September 22, 2022
Years published: 1991, 1998, 2005, 2007, 2009, 2012, 2015, 2022
NORD gratefully acknowledges the ZC4H2 Research Foundation and Dr. V. Kalscheuer, Max Planck Institute for Molecular Genetics, Berlin, Germany, for the preparation of this report.
ZC4H2 Associated Rare Disorders (ZARD) 1 is an ultra-rare genetic condition with central and peripheral nervous system involvement caused by harmful changes (pathogenic variants) of the ZC4H2 gene. ZC4H2 is located on the X chromosome and encodes the ZC4H2 (zinc finger C4H2-type containing) protein essential for normal development. ZARD can manifest in a broad range of clinical severity. Clinical presentations of affected individuals who carry the same pathogenic ZC4H2 gene variant can vary within families and between families.1-3 Males and females can be affected.
Many conditions have been described as associated with pathogenic variants in the ZC4H2 gene. 2,4,5 These conditions are now thought to be included in the spectrum of ZARD 1. This previously used nomenclature describes limited populations of individual or family-specific cases, provides partial descriptions of the condition, and should no longer be used. These conditions include the following:
• Wieacker-Wolff syndrome, WRWF 2
• Miles-Carpenter syndrome 3
• ZC4H2 deficiency 4
• Wieacker syndrome
• contractures of the feet, muscle atrophy and oculomotor apraxia
• apraxia, oculomotor with congenital contractures and muscle atrophy
• Miles-Carpenter X-linked mental retardation syndrome; MCS
• mental retardation, X-linked, syndromic 4; MRXS4
• mental retardation, X-linked with congenital contractures and low fingertip arches
• Wieacker-Wolff syndrome, female restricted; WRWFFR
Patients with ZARD can have multiple disabilities and health concerns. These can include orthopedic and musculoskeletal conditions and neurological/neuromuscular conditions. The most common clinical features include:
• arthrogryposis multiplex congenita (multiple joint contractures before birth that involve at least two different body areas; sometimes caused by decreased fetal movement)
• joint and soft-tissue abnormalities often expressed as contractures
• hand and feet deformities
• hip deformities
• muscular atrophy
• osteopenia (weak bones)
• scoliosis (sideways curvature of the spine)
• motor planning impairments, generalized or localized
• mobility impairments
• variable muscle tone
• difficulty eating and breathing
• speech disorders often including apraxia of speech that can make it difficult for a child to connect syllables, words and phrases
• oculomotor apraxia (abnormal eye movements)
• tethered cord (spinal cord attached to surrounding tissues in the spine)
• global developmental delay (longer time for a child to reach developmental milestones)
• intellectual disabilities
• learning difficulties
An affected individual can have the full range of symptoms or only some of them. 1-4,6,7
MRI brain and spine images can show variable and global brain atrophy, delayed central nervous system myelination, abnormality of periventricular white matter, corpus callosum abnormality, abnormal cortical gyration, ventriculomegaly, tethered cord and hydromyelia. 1
There are some gender specific clinical features such as cardiovascular (heart and blood vessel) associated clinical features, hypogonadism (low testosterone) and hypoglycemia (low blood sugar) that have so far only been reported in affected males.1
Arthrogryposis multiplex congenita (AMC) and muscular atrophy, which are observed in most affected males and females, could be a possible secondary consequence of reduced fetal movement. Like affected individuals with other types of arthrogryposis multiplex congenita who develop joint contractures during pregnancy, abnormal fetal movement during pregnancy can be identified using real time ultrasound prenatally. However, AMC and abnormal fetal movements can occur late in pregnancy and therefore suspicion of the diagnosis can be easily missed. 1
There is currently no evidence of any progressive or regressive nature in the condition. Life expectancy is yet undetermined.
ZARD is caused by harmful changes of the X chromosome linked ZC4H2 gene. Males and females can be affected. ZC4H2 gene variants can be inherited or occur spontaneously, meaning there is no family history of the disorder (de novo). 1
Males have one X chromosome and one Y chromosome. If a male has a pathogenic ZC4H2 gene variant (inherited from his mother or de novo), he will develop the disease.
In very rare cases, healthy males may have somatic/germline mosaicism for a pathogenic ZC4H2 gene variant. They will pass this variant to all their daughters, who will be carriers. Males cannot pass the ZC4H2 gene variant to their sons because they always pass their Y chromosome instead of their X chromosome to male offspring.
Females have two X chromosomes but many genes of one of the X chromosomes are silenced to correct a dosage imbalance through a process which is called X-inactivation. ZC4H2 is one of these many genes which is silenced through this process (subject to X-inactivation). 3 Results obtained so far by performing X-inactivation studies in blood and skin fibroblasts of carrier females indicated that X-inactivation status does not predict the clinical outcome. 1
Variants of the ZC4H2 gene can be inherited from the healthy or mildly affected mother who carries the variant on one of her X chromosomes. 1 Female carriers have a 25% chance with each pregnancy to pass on the ZC4H2 variant to a daughter, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with ZARD, and a 25% chance to have an unaffected son.
Females with a maternally inherited ZC4H2 gene variant may be unaffected or mildly affected. In contrast, females who carry a de novo pathogenic ZC4H2 variant can present with a highly variable clinical expression which ranges from mild to severe 1
In very rare cases, healthy females who carry a ZC4H2 variant in a small number of somatic cells and germ cells (gonosomal mosaicism) can pass the variant to their children. 1
The ZC4H2 gene is expressed in all human tissues. Understanding of ZC4H2’s gene functions and the functions of its corresponding ZC4H2 protein is currently limited. There is currently no evidence for a clear relationship between the genetic abnormality and the clinical features.
The spectrum of ZC4H2 gene abnormalities comprises novel (not reported before) and recurrent (present in at least two unrelated families) mostly inherited missense variants which cause a single amino acid exchange in the ZC4H2 protein in affected male individuals, and de novo missense, splicing, frameshift, nonsense and partial ZC4H2 deletions on one of the X chromosomes in carrier females and are predicted to be loss-of function alleles in affected female individuals suggesting ZC4H2 insufficiency as the most likely pathological mechanism leading to the clinical phenotype in females.
Thus far, missense variants cluster in the last exon of the ZC4H2 gene, which encodes the zinc-finger domain and the most C-terminal part of the protein.
Analysis of the in vivo expression pattern of the mouse Zc4h2 gene during neurodevelopment in various brain regions and spinal cord of different developmental stages revealed that in all brain areas investigated, Zc4h2 gene expression was highest during embryonic development and declined after birth, suggesting an important function during mouse brain development. 3
In zebrafish zc4h2 is primarily expressed in brain cells called “myelinating oligodendrocytes”, with decrease in expression as these mature into another type of brain cells. 6 This may suggest a function of ZC4H2 in myelination – which has not been studied to date.
It is believed that the ZC4H2 protein plays an important role in the development of the neurologic system during the early stages of human development, particularly through the development of neuromuscular junctions, spinal cord motor-neuron differentiation and neural tube formation. 3,6,8
Harmful ZC4H2 gene variants have been identified in many ethnic groups, with both males and females being affected who present with a broad spectrum of severity.
To date, there are less than 250 diagnosed patients with ZARD worldwide. 1,3,6,7,9-21
About 30% are males and 70% are females. 7
There are several genetic diseases that may be characterized by similar or overlapping symptoms to those that may occur with ZARD with varying clinical severity, including arthrogryposis multiplex congenita, hand and feet deformities such as talipes equinovarus and/or camptodactyly.
Clinical genetic differential diagnosis in males: 1
developmental and epileptic encephalopathy 1
alpha-thalassemia X-linked intellectual disability syndrome
FG syndrome 4
Uruguay faciocardiomusculoskeletal syndrome
intellectual developmental disorder, X-linked, Turner type
myotubular myopathy, X-linked
intellectual developmental disorder, X-linked syndromic, Christianson type
spinal muscular atrophy, X-linked 2, infantile
A diagnosis of ZARD may be considered based upon a thorough clinical evaluation, a detailed patient and family history and the identification of characteristic findings. Molecular genetic testing for ZC4H2 gene variants (gene sequencing, panel next generation sequencing and microarray analysis) is available to confirm the diagnosis.
The diagnosis of ZARD is established in a male with suggestive findings and a de novo or inherited pathogenic variant in the ZC4H2 gene identified by molecular genetic testing.
The diagnosis of ZARD is usually established in a female with suggestive findings and a de novo or inherited pathogenic variant in ZC4H2 identified by molecular genetic testing.
Identification of a ZC4H2 variant in a male or female interpreted as variant of uncertain clinical significance (VUS) does not establish the diagnosis or rule out the diagnosis of ZARD.
If a ZC4H2 gene variant is not identified, molecular genetic testing for genes associated with similar conditions may be suggested.
There is currently no cure or effective treatment for this ultra-rare condition. Current treatments consist mainly of different supportive therapies and medical interventions when necessary. However, there is an observed correlation between early therapeutic and supportive interventions (pre-verbal and speech as well as physical therapies) and favorable short- and long-term outcomes. 7
Surgery may be necessary to treat specific congenital or structural malformations associated with ZARD.
Genetic counseling is recommended for affected individuals and their families to clarify the genetic and clinical characteristics, inheritance and recurrence risks of the condition in their families.
The Orphan Disease Center at the University of Pennsylvania has a JumpStart program to establish and progress research in rare diseases. The ZC4H2 Research Foundation partners with JumpStart to promote ZARD research.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
1. Frints SGM, et al. Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita. Hum Mutat. 2019; 40:
2. Miles JH & Carpenter NJ. Unique X-linked mental retardation syndrome with fingertip arches and contractures linked to Xq21.31. Am J Med Genet. 1991; 38: 215-23.
3. Hirata H, et al. ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic
plasticity. Am J Hum Genet. 2013; 92: 681-95.
4. Wieacker P, Wolff G, Wienker TF & Sauer M. A new X-linked syndrome with muscle atrophy, congenital contractures, and oculomotor apraxia. Am J Med Genet. 1985; 20: 597-606.
5. Wikipedia. https://en.wikipedia.org/wiki/ZC4H2_deficiency.
6. May M, et al. ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons. Hum Mol Genet, 2015; 24: 4848-61.
7. The ZC4H2 Research Foundation.
8. Kim J, et al. Rnf220 cooperates with Zc4h2 to specify spinal progenitor domains. Development. 2018; 145.
9. Piccolo G, et al. Neuromuscular and neuroendocrinological features associated with ZC4H2-related arthrogryposis multiplex congenita in a Sicilian family:a case report. Front
Neurol. 2021; 12: 704747.
10. Zanzottera C, et al. ZC4H2 deletions can cause severe phenotype in female carriers. Am J Med Genet A. 2017; 173: 1358-1363.
11. Godfrey ND, Dowlatshahi S, Martin MM & Rothkopf DM. Wieacker-Wolff syndrome with associated cleft palate in a female case. Am J Med Genet A. 2018; 176: 167-170.
12. Kondo, D, et al. A novel ZC4H2 gene mutation, K209N, in Japanese siblings with arthrogryposis multiplex congenita and intellectual disability: characterization of the K209N
mutation and clinical findings. Brain Dev. 2018; 40: 760-767.
13. Okubo, Y, et al. A severe female case of arthrogryposis multiplex congenita with brain atrophy, spastic quadriplegia and intellectual disability caused by ZC4H2 mutation. Brain
Dev. 2018; 40: 334-338.
14. Nagara S, Fukaya S, Muramatsu Y, Kaname T & Tanaka T. A case report of rare ZC4H2-associated disorders associated with three large hernias. Pediatr Int. 2020; 62: 985-986.
15. Wang D, et al. A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome. Mol Genet Genomic Med. 2020; 8: e1100.
16. Deneufbourg C, Duquenne A, Biard JM & Sznajer Y. Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a “de novo” ZC4H2 gene partial
deletion. Clin Case Rep. 2021; 9: e04718.
17. Godfrey D, et al. A 7-year old female with arthrogryposis multiplex congenita, Duane retraction syndrome, and Marcus Gunn phenomenon due to a ZC4H2 gene mutation: a clinical
presentation of the Wieacker-Wolff syndrome. Ophthalmic Genet. 2021; 42: 612-614.
18. Latypova X et al. A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita. Genes (Basel) 2021; 12.
19. Taskiran EZ, et al. Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability. J Intellect Disabil. 2021; Res 65: 577-588.
20. Herman I, et al. Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular
diagnoses. Am J Med Genet A 2022; 188: 735-750.
21. Comlekoglu T, et al. Ophthalmic abnormalities in Wieacker-Wolff syndrome. J AAPOS. 2022; Feb 1;S1091-8531(22)00021-0.
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