Wieacker-Wolff Syndrome

Mendelian MONDO:0010758 Pathograph 21 Mendelian neurodevelopmental disorder congenital nervous system disorder Wieacker-Wolff syndrome spectrum

Wieacker-Wolff syndrome is an ultra-rare X-linked ZC4H2-associated neurodevelopmental and neuromuscular disorder. It is characterized by congenital contractures or arthrogryposis, distal muscle atrophy or weakness, ocular movement abnormalities including oculomotor apraxia, developmental delay or intellectual disability, and variable speech, skeletal, foot, and ophthalmic findings. ZC4H2 pathogenic variants disrupt central and peripheral nervous-system development and function through impaired synaptic plasticity, abnormal dendritic-spine regulation, altered ZC4H2 protein trafficking, and abnormal motor-neuron development.

Ask OpenScientist

Ask a research question about Wieacker-Wolff Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

2
Definitions
1
Inheritance
5
Pathophys.
20
Phenotypes
21
Pathograph
1
Genes
2
Treatments
7
References
1
Deep Research
📘

Definitions

2
Orphanet Wieacker-Wolff syndrome definition
Orphanet defines Wieacker-Wolff syndrome as a severe X-linked recessive neurodevelopmental disorder with severe contractures or arthrogryposis and intellectual disability.
OTHER
Show evidence (1 reference)
ORPHA:3454 SUPPORT Other
"Intellectual disability-developmental delay-contractures syndrome, formerly known as Wieacker-Wolff syndrome, is a severe X-linked recessive neurodevelopmental disorder characterized by severe contractures (arthrogryposis) and intellectual disability."
Orphanet provides the structured clinical definition.
ZC4H2-associated neurodevelopmental disorder definition
The ZC4H2 discovery study defines the condition as a clinically variable neurodevelopmental disorder of the central and peripheral nervous systems that can affect familial and simplex cases of both sexes.
OTHER
Show evidence (1 reference)
PMID:23623388 SUPPORT Human Clinical
"We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes."
Human genetic evidence supports modeling Wieacker-Wolff syndrome as a ZC4H2-associated neurodevelopmental spectrum.
👪

Inheritance

1
X-linked recessive inheritance HP:0001419
Orphanet records X-linked recessive inheritance, and the original clinical description and later molecular studies describe affected males in X-linked pedigrees. Female heterozygotes can also be affected, particularly with de novo deletions or truncating variants, so this entry treats WWS as an X-linked ZC4H2 spectrum rather than a male-only phenotype.
X-linked recessive inheritance
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"X-linked recessive"
Orphanet records X-linked recessive inheritance.
PMID:29150902 SUPPORT Human Clinical
"It is traditionally described in males as an X-linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations."
This review/case report summarizes the traditional X-linked recessive presentation.
⚙

Pathophysiology

5
ZC4H2 variant-mediated protein dysfunction
Germline or de novo ZC4H2 variants, including missense, deletion, rearrangement, and truncating alleles, impair ZC4H2 function and protein trafficking, initiating the Wieacker-Wolff syndrome mechanism.
ZC4H2 link
intracellular protein localization link ⚠ ABNORMAL
Downstream
Impaired synaptic plasticity and dendritic spine regulation ZC4H2 localizes to excitatory synapses and pathogenic variants alter dendritic spine density.
Motor neuron developmental dysfunction ZC4H2 disruption impairs motor-neuron development in zebrafish models.
Show evidence (3 references)
PMID:23623388 SUPPORT Human Clinical
"We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy."
Human genetic evidence places ZC4H2 variants at the proximal mechanism.
PMID:31885220 SUPPORT In Vitro
"The results showed that wild-type ZC4H2 had perinuclear and nuclear punctate pattern of EGFP signals in the cells"
Cell-expression experiments establish the normal subcellular localization pattern used to interpret mutant trafficking.
PMID:31885220 SUPPORT In Vitro
"indicating the mutant protein's trafficking was altered."
In vitro localization data support abnormal protein trafficking for a truncating WWS variant.
Impaired synaptic plasticity and dendritic spine regulation
Altered ZC4H2 at excitatory synapses changes dendritic spine density and synaptic plasticity, providing a cellular mechanism for developmental delay, intellectual disability, and speech/language involvement.
neuron link
regulation of synaptic plasticity link ⚠ ABNORMAL neuron projection morphogenesis link ⚠ ABNORMAL
dendritic spine link
Downstream
Mild intellectual disability Synaptic and dendritic-spine disruption is modeled as a cellular substrate for intellectual disability.
Global developmental delay Abnormal neuronal connectivity and plasticity are consistent with global developmental delay in affected children.
Abnormal speech pattern Speech delay or absent speech is nearly constant in reported ZC4H2-associated cases.
Show evidence (1 reference)
PMID:23623388 SUPPORT Model Organism
"In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density."
Mouse neuronal data support abnormal ZC4H2-dependent synaptic and dendritic-spine regulation.
Motor neuron developmental dysfunction
ZC4H2 knockdown impairs alpha-motoneuron development and causes abnormal swimming in zebrafish, supporting a peripheral motor-neuron mechanism for movement disorder, distal amyotrophy, weakness, and contracture formation.
motor neuron link
spinal cord motor neuron differentiation link ⚠ ABNORMAL motor neuron axon guidance link ⚠ ABNORMAL
Downstream
Distal amyotrophy Motor-neuron dysfunction is modeled as contributing to distal muscle atrophy.
Abnormality of movement ZC4H2 knockdown causes abnormal movement in the zebrafish model.
Oculomotor apraxia Oculomotor apraxia is modeled as part of the broader motor-control phenotype.
Fetal akinesia Motor-neuron and neuromuscular dysfunction reduces fetal movement.
Show evidence (1 reference)
PMID:23623388 SUPPORT Model Organism
"In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development."
Zebrafish model data support abnormal motor-neuron development downstream of ZC4H2 loss.
Fetal akinesia
The ZC4H2 neuromuscular mechanism reduces fetal movement, producing fetal hypokinesia and akinesia detectable as reduced antenatal motion.
Downstream
Arthrogryposis Reduced fetal movement prevents normal joint development, causing antenatal contractures.
Show evidence (1 reference)
PMID:34484757 SUPPORT Human Clinical
"The available phenotype—two males and three females—encompasses clubfoot/feet, hypo/akinesia, rocker‐bottom feet, contractures, AMC, and edema."
Prenatal WWS cases document fetal hypo/akinesia as part of the antenatal presentation.
Arthrogryposis
Fetal akinesia prevents normal joint movement in utero, producing multiple antenatal joint contractures (arthrogryposis multiplex congenita), congenital foot contractures, clubfoot, clinodactyly, and reduced joint mobility.
Downstream
Arthrogryposis multiplex congenita Fetal akinesia causes multiple antenatal contractures.
Limitation of joint mobility Contractures reduce joint mobility.
Congenital foot contractures Foot contractures are part of the congenital contracture phenotype.
Talipes equinovarus Clubfoot is repeatedly reported in prenatal and postnatal WWS cases.
Clinodactyly of the 5th finger Clinodactyly is modeled as part of the congenital distal-limb contracture spectrum.
Camptodactyly of finger Camptodactyly is part of the congenital distal-limb contracture spectrum.
Hip dislocation Hip dislocation is reported with the congenital contracture and lower-limb phenotype.
Show evidence (1 reference)
PMID:23623388 SUPPORT Human Clinical
"Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia."
The discovery paper establishes fetal akinesia as the proximal cause of multiple antenatal joint contractures.
⬡

Pathograph

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

Phenotypes

20
Eye 4
Strabismus OCCASIONAL Strabismus (HP:0000486)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0000486 | Strabismus | Occasional (29-5%)"
Orphanet records strabismus as occasional.
PMID:35121145 SUPPORT Human Clinical
"Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia."
Ophthalmic review supports strabismus as a reported eye manifestation.
Abnormality of eye movement VERY_FREQUENT Abnormality of eye movement (HP:0000496)
Show evidence (1 reference)
ORPHA:3454 SUPPORT Other
"HP:0000496 | Abnormality of eye movement | Very frequent (99-80%)"
Orphanet records abnormality of eye movement as very frequent.
Ptosis OCCASIONAL Ptosis (HP:0000508)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0000508 | Ptosis | Occasional (29-5%)"
Orphanet records ptosis as occasional.
PMID:35121145 SUPPORT Human Clinical
"Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia."
Ophthalmic review supports ptosis as a reported eye manifestation.
Oculomotor apraxia VERY_FREQUENT Oculomotor apraxia (HP:0000657)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0000657 | Oculomotor apraxia | Very frequent (99-80%)"
Orphanet records oculomotor apraxia as very frequent.
PMID:35121145 SUPPORT Human Clinical
"Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia."
Ophthalmic review supports oculomotor apraxia as a reported eye manifestation.
Head and Neck 1
Cleft palate Cleft palate (HP:0000175)
Show evidence (1 reference)
PMID:29150902 SUPPORT Human Clinical
"The purpose of this paper is to present a female individual with a classic phenotype and cleft palate, a previously undescribed finding in this syndrome."
A female WWS case report directly supports cleft palate as an additional manifestation.
Limbs 1
Talipes equinovarus Talipes equinovarus (HP:0001762)
Show evidence (2 references)
PMID:34484757 SUPPORT Human Clinical
"The available phenotype—two males and three females—encompasses clubfoot/feet, hypo/akinesia, rocker‐bottom feet, contractures, AMC, and edema."
Prenatal cases include clubfoot/feet.
PMID:34484757 SUPPORT Human Clinical
"a high forehead, rotated ears, flat philtrum, metacarpophalangeal contractures, camptodactyly, club feet, and distal limb muscle atrophy, hip dislocation, and/or joint flexion contractures."
The review identifies club feet among recurrent phenotypic features.
Musculoskeletal 4
Limitation of joint mobility VERY_FREQUENT Limitation of joint mobility (HP:0001376)
Show evidence (1 reference)
ORPHA:3454 SUPPORT Other
"HP:0001376 | Limitation of joint mobility | Very frequent (99-80%)"
Orphanet records limitation of joint mobility as very frequent.
Scoliosis OCCASIONAL Scoliosis (HP:0002650)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0002650 | Scoliosis | Occasional (29-5%)"
Orphanet records scoliosis as occasional.
PMID:31885220 SUPPORT Human Clinical
"X-rays of the spine, hand and foot showed waist scoliosis, camptodactyly of the fingers, extorsion of the hands, and vertical talus."
A molecularly confirmed WWS case had scoliosis on radiography.
Kyphosis OCCASIONAL Kyphosis (HP:0002808)
Show evidence (1 reference)
ORPHA:3454 SUPPORT Other
"HP:0002808 | Kyphosis | Occasional (29-5%)"
Orphanet records kyphosis as occasional.
Generalized hypotonia Generalized hypotonia (HP:0001290)
Show evidence (1 reference)
PMID:31885220 SUPPORT Human Clinical
"During physical examination, she could not control her head and presented with truncal hypotonia as well as AMC."
A molecularly confirmed WWS case had truncal hypotonia.
Nervous System 4
Mild intellectual disability VERY_FREQUENT Mild intellectual disability (HP:0001256)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0001256 | Intellectual disability, mild | Very frequent (99-80%)"
Orphanet records mild intellectual disability as very frequent.
PMID:23623388 SUPPORT Human Clinical
"We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID)."
The discovery study links the AMC phenotype to intellectual disability.
Global developmental delay VERY_FREQUENT Global developmental delay (HP:0001263)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0001263 | Global developmental delay | Very frequent (99-80%)"
Orphanet records global developmental delay as very frequent.
PMID:31885220 SUPPORT Human Clinical
"At 3 months of age, she was taken to our hospital because of global developmental delay."
A molecularly confirmed WWS case had global developmental delay.
Abnormal speech pattern VERY_FREQUENT Abnormal speech pattern (HP:0002167)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0002167 | Abnormality of speech or vocalization | Very frequent (99-80%)"
Orphanet records abnormality of speech or vocalization as very frequent.
PMID:34484757 SUPPORT Human Clinical
"Speech delay/ absence of speech are almost constant."
The case review supports frequent speech delay or absence of speech.
Abnormality of movement VERY_FREQUENT Abnormality of movement (HP:0100022)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0100022 | Abnormality of movement | Very frequent (99-80%)"
Orphanet records abnormality of movement as very frequent.
PMID:23623388 SUPPORT Model Organism
"All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants."
The zebrafish model supports abnormal movement downstream of ZC4H2 disruption.
Other 6
Distal amyotrophy VERY_FREQUENT Distal amyotrophy (HP:0003693)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0003693 | Distal amyotrophy | Very frequent (99-80%)"
Orphanet records distal amyotrophy as very frequent.
PMID:34484757 SUPPORT Human Clinical
"Speech delay/ absence of speech are almost constant.1 Additionally, phenotypic features appeared to be constantly present: a high forehead, rotated ears, flat philtrum, metacarpophalangeal contractures, camptodactyly, club feet, and distal limb muscle atrophy, hip dislocation, and/or joint..."
The case review supports distal limb muscle atrophy among recurrent features.
Clinodactyly of the 5th finger VERY_FREQUENT Clinodactyly of the 5th finger (HP:0004209)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0004209 | Clinodactyly of the 5th finger | Very frequent (99-80%)"
Orphanet records clinodactyly of the fifth finger as very frequent.
PMID:34484757 SUPPORT Human Clinical
"the presence of a pterygium was suspected and a clinodactyly on the left hand—fifth finger was noted."
Prenatal ultrasound described fifth-finger clinodactyly.
Camptodactyly of finger VERY_FREQUENT Camptodactyly of finger (HP:0100490)
Show evidence (2 references)
PMID:34484757 SUPPORT Human Clinical
"Speech delay/ absence of speech are almost constant.1 Additionally, phenotypic features appeared to be constantly present: a high forehead, rotated ears, flat philtrum, metacarpophalangeal contractures, camptodactyly, club feet, and distal limb muscle atrophy, hip dislocation, and/or joint..."
The case review describes camptodactyly among constantly present phenotypic features.
PMID:31885220 SUPPORT Human Clinical
"X-rays of the spine, hand and foot showed waist scoliosis, camptodactyly of the fingers, extorsion of the hands, and vertical talus."
A molecularly confirmed WWS case had camptodactyly on radiography.
Congenital foot contractures VERY_FREQUENT Congenital foot contractures (HP:0005745)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"HP:0005745 | Congenital foot contractures | Very frequent (99-80%)"
Orphanet records congenital foot contractures as very frequent.
PMID:29150902 SUPPORT Human Clinical
"It is traditionally described in males as an X-linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations."
The review/case report supports congenital foot contractures.
Arthrogryposis multiplex congenita Arthrogryposis multiplex congenita (HP:0002804)
Show evidence (2 references)
ORPHA:3454 SUPPORT Other
"severe contractures (arthrogryposis)"
Orphanet definition identifies arthrogryposis as a core feature.
PMID:23623388 SUPPORT Human Clinical
"We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy."
Human families with ZC4H2 variants had X-linked AMC plus intellectual disability.
Hip dislocation VERY_FREQUENT Hip dislocation (HP:0002827)
Show evidence (2 references)
PMID:34484757 SUPPORT Human Clinical
"Speech delay/ absence of speech are almost constant.1 Additionally, phenotypic features appeared to be constantly present: a high forehead, rotated ears, flat philtrum, metacarpophalangeal contractures, camptodactyly, club feet, and distal limb muscle atrophy, hip dislocation, and/or joint..."
The case review describes hip dislocation among constantly present phenotypic features.
PMID:31885220 SUPPORT Human Clinical
"pelvic MRI at 2 months showed right hip dislocation"
A molecularly confirmed WWS case had right hip dislocation on pelvic MRI.
🧬

Genetic Associations

1
ZC4H2 pathogenic variants (X-linked germline ZC4H2 point mutations, rearrangements, deletions, or truncating variants causing Wieacker-Wolff syndrome)
Show evidence (3 references)
ORPHA:3454 SUPPORT Other
"ZC4H2 | zinc finger C4H2-type containing | hgnc:24931 | Disease-causing germline mutation(s) in"
Orphanet identifies ZC4H2 as the disease-causing germline gene.
PMID:23623388 SUPPORT Human Clinical
"We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy."
Human family and simplex sequencing directly support ZC4H2 as causal.
PMID:31885220 SUPPORT Human Clinical
"We identified a heterozygous nonsense mutation in the ZC4H2 gene (c.199C>T, p. R67X) in this patient but not in her father and mother, indicating that the patient has a de novo mutation"
A de novo nonsense ZC4H2 variant supports the simplex female presentation.
💊

Treatments

2
Rehabilitation and physical therapy
Action: physical therapy MAXO:0000011
Rehabilitation and physical therapy are used as supportive management for the contracture, hypotonia, motor-delay, and mobility phenotype.
Target Phenotypes: Arthrogryposis multiplex congenita ↗ Limitation of joint mobility ↗ Generalized hypotonia ↗
Show evidence (1 reference)
PMID:31885220 SUPPORT Human Clinical
"Since then, she has received rehabilitation training at a local healthcare center."
A molecularly confirmed WWS case received rehabilitation training for the motor phenotype.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling addresses X-linked inheritance, recurrence risk, potential germline mosaicism, and prenatal molecular diagnostic options when fetal arthrogryposis suggests WWS.
Show evidence (2 references)
PMID:23623388 SUPPORT Human Clinical
"Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families."
The discovery paper explicitly links WWS pathophysiology to genetic counseling.
PMID:34484757 SUPPORT Human Clinical
"Precise genetic counseling may be obtained from deletion on Xq11.2 as for ZC4H2 gene sequencing diagnostic for Wieacker-Wolff syndrome."
Prenatal molecular diagnosis is explicitly tied to genetic counseling.
{ }

Source YAML

click to show 
name: Wieacker-Wolff Syndrome
creation_date: "2026-05-08T07:43:05Z"
updated_date: "2026-05-08T07:43:05Z"
category: Mendelian
synonyms:
- WWS
- WRWF
- WRWFXLR
- Wieacker syndrome
- Wieacker-Wolff syndrome, X-linked
- Wieacker-Wolff syndrome, X-linked recessive
- Foot contractures-muscle atrophy-oculomotor apraxia syndrome
- Intellectual disability-developmental delay-contractures syndrome
- Miles-Carpenter syndrome
- X-linked intellectual disability, Miles-Carpenter type
- ZC4H2-associated rare disorders
- ZARD
description: >-
  Wieacker-Wolff syndrome is an ultra-rare X-linked ZC4H2-associated
  neurodevelopmental and neuromuscular disorder. It is characterized by
  congenital contractures or arthrogryposis, distal muscle atrophy or weakness,
  ocular movement abnormalities including oculomotor apraxia, developmental
  delay or intellectual disability, and variable speech, skeletal, foot, and
  ophthalmic findings. ZC4H2 pathogenic variants disrupt central and peripheral
  nervous-system development and function through impaired synaptic plasticity,
  abnormal dendritic-spine regulation, altered ZC4H2 protein trafficking, and
  abnormal motor-neuron development.
disease_term:
  preferred_term: Wieacker-Wolff syndrome
  term:
    id: MONDO:0010758
    label: Wieacker-Wolff syndrome
parents:
- Mendelian neurodevelopmental disorder
- congenital nervous system disorder
- Wieacker-Wolff syndrome spectrum
external_assertions:
- name: Orphanet Wieacker-Wolff syndrome structured disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:3454
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=3454
  description: >-
    ORPHA:3454 supplies the primary Wieacker-Wolff syndrome definition,
    synonyms, X-linked recessive inheritance, neonatal onset, ultra-rare
    prevalence, ZC4H2 gene association, HPO phenotype frequencies, and
    MONDO/OMIM cross-references used in this entry.
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZC4H2 | zinc finger C4H2-type containing | hgnc:24931 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies ZC4H2 as the disease-causing germline gene for Wieacker-Wolff syndrome.
- name: Orphanet Miles-Carpenter legacy record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:85283
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=85283
  description: >-
    ORPHA:85283 is a sparse legacy Orphanet record for X-linked intellectual
    disability, Miles-Carpenter type, a synonym/cross-reference now aggregated
    under MONDO:0010758 rather than modeled here as a separate clinical subtype.
  evidence:
  - reference: ORPHA:85283
    reference_title: X-linked intellectual disability, Miles-Carpenter type
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "X-linked intellectual disability, Miles-Carpenter type"
    explanation: The legacy Orphanet title supports Miles-Carpenter type as a synonym/cross-reference for the spectrum.
definitions:
- name: Orphanet Wieacker-Wolff syndrome definition
  definition_type: OTHER
  description: >-
    Orphanet defines Wieacker-Wolff syndrome as a severe X-linked recessive
    neurodevelopmental disorder with severe contractures or arthrogryposis and
    intellectual disability.
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Intellectual disability-developmental delay-contractures syndrome, formerly known as Wieacker-Wolff syndrome, is a severe X-linked recessive neurodevelopmental disorder characterized by severe contractures (arthrogryposis) and intellectual disability."
    explanation: Orphanet provides the structured clinical definition.
- name: ZC4H2-associated neurodevelopmental disorder definition
  definition_type: OTHER
  description: >-
    The ZC4H2 discovery study defines the condition as a clinically variable
    neurodevelopmental disorder of the central and peripheral nervous systems
    that can affect familial and simplex cases of both sexes.
  evidence:
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes."
    explanation: Human genetic evidence supports modeling Wieacker-Wolff syndrome as a ZC4H2-associated neurodevelopmental spectrum.
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Orphanet records X-linked recessive inheritance, and the original clinical
    description and later molecular studies describe affected males in
    X-linked pedigrees. Female heterozygotes can also be affected, particularly
    with de novo deletions or truncating variants, so this entry treats WWS as
    an X-linked ZC4H2 spectrum rather than a male-only phenotype.
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "X-linked recessive"
    explanation: Orphanet records X-linked recessive inheritance.
  - reference: PMID:29150902
    reference_title: Wieacker-Wolff syndrome with associated cleft palate in a female case.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is traditionally described in males as an X-linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations."
    explanation: This review/case report summarizes the traditional X-linked recessive presentation.
prevalence:
- population: Worldwide
  percentage: <1 per 1,000,000
  notes: Orphanet and a prenatal case review classify Wieacker-Wolff syndrome as ultra-rare.
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records worldwide point prevalence below one per million.
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevalence is estimated to be <1/1,000,000."
    explanation: The prenatal case review independently supports ultra-rare prevalence.
progression:
- phase: Onset
  age_range: Neonatal
  notes: Orphanet records neonatal onset for the disorder.
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset.
- phase: Prenatal presentation
  age_range: Antenatal
  notes: >-
    Fetal akinesia and arthrogryposis can be detected prenatally, especially
    when ultrasound shows unusual arthrogryposis with lower-limb anomalies.
  evidence:
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unusual fetal arthrogryposis on ultrasound should draw attention to look for additional lower limb anomalies."
    explanation: Prenatal ultrasound evidence supports antenatal recognition in some cases.
genetic:
- name: ZC4H2 pathogenic variants
  gene_term:
    preferred_term: ZC4H2
    term:
      id: hgnc:24931
      label: ZC4H2
  association: X-linked germline ZC4H2 point mutations, rearrangements, deletions, or truncating variants causing Wieacker-Wolff syndrome
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported pathogenic variation includes X-linked familial missense variants,
    rearrangements, small deletions, and de novo heterozygous deletions or
    truncating variants in affected females. Functional studies support altered
    ZC4H2 localization, dendritic spine effects, and motor-neuron developmental
    defects.
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZC4H2 | zinc finger C4H2-type containing | hgnc:24931 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies ZC4H2 as the disease-causing germline gene.
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy."
    explanation: Human family and simplex sequencing directly support ZC4H2 as causal.
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a heterozygous nonsense mutation in the ZC4H2 gene (c.199C>T, p. R67X) in this patient but not in her father and mother, indicating that the patient has a de novo mutation"
    explanation: A de novo nonsense ZC4H2 variant supports the simplex female presentation.
pathophysiology:
- name: ZC4H2 variant-mediated protein dysfunction
  description: >-
    Germline or de novo ZC4H2 variants, including missense, deletion,
    rearrangement, and truncating alleles, impair ZC4H2 function and protein
    trafficking, initiating the Wieacker-Wolff syndrome mechanism.
  genes:
  - preferred_term: ZC4H2
    term:
      id: hgnc:24931
      label: ZC4H2
  biological_processes:
  - preferred_term: intracellular protein localization
    modifier: ABNORMAL
    term:
      id: GO:0008104
      label: intracellular protein localization
  evidence:
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy."
    explanation: Human genetic evidence places ZC4H2 variants at the proximal mechanism.
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results showed that wild-type ZC4H2 had perinuclear and nuclear punctate pattern of EGFP signals in the cells"
    explanation: Cell-expression experiments establish the normal subcellular localization pattern used to interpret mutant trafficking.
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "indicating the mutant protein's trafficking was altered."
    explanation: In vitro localization data support abnormal protein trafficking for a truncating WWS variant.
  downstream:
  - target: Impaired synaptic plasticity and dendritic spine regulation
    causal_link_type: DIRECT
    description: >-
      ZC4H2 localizes to excitatory synapses and pathogenic variants alter
      dendritic spine density.
    evidence:
    - reference: PMID:23623388
      reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density."
      explanation: Neuronal model evidence directly links altered ZC4H2 to synaptic and dendritic-spine biology.
  - target: Motor neuron developmental dysfunction
    causal_link_type: DIRECT
    description: ZC4H2 disruption impairs motor-neuron development in zebrafish models.
    evidence:
    - reference: PMID:23623388
      reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development."
      explanation: Zebrafish knockdown directly supports a motor-neuron developmental mechanism.
- name: Impaired synaptic plasticity and dendritic spine regulation
  description: >-
    Altered ZC4H2 at excitatory synapses changes dendritic spine density and
    synaptic plasticity, providing a cellular mechanism for developmental delay,
    intellectual disability, and speech/language involvement.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of synaptic plasticity
    modifier: ABNORMAL
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
  - preferred_term: neuron projection morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048812
      label: neuron projection morphogenesis
  cellular_components:
  - preferred_term: dendritic spine
    term:
      id: GO:0043197
      label: dendritic spine
  evidence:
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density."
    explanation: Mouse neuronal data support abnormal ZC4H2-dependent synaptic and dendritic-spine regulation.
  downstream:
  - target: Mild intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Synaptic and dendritic-spine disruption is modeled as a cellular substrate
      for intellectual disability.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal neuronal connectivity and plasticity are consistent with global
      developmental delay in affected children.
  - target: Abnormal speech pattern
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Speech delay or absent speech is nearly constant in reported ZC4H2-associated cases.
- name: Motor neuron developmental dysfunction
  description: >-
    ZC4H2 knockdown impairs alpha-motoneuron development and causes abnormal
    swimming in zebrafish, supporting a peripheral motor-neuron mechanism for
    movement disorder, distal amyotrophy, weakness, and contracture formation.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: spinal cord motor neuron differentiation
    modifier: ABNORMAL
    term:
      id: GO:0021522
      label: spinal cord motor neuron differentiation
  - preferred_term: motor neuron axon guidance
    modifier: ABNORMAL
    term:
      id: GO:0008045
      label: motor neuron axon guidance
  evidence:
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development."
    explanation: Zebrafish model data support abnormal motor-neuron development downstream of ZC4H2 loss.
  downstream:
  - target: Distal amyotrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Motor-neuron dysfunction is modeled as contributing to distal muscle atrophy.
  - target: Abnormality of movement
    causal_link_type: DIRECT
    description: ZC4H2 knockdown causes abnormal movement in the zebrafish model.
  - target: Oculomotor apraxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Oculomotor apraxia is modeled as part of the broader motor-control phenotype.
  - target: Fetal akinesia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - neuromuscular weakness reducing antenatal movement
    description: Motor-neuron and neuromuscular dysfunction reduces fetal movement.
- name: Fetal akinesia
  description: >-
    The ZC4H2 neuromuscular mechanism reduces fetal movement, producing fetal
    hypokinesia and akinesia detectable as reduced antenatal motion.
  evidence:
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The available phenotype—two males and three females—encompasses clubfoot/feet, hypo/akinesia, rocker‐bottom feet, contractures, AMC, and edema."
    explanation: Prenatal WWS cases document fetal hypo/akinesia as part of the antenatal presentation.
  downstream:
  - target: Arthrogryposis
    causal_link_type: DIRECT
    description: Reduced fetal movement prevents normal joint development, causing antenatal contractures.
- name: Arthrogryposis
  description: >-
    Fetal akinesia prevents normal joint movement in utero, producing multiple
    antenatal joint contractures (arthrogryposis multiplex congenita),
    congenital foot contractures, clubfoot, clinodactyly, and reduced joint
    mobility.
  evidence:
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia."
    explanation: The discovery paper establishes fetal akinesia as the proximal cause of multiple antenatal joint contractures.
  downstream:
  - target: Arthrogryposis multiplex congenita
    causal_link_type: DIRECT
    description: Fetal akinesia causes multiple antenatal contractures.
  - target: Limitation of joint mobility
    causal_link_type: DIRECT
    description: Contractures reduce joint mobility.
  - target: Congenital foot contractures
    causal_link_type: DIRECT
    description: Foot contractures are part of the congenital contracture phenotype.
  - target: Talipes equinovarus
    causal_link_type: DIRECT
    description: Clubfoot is repeatedly reported in prenatal and postnatal WWS cases.
  - target: Clinodactyly of the 5th finger
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinodactyly is modeled as part of the congenital distal-limb contracture spectrum.
  - target: Camptodactyly of finger
    causal_link_type: DIRECT
    description: Camptodactyly is part of the congenital distal-limb contracture spectrum.
  - target: Hip dislocation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hip dislocation is reported with the congenital contracture and lower-limb phenotype.
phenotypes:
- name: Strabismus
  category: Ophthalmic
  frequency: OCCASIONAL
  description: Strabismus is an occasional ophthalmic feature.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000486 | Strabismus | Occasional (29-5%)"
    explanation: Orphanet records strabismus as occasional.
  - reference: PMID:35121145
    reference_title: Ophthalmic abnormalities in Wieacker-Wolff syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia."
    explanation: Ophthalmic review supports strabismus as a reported eye manifestation.
- name: Abnormality of eye movement
  category: Ophthalmic
  frequency: VERY_FREQUENT
  description: Abnormal ocular movements are very frequent.
  phenotype_term:
    preferred_term: Abnormality of eye movement
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000496 | Abnormality of eye movement | Very frequent (99-80%)"
    explanation: Orphanet records abnormality of eye movement as very frequent.
- name: Ptosis
  category: Ophthalmic
  frequency: OCCASIONAL
  description: Ptosis is an occasional ophthalmic feature.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000508 | Ptosis | Occasional (29-5%)"
    explanation: Orphanet records ptosis as occasional.
  - reference: PMID:35121145
    reference_title: Ophthalmic abnormalities in Wieacker-Wolff syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia."
    explanation: Ophthalmic review supports ptosis as a reported eye manifestation.
- name: Oculomotor apraxia
  category: Ophthalmic
  frequency: VERY_FREQUENT
  description: Oculomotor apraxia or ophthalmic dyspraxia is a very frequent feature.
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000657 | Oculomotor apraxia | Very frequent (99-80%)"
    explanation: Orphanet records oculomotor apraxia as very frequent.
  - reference: PMID:35121145
    reference_title: Ophthalmic abnormalities in Wieacker-Wolff syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia."
    explanation: Ophthalmic review supports oculomotor apraxia as a reported eye manifestation.
- name: Mild intellectual disability
  category: Neurological
  frequency: VERY_FREQUENT
  description: Mild intellectual disability is very frequent in the Orphanet record.
  phenotype_term:
    preferred_term: Intellectual disability, mild
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001256 | Intellectual disability, mild | Very frequent (99-80%)"
    explanation: Orphanet records mild intellectual disability as very frequent.
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID)."
    explanation: The discovery study links the AMC phenotype to intellectual disability.
- name: Global developmental delay
  category: Neurological
  frequency: VERY_FREQUENT
  description: Global developmental delay is very frequent.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
    explanation: Orphanet records global developmental delay as very frequent.
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 3 months of age, she was taken to our hospital because of global developmental delay."
    explanation: A molecularly confirmed WWS case had global developmental delay.
- name: Limitation of joint mobility
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Limited joint mobility is a very frequent manifestation of the contracture phenotype.
  phenotype_term:
    preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001376 | Limitation of joint mobility | Very frequent (99-80%)"
    explanation: Orphanet records limitation of joint mobility as very frequent.
- name: Abnormal speech pattern
  category: Neurological
  frequency: VERY_FREQUENT
  description: Speech delay or absent speech is very frequent.
  phenotype_term:
    preferred_term: Abnormality of speech or vocalization
    term:
      id: HP:0002167
      label: Abnormal speech pattern
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002167 | Abnormality of speech or vocalization | Very frequent (99-80%)"
    explanation: Orphanet records abnormality of speech or vocalization as very frequent.
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech delay/ absence of speech are almost constant."
    explanation: The case review supports frequent speech delay or absence of speech.
- name: Scoliosis
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: Scoliosis is an occasional skeletal feature.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002650 | Scoliosis | Occasional (29-5%)"
    explanation: Orphanet records scoliosis as occasional.
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-rays of the spine, hand and foot showed waist scoliosis, camptodactyly of the fingers, extorsion of the hands, and vertical talus."
    explanation: A molecularly confirmed WWS case had scoliosis on radiography.
- name: Kyphosis
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: Kyphosis is an occasional skeletal feature.
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002808 | Kyphosis | Occasional (29-5%)"
    explanation: Orphanet records kyphosis as occasional.
- name: Distal amyotrophy
  category: Neuromuscular
  frequency: VERY_FREQUENT
  description: Distal amyotrophy is very frequent and reflects distal muscle wasting.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003693 | Distal amyotrophy | Very frequent (99-80%)"
    explanation: Orphanet records distal amyotrophy as very frequent.
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech delay/ absence of speech are almost constant.1 Additionally, phenotypic features appeared to be constantly present: a high forehead, rotated ears, flat philtrum, metacarpophalangeal contractures, camptodactyly, club feet, and distal limb muscle atrophy, hip dislocation, and/or joint flexion contractures."
    explanation: The case review supports distal limb muscle atrophy among recurrent features.
- name: Clinodactyly of the 5th finger
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Fifth-finger clinodactyly is very frequent.
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004209 | Clinodactyly of the 5th finger | Very frequent (99-80%)"
    explanation: Orphanet records clinodactyly of the fifth finger as very frequent.
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the presence of a pterygium was suspected and a clinodactyly on the left hand—fifth finger was noted."
    explanation: Prenatal ultrasound described fifth-finger clinodactyly.
- name: Camptodactyly of finger
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Camptodactyly is described among constantly present ZC4H2-associated features.
  phenotype_term:
    preferred_term: Camptodactyly of finger
    term:
      id: HP:0100490
      label: Camptodactyly of finger
  evidence:
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech delay/ absence of speech are almost constant.1 Additionally, phenotypic features appeared to be constantly present: a high forehead, rotated ears, flat philtrum, metacarpophalangeal contractures, camptodactyly, club feet, and distal limb muscle atrophy, hip dislocation, and/or joint flexion contractures."
    explanation: The case review describes camptodactyly among constantly present phenotypic features.
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-rays of the spine, hand and foot showed waist scoliosis, camptodactyly of the fingers, extorsion of the hands, and vertical talus."
    explanation: A molecularly confirmed WWS case had camptodactyly on radiography.
- name: Congenital foot contractures
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Congenital foot contractures are very frequent.
  phenotype_term:
    preferred_term: Congenital foot contractures
    term:
      id: HP:0005745
      label: Congenital foot contractures
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005745 | Congenital foot contractures | Very frequent (99-80%)"
    explanation: Orphanet records congenital foot contractures as very frequent.
  - reference: PMID:29150902
    reference_title: Wieacker-Wolff syndrome with associated cleft palate in a female case.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is traditionally described in males as an X-linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations."
    explanation: The review/case report supports congenital foot contractures.
- name: Abnormality of movement
  category: Neurological
  frequency: VERY_FREQUENT
  description: Abnormal movement is very frequent.
  phenotype_term:
    preferred_term: Abnormality of movement
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100022 | Abnormality of movement | Very frequent (99-80%)"
    explanation: Orphanet records abnormality of movement as very frequent.
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants."
    explanation: The zebrafish model supports abnormal movement downstream of ZC4H2 disruption.
- name: Arthrogryposis multiplex congenita
  category: Musculoskeletal
  description: Multiple congenital contractures are a defining manifestation.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: ORPHA:3454
    reference_title: Wieacker-Wolff syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "severe contractures (arthrogryposis)"
    explanation: Orphanet definition identifies arthrogryposis as a core feature.
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy."
    explanation: Human families with ZC4H2 variants had X-linked AMC plus intellectual disability.
- name: Talipes equinovarus
  category: Musculoskeletal
  description: Clubfoot is a recurrent prenatal and postnatal finding.
  phenotype_term:
    preferred_term: Clubfoot
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The available phenotype—two males and three females—encompasses clubfoot/feet, hypo/akinesia, rocker‐bottom feet, contractures, AMC, and edema."
    explanation: Prenatal cases include clubfoot/feet.
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a high forehead, rotated ears, flat philtrum, metacarpophalangeal contractures, camptodactyly, club feet, and distal limb muscle atrophy, hip dislocation, and/or joint flexion contractures."
    explanation: The review identifies club feet among recurrent phenotypic features.
- name: Hip dislocation
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Hip dislocation is described among constantly present ZC4H2-associated features.
  phenotype_term:
    preferred_term: Hip dislocation
    term:
      id: HP:0002827
      label: Hip dislocation
  evidence:
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech delay/ absence of speech are almost constant.1 Additionally, phenotypic features appeared to be constantly present: a high forehead, rotated ears, flat philtrum, metacarpophalangeal contractures, camptodactyly, club feet, and distal limb muscle atrophy, hip dislocation, and/or joint flexion contractures."
    explanation: The case review describes hip dislocation among constantly present phenotypic features.
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pelvic MRI at 2 months showed right hip dislocation"
    explanation: A molecularly confirmed WWS case had right hip dislocation on pelvic MRI.
- name: Generalized hypotonia
  category: Neuromuscular
  description: Hypotonia can accompany the congenital neuromuscular presentation.
  phenotype_term:
    preferred_term: Truncal hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During physical examination, she could not control her head and presented with truncal hypotonia as well as AMC."
    explanation: A molecularly confirmed WWS case had truncal hypotonia.
- name: Cleft palate
  category: Craniofacial
  description: Cleft palate has been reported as an additional craniofacial manifestation in a female case.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:29150902
    reference_title: Wieacker-Wolff syndrome with associated cleft palate in a female case.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this paper is to present a female individual with a classic phenotype and cleft palate, a previously undescribed finding in this syndrome."
    explanation: A female WWS case report directly supports cleft palate as an additional manifestation.
histopathology: []
biochemical: []
environmental: []
treatments:
- name: Rehabilitation and physical therapy
  description: >-
    Rehabilitation and physical therapy are used as supportive management for
    the contracture, hypotonia, motor-delay, and mobility phenotype.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  - preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  - preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since then, she has received rehabilitation training at a local healthcare center."
    explanation: A molecularly confirmed WWS case received rehabilitation training for the motor phenotype.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses X-linked inheritance, recurrence risk,
    potential germline mosaicism, and prenatal molecular diagnostic options
    when fetal arthrogryposis suggests WWS.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families."
    explanation: The discovery paper explicitly links WWS pathophysiology to genetic counseling.
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Precise genetic counseling may be obtained from deletion on Xq11.2 as for ZC4H2 gene sequencing diagnostic for Wieacker-Wolff syndrome."
    explanation: Prenatal molecular diagnosis is explicitly tied to genetic counseling.
diagnosis:
- name: ZC4H2 molecular testing
  description: >-
    Exome sequencing, molecular karyotype, copy-number analysis, and targeted
    ZC4H2 sequencing can confirm pathogenic ZC4H2 variants in individuals or
    fetuses with WWS-compatible contractures, developmental delay, and ocular
    movement abnormalities.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: MAXO:0009004
      label: clinical whole-exome sequencing
  evidence:
  - reference: PMID:23623388
    reference_title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases."
    explanation: The discovery study supports sequencing and copy-number methods for molecular diagnosis.
  - reference: PMID:31885220
    reference_title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "METHODS: Whole-exome sequencing was performed to identify the mutations."
    explanation: A de novo nonsense ZC4H2 case was detected by whole-exome sequencing.
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ZC4H2 gene deletion/mutation has to be included in the differential diagnosis of AMC in prenatal setting."
    explanation: Prenatal arthrogryposis should prompt testing for ZC4H2 deletion or mutation.
- name: Prenatal ultrasound assessment of arthrogryposis
  description: >-
    Prenatal ultrasound can identify unusual arthrogryposis, clubfoot,
    reduced limb movements, limb thinning, and other lower-limb anomalies that
    prompt ZC4H2-focused molecular diagnosis.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unusual fetal arthrogryposis on ultrasound should draw attention to look for additional lower limb anomalies."
    explanation: The prenatal case report supports ultrasound-based clinical recognition.
  - reference: PMID:34484757
    reference_title: Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The complete ultrasound showed normal growth parameters and no other anomaly but for skin and limb evaluation."
    explanation: Detailed ultrasound assessment documented the limb findings that prompted diagnosis.
clinical_trials: []
references:
- reference: ORPHA:3454
  title: Wieacker-Wolff syndrome
  findings:
  - statement: >-
      Orphanet provides the structured disease definition, X-linked recessive
      inheritance, neonatal onset, ultra-rare prevalence, ZC4H2 gene
      association, phenotype frequencies, and cross-references.
    supporting_text: "ZC4H2 | zinc finger C4H2-type containing | hgnc:24931 | Disease-causing germline mutation(s) in"
- reference: ORPHA:85283
  title: X-linked intellectual disability, Miles-Carpenter type
  findings:
  - statement: >-
      Orphanet provides a sparse legacy record for the Miles-Carpenter synonym
      aggregated under the Wieacker-Wolff syndrome spectrum.
    supporting_text: "X-linked intellectual disability, Miles-Carpenter type"
- reference: PMID:23623388
  title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
  findings:
  - statement: >-
      Human genetic, mouse neuronal, and zebrafish model evidence links ZC4H2
      variants to X-linked AMC plus intellectual disability through synaptic,
      dendritic-spine, and motor-neuron mechanisms.
    supporting_text: "We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy."
- reference: PMID:35121145
  title: Ophthalmic abnormalities in Wieacker-Wolff syndrome.
  findings:
  - statement: >-
      Ophthalmic review/case evidence supports ptosis, strabismus, and
      oculomotor apraxia as common eye manifestations.
    supporting_text: "Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia."
- reference: PMID:34484757
  title: "Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a \"de novo\" ZC4H2 gene partial deletion."
  findings:
  - statement: >-
      Prenatal case evidence supports ultrasound recognition of arthrogryposis,
      clubfoot, hypo/akinesia, contractures, and ZC4H2-focused molecular
      diagnosis with genetic counseling.
    supporting_text: "Unusual fetal arthrogryposis on ultrasound should draw attention to look for additional lower limb anomalies."
- reference: PMID:31885220
  title: A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
  findings:
  - statement: >-
      A de novo female case supports nonsense ZC4H2 variants, whole-exome
      diagnosis, truncal hypotonia, scoliosis, rehabilitation, and abnormal
      mutant ZC4H2 trafficking.
    supporting_text: "We identified a heterozygous nonsense mutation in the ZC4H2 gene (c.199C>T, p. R67X) in this patient but not in her father and mother, indicating that the patient has a de novo mutation"
- reference: PMID:29150902
  title: Wieacker-Wolff syndrome with associated cleft palate in a female case.
  findings:
  - statement: >-
      A female case report supports the traditional X-linked recessive clinical
      description and adds cleft palate as a reported manifestation.
    supporting_text: "It is traditionally described in males as an X-linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations."
notes: >-
  ORPHA:3454 is the primary structured Orphanet record. ORPHA:85283 is retained
  only as a legacy Miles-Carpenter synonym/cross-reference because its
  structured cache has no separate definition, phenotypes, inheritance, or gene
  assertion. The older literature describes male X-linked recessive pedigrees,
  while newer reports show that heterozygous females with de novo deletions or
  truncating variants can be affected; this entry therefore models the broader
  ZC4H2-associated Wieacker-Wolff syndrome spectrum.
📚

References & Deep Research

References

7
ORPHA:3454
Wieacker-Wolff syndrome
1 finding
Orphanet provides the structured disease definition, X-linked recessive inheritance, neonatal onset, ultra-rare prevalence, ZC4H2 gene association, phenotype frequencies, and cross-references.
"ZC4H2 | zinc finger C4H2-type containing | hgnc:24931 | Disease-causing germline mutation(s) in"
ORPHA:85283
X-linked intellectual disability, Miles-Carpenter type
1 finding
Orphanet provides a sparse legacy record for the Miles-Carpenter synonym aggregated under the Wieacker-Wolff syndrome spectrum.
"X-linked intellectual disability, Miles-Carpenter type"
PMID:23623388
ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
1 finding
Human genetic, mouse neuronal, and zebrafish model evidence links ZC4H2 variants to X-linked AMC plus intellectual disability through synaptic, dendritic-spine, and motor-neuron mechanisms.
"We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy."
PMID:35121145
Ophthalmic abnormalities in Wieacker-Wolff syndrome.
1 finding
Ophthalmic review/case evidence supports ptosis, strabismus, and oculomotor apraxia as common eye manifestations.
"Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia."
PMID:34484757
Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a "de novo" ZC4H2 gene partial deletion.
1 finding
Prenatal case evidence supports ultrasound recognition of arthrogryposis, clubfoot, hypo/akinesia, contractures, and ZC4H2-focused molecular diagnosis with genetic counseling.
"Unusual fetal arthrogryposis on ultrasound should draw attention to look for additional lower limb anomalies."
PMID:31885220
A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
1 finding
A de novo female case supports nonsense ZC4H2 variants, whole-exome diagnosis, truncal hypotonia, scoliosis, rehabilitation, and abnormal mutant ZC4H2 trafficking.
"We identified a heterozygous nonsense mutation in the ZC4H2 gene (c.199C>T, p. R67X) in this patient but not in her father and mother, indicating that the patient has a de novo mutation"
PMID:29150902
Wieacker-Wolff syndrome with associated cleft palate in a female case.
1 finding
A female case report supports the traditional X-linked recessive clinical description and adds cleft palate as a reported manifestation.
"It is traditionally described in males as an X-linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations."

Deep Research

1
Wieacker-Wolff Syndrome Deep Research Fallback ▸

Wieacker-Wolff Syndrome Deep Research Fallback

Scope

This fallback artifact supports curation of Wieacker-Wolff syndrome, represented by MONDO:0010758 and structured Orphanet records ORPHA:3454 and ORPHA:85283.

Structured Sources

  • ORPHA:3454 provides the primary Wieacker-Wolff syndrome definition, synonym, X-linked recessive inheritance, neonatal onset, ultra-rare worldwide prevalence, ZC4H2 gene association, HPO phenotype frequencies, and MONDO/OMIM cross-references.
  • ORPHA:85283 provides a sparse legacy record for X-linked intellectual disability, Miles-Carpenter type. It is used only as a synonym/cross-reference source because the cache has no separate definition, phenotype table, inheritance, or gene assertion.

PubMed Sources Used

  • PMID:23623388: ZC4H2 discovery report linking X-linked arthrogryposis multiplex congenita plus intellectual disability to ZC4H2 mutations, with mouse neuronal evidence for altered dendritic spine density and zebrafish evidence for impaired alpha-motoneuron development.
  • PMID:35121145: ophthalmic case report/review supporting ptosis, strabismus, oculomotor apraxia, arthrogryposis, and facial/bulbar weakness.
  • PMID:34484757: prenatal case report supporting ultrasound recognition of fetal arthrogryposis, lower-limb anomalies, ZC4H2 deletion/sequencing, and genetic counseling.
  • PMID:31885220: de novo female nonsense-variant case supporting whole-exome diagnosis, truncal hypotonia, scoliosis, rehabilitation training, and altered mutant ZC4H2 protein trafficking.
  • PMID:29150902: female case report supporting the traditional X-linked recessive description and cleft palate as a reported manifestation.

Curation Boundaries

  • ORPHA:3454 phenotype frequencies are used only where directly supported by exact Orphanet phenotype rows. Additional PubMed-only phenotypes are included without frequency unless the cited source provides a quantitative frequency.
  • ORPHA:85283 is not modeled as a distinct subtype because the local structured cache is a title/cross-reference-only legacy record.
  • Treatment curation is limited to rehabilitation/physical therapy and genetic counseling because the cached sources do not provide disease-modifying or drug-specific therapy evidence.

Provider Attempts

  • timeout 75s just research-disorder openai Wieacker_Wolff_Syndrome remained silent after the startup line and was terminated by the timeout with exit 124 before producing an OpenAI provider artifact.
  • timeout 75s just research-disorder falcon Wieacker_Wolff_Syndrome was terminated by the timeout with exit 124 before producing a Falcon provider artifact.

The curation was completed from structured Orphanet rows and cached PubMed evidence to avoid blocking on provider availability.