A number sign (#) is used with this entry because Wieacker-Wolff syndrome (WRWF) is caused by hemizygous or heterozygous mutation in the ZC4H2 gene (300897) on chromosome Xq11.

See also female-restricted WRWF (WRWFFR; 301041), caused by heterozygous, often de novo, mutation in the ZC4H2 gene. Both disorders share overlapping features and represent a phenotypic spectrum.

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).

Wieacker et al. (1985) described an apparently novel X-linked syndrome in 6 men in 4 sibships of 3 generations of a family, genealogically connected through presumably carrier females. All had congenital contractures of the feet at birth, a slowly progressive predominantly distal muscle atrophy, dyspraxia of the eyes, face and tongue muscles, and mild mental retardation. Hirata et al. (2013) provided follow-up of the family reported by Wieacker et al. (1985). Affected males showed signs of a developmental defect of neuromuscular transmission, as evidenced by congenital equinovarus foot deformity and ptosis.

In 4 generations of a Missouri kindred, Miles and Carpenter (1991) observed 3 brothers and a male cousin with mental retardation in association with exotropia, microcephaly, distal muscle wasting, and 10 low digital arches. Six women who might represent heterozygotes were found to have 8 to 10 low digital arches; 5 of these women had exotropia. May et al. (2015) reported follow-up of the family (K8070) reported by Miles and Carpenter (1991). Additional features noted in the males included short stature, high-arched palate, narrow shoulders and thorax, kyphosis/lordosis/scoliosis, delayed motor development, hypotonia, camptodactyly, ulnar deviation of the fingers, knee or elbow contractures, and foot abnormalities such as clubfoot, rocker-bottom feet, or flat feet. All had distal muscle weakness and 3 had spasticity and hyperreflexia. More variable features included poor feeding, ptosis, long philtrum, carp-shaped mouth, and broad alveolar ridges. Only 1 had seizures. Carrier females were more mildly affected and showed some similar features.

Hirata et al. (2013) identified a second family with a similar, but more severe phenotype. Affected individuals presented with neonatal respiratory distress, arthrogryposis multiplex congenita, muscle weakness, and ptosis, suggesting dysfunction of neuromuscular transmission in utero. Histologic investigation did not show evidence of a demyelinating or axonal neuropathy or a myopathy. As development progressed, it became clear that the affected boys were also severely intellectually disabled. In both families, central neurologic dysfunction was manifest as impaired intellectual development, spasticity, and seizures. Heterozygous females showed mild intellectual disability; some showed minor dysmorphic signs, such as camptodactyly and equinovarus feet.

A third family identified by Hirata et al. (2013) had previously been reported by Hennekam et al. (1991). That family had 5 affected males in 3 sibships connected through females. Affected males had severe arthrogryposis and muscle weakness in the pre- and postnatal periods, resulting in death within the first weeks or months of life. The 1 surviving boy was had severely impaired intellectual development. Features included respiratory insufficiency, swallowing difficulties, multiple contractures of the hands and limbs, clubfeet, kyphoscoliosis, hip dislocation, and chest deformities. Facial features included carp-like mouth, narrow palate, micrognathia, long philtrum, upturned nares, and short neck. Several female carriers showed mild features in the form of clubfoot, contractures, hyperkyphosis, and slight muscle weakness. One manifesting carrier was affected more severely with mental retardation. Muscle biopsy suggested a degenerative muscle disorder. Two more families with a similar disorder were subsequently identified by Hirata et al. (2013); 1 had been ascertained due to a diagnosis of cerebral palsy. Cranial MRI of several patients in the whole cohort studied by Hirata et al. (2013) showed several abnormalities, including delayed myelination, cerebral atrophy, and gyral disorganization.

May et al. (2015) reported 3 previously unreported families with X-linked syndromic mental retardation. There were 10 affected males and 10 carrier females. There was phenotypic variability between the families, but all male patients had impaired intellectual development. Common features in affected males included short stature, microcephaly, delayed motor development, contractures, spinal deformities, foot abnormalities, and high-arched palate. Variable neuromuscular features included distal muscles weakness, spasticity, drooling, hypotonia, and seizures, all of which tended to run within families. Affected males in 1 family showed palmar hyperkeratosis and small testes/penis. Females in some of the families showed milder features.

Frints et al. (2019) reported 11 males from 6 unrelated families (families 1, 4-6, 9, and 19) with WRWF. Two additional male patients (families 18 and 24) were sporadic cases with de novo missense variants. Some affected fetuses showed signs of the disorder in utero: these included clubfoot or rocker bottom feet, fetal hypo/akinesia, contractures, AMC, and nuchal edema. After birth and during early childhood, common features of these patients included flexion contractures of the small and large joints, hip dislocation, kyphosis, narrow chest, foot deformities, laryngomalacia, and breathing and feeding difficulties, sometimes necessitating a feeding tube. The patients had global developmental delay with poor or absent speech, delayed walking or inability to walk, poor growth with short stature and microcephaly, hypotonia, oromotor dysfunction with dysarthria, dysphagia, and drooling, encopresis, micropenis, cryptorchidism, tetraplegia, spasticity, oculomotor apraxia, and obstructive sleep apnea. About half had seizures. Brain imaging showed nonspecific findings, such as delayed myelination, enlarged ventricles, and brain atrophy. Dysmorphic features, while common, were variable. Features observed in over 40% of patients included facial weakness, high forehead, high anterior hairline, low-set or posteriorly rotated ears, deep-set eyes, ptosis, upslanting palpebral fissures, strabismus, anteverted nares, microretrognathia, long philtrum, broad alveolar ridges, tent-shaped mouth, and high-arched palate. The authors also provided a detailed review of the clinical features of previously reported patients.

Carrier Females

Heterozygous female carriers of ZC4H2 mutations that are pathogenic in males in the hemizygous state may either be asymptomatic or show mild features of the disorder, including contractures, poor growth, poor speech or intellectual disability, spasticity, and muscle weakness. Frints et al. (2019) provided follow-up of the large family (family 7) originally reported by Hennekam et al. (1991) and Hirata et al. (2013). There were 9 female mutation carriers, 6 of whom were affected. Three of these women had a late-onset, slowly progressive neurodegenerative phenotype manifest as impaired gait due to muscle weakness and distal muscle wasting, as well as anosmia and urinary incontinence. Frints et al. (2019) also reported 11 males from 6 unrelated families with WRWF. In 3 families (families 5, 6, and 9), the mutation was inherited from a mildly affected mother.

The transmission pattern of congenital arthrogryposis in the families reported by Wieacker et al. (1985), Hennekam et al. (1991), and Hirata et al. (2013) was consistent with X-linked recessive inheritance.

The transmission pattern of WRWF in the families reported by Frints et al. (2019) was consistent with X-linked inheritance with evidence of incomplete penetrance and variable expressivity in female mutation carriers.

Wieacker et al. (1985) excluded close linkage of the disorder to the Xg locus on Xp and to a DNA polymorphism on Xq. Wieacker et al. (1987) found a maximum lod score of 3.225 at a recombination fraction of 0.0 between the disorder and DXYS1. This places the syndrome in the proximal part of the long arm of the X chromosome. Kloos et al. (1997) used highly polymorphic short terminal repeat markers between Xp21 and Xq24 to refine the localization of the Wieacker syndrome locus. Recombinant events placed the locus in the pericentromeric region between PFC and DXS339, a critical segment of approximately 8 cM.

By linkage analysis of a 4-generation Missouri kindred with MRXS4, Miles and Carpenter (1991) found linkage to a locus near Xq21.31 (peak lod score of 2.78 at theta = 0.0 was calculated for linkage of the syndrome locus and DXYS1). HGM11 stated the probable location as Xq13-q22.

In affected members of 5 unrelated families with Wieacker-Wolff syndrome, including the families reported by Wieacker et al. (1985) and Hennekam et al. (1991), Hirata et al. (2013) identified 4 different missense mutations in the ZC4H2 gene (300897.0001-300897.0004). The mutations were found by exome sequencing in some of the families. Expression of 3 of the mutations in mouse primary neurons caused a significant decrease in synapse number and density, and none of the mutations were able to rescue the swimming defect of zebrafish morphants. The findings indicated that mutations in the ZC4H2 gene cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems.

In affected members of 4 unrelated families with WRWF, including the original family reported by Miles and Carpenter (1991) as having Miles-Carpenter syndrome, May et al. (2015) identified mutations in the ZC4H2 gene (300897.0004-300897.0007). The mutations were found by various methods, including whole-genome sequencing, X-chromosome exome sequencing, and direct sequencing of the ZC4H2 gene: all mutations were confirmed by Sanger sequencing and segregated with the disorder in the families. There were 3 missense mutations and 1 splice site mutation. Molecular modeling of the mutant proteins suggested that all the missense mutations would destabilize the protein and result in a loss of function. Based on knockdown of the gene in zebrafish (see ANIMAL MODEL), May et al. (2015) suggested that ZC4H2 mutations adversely affect interneuron fate and connectivity throughout the brain and spinal cord, including a loss of GABAergic neurons. Clinical variability likely results from mutations affecting different isoforms as well as having different effects on the protein.

Frints et al. (2019) reported 11 males from 6 unrelated families (families 1, 4-6, 9, and 19) with hemizygous missense mutations in the ZC4H2 gene inherited from an unaffected or mildly affected mother (see, e.g., 300897.0002 and 300897.0011). The mutations, which were found by whole-exome or whole-genome sequencing, segregated with the disorder in the families. Two additional male patients (families 18 and 24) had de novo hemizygous missense variants (see, e.g., 300897.0002). All missense variants affected highly conserved residues, and none were found in the 1000 Genomes Project or gnomAD database. Expression of 2 mutations, A200V and H70Q, failed to rescue swimming defects in zc4h2-null zebrafish, suggesting that the mutations are pathogenic and likely result in decreased protein function. Frints et al. (2019) noted that complete loss-of-function ZC4H2 mutations are almost never observed in male patients.

In a boy with sporadic occurrence of WRWF, Hirata et al. (2013) identified a de novo paracentric inversion on the X chromosome with breakpoints at Xq11.2, involving ZC4H2, and Xq28, which did not contain any known genes. RT-PCR on patient cells showed no detectable ZC4H2 transcripts, indicating that the rearrangement abolished ZC4H2 expression. In addition, whole-genome microarray analysis identified small heterozygous deletions at Xq11.2 in 2 mildly affected girls. The girls had distal muscle weakness, camptodactyly, equinovarus foot deformity or contracture of the Achilles tendon, language deficits, and intellectual disability. The deletions were 826 and 321 Kb, respectively, and included ZC4H2, but no adjacent genes. These findings indicated that heterozygous deletions of ZC4H2 can result in a clinical phenotype, even in females.

Zanzottera et al. (2017) reported a girl with a severe Wieacker-Wolff phenotype who had a 429-kb deletion on Xq11.2 that included ZC4H2 as the only known gene. The girl, born to healthy nonconsanguineous parents, had severe neurodevelopmental impairment, distinctive hand creases, and unusual electrophysiological At birth, she showed normal growth parameters, micrognathia, strabismus, and arthrogryposis multiplex congenita. She had bilateral hip subluxation, severe swallowing difficulties requiring tube feeding, and delayed motor and cognitive development. At age 13 years, she was not able to stand and language was restricted to a small number of single words. Height was below the 3rd centile with normal weight and head circumference. She had an unusual face (brachycephaly, low insertion of the columella, mild retrognathia, abnormal helix, ptosis, prominent nose, thin upper vermilion, downturned corners of the mouth). She also had small hands with decreased creases and contractures, ulnar and radial deviations of fingers, fixed extension of knees and clubfeet, webbing of fingers, and decreased palmar creases. Neurologic exam showed hypotonia with lower limb spasticity, brisk deep tendon reflexes of the upper limbs, and marked ankle hyperreflexia with clonus. MRI of her vertebral column showed stenosis of the spinal canal and a markedly pointed and anteriorly curved coccyx. Testing of X-inactivation in lymphocytes from the patient demonstrated random (not skewed) inactivation. Zanzottera et al. (2017) suggested that females with ZC4H2 deletions can be as severely affected as males with Wieacker-Wolff syndrome. They also noted that the variable phenotype found in affected individuals with Wieacker-Wolff syndrome make clinical recognition a challenge.

Okubo et al. (2018) reported a 4-year-old girl, born to healthy nonconsanguineous parents, with a severe phenotype with features of Wieacker-Wolff syndrome who had a 395-kb deletion on Xq11.2 that included ZC4H2 as the only known gene. At birth the patient had multiple joint contractures at elbows, knees, shoulders, and hips, with overlapping fingers and toes, congenital clubfeet, and cleft palate. She had poor feeding requiring placement of a G-tube. At age 6 months, she had no head control with truncal hypotonia, and exaggerated deep tendon reflexes with ankle clonus, consistent with spastic quadriplegia. Brain MRI at 6 months showed enlarged posterior horns of the lateral ventricles, thinning of the corpus callosum, and mildly delayed myelination; by age 2 years, the MRI showed no apparent delayed myelination, but progressive diffuse cerebral atrophy, suggesting a progressive nature of cerebral dysfunction associated with this condition. At age 4 years, she was noted to have profound developmental delay and remarkable physical findings including prominent facial palsy, strabismus, carp-shaped mouth, ptosis, cleft palate, kyphoscoliosis, overlapping fingers and toes, and multiple contractures. EEG showed no epileptic discharges, but disorganized theta range activities during wakefulness and no spindles at sleep.

May et al. (2015) found expression of the zc4h2 zebrafish ortholog in the developing central nervous system, mainly in differentiating progenitors and mature neurons and/or glia. Expression was localized mainly in the nucleus. Zc4h2-null zebrafish showed abnormal flexion of the pectoral fins and active movements of the pectoral fins, continuous swimming movements, and balance problems. They also had abnormally positioned eyes, an open mouth, and continuous jaw movements. These abnormalities were associated with a loss of markers of the V2a and V2b interneurons in the hindbrain and spinal cord, as well as a significant reduction in the number of GABAergic interneurons in the midbrain tegmentum, as demonstrated by decreased gad1 (605363) expression. Wildtype human ZC4H2 was able to restore the behavioral abnormalities of mutant fish as well as gad1 expression.