allele classes in the delineating series and calls them
      essential (as opposed to cytokine-selective) loss of function.
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Loss of exon 13 in the c.1699+4A>G splice variant abrogates folding of GP130 membrane-proximal domain D6 impairing transmembrane signal transmission"
    explanation: >-
      Gives the structural reason the splice allele is a null rather than a
      hypomorph, which is what places it in the complete-loss class.
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These variants affect the extracellular domains of GP130 likely leading to the expression of truncated soluble GP130 variants"
    explanation: >-
      Establishes that the truncating STWS2 alleles remove the receptor from the
      membrane rather than producing a signaling-competent stump.
  downstream:
  - target: Pan-IL-6-Family GP130 Signaling Failure
- name: Pan-IL-6-Family GP130 Signaling Failure
  biological_scale: CELLULAR
  description: >-
    GP130 is the shared transducer of the whole IL-6 cytokine family, so its
    complete loss silences every member at once — IL-6, IL-11, IL-27, oncostatin
    M and LIF have all been shown unresponsive in patient cells. This is the
    node that separates STWS2 from STWS1: LIFR loss removes only the
    LIF-receiving chain, leaving IL-6, IL-11 and IL-27 signaling intact. It also
    separates STWS2 from the IL6ST hyper-IgE and craniosynostosis phenotypes,
    which are cytokine-selective defects that spare LIF. Lentiviral
    reconstitution of GP130 in patient cells restores signaling, which is the
    strongest available evidence that the failure is the direct consequence of
    the genotype.
  biological_processes:
  - preferred_term: interleukin-6-mediated signaling pathway
    term:
      id: GO:0070102
      label: interleukin-6-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
  - preferred_term: interleukin-11-mediated signaling pathway
    term:
      id: GO:0038154
      label: interleukin-11-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
  - preferred_term: interleukin-27-mediated signaling pathway
    term:
      id: GO:0070106
      label: interleukin-27-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
  - preferred_term: oncostatin-M-mediated signaling pathway
    term:
      id: GO:0038165
      label: oncostatin-M-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
  - preferred_term: leukemia inhibitory factor signaling pathway
    term:
      id: GO:0048861
      label: leukemia inhibitory factor signaling pathway
    modifier: LOSS_OF_FUNCTION
  - preferred_term: JAK-STAT cascade
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF)."
    explanation: >-
      Direct patient-cell readout that all five tested GP130-dependent cytokines
      fail, which is the defining property of this node.
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect."
    explanation: >-
      Rescue experiment establishing that the signaling failure is caused by the
      IL6ST genotype rather than by a co-segregating factor.
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines."
    explanation: >-
      States why one receptor loss silences a whole cytokine family, which is
      the premise of this node.
  - reference: PMID:33771552
    reference_title: "Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome."
    explanation: >-
      Structural work showing that losing LIF signaling on top of the IL-6/IL-11
      defect is what converts an IL6ST hyper-IgE genotype into a
      Stuve-Wiedemann one — the boundary this node draws.
  downstream:
  - target: Failed LIF-Dependent Skeletal Development
  - target: Autonomic and Respiratory Dysfunction
  - target: Loss of IL-6 and IL-11 Dependent Hematopoietic, Epithelial and Hepatic Responses
- name: Failed LIF-Dependent Skeletal Development
  biological_scale: TISSUE
  description: >-
    Absent LIF-family signaling in the developing skeleton produces the bent-bone
    phenotype. That this arm is LIF-driven rather than IL-6- or IL-11-driven is
    inferred from the near-identity of the STWS2 and STWS1 skeletal phenotypes:
    LIFR loss removes only LIF-family input, and reproduces the same bowing,
    shortening and defective mineralization.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
    modifier: DECREASED
  - preferred_term: chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development."
    explanation: >-
      The authors' own attribution of the pre- and perinatal developmental
      phenotype to the LIF arm specifically.
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Similarities of patients with loss of LIFR signaling and patients that had complete absence of GP130 suggest that LIF is essential during embryonic development."
    explanation: >-
      States the STWS1/STWS2 phenotype-comparison argument this node rests on.
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."
    explanation: >-
      Gives the skeletal findings of the most completely described IL6ST case.
  downstream:
  - target: Bowing of the Long Bones
  - target: Short Long Bones
  - target: Narrow Thorax
  - target: Abnormal Bone Mineralization
  - target: Joint Dislocations
  - target: Dolichocephaly
- name: Autonomic and Respiratory Dysfunction
  biological_scale: TISSUE
  description: >-
    As in LIFR-related STWS1, loss of LIF-family signaling in autonomic and
    sensory neurons produces neonatal dysautonomia, and the neonate presents
    with lung dysfunction that, combined with the narrow thorax, is the usual
    proximate cause of perinatal death.
  biological_processes:
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response."
    explanation: >-
      Establishes neonatal lung dysfunction as a defining feature of the
      delineating series.
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stüve-Wiedemann syndrome is a rare skeletal dysplasia characterized by severe shortening and bowing of the long bones and by immunological and autonomous dysfunction, usually resulting in early death."
    explanation: >-
      Places autonomic ("autonomous") dysfunction in the defining description of
      the syndrome, for which both genes are causative.
  downstream:
  - target: Neonatal Respiratory Distress
  - target: Abnormal Autonomic Nervous System Physiology
- name: Loss of IL-6 and IL-11 Dependent Hematopoietic, Epithelial and Hepatic Responses
  biological_scale: ORGANISM
  description: >-
    This node is what "extended" Stuve-Wiedemann syndrome means. IL-11 is
    required for megakaryocytopoiesis and IL-6 for the hepatic acute-phase
    response; both are intact in STWS1 and both are lost in STWS2. The resulting
    congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities and
    absent acute-phase response are the features that distinguish the IL6ST
    disorder clinically from the LIFR one, and they are the mechanistic
    signature of losing the shared transducer rather than one ligand chain.
  biological_processes:
  - preferred_term: acute-phase response
    term:
      id: GO:0006953
      label: acute-phase response
    modifier: LOSS_OF_FUNCTION
  - preferred_term: interleukin-11-mediated signaling pathway
    term:
      id: GO:0038154
      label: interleukin-11-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"
    explanation: >-
      Enumerates exactly the extra-skeletal features this node accounts for.
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling."
    explanation: >-
      Frames the complete-loss genotype against the selective ones, which is why
      these additional features appear only here.
  downstream:
  - target: Congenital Thrombocytopenia
  - target: Eczematoid Dermatitis
  - target: Abnormal Renal Morphology
  - target: Defective Acute-Phase Response
phenotypes:
- name: Bowing of the Long Bones
  category: Skeletal
  description: >-
    Severe bowing of the long bones, detectable prenatally; the defining
    radiographic sign that places the disorder in the ISDS bent-bone group.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stüve-Wiedemann syndrome is a rare skeletal dysplasia characterized by severe shortening and bowing of the long bones and by immunological and autonomous dysfunction, usually resulting in early death."
    explanation: >-
      Bowing of the long bones is given as a defining feature.
- name: Short Long Bones
  category: Skeletal
  description: >-
    Severe shortening of the limb long bones, present alongside the bowing from
    the second trimester.
  phenotype_term:
    preferred_term: Short long bone
    term:
      id: HP:0003026
      label: Short long bone
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report on a sixth case that came to attention at 21 weeks of gestation with short and bowed long bones."
    explanation: >-
      Documents shortening together with bowing at 21 weeks of gestation.
- name: Narrow Thorax
  category: Skeletal
  description: >-
    Narrow upper thorax, which contributes to the neonatal respiratory failure.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."
    explanation: >-
      Records a narrow upper thorax on postmortem examination.
- name: Abnormal Bone Mineralization
  category: Skeletal
  description: >-
    Abnormal ossification/mineralization of the skeleton on postmortem
    examination.
  phenotype_term:
    preferred_term: Abnormal bone ossification
    term:
      id: HP:0011849
      label: Abnormal bone ossification
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."
    explanation: >-
      Reports abnormal bone mineralization directly.
- name: Joint Dislocations
  category: Skeletal
  description: >-
    Joint dislocations noted at delivery in the fetal case.
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."
    explanation: >-
      Reports joint dislocations directly.
- name: Dolichocephaly
  category: Craniofacial
  description: >-
    Dolichocephalic head shape observed in the fetal case.
  phenotype_term:
    preferred_term: Dolichocephaly
    term:
      id: HP:0000268
      label: Dolichocephaly
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."
    explanation: >-
      Reports dolichocephalus directly.
- name: Neonatal Respiratory Distress
  category: Respiratory
  description: >-
    Neonatal lung dysfunction, one of the two defining features of the
    delineating series and the usual proximate cause of death in liveborn
    infants.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response."
    explanation: >-
      Neonatal lung dysfunction is named as a defining feature.
- name: Abnormal Autonomic Nervous System Physiology
  category: Neurologic
  description: >-
    Dysautonomia of the Stuve-Wiedemann type — the autonomic instability shared
    with the LIFR form.
  phenotype_term:
    preferred_term: Abnormal autonomic nervous system physiology
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stüve-Wiedemann syndrome is a rare skeletal dysplasia characterized by severe shortening and bowing of the long bones and by immunological and autonomous dysfunction, usually resulting in early death."
    explanation: >-
      "Autonomous dysfunction" (dysautonomia) is given as a defining feature of
      the syndrome for which IL6ST is one of the two causative genes.
- name: Congenital Thrombocytopenia
  category: Hematologic
  description: >-
    Congenital thrombocytopenia, an extra-skeletal feature that separates the
    IL6ST form from the LIFR form and is consistent with loss of IL-11-driven
    megakaryocytopoiesis.
  phenotype_term:
    preferred_term: Congenital thrombocytopenia
    term:
      id: HP:0001905
      label: Congenital thrombocytopenia
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"
    explanation: >-
      Lists congenital thrombocytopenia among the additional features.
- name: Eczematoid Dermatitis
  category: Dermatologic
  description: >-
    Eczematoid dermatitis, reported in the delineating series and shared with
    the IL6ST hyper-IgE phenotypes.
  phenotype_term:
    preferred_term: Eczematoid dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"
    explanation: >-
      Lists eczematoid dermatitis among the additional features.
- name: Abnormal Renal Morphology
  category: Renal
  description: >-
    Renal abnormalities, described in the delineating series and catalogued as
    renal malformation in the GP130 variant taxonomy.
  phenotype_term:
    preferred_term: Abnormal renal morphology
    term:
      id: HP:0012210
      label: Abnormal renal morphology
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"
    explanation: >-
      Lists renal abnormalities among the additional features.
- name: Defective Acute-Phase Response
  category: Immunologic
  description: >-
    Defective acute-phase response — the direct clinical readout of absent
    IL-6-driven hepatic signaling, and a laboratory finding that should not be
    expected in LIFR-related STWS1.
  phenotype_term:
    preferred_term: Decreased circulating C-reactive protein concentration
    term:
      id: HP:0032437
      label: Decreased circulating C-reactive protein concentration
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response"
    explanation: >-
      Lists a defective acute-phase response among the additional features. The
      HP binding is to the C-reactive protein readout, which is the measurable
      form the defect takes; "defective acute-phase response" itself has no
      HP term.
genetic:
- name: IL6ST
  gene_term:
    preferred_term: IL6ST
    term:
      id: hgnc:6021
      label: IL6ST
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    IL6ST encodes GP130. Biallelic essential loss-of-function alleles cause
    STWS2. The published STWS2 alleles are c.841C>T (p.Arg281*), the essential
    splice variant c.1699+4A>G causing exon 13 skipping, and p.Ser375*. Note
    that a different substitution at the same codon as the nonsense allele,
    p.Arg281Gln, causes an IL-11-selective craniosynostosis phenotype rather
    than STWS2 — the residue is not what matters, the completeness of the loss
    is.
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping)."
    explanation: >-
      Establishes IL6ST as the causal gene for this disorder.
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prenatal trio exome sequencing revealed the homozygous novel variant p.(Ser375∗) in IL6ST in the fetus."
    explanation: >-
      Adds an independent truncating allele in an independent family.
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A patient with craniosynostosis and dental anomalies but no immune dysregulation carried a homozygous missense variant p.R281Q"
    explanation: >-
      Documents the same-codon contrast: a missense at Arg281 gives an
      IL-11-selective phenotype, whereas the nonsense allele at that codon gives
      STWS2.
experimental_models:
- name: Lentiviral GP130 reconstitution in patient-derived cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: PATIENT_DERIVED
  description: >-
    Patient-derived cells carrying a biallelic IL6ST null genotype, transduced
    with a lentivirus expressing wild-type GP130. This is the isogenic-repair
    arm of the delineating study and is what upgrades the signaling failure
    from a correlation with the genotype to a consequence of it.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:31914175
  modeled_mechanisms:
  - target: Pan-IL-6-Family GP130 Signaling Failure
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      Restoring GP130 in the patient's own cells reverses the signaling defect,
      establishing that the loss of IL-6-family responses follows from the IL6ST
      genotype rather than from a co-segregating variant or a culture artifact.
    limitations: >-
      A cellular rescue only. It says nothing about whether restoring GP130 in a
      developing skeleton or autonomic nervous system would rescue the disease
      phenotype, and the disorder is prenatal and multi-organ — a gap recorded
      separately as discussions#stws2_gp130_reconstitution_delivery_gap.
    readouts:
    - name: Cellular response to GP130-dependent cytokines
      target: Pan-IL-6-Family GP130 Signaling Failure
      direction: RESTORED
      interpretation: >-
        The signaling defect measured across IL-6, IL-11, IL-27, OSM and LIF is
        reversed when GP130 is restored.
      evidence:
      - reference: PMID:31914175
        reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect."
        explanation: >-
          Reports the rescue directly, in the patient's own cells.
  evidence:
  - reference: PMID:31914175
    reference_title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect."
    explanation: >-
      Establishes this reconstitution system as informative for the GP130
      signaling node, since it manipulates exactly the receptor that node is
      about.
treatments:
- name: Neonatal Intensive and Supportive Care
  description: >-
    There is no disease-modifying therapy. Management is intensive neonatal and
    supportive care directed at the respiratory failure, the autonomic
    instability and the feeding difficulties.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The therapeutic implication for patients with pathogenic IL6ST variants depends on the underlying condition ranging from intensive neonatal and supportive care in patients with Stuve-Wiedemann syndrome"
    explanation: >-
      States intensive neonatal and supportive care as the management for the
      Stuve-Wiedemann end of the IL6ST spectrum.
- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence risk of 25% for the parents of an affected
    child. All reported cases have been homozygous, so carrier testing of both
    parents and prenatal or preimplantation testing are the relevant options.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prenatal trio exome sequencing revealed the homozygous novel variant p.(Ser375∗) in IL6ST in the fetus."
    explanation: >-
      Demonstrates that prenatal molecular diagnosis of this disorder is
      achievable, which is what genetic counseling is offering.
progression:
- phase: Prenatal onset
  age_range: Second trimester onward
  notes: >-
    Short and bowed long bones are detectable on ultrasound from the second
    trimester, and prenatal exome sequencing has established the diagnosis in
    utero. Intrauterine fetal death has been reported.
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report on a sixth case that came to attention at 21 weeks of gestation with short and bowed long bones."
    explanation: >-
      Documents prenatal detectability at 21 weeks of gestation.
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fetus died in utero in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization."
    explanation: >-
      Records intrauterine fetal death as one outcome of this disorder.
- phase: Perinatal lethality
  age_range: Birth to early infancy
  notes: >-
    Death is usually prenatal or perinatal, driven by the neonatal lung
    dysfunction and dysautonomia. Survival beyond early childhood has been
    recorded but is exceptional. Curated here rather than as a `phenotypes`
    entry because the HPO death terms (HP:0003811 Neonatal death, HP:0001522
    Death in infancy) sit in the Mortality/Aging branch rather than under
    HP:0000118 phenotypic abnormality, so they are outside the PhenotypeTerm
    dynamic enum.
  evidence:
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite this prediction, complete loss of GP130 has been described in patients with pathognomonic features of Stüve-Wiedemann Syndrome, a lethal neonatal condition characterized by severe skeletal dysplasia and dysautonomia originally associated with loss-of-function mutations in LIFR"
    explanation: >-
      Characterizes the complete-GP130-loss phenotype as a lethal neonatal
      condition.
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In exceptional instances, patients can survive early childhood"
    explanation: >-
      Qualifies the lethality: survival occurs but is exceptional, so this is
      recorded as the usual rather than the invariable outcome.
differential_diagnoses:
- name: LIFR-Related Stuve-Wiedemann Syndrome
  disease_term:
    preferred_term: Stuve-Wiedemann syndrome 1
    term:
      id: MONDO:0800043
      label: Stüve-Wiedemann syndrome 1
  description: >-
    The other Stuve-Wiedemann gene, and clinically the closest mimic — the
    skeletal and autonomic phenotypes are largely indistinguishable. What
    separates them is the extra-skeletal panel: congenital thrombocytopenia,
    eczematoid dermatitis, renal anomalies and an absent acute-phase response
    point to IL6ST, because LIFR loss spares IL-6, IL-11 and IL-27. Molecular
    testing settles it.
  evidence:
  - reference: PMID:40835206
    reference_title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic loss-of-function variants in either the leukemia inhibitory factor receptor encoding LIFR or the interleukin-6 cytokine family signal transducer encoding IL6ST are causative."
    explanation: >-
      Establishes that the same clinical syndrome has two causative genes, which
      is what makes this a differential rather than a separate presentation.
- name: IL6ST-related autosomal recessive hyper-IgE syndrome
  description: >-
    The same gene with a cytokine-selective rather than complete defect. These
    variants impair IL-6 and IL-11 signaling while sparing LIF, and the result
    is hyper-IgE syndrome with skeletal abnormalities and craniosynostosis, not
    a bent-bone dysplasia. The distinguishing question is whether LIF signaling
    survives.
  evidence:
  - reference: PMID:33771552
    reference_title: "Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling."
    explanation: >-
      Defines the selective IL6ST phenotype and names LIF sparing as what makes
      it a different disease from STWS2.
- name: Campomelic dysplasia (SOX9)
  disease_term:
    preferred_term: campomelic dysplasia
    term:
      id: MONDO:0007251
      label: campomelic dysplasia
  description: >-
    The other perinatally lethal bent-bone dysplasia with a narrow thorax and
    respiratory failure, and the main non-Stuve-Wiedemann differential on a
    prenatal scan showing bowed femora. Campomelic dysplasia is dominant and de
    novo, adds Pierre-Robin sequence and 46,XY sex reversal, and lacks the
    dysautonomia and the hematologic and acute-phase findings.
  notes: >-
    Both disorders sit in ISDS 2023 group 20 (NOS 20-0030 and NOS 20-0010), so
    the shared radiographic sign this differential turns on is recorded in the
    two entries' isds_skeletal_category assignments. That placement comes from
    the nosology's disorder table, which is not part of the cached abstract or
    body text, so it carries no evidence snippet here.
discussions:
- discussion_id: stws2_lif_versus_pan_family_skeletal_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Failed LIF-Dependent Skeletal Development
  prompt: >-
    Is the bent-bone phenotype of STWS2 driven by loss of LIF signaling alone,
    or do the concurrently lost IL-6, IL-11, IL-27 and OSM arms contribute to
    the skeletal phenotype in a way that the LIFR-null comparison cannot detect?
  rationale: >-
    The attribution of the skeletal arm to LIF rests entirely on a phenotype
    comparison: STWS1 loses only LIF-family input and looks the same. That is
    an argument from similarity across two tiny case series, and it cannot
    exclude a contribution from IL-11, which has an established role in bone.
    Distinguishing them matters because it decides whether a
    signaling-restoration strategy would need to restore GP130 or could target
    the LIF axis alone. No IL6ST-null animal model of the skeletal phenotype has
    been reported alongside a LIFR-null comparison in the same study.
  evidence:
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Similarities of patients with loss of LIFR signaling and patients that had complete absence of GP130 suggest that LIF is essential during embryonic development."
    explanation: >-
      The word "suggest" is the authors' own hedge, and marks this as an
      inference from phenotypic similarity rather than a demonstrated
      attribution.
- discussion_id: stws2_gp130_reconstitution_delivery_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#
  prompt: >-
    Is there any tractable therapeutic strategy for complete GP130 loss, given
    that hematopoietic-restricted correction cannot reach the skeletal and
    autonomic compartments?
  rationale: >-
    Lentiviral reconstitution of GP130 rescues signaling in patient-derived
    cells, so the defect is correctable in principle. But the disorder is
    prenatal and multi-organ, and allogeneic bone marrow transplantation — the
    approach borrowed from STAT3 hyper-IgE — corrects only the hematopoietic
    compartment. Whether any delivery route could reach chondrocytes and
    autonomic neurons early enough is unaddressed in the literature.
  evidence:
  - reference: PMID:38133879
    reference_title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "this will not be effective in treating the multi-organ manifestations of severe Stüve-Wiedemann syndrome."
    explanation: >-
      States that hematopoietic correction cannot address the multi-organ
      phenotype, which is the gap this discussion records.
references:
- reference: PMID:31914175
  title: "Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome."
- reference: PMID:40835206
  title: "A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST."
- reference: PMID:38133879
  title: "The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants."
- reference: PMID:33771552
  title: "Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome."
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."

📚

References & Deep Research

References

5

PMID:31914175

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.

No top-level findings curated for this source.

PMID:40835206

A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST.

No top-level findings curated for this source.

PMID:38133879

The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants.

No top-level findings curated for this source.

PMID:33771552

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome.

No top-level findings curated for this source.

PMID:36779427

Nosology of genetic skeletal disorders: 2023 revision.

No top-level findings curated for this source.

IL6ST-Related Stuve-Wiedemann Syndrome

Ask OpenScientist

OpenScientist Report

Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Progression

Prevalence

Differential Diagnoses

Experimental Models

Source YAML

References & Deep Research

References