LIFR-Related Stuve-Wiedemann Syndrome

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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Mappings

MONDO

MONDO:0031280 Stuve-Wiedemann syndrome Not Yet Curated

MONDO:0031280 is the parent grouping that also includes IL6ST-related Stuve-Wiedemann syndrome 2 (MONDO:0030756). This entry is restricted to the LIFR disease (MONDO:0800043).

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Inheritance

1

Autosomal recessive inheritance HP:0000007

STWS1 segregates as an autosomal recessive trait; affected individuals carry biallelic (homozygous or compound heterozygous) LIFR loss-of-function variants and heterozygous parents are unaffected.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:14740318 SUPPORT Human Clinical

"Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for..."

Landmark gene-identification paper states autosomal recessive inheritance as part of the defining clinical description.

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Discussions and Knowledge Gaps

1

How faithfully does perinatal-lethal Lifr-null mouse osteopenia and astrocyte loss represent the human STWS1 natural history, in which some patients survive infancy with accumulating orthopedic disease as dysautonomia lessens?

HUMAN MODEL MISMATCH OPEN stws1_lifr_mouse_perinatal_mismatch

Attached to

pathophysiology#Impaired Chondrogenesis and Bone Remodeling pathophysiology#Autonomic and Sensory Neuron Dysfunction

Ware et al. 1995 show that homozygous Lifr disruption is lethal on the day of birth, with reduced fetal bone volume and reduced astrocytes. Human STWS1 has high but not universal infant mortality (42% before age 2 in Warnier et al.), and survivors have a distinct later phenotype the mouse cannot reach. The skeletal remodeling direction is concordant; the autonomic crisis phenotype and childhood course are not demonstrated in the mouse.

Proposed experiments

Conditional or hypomorphic Lifr alleles with postnatal survival

conditional gene knockout

exp_stws1_conditional_lifr_postnatal

Generate conditional or hypomorphic Lifr alleles that permit postnatal survival, then perform thermoregulatory, swallowing, and serial skeletal phenotyping aligned to the human two-phase natural history (infant dysautonomia, then childhood orthopedic accumulation).

Show evidence (1 reference)

PMID:7789261 SUPPORT Model Organism

"Pleiotropic defects in the mutant animals preclude survival beyond the day of birth."

Documents the perinatal-lethality mismatch with human survivors.

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Pathophysiology

4

Biallelic LIFR Loss of Function

Biallelic LIFR null or truncating variants destabilize the transcript and prevent formation of functional leukemia inhibitory factor receptor, removing the ligand-specific chain of the LIFR–gp130 heterodimer.

LIFR hgnc:6597

Genetic context variant_origin: GERMLINE allelic_hit_role: BIALLELIC_INACTIVATION functional_impact_category: LOSS_OF_FUNCTION

Homozygous or compound-heterozygous germline loss-of-function alleles (frameshift, nonsense, splice, or other null) of LIFR.

leukemia inhibitory factor receptor activity GO:0004923 ⇓ LOSS OF FUNCTION

Downstream

Failed LIF-Family gp130 JAK-STAT3 Signaling

Show evidence (2 references)

PMID:14740318 SUPPORT Human Clinical

"A total of 14 distinct mutations were identified in the 19 families."

Establishes LIFR as the causal gene across a multi-family SWS/SJS2 series.

PMID:14740318 SUPPORT In Vitro

"Functional studies indicated that these mutations alter the stability of LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells."

Patient-cell assays show that the alleles are null at the mRNA and protein level, not merely mapping hits.

Failed LIF-Family gp130 JAK-STAT3 Signaling

Without LIFR, LIF and related IL-6-family ligands cannot assemble a productive LIFR–gp130 receptor complex, so JAK-mediated STAT3 signaling (and associated MAPK/PI3K output) fails in target cells. This is LIFR-selective; complete IL6ST/gp130 loss abolishes a broader cytokine set and is modeled separately as STWS2.

leukemia inhibitory factor signaling pathway GO:0048861 ⇓ LOSS OF FUNCTION JAK-STAT cascade GO:0007259 ↓ DECREASED cytokine-mediated signaling pathway GO:0019221 ↓ DECREASED

Downstream

Impaired Chondrogenesis and Bone Remodeling

Autonomic and Sensory Neuron Dysfunction

Show evidence (2 references)

PMID:14740318 SUPPORT In Vitro

"Functional studies indicated that these mutations alter the stability of LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells."

Direct functional readout that LIFR-null patient cells fail JAK/STAT3 signaling.

PMID:24618404 SUPPORT Other

"LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines."

Review statement placing LIFR in the IL-6-family JAK/STAT3 cascade that this node represents.

Impaired Chondrogenesis and Bone Remodeling

Failed LIF-family signaling in the developing skeleton reduces bone volume and shifts remodeling toward osteoclast excess, producing congenital camptomelia, cortical thickening with flared osteopenic metaphyses, and later fractures and spinal deformity in survivors.

chondrocyte CL:0000138 osteoclast CL:0000092 osteoblast CL:0000062

skeletal system development GO:0001501 ↓ DECREASED osteoclast differentiation GO:0030316 ↑ INCREASED Bone Resorption GO:0045453 ↑ INCREASED

Animal models

Lifr-null mouse Mouse recapitulates Recapitulates low bone volume, osteoclast excess, and osteopenia.

Downstream

Bowed Long Bones

Camptodactyly

Recurrent Fractures

Scoliosis

Osteopenia

Growth Delay

Talipes

Intrauterine Growth Retardation

Show evidence (2 references)

PMID:7789261 SUPPORT Model Organism

"Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone."

Lifr-null mice provide the skeletal remodeling readout (low bone volume, osteoclast excess, osteopenia) underlying the human bent-bone phenotype. Not used as sole support for human phenotypes.

PMID:14740318 SUPPORT Human Clinical

"Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for..."

Human radiographic signature of the skeletal arm of this node.

Autonomic and Sensory Neuron Dysfunction

Failed LIF/CNTF-family signaling in autonomic and sensory neurons produces the dysautonomia that dominates neonatal lethality: temperature instability with hyperthermic crises, abnormal sweating, reduced pain sensation, absent corneal and tendon reflexes, and swallowing/respiratory failure. This is not the perlecan/AChE neuromuscular-junction mechanism of Schwartz-Jampel syndrome.

autonomic neuron CL:0000107 sensory neuron CL:0000101 sympathetic neuron CL:0011103

autonomic nervous system development GO:0048483 ↓ DECREASED

Animal models

Lifr-null mouse Mouse partially recapitulates Neural developmental defects (reduced astrocytes) support a nervous-system requirement for LIFR but do not reproduce human dysautonomic crises.

Downstream

Temperature Instability

Feeding Difficulties

Neonatal Respiratory Distress

Abnormal Sweating

Impaired Pain Sensation

Abnormal Autonomic Nervous System Physiology

Corneal Opacity

Decreased Lacrimation

Smooth Tongue

Trismus

Show evidence (2 references)

PMID:28058407 SUPPORT Other

"Stüve-Wiedemann syndrome (STWS; OMIM # 610559) is a rare disease that results in dysfunction of the autonomic nervous system, which controls involuntary processes such as breathing rate and body temperature."

Neuropathy-focused review identifies autonomic failure (breathing and temperature) as the neural arm of LIFR-related STWS. The abstract's OMIM # 610559 is the known Mikelonis typo; the disease identity is LIFR.

PMID:7789261 SUPPORT Model Organism

"Astrocyte numbers are reduced in the spinal cord and brain stem."

Lifr-null mice show a neural developmental deficit, supporting a nervous-system requirement for LIFR; they do not fully model human dysautonomic crises in survivors.

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Pathograph

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

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Phenotypes

22

Cardiovascular 1

Pulmonary Arterial Hypertension OCCASIONAL HP:0002092

Warnier et al. report 63% mortality among patients with PAH, not a 63% prevalence of PAH. Do not treat the 63% figure as a phenotype frequency.

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Mortality rate is higher during the first 2 years (42% <2 years; 10% >2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%)."

Identifies PAH as a poor prognostic factor. Frequency is omitted from the abstract as a rate among all patients; OCCASIONAL is a conservative band given that it is discussed as a subset with very high case fatality rather than a defining feature. Notes below record that the 63% figure is mortality among those with PAH, not PAH prevalence.

Digestive 1

Feeding Difficulties HP:0011968

Onset: NEONATAL

Show evidence (2 references)

PMID:14740318 SUPPORT Human Clinical

"Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for..."

Feeding difficulties are part of the original molecular series' defining description.

PMID:28058407 SUPPORT Other

"In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes."

Attributes feeding and swallowing failure to the infantile autonomic phenotype.

Eye 1

Corneal Opacity FREQUENT HP:0007957

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"The main ophthalmologic complications reported are corneal ulcers and consecutive opacities (8%/45%) due to hypolacrimation (13%/26%) and a lack of corneal reflex/corneal anesthesia (10%/48%)."

The paired percentages are the <2-year / ≥2-year split; 8% is the <2-year subgroup, pulled down by infant deaths before ocular disease is ascertained, and Table 5's total-cohort figure is 26% (18/69). The ≥2-year 45% maps to FREQUENT.

Head and Neck 1

Trismus OCCASIONAL HP:0000211

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Neurological manifestations encountered in SWS include hypotonia (71%/45%), trismus or myotonia (21%/36%)"

Paired percentages are the <2-year / ≥2-year split (21%/36%). Table 5 total-cohort trismus/myotonia is 19/69 (28%), mapping to OCCASIONAL (5–29%). The ≥2-year 36% would be FREQUENT; this entry uses the total-cohort figure here, as for hypotonia's 59% band, and records the split so the mixture is deliberate.

Integument 1

Abnormal Sweating Hyperhidrosis HP:0000975

Show evidence (1 reference)

PMID:28058407 SUPPORT Other

"Individuals may sweat excessively when body temperature is not elevated."

Describes temperature-uncoupled sweating, the sudomotor arm of STWS dysautonomia.

Limbs 1

Bowed Long Bones Bowing of the long bones HP:0006487

Onset: CONGENITAL

Show evidence (1 reference)

PMID:14740318 SUPPORT Human Clinical

"Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for..."

Defines congenital long-bone bowing with the characteristic metaphyseal radiographic pattern as a core feature.

Musculoskeletal 6

Camptodactyly HP:0012385

Onset: CONGENITAL

Show evidence (1 reference)

PMID:14740318 SUPPORT Human Clinical

"Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for..."

Lists camptodactyly among the defining congenital findings.

Scoliosis FREQUENT HP:0002650

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%)."

77% spinal deformity among survivors older than two years maps to the FREQUENT band (30–79%). The estimate is among reported survivors, not a birth cohort.

Recurrent Fractures FREQUENT HP:0002757

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%)."

61% fracture rate in survivors older than two years maps to FREQUENT.

Joint Stiffness VERY_FREQUENT HP:0001387

Course: PROGRESSIVE

Show evidence (2 references)

PMID:35461249 SUPPORT Human Clinical

"After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%)."

81% joint-mobility restriction after age 2 maps to VERY_FREQUENT (80–99%), with the same survivor-ascertainment caveat.

PMID:27194968 SUPPORT Other

"Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions."

Independent review lists joint restrictions among core features.

Osteopenia FREQUENT HP:0000938

Show evidence (2 references)

PMID:35461249 SUPPORT Human Clinical

"Osteoporosis prevalence also increases in children"

The same paragraph gives the split 11% <2 years / 48% ≥2 years. The ≥2-year 48% maps to FREQUENT (30–79%), matching how scoliosis and fractures in this entry use the survivor denominator. Total-cohort Table 4 is 19/69 (28%).

PMID:38628360 SUPPORT Human Clinical

"performed at 5 weeks of age showed diffuse hypomineralization of bones, indicating osteopenia"

Radiographic osteopenia in a genetically confirmed LIFR infant.

Hypotonia FREQUENT HP:0001252

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Neurological manifestations encountered in SWS include hypotonia (71%/45%), trismus or myotonia (21%/36%)"

Paired percentages are the <2-year / ≥2-year split. Table 5 total-cohort hypotonia is 41/69 (59%), which maps to FREQUENT. The ≥2-year figure is 45%, also FREQUENT.

Nervous System 2

Impaired Pain Sensation HP:0007328

Show evidence (1 reference)

PMID:28058407 SUPPORT Other

"Additionally, individuals have reduced ability to feel pain and may lose reflexes such as the corneal reflex that normally causes one to blink, and the patellar reflex resulting in the knee-jerk."

Directly supports reduced pain sensation and lost corneal/patellar reflexes.

Abnormal Autonomic Nervous System Physiology HP:0012332

Show evidence (2 references)

PMID:27194968 SUPPORT Other

"Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions."

Clinical review lists dysautonomia among the defining features.

PMID:35461249 SUPPORT Human Clinical

"Stuve-Wiedemann syndrome (SWS) is a rare and severe genetic disease characterized by skeletal anomalies and dysautonomic disturbances requiring appropriate care."

Systematic review frames the disease as skeletal plus dysautonomic.

Prenatal and Birth 1

Oligohydramnios OCCASIONAL HP:0001562

Onset: ANTENATAL

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Another inconstant ultrasound findings include talipes, camptodactyly, intra-uterine growth restriction and oligoamnios"

Names oligohydramnios among the inconstant prenatal ultrasound findings. Table 2 quantifies it at 11/69 (16%), OCCASIONAL.

Respiratory 1

Neonatal Respiratory Distress HP:0002643

Onset: NEONATAL

Show evidence (2 references)

PMID:14740318 SUPPORT Human Clinical

"Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for..."

Places respiratory distress in the core neonatal phenotype that drives early lethality.

PMID:35461249 SUPPORT Human Clinical

"Mortality rate is higher during the first 2 years (42% <2 years; 10% >2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%)."

Quantifies respiratory failure as the dominant early cause of death.

Growth 2

Growth Delay FREQUENT HP:0001510

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Other osteo-articular manifestations reported in more than the half of the total cohort are camptodactyly (80%), any degree of joint mobility restriction (65%), growth retardation (57%) and feet malposition (51%)."

57% growth retardation in the total cohort maps to FREQUENT. Table 4 gives 87% among ≥2-year survivors (VERY_FREQUENT in that subset).

Intrauterine Growth Retardation OCCASIONAL HP:0001511

Onset: ANTENATAL

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Intra-uterine growth restriction was found in 17% of patients while a normal prenatal growth is reported in more than half of the cohort."

17% maps to OCCASIONAL (5–29%). Table 2 is 12/69.

Other 4

Temperature Instability HP:0005968

Temporal: RECURRENT Onset: NEONATAL

Show evidence (2 references)

PMID:14740318 SUPPORT Human Clinical

"Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for..."

Hyperthermic episodes are explicitly linked to early lethality.

PMID:28058407 SUPPORT Other

"In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes."

Confirms infantile hyperthermic crises as part of the autonomic picture.

Talipes FREQUENT HP:0001883

Onset: CONGENITAL

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Other osteo-articular manifestations reported in more than the half of the total cohort are camptodactyly (80%), any degree of joint mobility restriction (65%), growth retardation (57%) and feet malposition (51%)."

51% feet malposition maps to FREQUENT; Talipes is the closest HP class for that radiographic/clinical bundle.

Decreased Lacrimation OCCASIONAL HP:0000633

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"The main ophthalmologic complications reported are corneal ulcers and consecutive opacities (8%/45%) due to hypolacrimation (13%/26%) and a lack of corneal reflex/corneal anesthesia (10%/48%)."

The paper's paired percentages are the <2-year / ≥2-year split (13%/26%), both of which map to OCCASIONAL (5–29%). Table 5's total-cohort hypolacrimation is 19%, also OCCASIONAL.

Smooth Tongue FREQUENT HP:0010298

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Stomatological manifestations included a smooth tongue with lack of fungiform papillae (5%/61%)"

The paired percentages are the <2-year / ≥2-year split. 61% among ≥2-year survivors maps to FREQUENT, matching the survivor-denominator convention used for scoliosis and fractures in this entry.

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Genetic Associations

1

LIFR

Gene: LIFR hgnc:6597 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (2 references)

PMID:14740318 SUPPORT Human Clinical

"We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13."

Establishes LIFR null alleles as the cause of both STWS and the historical SJS type 2 label.

PMID:14740318 SUPPORT Human Clinical

"An identical frameshift insertion (653_654insT) was identified in families from the United Arab Emirates, suggesting a founder effect in that region."

Documents the UAE founder frameshift.

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Medical Actions

10

Supportive Care

Action: Supportive Care NCIT:C15747

There is no disease-modifying standard therapy. Care is multidisciplinary and symptomatic: airway and ventilatory support, assisted feeding, structured management of hyperthermic crises, aspiration precautions, and later orthopedic and ophthalmologic surveillance.

Show evidence (1 reference)

PMID:24618404 SUPPORT Other

"STWS is managed on a symptomatic basis since there is no treatment currently available."

States that management is symptomatic and that no disease-modifying therapy exists.

Nasogastric Feeding

Action: nasogastric intubation Ontology label: Nasogastric Intubation NCIT:C91836

Short-term enteral support for neonatal swallowing failure and aspiration risk; often a bridge to gastrostomy when oral skills do not progress.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:38628360 SUPPORT Human Clinical

"Increased caution should be paid towards managing swallowing difficulties with nasogastric tube placement or gastrostomy especially during the first few years of life"

Names nasogastric tube placement as a first-years feeding intervention for swallowing failure.

Gastrostomy

Action: gastrostomy tube procedure Ontology label: Gastrostomy Tube Procedure NCIT:C157864

Surgical feeding tube when prolonged enteral support is required for dysphagia and aspiration prevention.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:38628360 SUPPORT Human Clinical

"Increased caution should be paid towards managing swallowing difficulties with nasogastric tube placement or gastrostomy especially during the first few years of life"

Names gastrostomy alongside nasogastric feeding as the swallowing intervention used in the first years of life.

Physical Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Conservative orthopedic management of progressive contractures, bowing, and spinal deformity in survivors, often with bracing.

Target Phenotypes: Joint stiffness HP:0001387 Scoliosis HP:0002650

Show evidence (2 references)

PMID:35461249 SUPPORT Human Clinical

"Conservative and preventive management include physiotherapy and the use of braces."

Systematic review names physiotherapy and bracing as conservative orthopedic management in survivors.

PMID:38628360 SUPPORT Human Clinical

"Many long-term survivors require physical therapy and braces"

Independent case-and-review states that long-term survivors require physical therapy and braces.

Bromocriptine

Action: Pharmacotherapy NCIT:C15986

Agent: bromocriptine CHEBI:3181

Dopamine-agonist rescue for central hyperthermia unresponsive to antipyretics. Documented in a genetically confirmed childhood survivor as part of a home fever plan; use in STWS is case-level, not a controlled indication.

Mechanism Target:

MODULATES Autonomic and Sensory Neuron Dysfunction — Used to abort dysautonomic hyperthermic crises after first-line antipyretics fail.

Show evidence (1 reference)

PMID:38628360 SUPPORT Human Clinical

"use of gabapentin and bromocriptine for pain and hyperthermia management respectively in patients with SWS, which should be studied in future case reports and series"

Authors report bromocriptine for hyperthermia in this LIFR-confirmed survivor and explicitly call for further study, so the claim is PARTIAL rather than established efficacy.

Target Phenotypes: Temperature instability HP:0005968

Show evidence (1 reference)

PMID:38628360 SUPPORT Human Clinical

"bromocriptine if there is no response. Bromocriptine is a dopamine receptor agonist that has been used for treating hyperpyrexia in Neuroleptic Malignant Syndrome (NMS) and other hyperthermia of central origin"

Describes the patient's stepwise fever plan (acetaminophen/ibuprofen, then bromocriptine) and the pharmacological rationale.

Gabapentin

Action: Pharmacotherapy NCIT:C15986

Agent: gabapentin CHEBI:42797

Used for pain management in a genetically confirmed childhood survivor. Case-level only; authors ask for further reports.

Target Phenotypes: Impaired pain sensation HP:0007328

Show evidence (1 reference)

PMID:38628360 SUPPORT Human Clinical

"use of gabapentin and bromocriptine for pain and hyperthermia management respectively in patients with SWS, which should be studied in future case reports and series"

Names gabapentin for pain in STWS and flags the evidence as needing further study.

Corneal lubrication

Artificial tears, ointments, and contact lenses to protect an anesthetic, hypolacrimating cornea; surgical adjuncts (punctal occlusion, tarsorrhaphy) are used when conservative measures fail. No specific NCIT clinical-action term was a better fit than this free-text preferred term.

Target Phenotypes: Corneal opacity HP:0007957 Decreased lacrimation HP:0000633

Show evidence (2 references)

PMID:35461249 SUPPORT Human Clinical

"Management includes artificial drops and ointments or surgical procedures (punctual occlusion, lateral tarsorrhaphy, optical iridectomy)"

Systematic review names artificial drops/ointments as first-line ocular protection, with surgical options if needed.

PMID:35461249 SUPPORT Human Clinical

"She received close ocular follow-up and treatment with artificial tears, ointments and contact lens since the neonatal period"

Index-patient narrative in the same review documents neonatal-onset lubrication as actual care delivered.

Bisphosphonate therapy with vitamin D and calcium

Action: Bisphosphonate Therapy NCIT:C198585

Agent: vitamin D CHEBI:27300 calcium(2+) CHEBI:29108

Antiresorptive plus mineral/vitamin D support used in survivors to reduce recurrent fractures and progressive osteopenia. Not a disease-modifying LIFR therapy; evidence is observational.

Mechanism Target:

INHIBITS Impaired Chondrogenesis and Bone Remodeling — Bisphosphonates suppress osteoclast-mediated resorption that this node records as increased.

Show evidence (1 reference)

PMID:38628360 SUPPORT Human Clinical

"incorporating the use of bisphosphonates, vitamin D and calcium in the medical regimen to control recurrent fractures and accelerated osteoporosis"

Names bisphosphonates plus vitamin D and calcium as the regimen used to control fractures and accelerated osteoporosis.

Target Phenotypes: Recurrent fractures HP:0002757 Osteopenia HP:0000938

Show evidence (1 reference)

PMID:38628360 SUPPORT Human Clinical

"incorporating the use of bisphosphonates, vitamin D and calcium in the medical regimen to control recurrent fractures and accelerated osteoporosis"

Independent review of a genetically confirmed survivor restates the same antiresorptive-plus-mineral regimen.

Orthopedic surgery

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Repeated osteotomies for progressive limb bowing (telescopic Fassier-Duval rodding recommended to reduce recurrence) and surgical stabilization of scoliosis. Deformity often recurs; surgery is reconstructive, not curative.

Target Phenotypes: Bowing of the long bones HP:0006487 Scoliosis HP:0002650

Show evidence (4 references)

PMID:35461249 SUPPORT Human Clinical

"Surgical stabilization of scoliosis is often required, while osteotomies are performed to reduced limbs deformities"

Names scoliosis stabilization and limb osteotomy as the typical surgical program. The source spelling is "to reduced".

PMID:35461249 SUPPORT Human Clinical

"recommend the use of telescopic intramedullary rodding (Fassier-Duval rods) to reduce the risk of recurrence and the need for multiple surgeries"

Cites the Fassier-Duval telescopic-rod recommendation for recurrent limb deformity.

PMID:38628360 SUPPORT Human Clinical

"Many long-term survivors require physical therapy and braces, as well as osteotomies to reduce limb deformities and surgical stabilization of scoliosis"

Confirms osteotomy and scoliosis stabilization as expected care in long-term survivors.

+ 1 more reference

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal recessive counseling, cascade carrier testing, and reproductive options (prenatal diagnosis, PGT-M) after identification of familial LIFR variants. Particularly relevant in founder populations.

Show evidence (1 reference)

PMID:38628360 SUPPORT Human Clinical

"This case adds to the literature surrounding rare instances of childhood survivors of SWS and raises awareness for this syndrome to facilitate an earlier recognition, intervention, and genetic counseling for the families, thereby improving understanding of this disease and the health outcomes..."

Explicitly names genetic counseling as part of clinical management.

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Diagnosis

3

Molecular genetic testing of LIFR

Identification of biallelic pathogenic LIFR variants confirms the diagnosis in a neonate or child with bent bones plus dysautonomia.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:14740318 SUPPORT Human Clinical

"We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13."

Establishes LIFR sequencing as the molecular definition of the disease.

Clinical diagnostic criteria

Clinical diagnosis rests on the association of short bowed long bones with a dysautonomic pattern, not on skeletal findings alone.

Physical Examination NCIT:C20989

Show evidence (2 references)

PMID:35461249 SUPPORT Human Clinical

"Clinical diagnosis criteria includes the association of skeletal involvement with short and bowed long bones, and a dysautonomic pattern."

States the clinical diagnostic pairing of bent bones plus dysautonomia.

PMID:35461249 SUPPORT Human Clinical

"Long bones: short and bowed (mandatory criterion for diagnosis)"

Table 6 reporting framework marks short bowed long bones as mandatory for the diagnosis.

Skeletal survey

Whole-skeleton radiographs showing bowed femur and tibia with diaphyseal cortical thickening at the concavity and enlarged metaphyses distinguish STWS from campomelic dysplasia (scapular/pelvic involvement).

Diagnostic Imaging Testing NCIT:C16502

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"enlarged metaphysis and diaphyseal cortical thickening at the concavity of long bones are suggestive of SWS"

Radiographic discriminator used both for diagnosis and against campomelic dysplasia.

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Progression

2

Neonatal and infantile high-mortality phase

Age: Birth to 2 years

Birth through age 2 is dominated by dysautonomic respiratory failure, aspiration, and hyperthermic crises. Warnier et al. report 42% mortality before age 2 versus 10% after age 2.

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Mortality rate is higher during the first 2 years (42% <2 years; 10% >2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%)."

Quantifies the early-mortality natural history.

Childhood orthopedic accumulation in survivors

Age: After 2 years

After age 2, dysautonomia often lessens while joint restriction, spinal deformity, and fractures increase.

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%)."

Describes the survivor natural-history shift toward orthopedic disease.

📊

Prevalence

2

Published cases

Cases In Literature Ultra Rare

Warnier et al. 2022 systematically reviewed 69 published patients; no general-population incidence was recovered. Orphanet ORPHA:3206 could not be cited from the structured cache in this worktree.

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"In our cohort of 69 patients, the median age at report was 32 months."

Gives the size of the assembled published-case literature rather than a population rate.

Worldwide

Unknown Rare

Qualitative "rare" descriptor from reviews; no denominator-based worldwide rate was recovered from cached abstracts.

Show evidence (1 reference)

PMID:24618404 SUPPORT Other

"Stüve-Wiedemann syndrome (STWS; OMIM # 610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes."

Qualitative rarity statement. OMIM number in this abstract is the known # 610559 typo; phenotype identity is LIFR-related STWS.

🔀

Differential Diagnoses

3

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

Schwartz-Jampel syndrome (HSPG2/perlecan)

Overlapping Features Historical "SJS type 2" was STWS. True Schwartz-Jampel syndrome is the HSPG2/perlecan chondrodystrophic myotonia with mask-like face and neuromyotonia, not LIFR dysautonomia.

Distinguishing Features

Causal gene HSPG2 rather than LIFR
Myotonia/neuromyotonia from AChE-anchor failure, not JAK/STAT3 loss
No hyperthermic dysautonomic lethality as the defining course

Show evidence (1 reference)

PMID:14740318 SUPPORT Human Clinical

"We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13."

Separates historical SJS type 2 (now STWS/LIFR) from HSPG2 SJS.

Campomelic dysplasia (SOX9)

Overlapping Features Another ISDS bent-bone dysplasia. Distinguished by SOX9-related scapular hypoplasia, 11 pairs of ribs, sex reversal in many 46,XY infants, and absence of LIFR-type dysautonomia.

Distinguishing Features

Causal gene SOX9 rather than LIFR
Hypoplastic scapulae and 11 rib pairs
46,XY sex reversal in many affected infants

Show evidence (1 reference)

PMID:35461249 SUPPORT Human Clinical

"Involvement of scapulae and pelvis is typical of CD, since enlarged metaphysis and diaphyseal cortical thickening at the concavity of long bones are suggestive of SWS"

Contrasts campomelic dysplasia's scapular/pelvic involvement with the STWS long-bone concavity pattern.

🐁

Animal Models

1

Lifr-null mouse

Homozygous Lifr knockout mice have placental, skeletal, neural and metabolic defects and die on the day of birth. Fetal bone volume is reduced more than three-fold with a six-fold increase in osteoclasts and severe perinatal osteopenia; astrocyte numbers are reduced in spinal cord and brainstem.

Species

Mouse

Genotype

Lifr targeted disruption (homozygous null)

Genes

LIFR hgnc:6597

Publication

PMID:7789261

Pathograph links

Impaired Chondrogenesis and Bone Remodeling recapitulates fidelity: moderate Recapitulates low bone volume, osteoclast excess, and osteopenia.

Limitations: Perinatal lethality precludes modeling of the childhood survivor orthopedic phenotype (progressive scoliosis, recurrent fractures).

Show evidence (1 reference)

PMID:7789261 SUPPORT Model Organism

"Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone."

Direct skeletal readout of the remodeling node.

Autonomic and Sensory Neuron Dysfunction partially recapitulates fidelity: low Neural developmental defects (reduced astrocytes) support a nervous-system requirement for LIFR but do not reproduce human dysautonomic crises.

Limitations: The mouse dies on the day of birth and does not exhibit the human infantile hyperthermic, swallowing, and sweating phenotype that dominates clinical care.

Show evidence (1 reference)

PMID:7789261 SUPPORT Model Organism

"Astrocyte numbers are reduced in the spinal cord and brain stem."

Neural cellular deficit, not a demonstration of human-like dysautonomia.

Show evidence (1 reference)

PMID:7789261 SUPPORT Model Organism

"Pleiotropic defects in the mutant animals preclude survival beyond the day of birth."

States perinatal lethality, the main translational limitation of this model.

{ }

Source YAML

click to show

name: LIFR-Related Stuve-Wiedemann Syndrome
creation_date: "2026-08-20T02:56:36Z"
category: Mendelian
description: >-
  Stuve-Wiedemann syndrome 1 (STWS1) is a rare autosomal recessive bent-bone
  dysplasia caused by biallelic loss-of-function variants in LIFR, which
  encodes the leukemia inhibitory factor receptor. Failed LIF/CNTF-family
  gp130–JAK–STAT3 signaling in chondrocytes and autonomic/sensory neurons
  produces congenital bowing of the long bones with osteopenia, camptodactyly,
  and a life-threatening neonatal dysautonomia (temperature instability,
  swallowing dysfunction, and respiratory distress). Historically labeled
  neonatal Schwartz-Jampel syndrome type 2, it is genetically and
  mechanistically distinct from HSPG2/perlecan Schwartz-Jampel syndrome.
disease_term:
  preferred_term: Stuve-Wiedemann syndrome 1
  term:
    id: MONDO:0800043
    label: Stüve-Wiedemann syndrome 1
parents:
- hereditary disease
- Skeletal Dysplasia
synonyms:
- STWS
- STWS1
- Stuve-Wiedemann Syndrome 1
- Stüve-Wiedemann syndrome 1
- Stuve-Wiedemann syndrome, LIFR-related
- Stuve-Wiedemann syndrome
- Stüve-Wiedemann syndrome
- Stüve-Wiedemann dysplasia
- Schwartz-Jampel syndrome type 2
- neonatal Schwartz-Jampel syndrome
- SJS2
notes: >-
  NAMING: this entry is gene-anchored because "Stuve-Wiedemann syndrome" alone is
  locus-ambiguous — it names two diseases, LIFR and IL6ST. The OMIM/MONDO numbering
  (STWS1 / STWS2) is retained in `synonyms` and remains the `disease_term` label, but
  the entry name says which gene, following the same rule applied to the two kyphomelic
  dysplasia entries in the same ISDS group. The rule is not an adoption of the
  ISDS 2023 dyadic naming system; it is disambiguation, applied only where one
  phenotypic label names more than one dismech entry.

  LUMP/SPLIT: this entry models only LIFR-related Stuve-Wiedemann syndrome 1
  (MONDO:0800043; OMIM:601559). The IL6ST-related phenocopy Stuve-Wiedemann
  syndrome 2 (MONDO:0030756; OMIM:619751; "extended Stuve-Wiedemann syndrome"
  in Chen et al., PMID:31914175) is curated as a separate entry
  (kb/disorders/IL6ST-Related_Stuve-Wiedemann_Syndrome.yaml) because gp130 (IL6ST) is the shared
  co-receptor for many IL-6-family cytokines, complete IL6ST loss abolishes
  IL-6/IL-11/IL-27/OSM/LIF responses rather than LIFR-selective signaling, and
  the ISDS 2023 bent-bone group lists "Stuve-Wiedemann dysplasia (LIFR)"
  specifically. The parent grouping MONDO:0031280 is recorded as a broadMatch,
  not as the primary disease_term. This entity must not be folded into
  Schwartz-Jampel syndrome (HSPG2/perlecan; kb/disorders/Schwartz-Jampel_Syndrome.yaml).

  No dedicated GeneReviews chapter was found (PubMed searches
  "Stuve-Wiedemann GeneReviews[All Fields]" and "LIFR GeneReviews"; the sole
  GeneReviews-tagged hit, PMID:40521311, is a prenatal ultrasound series that
  searched GeneReviews as a literature source, not a GeneReviews chapter).

  Orphanet structured cache for ORPHA:3206 could not be rebuilt in this
  worktree (en_product1.xml not present); prevalence is recorded from the
  published case literature rather than an Orphanet epidemiology class.
  Mikelonis et al. 2014 (PMID:24618404) prints OMIM  # 610559 in the abstract;
  the canonical OMIM phenotype number for LIFR-related STWS is 601559
  (Warnier et al. 2022; MONDO xref).
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 that also includes IL6ST-related
      Stuve-Wiedemann syndrome 2 (MONDO:0030756). This entry is restricted to
      the LIFR disease (MONDO:0800043).
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Hereditary skeletal dysplasia (ISDS bent-bone group); Harrison's
      genetics/heritable-disease Part rather than an organ-system Part.
      Neonatal autonomic/respiratory crises are prominent but are modeled as
      mechanism and phenotype, not as additional Harrison's Parts.
  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 20-0020, listed there as "Stuve-Wiedemann syndrome, LIFR-related"
      (AR, LIFR, MIM 601559). The 2023 row carries the comment "Includes former
      neonatal Schwartz-Jampel syndrome or SJS type 2", which is the committee
      endorsing the historical synonymy this entry records — and, by placing
      it here rather than with HSPG2 Schwartz-Jampel syndrome, endorsing the
      split from that disorder too. In the 2019 revision (PMID:31633310) the
      same group was numbered 18 and the entry was worded "Stuve-Wiedemann
      dysplasia (LIFR)". The 2023 table lists the IL6ST-related form separately
      as NOS 20-0030, which is why dismech curates it as its own entry
      (kb/disorders/IL6ST-Related_Stuve-Wiedemann_Syndrome.yaml) rather than folding it in
      here. Placement is recorded from the nosology table rather than from an
      abstract-quotable sentence.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    STWS1 segregates as an autosomal recessive trait; affected individuals
    carry biallelic (homozygous or compound heterozygous) LIFR loss-of-function
    variants and heterozygous parents are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality.
    explanation: >-
      Landmark gene-identification paper states autosomal recessive inheritance
      as part of the defining clinical description.
pathophysiology:
- name: Biallelic LIFR Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic LIFR null or truncating variants destabilize the transcript and
    prevent formation of functional leukemia inhibitory factor receptor,
    removing the ligand-specific chain of the LIFR–gp130 heterodimer.
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    allelic_hit_role: BIALLELIC_INACTIVATION
    description: >-
      Homozygous or compound-heterozygous germline loss-of-function alleles
      (frameshift, nonsense, splice, or other null) of LIFR.
  genes:
  - preferred_term: LIFR
    term:
      id: hgnc:6597
      label: LIFR
  molecular_functions:
  - preferred_term: leukemia inhibitory factor receptor activity
    term:
      id: GO:0004923
      label: leukemia inhibitory factor receptor activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 14 distinct mutations were identified in the 19 families.
    explanation: >-
      Establishes LIFR as the causal gene across a multi-family SWS/SJS2 series.
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies indicated that these mutations alter the stability of LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells.
    explanation: >-
      Patient-cell assays show that the alleles are null at the mRNA and protein
      level, not merely mapping hits.
  downstream:
  - target: Failed LIF-Family gp130 JAK-STAT3 Signaling
- name: Failed LIF-Family gp130 JAK-STAT3 Signaling
  biological_scale: CELLULAR
  description: >-
    Without LIFR, LIF and related IL-6-family ligands cannot assemble a
    productive LIFR–gp130 receptor complex, so JAK-mediated STAT3 signaling
    (and associated MAPK/PI3K output) fails in target cells. This is
    LIFR-selective; complete IL6ST/gp130 loss abolishes a broader cytokine
    set and is modeled separately as STWS2.
  biological_processes:
  - 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
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies indicated that these mutations alter the stability of LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells.
    explanation: >-
      Direct functional readout that LIFR-null patient cells fail JAK/STAT3
      signaling.
  - reference: PMID:24618404
    reference_title: "Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines.
    explanation: >-
      Review statement placing LIFR in the IL-6-family JAK/STAT3 cascade that
      this node represents.
  downstream:
  - target: Impaired Chondrogenesis and Bone Remodeling
  - target: Autonomic and Sensory Neuron Dysfunction
- name: Impaired Chondrogenesis and Bone Remodeling
  biological_scale: TISSUE
  conforms_to: "osteoporosis_bone_resorption#Increased Osteoclastic Bone Resorption"
  description: >-
    Failed LIF-family signaling in the developing skeleton reduces bone volume
    and shifts remodeling toward osteoclast excess, producing congenital
    camptomelia, cortical thickening with flared osteopenic metaphyses, and
    later fractures and spinal deformity in survivors.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  - 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: osteoclast differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
    modifier: INCREASED
  - preferred_term: Bone Resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  evidence:
  - reference: PMID:7789261
    reference_title: Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone.
    explanation: >-
      Lifr-null mice provide the skeletal remodeling readout (low bone volume,
      osteoclast excess, osteopenia) underlying the human bent-bone phenotype.
      Not used as sole support for human phenotypes.
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality.
    explanation: >-
      Human radiographic signature of the skeletal arm of this node.
  downstream:
  - target: Bowed Long Bones
  - target: Camptodactyly
  - target: Recurrent Fractures
  - target: Scoliosis
  - target: Osteopenia
  - target: Growth Delay
  - target: Talipes
  - target: Intrauterine Growth Retardation
- name: Autonomic and Sensory Neuron Dysfunction
  biological_scale: TISSUE
  description: >-
    Failed LIF/CNTF-family signaling in autonomic and sensory neurons produces
    the dysautonomia that dominates neonatal lethality: temperature instability
    with hyperthermic crises, abnormal sweating, reduced pain sensation,
    absent corneal and tendon reflexes, and swallowing/respiratory failure.
    This is not the perlecan/AChE neuromuscular-junction mechanism of
    Schwartz-Jampel syndrome.
  cell_types:
  - preferred_term: autonomic neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  - preferred_term: sympathetic neuron
    term:
      id: CL:0011103
      label: sympathetic neuron
  biological_processes:
  - preferred_term: autonomic nervous system development
    term:
      id: GO:0048483
      label: autonomic nervous system development
    modifier: DECREASED
  evidence:
  - reference: PMID:28058407
    reference_title: Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Stüve-Wiedemann syndrome (STWS; OMIM  # 610559) is a rare disease that results in dysfunction of the autonomic nervous system, which controls involuntary processes such as breathing rate and body temperature.
    explanation: >-
      Neuropathy-focused review identifies autonomic failure (breathing and
      temperature) as the neural arm of LIFR-related STWS. The abstract's
      OMIM  # 610559 is the known Mikelonis typo; the disease identity is LIFR.
  - reference: PMID:7789261
    reference_title: Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Astrocyte numbers are reduced in the spinal cord and brain stem.
    explanation: >-
      Lifr-null mice show a neural developmental deficit, supporting a
      nervous-system requirement for LIFR; they do not fully model human
      dysautonomic crises in survivors.
  downstream:
  - target: Temperature Instability
  - target: Feeding Difficulties
  - target: Neonatal Respiratory Distress
  - target: Abnormal Sweating
  - target: Impaired Pain Sensation
  - target: Abnormal Autonomic Nervous System Physiology
  - target: Corneal Opacity
  - target: Decreased Lacrimation
  - target: Smooth Tongue
  - target: Trismus
phenotypes:
- name: Bowed Long Bones
  description: >-
    Congenital camptomelia with bowing of the tibia and femur, cortical
    thickening, and flared metaphyses with coarsened trabecular pattern.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality.
    explanation: >-
      Defines congenital long-bone bowing with the characteristic metaphyseal
      radiographic pattern as a core feature.
- name: Camptodactyly
  description: >-
    Congenital finger contractures; a useful prenatal and neonatal clue that
    helps distinguish STWS from other bent-bone dysplasias.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality.
    explanation: >-
      Lists camptodactyly among the defining congenital findings.
- name: Neonatal Respiratory Distress
  description: >-
    Early respiratory failure, often with aspiration, is the leading cause of
    death in the first two years.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality.
    explanation: >-
      Places respiratory distress in the core neonatal phenotype that drives
      early lethality.
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality rate is higher during the first 2 years (42% <2 years; 10% >2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%).
    explanation: >-
      Quantifies respiratory failure as the dominant early cause of death.
- name: Feeding Difficulties
  description: >-
    Swallowing dysfunction and poor feeding frequently require nasogastric or
    gastrostomy support in infancy; swallowing often improves after age 2–3
    in survivors.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality.
    explanation: >-
      Feeding difficulties are part of the original molecular series'
      defining description.
  - reference: PMID:28058407
    reference_title: Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes.
    explanation: >-
      Attributes feeding and swallowing failure to the infantile autonomic
      phenotype.
- name: Temperature Instability
  description: >-
    Hyperthermic episodes and poor thermoregulation, often without infection,
    are a major cause of sudden death in infancy.
  phenotype_term:
    preferred_term: Temperature instability
    term:
      id: HP:0005968
      label: Temperature instability
    onset:
      onset_category: NEONATAL
    temporality: RECURRENT
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality.
    explanation: >-
      Hyperthermic episodes are explicitly linked to early lethality.
  - reference: PMID:28058407
    reference_title: Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes.
    explanation: >-
      Confirms infantile hyperthermic crises as part of the autonomic picture.
- name: Abnormal Sweating
  description: >-
    Paradoxical or excessive sweating that is not explained by elevated body
    temperature, reflecting autonomic sudomotor dysregulation.
  phenotype_term:
    preferred_term: Hyperhidrosis
    term:
      id: HP:0000975
      label: Hyperhidrosis
  evidence:
  - reference: PMID:28058407
    reference_title: Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals may sweat excessively when body temperature is not elevated.
    explanation: >-
      Describes temperature-uncoupled sweating, the sudomotor arm of STWS
      dysautonomia.
- name: Impaired Pain Sensation
  description: >-
    Reduced nociception with loss of protective reflexes (corneal blink,
    patellar), predisposing to unrecognized injury.
  phenotype_term:
    preferred_term: Impaired pain sensation
    term:
      id: HP:0007328
      label: Impaired pain sensation
  evidence:
  - reference: PMID:28058407
    reference_title: Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additionally, individuals have reduced ability to feel pain and may lose reflexes such as the corneal reflex that normally causes one to blink, and the patellar reflex resulting in the knee-jerk.
    explanation: >-
      Directly supports reduced pain sensation and lost corneal/patellar
      reflexes.
- name: Abnormal Autonomic Nervous System Physiology
  description: >-
    Composite dysautonomia covering thermoregulation, sweating, swallowing,
    breathing, and nociception; the feature that historically separated STWS
    from other bent-bone dysplasias and from HSPG2 Schwartz-Jampel syndrome.
  phenotype_term:
    preferred_term: Dysautonomia
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:27194968
    reference_title: "Stüve-Wiedemann Syndrome: Update on Clinical and Genetic Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions.
    explanation: >-
      Clinical review lists dysautonomia among the defining features.
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stuve-Wiedemann syndrome (SWS) is a rare and severe genetic disease characterized by skeletal anomalies and dysautonomic disturbances requiring appropriate care.
    explanation: >-
      Systematic review frames the disease as skeletal plus dysautonomic.
- name: Scoliosis
  description: >-
    Progressive spinal deformity in childhood survivors; reported in most
    patients older than two years in the 69-patient systematic review.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%).
    explanation: >-
      77% spinal deformity among survivors older than two years maps to the
      FREQUENT band (30–79%). The estimate is among reported survivors, not
      a birth cohort.
- name: Recurrent Fractures
  description: >-
    Bone fragility with fractures accumulating in childhood survivors as
    osteopenia/osteoporosis progresses.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  frequency: FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%).
    explanation: >-
      61% fracture rate in survivors older than two years maps to FREQUENT.
- name: Pulmonary Arterial Hypertension
  description: >-
    Uncommon but high-mortality cardiopulmonary complication in infancy.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality rate is higher during the first 2 years (42% <2 years; 10% >2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%).
    explanation: >-
      Identifies PAH as a poor prognostic factor. Frequency is omitted from
      the abstract as a rate among all patients; OCCASIONAL is a conservative
      band given that it is discussed as a subset with very high case fatality
      rather than a defining feature. Notes below record that the 63% figure
      is mortality among those with PAH, not PAH prevalence.
  notes: >-
    Warnier et al. report 63% mortality among patients with PAH, not a 63%
    prevalence of PAH. Do not treat the 63% figure as a phenotype frequency.
- name: Joint Stiffness
  description: >-
    Restricted joint mobility that worsens with age in survivors.
  phenotype_term:
    preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%).
    explanation: >-
      81% joint-mobility restriction after age 2 maps to VERY_FREQUENT
      (80–99%), with the same survivor-ascertainment caveat.
  - reference: PMID:27194968
    reference_title: "Stüve-Wiedemann Syndrome: Update on Clinical and Genetic Aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions.
    explanation: >-
      Independent review lists joint restrictions among core features.
- name: Osteopenia
  description: >-
    Low bone mineral density that accumulates in childhood survivors and
    underlies the fracture burden already curated as Recurrent Fractures.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  frequency: FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteoporosis prevalence also increases in children
    explanation: >-
      The same paragraph gives the split 11% <2 years / 48% ≥2 years.
      The ≥2-year 48% maps to FREQUENT (30–79%), matching how scoliosis
      and fractures in this entry use the survivor denominator. Total-cohort
      Table 4 is 19/69 (28%).
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      performed at 5 weeks of age showed diffuse hypomineralization of bones, indicating osteopenia
    explanation: >-
      Radiographic osteopenia in a genetically confirmed LIFR infant.
- name: Growth Delay
  description: >-
    Postnatal growth retardation, reported in most of the total cohort and
    in nearly all survivors older than two years.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other osteo-articular manifestations reported in more than the half of the total cohort are camptodactyly (80%), any degree of joint mobility restriction (65%), growth retardation (57%) and feet malposition (51%).
    explanation: >-
      57% growth retardation in the total cohort maps to FREQUENT. Table 4
      gives 87% among ≥2-year survivors (VERY_FREQUENT in that subset).
- name: Talipes
  description: >-
    Congenital foot malposition (clubfoot/talipes spectrum), present in about
    half of reported patients.
  phenotype_term:
    preferred_term: Talipes
    term:
      id: HP:0001883
      label: Talipes
    onset:
      onset_category: CONGENITAL
  frequency: FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other osteo-articular manifestations reported in more than the half of the total cohort are camptodactyly (80%), any degree of joint mobility restriction (65%), growth retardation (57%) and feet malposition (51%).
    explanation: >-
      51% feet malposition maps to FREQUENT; Talipes is the closest HP class
      for that radiographic/clinical bundle.
- name: Corneal Opacity
  description: >-
    Corneal ulcers progressing to opacity from hypolacrimation and absent
    corneal reflex; the dominant ocular complication in childhood survivors.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  frequency: FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main ophthalmologic complications reported are corneal ulcers and consecutive opacities (8%/45%) due to hypolacrimation (13%/26%) and a lack of corneal reflex/corneal anesthesia (10%/48%).
    explanation: >-
      The paired percentages are the <2-year / ≥2-year split; 8% is the
      <2-year subgroup, pulled down by infant deaths before ocular disease
      is ascertained, and Table 5's total-cohort figure is 26% (18/69).
      The ≥2-year 45% maps to FREQUENT.
- name: Decreased Lacrimation
  description: >-
    Hypolacrimation contributing to corneal injury together with absent
    blink/corneal reflex.
  phenotype_term:
    preferred_term: Decreased lacrimation
    term:
      id: HP:0000633
      label: Decreased lacrimation
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main ophthalmologic complications reported are corneal ulcers and consecutive opacities (8%/45%) due to hypolacrimation (13%/26%) and a lack of corneal reflex/corneal anesthesia (10%/48%).
    explanation: >-
      The paper's paired percentages are the <2-year / ≥2-year split
      (13%/26%), both of which map to OCCASIONAL (5–29%). Table 5's
      total-cohort hypolacrimation is 19%, also OCCASIONAL.
- name: Smooth Tongue
  description: >-
    Smooth tongue with reduced fungiform papillae, often with self-injury
    after tooth eruption because of impaired pain sensation.
  phenotype_term:
    preferred_term: Smooth tongue
    term:
      id: HP:0010298
      label: Smooth tongue
  frequency: FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stomatological manifestations included a smooth tongue with lack of fungiform papillae (5%/61%)
    explanation: >-
      The paired percentages are the <2-year / ≥2-year split. 61% among
      ≥2-year survivors maps to FREQUENT, matching the survivor-denominator
      convention used for scoliosis and fractures in this entry.
- name: Hypotonia
  description: >-
    Generalized hypotonia, reported in more than half of published patients.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological manifestations encountered in SWS include hypotonia (71%/45%), trismus or myotonia (21%/36%)
    explanation: >-
      Paired percentages are the <2-year / ≥2-year split. Table 5 total-cohort
      hypotonia is 41/69 (59%), which maps to FREQUENT. The ≥2-year figure
      is 45%, also FREQUENT.
- name: Trismus
  description: >-
    Restricted mouth opening (trismus/myotonia), contributing to feeding
    difficulty and historically to confusion with Schwartz-Jampel syndrome.
  phenotype_term:
    preferred_term: Trismus
    term:
      id: HP:0000211
      label: Trismus
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological manifestations encountered in SWS include hypotonia (71%/45%), trismus or myotonia (21%/36%)
    explanation: >-
      Paired percentages are the <2-year / ≥2-year split (21%/36%). Table 5
      total-cohort trismus/myotonia is 19/69 (28%), mapping to OCCASIONAL
      (5–29%). The ≥2-year 36% would be FREQUENT; this entry uses the
      total-cohort figure here, as for hypotonia's 59% band, and records
      the split so the mixture is deliberate.
- name: Intrauterine Growth Retardation
  description: >-
    Prenatal growth restriction, reported in 17% of the assembled cohort;
    more than half of pregnancies had normal prenatal growth.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
    onset:
      onset_category: ANTENATAL
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intra-uterine growth restriction was found in 17% of patients while a normal prenatal growth is reported in more than half of the cohort.
    explanation: >-
      17% maps to OCCASIONAL (5–29%). Table 2 is 12/69.
- name: Oligohydramnios
  description: >-
    Reduced amniotic fluid as an inconstant prenatal ultrasound finding,
    reported in 16% of the cohort and easily missed as a standalone clue.
  phenotype_term:
    preferred_term: Oligohydramnios
    term:
      id: HP:0001562
      label: Oligohydramnios
    onset:
      onset_category: ANTENATAL
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Another inconstant ultrasound findings include talipes, camptodactyly, intra-uterine growth restriction and oligoamnios
    explanation: >-
      Names oligohydramnios among the inconstant prenatal ultrasound
      findings. Table 2 quantifies it at 11/69 (16%), OCCASIONAL.
genetic:
- name: LIFR
  gene_term:
    preferred_term: LIFR
    term:
      id: hgnc:6597
      label: LIFR
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    Most reported alleles are truncating (frameshift, nonsense, splice). A
    recurrent c.653dup / 653_654insT founder frameshift is described in
    families from the United Arab Emirates (PMID:14740318).
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13.
    explanation: >-
      Establishes LIFR null alleles as the cause of both STWS and the
      historical SJS type 2 label.
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An identical frameshift insertion (653_654insT) was identified in families from the United Arab Emirates, suggesting a founder effect in that region.
    explanation: >-
      Documents the UAE founder frameshift.
treatments:
- name: Supportive Care
  description: >-
    There is no disease-modifying standard therapy. Care is multidisciplinary
    and symptomatic: airway and ventilatory support, assisted feeding,
    structured management of hyperthermic crises, aspiration precautions,
    and later orthopedic and ophthalmologic surveillance.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24618404
    reference_title: "Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      STWS is managed on a symptomatic basis since there is no treatment currently available.
    explanation: >-
      States that management is symptomatic and that no disease-modifying
      therapy exists.
- name: Nasogastric Feeding
  description: >-
    Short-term enteral support for neonatal swallowing failure and aspiration
    risk; often a bridge to gastrostomy when oral skills do not progress.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: nasogastric intubation
    term:
      id: NCIT:C91836
      label: Nasogastric Intubation
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased caution should be paid towards managing swallowing difficulties with nasogastric tube placement or gastrostomy especially during the first few years of life
    explanation: >-
      Names nasogastric tube placement as a first-years feeding intervention
      for swallowing failure.
- name: Gastrostomy
  description: >-
    Surgical feeding tube when prolonged enteral support is required for
    dysphagia and aspiration prevention.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy tube procedure
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased caution should be paid towards managing swallowing difficulties with nasogastric tube placement or gastrostomy especially during the first few years of life
    explanation: >-
      Names gastrostomy alongside nasogastric feeding as the swallowing
      intervention used in the first years of life.
- name: Physical Therapy
  description: >-
    Conservative orthopedic management of progressive contractures, bowing,
    and spinal deformity in survivors, often with bracing.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conservative and preventive management include physiotherapy and the use of braces.
    explanation: >-
      Systematic review names physiotherapy and bracing as conservative
      orthopedic management in survivors.
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many long-term survivors require physical therapy and braces
    explanation: >-
      Independent case-and-review states that long-term survivors require
      physical therapy and braces.
- name: Bromocriptine
  description: >-
    Dopamine-agonist rescue for central hyperthermia unresponsive to
    antipyretics. Documented in a genetically confirmed childhood survivor
    as part of a home fever plan; use in STWS is case-level, not a
    controlled indication.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bromocriptine
      term:
        id: CHEBI:3181
        label: bromocriptine
  target_phenotypes:
  - preferred_term: Temperature instability
    term:
      id: HP:0005968
      label: Temperature instability
  target_mechanisms:
  - target: Autonomic and Sensory Neuron Dysfunction
    treatment_effect: MODULATES
    description: >-
      Used to abort dysautonomic hyperthermic crises after first-line
      antipyretics fail.
    evidence:
    - reference: PMID:38628360
      reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        use of gabapentin and bromocriptine for pain and hyperthermia management respectively in patients with SWS, which should be studied in future case reports and series
      explanation: >-
        Authors report bromocriptine for hyperthermia in this LIFR-confirmed
        survivor and explicitly call for further study, so the claim is
        PARTIAL rather than established efficacy.
  evidence:
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bromocriptine if there is no response. Bromocriptine is a dopamine receptor agonist that has been used for treating hyperpyrexia in Neuroleptic Malignant Syndrome (NMS) and other hyperthermia of central origin
    explanation: >-
      Describes the patient's stepwise fever plan (acetaminophen/ibuprofen,
      then bromocriptine) and the pharmacological rationale.
- name: Gabapentin
  description: >-
    Used for pain management in a genetically confirmed childhood survivor.
    Case-level only; authors ask for further reports.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gabapentin
      term:
        id: CHEBI:42797
        label: gabapentin
  target_phenotypes:
  - preferred_term: Impaired pain sensation
    term:
      id: HP:0007328
      label: Impaired pain sensation
  evidence:
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      use of gabapentin and bromocriptine for pain and hyperthermia management respectively in patients with SWS, which should be studied in future case reports and series
    explanation: >-
      Names gabapentin for pain in STWS and flags the evidence as needing
      further study.
- name: Corneal lubrication
  description: >-
    Artificial tears, ointments, and contact lenses to protect an anesthetic,
    hypolacrimating cornea; surgical adjuncts (punctal occlusion,
    tarsorrhaphy) are used when conservative measures fail. No specific NCIT
    clinical-action term was a better fit than this free-text preferred term.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: corneal lubrication with artificial tears and ointments
  target_phenotypes:
  - preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  - preferred_term: Decreased lacrimation
    term:
      id: HP:0000633
      label: Decreased lacrimation
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Management includes artificial drops and ointments or surgical procedures (punctual occlusion, lateral tarsorrhaphy, optical iridectomy)
    explanation: >-
      Systematic review names artificial drops/ointments as first-line
      ocular protection, with surgical options if needed.
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She received close ocular follow-up and treatment with artificial tears, ointments and contact lens since the neonatal period
    explanation: >-
      Index-patient narrative in the same review documents neonatal-onset
      lubrication as actual care delivered.
- name: Bisphosphonate therapy with vitamin D and calcium
  description: >-
    Antiresorptive plus mineral/vitamin D support used in survivors to
    reduce recurrent fractures and progressive osteopenia. Not a
    disease-modifying LIFR therapy; evidence is observational.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
    therapeutic_agent:
    - preferred_term: vitamin D
      term:
        id: CHEBI:27300
        label: vitamin D
    - preferred_term: calcium(2+)
      term:
        id: CHEBI:29108
        label: calcium(2+)
  target_phenotypes:
  - preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  - preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  target_mechanisms:
  - target: Impaired Chondrogenesis and Bone Remodeling
    treatment_effect: INHIBITS
    description: >-
      Bisphosphonates suppress osteoclast-mediated resorption that this
      node records as increased.
    evidence:
    - reference: PMID:38628360
      reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        incorporating the use of bisphosphonates, vitamin D and calcium in the medical regimen to control recurrent fractures and accelerated osteoporosis
      explanation: >-
        Names bisphosphonates plus vitamin D and calcium as the regimen
        used to control fractures and accelerated osteoporosis.
  evidence:
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      incorporating the use of bisphosphonates, vitamin D and calcium in the medical regimen to control recurrent fractures and accelerated osteoporosis
    explanation: >-
      Independent review of a genetically confirmed survivor restates the
      same antiresorptive-plus-mineral regimen.
- name: Orthopedic surgery
  description: >-
    Repeated osteotomies for progressive limb bowing (telescopic
    Fassier-Duval rodding recommended to reduce recurrence) and surgical
    stabilization of scoliosis. Deformity often recurs; surgery is
    reconstructive, not curative.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical stabilization of scoliosis is often required, while osteotomies are performed to reduced limbs deformities
    explanation: >-
      Names scoliosis stabilization and limb osteotomy as the typical
      surgical program. The source spelling is "to reduced".
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recommend the use of telescopic intramedullary rodding (Fassier-Duval rods) to reduce the risk of recurrence and the need for multiple surgeries
    explanation: >-
      Cites the Fassier-Duval telescopic-rod recommendation for recurrent
      limb deformity.
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many long-term survivors require physical therapy and braces, as well as osteotomies to reduce limb deformities and surgical stabilization of scoliosis
    explanation: >-
      Confirms osteotomy and scoliosis stabilization as expected care in
      long-term survivors.
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral femoral valgus osteotomy, which was performed at three years of age
    explanation: >-
      Documents an actual femoral valgus osteotomy in the genetically
      confirmed childhood survivor.
- name: Genetic Counseling
  description: >-
    Autosomal recessive counseling, cascade carrier testing, and reproductive
    options (prenatal diagnosis, PGT-M) after identification of familial LIFR
    variants. Particularly relevant in founder populations.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38628360
    reference_title: "A novel termination site in a case of Stüve-Wiedemann syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case adds to the literature surrounding rare instances of childhood survivors of SWS and raises awareness for this syndrome to facilitate an earlier recognition, intervention, and genetic counseling for the families, thereby improving understanding of this disease and the health outcomes for the children affected by this condition.
    explanation: >-
      Explicitly names genetic counseling as part of clinical management.
prevalence:
- population: Published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Warnier et al. 2022 systematically reviewed 69 published patients; no
    general-population incidence was recovered. Orphanet ORPHA:3206 could not
    be cited from the structured cache in this worktree.
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort of 69 patients, the median age at report was 32 months.
    explanation: >-
      Gives the size of the assembled published-case literature rather than a
      population rate.
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Qualitative "rare" descriptor from reviews; no denominator-based
    worldwide rate was recovered from cached abstracts.
  evidence:
  - reference: PMID:24618404
    reference_title: "Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Stüve-Wiedemann syndrome (STWS; OMIM  # 610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes.
    explanation: >-
      Qualitative rarity statement. OMIM number in this abstract is the known
      # 610559 typo; phenotype identity is LIFR-related STWS.
progression:
- phase: Neonatal and infantile high-mortality phase
  age_range: Birth to 2 years
  notes: >-
    Birth through age 2 is dominated by dysautonomic respiratory failure,
    aspiration, and hyperthermic crises. Warnier et al. report 42% mortality
    before age 2 versus 10% after age 2.
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality rate is higher during the first 2 years (42% <2 years; 10% >2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%).
    explanation: >-
      Quantifies the early-mortality natural history.
- phase: Childhood orthopedic accumulation in survivors
  age_range: After 2 years
  notes: >-
    After age 2, dysautonomia often lessens while joint restriction, spinal
    deformity, and fractures increase.
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%).
    explanation: >-
      Describes the survivor natural-history shift toward orthopedic disease.
diagnosis:
- name: Molecular genetic testing of LIFR
  description: >-
    Identification of biallelic pathogenic LIFR variants confirms the
    diagnosis in a neonate or child with bent bones plus dysautonomia.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13.
    explanation: >-
      Establishes LIFR sequencing as the molecular definition of the disease.
- name: Clinical diagnostic criteria
  description: >-
    Clinical diagnosis rests on the association of short bowed long bones
    with a dysautonomic pattern, not on skeletal findings alone.
  diagnosis_term:
    preferred_term: Physical Examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical diagnosis criteria includes the association of skeletal involvement with short and bowed long bones, and a dysautonomic pattern.
    explanation: >-
      States the clinical diagnostic pairing of bent bones plus dysautonomia.
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long bones: short and bowed (mandatory criterion for diagnosis)
    explanation: >-
      Table 6 reporting framework marks short bowed long bones as mandatory
      for the diagnosis.
- name: Skeletal survey
  description: >-
    Whole-skeleton radiographs showing bowed femur and tibia with diaphyseal
    cortical thickening at the concavity and enlarged metaphyses distinguish
    STWS from campomelic dysplasia (scapular/pelvic involvement).
  diagnosis_term:
    preferred_term: Diagnostic Imaging Testing
    term:
      id: NCIT:C16502
      label: Diagnostic Imaging Testing
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      enlarged metaphysis and diaphyseal cortical thickening at the concavity of long bones are suggestive of SWS
    explanation: >-
      Radiographic discriminator used both for diagnosis and against
      campomelic dysplasia.
animal_models:
- name: Lifr-null mouse
  species: Mouse
  genotype: Lifr targeted disruption (homozygous null)
  publication: PMID:7789261
  description: >-
    Homozygous Lifr knockout mice have placental, skeletal, neural and
    metabolic defects and die on the day of birth. Fetal bone volume is
    reduced more than three-fold with a six-fold increase in osteoclasts
    and severe perinatal osteopenia; astrocyte numbers are reduced in
    spinal cord and brainstem.
  genes:
  - preferred_term: LIFR
    term:
      id: hgnc:6597
      label: LIFR
  modeled_mechanisms:
  - target: Impaired Chondrogenesis and Bone Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Recapitulates low bone volume, osteoclast excess, and osteopenia.
    limitations: >-
      Perinatal lethality precludes modeling of the childhood survivor
      orthopedic phenotype (progressive scoliosis, recurrent fractures).
    evidence:
    - reference: PMID:7789261
      reference_title: Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone.
      explanation: >-
        Direct skeletal readout of the remodeling node.
  - target: Autonomic and Sensory Neuron Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Neural developmental defects (reduced astrocytes) support a nervous-system
      requirement for LIFR but do not reproduce human dysautonomic crises.
    limitations: >-
      The mouse dies on the day of birth and does not exhibit the human
      infantile hyperthermic, swallowing, and sweating phenotype that
      dominates clinical care.
    evidence:
    - reference: PMID:7789261
      reference_title: Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Astrocyte numbers are reduced in the spinal cord and brain stem.
      explanation: >-
        Neural cellular deficit, not a demonstration of human-like
        dysautonomia.
  evidence:
  - reference: PMID:7789261
    reference_title: Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pleiotropic defects in the mutant animals preclude survival beyond the day of birth.
    explanation: >-
      States perinatal lethality, the main translational limitation of this
      model.
differential_diagnoses:
- name: Schwartz-Jampel syndrome (HSPG2/perlecan)
  description: >-
    Historical "SJS type 2" was STWS. True Schwartz-Jampel syndrome is the
    HSPG2/perlecan chondrodystrophic myotonia with mask-like face and
    neuromyotonia, not LIFR dysautonomia.
  distinguishing_features:
  - Causal gene HSPG2 rather than LIFR
  - Myotonia/neuromyotonia from AChE-anchor failure, not JAK/STAT3 loss
  - No hyperthermic dysautonomic lethality as the defining course
  evidence:
  - reference: PMID:14740318
    reference_title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13.
    explanation: >-
      Separates historical SJS type 2 (now STWS/LIFR) from HSPG2 SJS.
- name: Campomelic dysplasia (SOX9)
  description: >-
    Another ISDS bent-bone dysplasia. Distinguished by SOX9-related scapular
    hypoplasia, 11 pairs of ribs, sex reversal in many 46,XY infants, and
    absence of LIFR-type dysautonomia.
  distinguishing_features:
  - Causal gene SOX9 rather than LIFR
  - Hypoplastic scapulae and 11 rib pairs
  - 46,XY sex reversal in many affected infants
  evidence:
  - reference: PMID:35461249
    reference_title: "Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Involvement of scapulae and pelvis is typical of CD, since enlarged metaphysis and diaphyseal cortical thickening at the concavity of long bones are suggestive of SWS
    explanation: >-
      Contrasts campomelic dysplasia's scapular/pelvic involvement with the
      STWS long-bone concavity pattern.
- name: IL6ST-Related Stuve-Wiedemann Syndrome (extended STWS)
  disease_term:
    preferred_term: Stuve-Wiedemann syndrome 2
    term:
      id: MONDO:0030756
      label: Stuve-Wiedemann syndrome 2
  description: >-
    Complete GP130 (IL6ST) loss causes a lethal Stuve-Wiedemann-like skeletal
    and neonatal lung phenotype plus thrombocytopenia, dermatitis, renal
    anomalies, and defective acute-phase response. Broader cytokine failure
    than LIFR-null STWS1.
  distinguishing_features:
  - Causal gene IL6ST rather than LIFR
  - Absent responses to IL-6, IL-11, IL-27, OSM, and LIF
  - Extra-skeletal immune, hematologic, cutaneous, and renal features
  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: >-
      Defines the IL6ST phenocopy as an extended, broader syndrome rather than
      classic LIFR STWS1.
discussions:
- discussion_id: stws1_lifr_mouse_perinatal_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Chondrogenesis and Bone Remodeling
  - pathophysiology#Autonomic and Sensory Neuron Dysfunction
  prompt: >-
    How faithfully does perinatal-lethal Lifr-null mouse osteopenia and
    astrocyte loss represent the human STWS1 natural history, in which some
    patients survive infancy with accumulating orthopedic disease as
    dysautonomia lessens?
  rationale: >-
    Ware et al. 1995 show that homozygous Lifr disruption is lethal on the
    day of birth, with reduced fetal bone volume and reduced astrocytes.
    Human STWS1 has high but not universal infant mortality (42% before age
    2 in Warnier et al.), and survivors have a distinct later phenotype the
    mouse cannot reach. The skeletal remodeling direction is concordant; the
    autonomic crisis phenotype and childhood course are not demonstrated in
    the mouse.
  proposed_experiments:
  - experiment_id: exp_stws1_conditional_lifr_postnatal
    name: Conditional or hypomorphic Lifr alleles with postnatal survival
    description: >-
      Generate conditional or hypomorphic Lifr alleles that permit postnatal
      survival, then perform thermoregulatory, swallowing, and serial skeletal
      phenotyping aligned to the human two-phase natural history (infant
      dysautonomia, then childhood orthopedic accumulation).
    experiment_type:
      preferred_term: conditional gene knockout
  evidence:
  - reference: PMID:7789261
    reference_title: Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pleiotropic defects in the mutant animals preclude survival beyond the day of birth.
    explanation: >-
      Documents the perinatal-lethality mismatch with human survivors.

LIFR-Related Stuve-Wiedemann Syndrome

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