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Wieacker-Wolff syndrome(WRWF)

MedGen UID:
163227
Concept ID:
C0796200
Disease or Syndrome
Synonyms: Apraxia, oculomotor, with congenital contractures and muscle atrophy; Contractures of feet, muscle atrophy, and oculomotor apraxia; Intellectual disability-developmental delay-contractures syndrome; Mental retardation, X-linked, syndromic 4; Mental retardation, X-linked, with congenital contractures and low fingertip arches; Miles-Carpenter syndrome; Wieacker syndrome; Wieacker-Wolff, X-linked recessive
SNOMED CT: Intellectual disability, developmental delay, contracture syndrome (722456001); Foot contracture, muscle atrophy, oculomotor apraxia syndrome (722456001); Wieacker Wolff syndrome (722456001)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): ZC4H2 (Xq11.2)
 
Monarch Initiative: MONDO:0010758
OMIM®: 314580
Orphanet: ORPHA3454

Definition

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). [from OMIM]

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Proximal placement of thumb
MedGen UID:
356033
Concept ID:
C1865572
Finding
Proximal mislocalization of the thumb.
Palmar hyperkeratosis
MedGen UID:
869284
Concept ID:
C4023710
Disease or Syndrome
Abnormal thickening of the skin localized to the palm of the hand.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
A defect in the understanding of complex motor commands and in the execution of certain learned movements, i.e., deficits in the cognitive components of learned movements.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Delayed myelination
MedGen UID:
224820
Concept ID:
C1277241
Finding
Delayed myelination.
Oculomotor apraxia
MedGen UID:
483686
Concept ID:
C3489733
Disease or Syndrome
Ocular motor apraxia is a deficiency in voluntary, horizontal, lateral, fast eye movements (saccades) with retention of slow pursuit movements. The inability to follow objects visually is often compensated by head movements. There may be decreased smooth pursuit, and cancellation of the vestibulo-ocular reflex.
Hip dislocation
MedGen UID:
42455
Concept ID:
C0019554
Injury or Poisoning
Displacement of the femur from its normal location in the hip joint.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature (anterior concavity) of the lumbar or cervical spine.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Retrognathia
MedGen UID:
19766
Concept ID:
C0035353
Congenital Abnormality
An abnormality in which the mandible is mislocalised posteriorly.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Narrow chest
MedGen UID:
96528
Concept ID:
C0426790
Finding
Reduced width of the chest from side to side, associated with a reduced distance from the sternal notch to the tip of the shoulder.
Camptodactyly
MedGen UID:
195780
Concept ID:
C0685409
Congenital Abnormality
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers or toes cannot be extended to 180 degrees by either active or passive extension.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Congenital foot contractures
MedGen UID:
870690
Concept ID:
C4025144
Congenital Abnormality
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Neonatal respiratory distress
MedGen UID:
924182
Concept ID:
C4281993
Finding
Respiratory difficulty as newborn.
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Habitual flow of saliva out of the mouth.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
U-Shaped upper lip vermilion
MedGen UID:
383857
Concept ID:
C1856202
Finding
Gentle upward curve of the upper lip vermilion such that the center is placed well superior to the commissures.
Broad alveolar ridges
MedGen UID:
347470
Concept ID:
C1857500
Finding
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
High anterior hairline
MedGen UID:
477667
Concept ID:
C3276036
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD above the mean. Alternatively, an apparently increased distance between the hairline and the glabella.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of strabismus with one or both eyes deviated outward.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVWieacker-Wolff syndrome
Follow this link to review classifications for Wieacker-Wolff syndrome in Orphanet.

Recent clinical studies

Diagnosis

Herman I, Jolly A, Du H, Dawood M, Abdel-Salam GMH, Marafi D, Mitani T, Calame DG, Coban-Akdemir Z, Fatih JM, Hegazy I, Jhangiani SN, Gibbs RA, Pehlivan D, Posey JE, Lupski JR
Am J Med Genet A 2022 Mar;188(3):735-750. Epub 2021 Nov 23 doi: 10.1002/ajmg.a.62565. PMID: 34816580Free PMC Article
Godfrey D, Torres A, Heidary G, Zahoor H, Lee A, Berry G, Engle E
Ophthalmic Genet 2021 Oct;42(5):612-614. Epub 2021 May 5 doi: 10.1080/13816810.2021.1923040. PMID: 33949289Free PMC Article
Godfrey ND, Dowlatshahi S, Martin MM, Rothkopf DM
Am J Med Genet A 2018 Jan;176(1):167-170. Epub 2017 Nov 17 doi: 10.1002/ajmg.a.38527. PMID: 29150902
Zanzottera C, Milani D, Alfei E, Rizzo A, D'Arrigo S, Esposito S, Pantaleoni C
Am J Med Genet A 2017 May;173(5):1358-1363. Epub 2017 Mar 27 doi: 10.1002/ajmg.a.38155. PMID: 28345801

Therapy

Zanzottera C, Milani D, Alfei E, Rizzo A, D'Arrigo S, Esposito S, Pantaleoni C
Am J Med Genet A 2017 May;173(5):1358-1363. Epub 2017 Mar 27 doi: 10.1002/ajmg.a.38155. PMID: 28345801

Prognosis

Kondo D, Noguchi A, Takahashi I, Kubota H, Yano T, Sato Y, Toyono M, Sawaishi Y, Takahashi T
Brain Dev 2018 Oct;40(9):760-767. Epub 2018 May 24 doi: 10.1016/j.braindev.2018.05.003. PMID: 29803542
Godfrey ND, Dowlatshahi S, Martin MM, Rothkopf DM
Am J Med Genet A 2018 Jan;176(1):167-170. Epub 2017 Nov 17 doi: 10.1002/ajmg.a.38527. PMID: 29150902

Clinical prediction guides

Herman I, Jolly A, Du H, Dawood M, Abdel-Salam GMH, Marafi D, Mitani T, Calame DG, Coban-Akdemir Z, Fatih JM, Hegazy I, Jhangiani SN, Gibbs RA, Pehlivan D, Posey JE, Lupski JR
Am J Med Genet A 2022 Mar;188(3):735-750. Epub 2021 Nov 23 doi: 10.1002/ajmg.a.62565. PMID: 34816580Free PMC Article
Kondo D, Noguchi A, Takahashi I, Kubota H, Yano T, Sato Y, Toyono M, Sawaishi Y, Takahashi T
Brain Dev 2018 Oct;40(9):760-767. Epub 2018 May 24 doi: 10.1016/j.braindev.2018.05.003. PMID: 29803542
Godfrey ND, Dowlatshahi S, Martin MM, Rothkopf DM
Am J Med Genet A 2018 Jan;176(1):167-170. Epub 2017 Nov 17 doi: 10.1002/ajmg.a.38527. PMID: 29150902
Zanzottera C, Milani D, Alfei E, Rizzo A, D'Arrigo S, Esposito S, Pantaleoni C
Am J Med Genet A 2017 May;173(5):1358-1363. Epub 2017 Mar 27 doi: 10.1002/ajmg.a.38155. PMID: 28345801

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