WRWF
MCID: WCK001
MIFTS: 40

Wieacker-Wolff Syndrome (WRWF)

Categories: Eye diseases, Fetal diseases, Genetic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Wieacker-Wolff Syndrome

MalaCards integrated aliases for Wieacker-Wolff Syndrome:

Name: Wieacker-Wolff Syndrome 57 58 36 13 39 70
Wieacker Syndrome 57 73 20 72 6
Intellectual Disability-Developmental Delay-Contractures Syndrome 20 58 29
Contractures of Feet, Muscle Atrophy, and Oculomotor Apraxia 57 20 72
Miles-Carpenter X-Linked Mental Retardation Syndrome 57 72 70
Mental Retardation, X-Linked, with Congenital Contractures and Low Fingertip Arches 57 72
Apraxia, Oculomotor, with Congenital Contractures and Muscle Atrophy 57 20
Mental Retardation, X-Linked, Syndromic 4 57 72
Mrxs4 57 72
Wrwf 57 72
Mcs 57 72
Oculomotor Apraxia with Congenital Contractures and Muscle Atrophy 72
Foot Contractures-Muscle Atrophy-Oculomotor Apraxia Syndrome 58
Miles-Carpenter X-Linked Mental Retardation Syndrome; Mcs 57
X-Linked Intellectual Disability, Miles-Carpenter Type 58
Mental Retardation, X-Linked, Syndromic 4; Mrxs4 57
Wieacker Wolff Syndrome 20
Wieacker-Wolf Syndrome 72
Wws 20

Characteristics:

Orphanet epidemiological data:

58
intellectual disability-developmental delay-contractures syndrome
Inheritance: Not applicable,X-linked recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Neonatal;
x-linked intellectual disability, miles-carpenter type
Inheritance: X-linked recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Childhood;

OMIM®:

57 (Updated 20-May-2021)
Miscellaneous:
onset in utero
carrier females may show mild features, such as mild contractures, club feet, and intellectual disability
two females with large deletions (429 kb and 395 kb) on 11q11.2 that include zc4h2 as the only known gene have been reported with severe features of wiecker-wolff syndrome

Inheritance:
x-linked recessive


HPO:

31
wieacker-wolff syndrome:
Onset and clinical course congenital onset
Inheritance x-linked recessive inheritance


Classifications:

Orphanet: 58  
Rare neurological diseases
Rare eye diseases
Developmental anomalies during embryogenesis


Summaries for Wieacker-Wolff Syndrome

GARD : 20 Intellectual disability - developmental delay - contractures syndrome is a rare, slowly progressive genetic disorder that is present at birth. It is characterized by contractures of the joints of the feet ( arthrogryposis multiplex congenita ), muscle degeneration ( atrophy ), mild intellectual disability and an impaired ability to move certain muscles of the eyes, face and tongue. Other symptoms might include spasticity and seizures. Intellectual disability-developmental delay-contractures syndrome is caused by mutations in the ZC4H2 gene and is inherited in an X-linked recessive fashion. Most people with intellectual disability-developmental delay-contractures syndrome are male; however carrier females have been reported to have mild symptoms. There is no known cure for intellectual disability-developmental delay-contractures syndrome. Treatment is symptomatic and supportive.

MalaCards based summary : Wieacker-Wolff Syndrome, also known as wieacker syndrome, is related to wieacker-wolff syndrome, female-restricted and miles-carpenter syndrome, and has symptoms including seizures, ophthalmoplegia and apnea. An important gene associated with Wieacker-Wolff Syndrome is ZC4H2 (Zinc Finger C4H2-Type Containing). Affiliated tissues include eye, tongue and heart, and related phenotypes are neurological speech impairment and global developmental delay

OMIM® : 57 Wieacker-Wolff syndrome (WRWF) is a severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia), which results in arthrogryposis multiplex congenita (AMC) apparent at birth. Affected boys are born with severe contractures, show delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and foot deformities. Additional features include global developmental delay with poor or absent speech and impaired intellectual development, feeding difficulties and poor growth, hypotonia, hypogenitalism, and spasticity. Carrier females may be unaffected or have mild features of the disorder (summary by Hirata et al., 2013 and Frints et al., 2019). (314580) (Updated 20-May-2021)

KEGG : 36 Wieacker-Wolff syndrome (WRWF) is a rare X-linked disorder characterized by congenital contractures of the feet at birth, muscle atrophy, dyspraxia of the eye, face, and tongue muscles, and mental retardation. WRWF is caused by mutations in the ZC4H2 gene, that is involved in human brain development.

UniProtKB/Swiss-Prot : 72 Wieacker-Wolf syndrome: A severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia). Affected boys are born with severe contractures, known as arthrogryposis, and have delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and pes equinovarus. Those that survive infancy show mental retardation. Carrier females may have mild features of the disorder.

Wikipedia : 73 Wieacker Syndrome or Wieacker-Wolff syndrome is a rare, severely disabling, genetic disorder. It is an... more...

Related Diseases for Wieacker-Wolff Syndrome

Diseases related to Wieacker-Wolff Syndrome via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 129)
# Related Disease Score Top Affiliating Genes
1 wieacker-wolff syndrome, female-restricted 11.8
2 miles-carpenter syndrome 11.7
3 walker-warburg syndrome 11.4
4 muscular dystrophy-dystroglycanopathy , type a, 1 11.2
5 hirschsprung disease 1 11.1
6 multiple chemical sensitivity 11.1
7 mast-cell leukemia 11.1
8 muscular dystrophy-dystroglycanopathy , type c, 1 10.9
9 muscular dystrophy-dystroglycanopathy , type b, 1 10.9
10 muscular dystrophy-dystroglycanopathy , type a, 2 10.9
11 muscular dystrophy-dystroglycanopathy , type a, 3 10.9
12 muscular dystrophy-dystroglycanopathy , type a, 5 10.9
13 muscular dystrophy-dystroglycanopathy , type a, 6 10.9
14 muscular dystrophy-dystroglycanopathy , type a, 7 10.9
15 muscular dystrophy-dystroglycanopathy , type a, 8 10.9
16 muscular dystrophy-dystroglycanopathy , type a, 10 10.9
17 muscular dystrophy-dystroglycanopathy , type a, 11 10.9
18 muscular dystrophy-dystroglycanopathy , type a, 12 10.9
19 muscular dystrophy-dystroglycanopathy , type a, 13 10.9
20 muscular dystrophy-dystroglycanopathy , type a, 9 10.9
21 congenital contractures 10.3
22 cleft palate, isolated 10.2
23 apraxia 10.2
24 agnosia 10.2
25 muscular atrophy 10.2
26 oculomotor apraxia 10.2
27 somatization disorder 10.2
28 muscular dystrophy, congenital, lmna-related 10.2
29 muscular dystrophy 10.2
30 ocular motor apraxia 10.1
31 leukemia 10.1
32 leukemia, acute lymphoblastic 10.1
33 acute monoblastic leukemia 10.0
34 cardiogenic shock 10.0
35 muscular dystrophy-dystroglycanopathy , type a, 4 10.0
36 muscular dystrophy-dystroglycanopathy , type b, 2 10.0
37 muscular dystrophy-dystroglycanopathy , type c, 2 10.0
38 lissencephaly 10.0
39 autosomal recessive disease 10.0
40 congenital muscular dystrophy-dystroglycanopathy type a2 10.0
41 fukuyama type muscular dystrophy 10.0
42 muscle eye brain disease 10.0
43 cobblestone lissencephaly 10.0
44 atherosclerosis susceptibility 9.9
45 cryoglobulinemia, familial mixed 9.9
46 alpha-thalassemia 9.9
47 leukemia, chronic myeloid 9.9
48 hemoglobin h disease 9.9
49 exanthem 9.9
50 allergic disease 9.9

Graphical network of the top 20 diseases related to Wieacker-Wolff Syndrome:



Diseases related to Wieacker-Wolff Syndrome

Symptoms & Phenotypes for Wieacker-Wolff Syndrome

Human phenotypes related to Wieacker-Wolff Syndrome:

58 31 (show top 50) (show all 59)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 neurological speech impairment 58 31 hallmark (90%) Very frequent (99-80%) HP:0002167
2 global developmental delay 58 31 hallmark (90%) Very frequent (99-80%) HP:0001263
3 intellectual disability, mild 58 31 hallmark (90%) Very frequent (99-80%) HP:0001256
4 abnormality of movement 58 31 hallmark (90%) Very frequent (99-80%) HP:0100022
5 clinodactyly of the 5th finger 58 31 hallmark (90%) Very frequent (99-80%) HP:0004209
6 limitation of joint mobility 58 31 hallmark (90%) Very frequent (99-80%) HP:0001376
7 oculomotor apraxia 58 31 occasional (7.5%) Very frequent (99-80%) HP:0000657
8 distal amyotrophy 58 31 hallmark (90%) Very frequent (99-80%) HP:0003693
9 congenital foot contractures 58 31 hallmark (90%) Very frequent (99-80%) HP:0005745
10 scoliosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0002650
11 ptosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0000508
12 kyphosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0002808
13 strabismus 58 31 occasional (7.5%) Occasional (29-5%) HP:0000486
14 exotropia 58 31 Very frequent (99-80%) HP:0000577
15 spasticity 31 HP:0001257
16 abnormality of eye movement 58 Very frequent (99-80%)
17 facial palsy 31 HP:0010628
18 high palate 31 HP:0000218
19 short neck 31 HP:0000470
20 hyperlordosis 31 HP:0003307
21 delayed speech and language development 31 HP:0000750
22 microcephaly 31 HP:0000252
23 smooth philtrum 31 HP:0000319
24 anteverted nares 31 HP:0000463
25 short stature 31 HP:0004322
26 intellectual disability, severe 58 Frequent (79-30%)
27 skeletal muscle atrophy 58 Frequent (79-30%)
28 retrognathia 31 HP:0000278
29 micrognathia 31 HP:0000347
30 low-set ears 31 HP:0000369
31 abnormal dermatoglyphics 58 Very frequent (99-80%)
32 talipes equinovarus 31 HP:0001762
33 neonatal respiratory distress 31 HP:0002643
34 upslanted palpebral fissure 31 HP:0000582
35 facial asymmetry 58 Frequent (79-30%)
36 long philtrum 31 HP:0000343
37 areflexia 31 HP:0001284
38 hip dislocation 31 HP:0002827
39 joint hyperflexibility 58 Frequent (79-30%)
40 apnea 31 HP:0002104
41 decreased fetal movement 31 HP:0001558
42 high anterior hairline 31 HP:0009890
43 dystonia 31 HP:0001332
44 narrow chest 31 HP:0000774
45 microcornea 58 Frequent (79-30%)
46 arthrogryposis multiplex congenita 31 HP:0002804
47 proximal placement of thumb 31 HP:0009623
48 feeding difficulties 31 HP:0011968
49 rocker bottom foot 58 Frequent (79-30%)
50 hypogonadism 58 Frequent (79-30%)

Symptoms via clinical synopsis from OMIM®:

57 (Updated 20-May-2021)
Neurologic Central Nervous System:
seizures
spasticity
dystonia
cerebral atrophy
delayed myelination
more
Head And Neck Eyes:
ptosis
exotropia
deep-set eyes
upslanting palpebral fissures
oculomotor apraxia (in some patients)

Head And Neck Head:
microcephaly

Head And Neck Face:
retrognathia
micrognathia
long philtrum
high forehead
flat philtrum
more
Respiratory:
neonatal respiratory distress
apnea

Skeletal Pelvis:
hip dislocation

Skeletal Hands:
camptodactyly
proximally placed thumbs
ulnar deviation of the fingers

Skin Nails Hair Skin:
palmar hyperkeratosis
low fingerprint arches

Skeletal:
joint contractures
arthrogryposis, congenital

Abdomen Gastrointestinal:
poor feeding
tube feeding

Head And Neck Nose:
upturned nares

Muscle Soft Tissue:
muscle weakness, severe
fat pads on the hands and feet

Skeletal Spine:
scoliosis
kyphosis
lordosis

Head And Neck Neck:
short neck

Growth Height:
short stature

Head And Neck Ears:
low-set ears
posteriorly rotated ears

Neurologic Peripheral Nervous System:
areflexia

Skin Nails Hair Hair:
high anterior hairline

Head And Neck Mouth:
broad alveolar ridges
drooling
high-arched palate
carp-shaped mouth

Chest External Features:
narrow shoulders
narrow thorax

Skeletal Feet:
club feet
equinovarus
proximally placed toes

Growth Other:
poor overall growth

Prenatal Manifestations Movement:
decreased fetal movements

Clinical features from OMIM®:

314580 (Updated 20-May-2021)

UMLS symptoms related to Wieacker-Wolff Syndrome:


seizures; ophthalmoplegia; apnea; muscle spasticity; facial paresis

Drugs & Therapeutics for Wieacker-Wolff Syndrome

Search Clinical Trials , NIH Clinical Center for Wieacker-Wolff Syndrome

Genetic Tests for Wieacker-Wolff Syndrome

Genetic tests related to Wieacker-Wolff Syndrome:

# Genetic test Affiliating Genes
1 Intellectual Disability-Developmental Delay-Contractures Syndrome 29 ZC4H2

Anatomical Context for Wieacker-Wolff Syndrome

MalaCards organs/tissues related to Wieacker-Wolff Syndrome:

40
Eye, Tongue, Heart, Skeletal Muscle, Myeloid, Brain, Skin

Publications for Wieacker-Wolff Syndrome

Articles related to Wieacker-Wolff Syndrome:

(show all 13)
# Title Authors PMID Year
1
Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita. 6 57
31206972 2019
2
ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons. 6 57
26056227 2015
3
ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity. 57 6
23623388 2013
4
A family with severe X-linked arthrogryposis. 57 6
1915520 1991
5
Unique X-linked mental retardation syndrome with fingertip arches and contractures linked to Xq21.31. 57 6
2018061 1991
6
A new X-linked syndrome with muscle atrophy, congenital contractures, and oculomotor apraxia. 6 57
4039531 1985
7
ZC4H2 deletions can cause severe phenotype in female carriers. 61 57
28345801 2017
8
Localization of the gene for Wieacker-Wolff syndrome in the pericentromeric region of the X chromosome. 57 61
9272167 1997
9
Close linkage of the Wieacker-Wolff syndrome to the DNA segment DXYS1 in proximal Xq. 61 57
2890303 1987
10
A severe female case of arthrogryposis multiplex congenita with brain atrophy, spastic quadriplegia and intellectual disability caused by ZC4H2 mutation. 57
29254829 2018
11
ZC4H2 stabilizes Smads to enhance BMP signalling, which is involved in neural development in Xenopus. 6
28814648 2017
12
A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome. 61
31885220 2020
13
Wieacker-Wolff syndrome with associated cleft palate in a female case. 61
29150902 2018

Variations for Wieacker-Wolff Syndrome

ClinVar genetic disease variations for Wieacker-Wolff Syndrome:

6 (show all 24)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 ZC4H2 NM_018684.4(ZC4H2):c.53G>A (p.Arg18Lys) SNV Pathogenic 378045 rs1057520299 GRCh37: X:64196205-64196205
GRCh38: X:64976325-64976325
2 ZC4H2 NM_018684.4(ZC4H2):c.22_23del (p.Met8fs) Deletion Pathogenic 488641 rs1555945816 GRCh37: X:64196235-64196236
GRCh38: X:64976355-64976356
3 ZC4H2 NM_018684.4(ZC4H2):c.427C>T (p.Gln143Ter) SNV Pathogenic 548020 rs1260869746 GRCh37: X:64139056-64139056
GRCh38: X:64919176-64919176
4 ZC4H2 NM_018684.4(ZC4H2):c.412C>T (p.Gln138Ter) SNV Pathogenic 689619 rs1602379828 GRCh37: X:64139071-64139071
GRCh38: X:64919191-64919191
5 ZC4H2 Deletion Pathogenic 598761 GRCh37: X:64171841-64267316
GRCh38:
6 ZC4H2 NM_018684.4(ZC4H2):c.225+5G>A SNV Pathogenic 378044 rs1057520298 GRCh37: X:64141692-64141692
GRCh38: X:64921812-64921812
7 ZC4H2 NM_018684.4(ZC4H2):c.197T>A (p.Leu66His) SNV Pathogenic 378042 rs1057520297 GRCh37: X:64141725-64141725
GRCh38: X:64921845-64921845
8 ZC4H2 NM_018684.4(ZC4H2):c.637C>T (p.Arg213Trp) SNV Pathogenic 50983 rs879255236 GRCh37: X:64137701-64137701
GRCh38: X:64917821-64917821
9 ZC4H2 NM_018684.4(ZC4H2):c.593G>A (p.Arg198Gln) SNV Pathogenic 50981 rs879255235 GRCh37: X:64137745-64137745
GRCh38: X:64917865-64917865
10 ZC4H2 NM_018684.4(ZC4H2):c.187G>C (p.Val63Leu) SNV Pathogenic 50980 rs398122938 GRCh37: X:64141735-64141735
GRCh38: X:64921855-64921855
11 ZC4H2 NM_018684.4(ZC4H2):c.576del (p.His193fs) Deletion Pathogenic 930303 GRCh37: X:64137762-64137762
GRCh38: X:64917882-64917882
12 ZC4H2 NM_018684.4(ZC4H2):c.601C>T (p.Pro201Ser) SNV Pathogenic 50982 rs398122939 GRCh37: X:64137737-64137737
GRCh38: X:64917857-64917857
13 ZC4H2 NM_018684.4(ZC4H2):c.650A>G (p.Lys217Arg) SNV Pathogenic 834097 GRCh37: X:64137688-64137688
GRCh38: X:64917808-64917808
14 ZC4H2 NM_018684.4(ZC4H2):c.243_246del (p.Lys81fs) Deletion Pathogenic 977161 GRCh37: X:64140113-64140116
GRCh38: X:64920233-64920236
15 ZC4H2 NM_018684.4(ZC4H2):c.598G>A (p.Ala200Thr) SNV Pathogenic 930963 GRCh37: X:64137740-64137740
GRCh38: X:64917860-64917860
16 ZC4H2 NM_018684.4(ZC4H2):c.199C>T (p.Arg67Ter) SNV Pathogenic/Likely pathogenic 429826 rs1131691616 GRCh37: X:64141723-64141723
GRCh38: X:64921843-64921843
17 ZC4H2 NM_018684.4(ZC4H2):c.592C>T (p.Arg198Trp) SNV Likely pathogenic 432364 rs137962226 GRCh37: X:64137746-64137746
GRCh38: X:64917866-64917866
18 ZC4H2 NM_018684.4(ZC4H2):c.375_377AGA[1] (p.Glu128del) Microsatellite Likely pathogenic 522752 rs750367160 GRCh37: X:64139979-64139981
GRCh38: X:64920099-64920101
19 ZC4H2 NM_018684.4(ZC4H2):c.535_538dup (p.Arg180fs) Duplication Likely pathogenic 986368 GRCh37: X:64138944-64138945
GRCh38: X:64919064-64919065
20 ZC4H2 NM_018684.4(ZC4H2):c.53+10513C>T SNV Likely pathogenic 977759 GRCh37: X:64185692-64185692
GRCh38: X:64965812-64965812
21 ZC4H2 NM_018684.4(ZC4H2):c.561G>T (p.Lys187Asn) SNV Uncertain significance 930316 GRCh37: X:64138922-64138922
GRCh38: X:64919042-64919042
22 ZC4H2 NM_018684.4(ZC4H2):c.170A>C (p.Gln57Pro) SNV Uncertain significance 931012 GRCh37: X:64141752-64141752
GRCh38: X:64921872-64921872
23 ZC4H2 NM_018684.4(ZC4H2):c.561+7G>A SNV Uncertain significance 982608 GRCh37: X:64138915-64138915
GRCh38: X:64919035-64919035
24 ZC4H2 NM_018684.4(ZC4H2):c.54-1G>A SNV not provided 585201 rs1569201245 GRCh37: X:64141869-64141869
GRCh38: X:64921989-64921989

UniProtKB/Swiss-Prot genetic disease variations for Wieacker-Wolff Syndrome:

72 (show all 11)
# Symbol AA change Variation ID SNP ID
1 ZC4H2 p.Val63Leu VAR_069621 rs398122938
2 ZC4H2 p.Arg198Gln VAR_069622 rs879255235
3 ZC4H2 p.Pro201Ser VAR_069623 rs398122939
4 ZC4H2 p.Arg213Trp VAR_069624 rs879255236
5 ZC4H2 p.Arg18Lys VAR_079397 rs105752029
6 ZC4H2 p.Leu66His VAR_079398 rs105752029
7 ZC4H2 p.His70Gln VAR_083954
8 ZC4H2 p.Ala200Thr VAR_083956
9 ZC4H2 p.Ala200Val VAR_083957
10 ZC4H2 p.Pro201His VAR_083958
11 ZC4H2 p.Lys217Arg VAR_083961

Expression for Wieacker-Wolff Syndrome

Search GEO for disease gene expression data for Wieacker-Wolff Syndrome.

Pathways for Wieacker-Wolff Syndrome

GO Terms for Wieacker-Wolff Syndrome

Sources for Wieacker-Wolff Syndrome

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 20-May-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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