What is ZC4H2 Deficiency?

ZC4H2 stands for “Zinc finger C4H2-type”. ZC4H2 is a gene located on the X-chromosome. This gene encodes a protein which is a member of the so-called zinc finger domain-containing protein family.

There is currently very limited understanding about the ZC4H2 gene and its protein function. It is believed that ZC4H2 plays an important role in the development of the neurologic system during the early stages of human development.

Mutations in the ZC4H2 gene may result in a variety of clinical symptoms. We refer to any deleterious mutation in ZC4H2 which results in such clinical symptoms as “ZC4H2 Deficiency”*.

Mutations in the ZC4H2 gene can be passed on from a parent to a child (hereditary or inherited) or happen spontaneously (sporadic or ‘de-novo’). When the mutation is hereditary, i.e. inherited from a carrier female, the sons are usually affected because males carry only a single X chromosome. The clinical symptoms in affected males are usually severe, while their carrier female siblings are usually unaffected or much less severely affected.

When the mutation happens ‘de-novo’ in non-hereditary cases -up to now mostly identified in females-, it can result in various different clinical presentations.

ZC4H2 Deficiency is considered an ultra-rare condition. Besides the few cases published to date, we currently know of 46 additional diagnosed children with ZC4H2 Deficiency worldwide.

There is no clear prediction of the symptoms that a mutation in the ZC4H2 gene may cause in each particular case, but we know that the disorder can range from mildly expressed to very severe in both males and females. A deleterious ZC4H2 mutation can result in multiple disabilities and health concerns, including several muscular and neurological issues. These can include Arthrogryposis Multiplex Congenita (joint contractures), muscular atrophy, difficulties to stand, walk or keep an upright position, difficulties to eat or breathe, joint dislocations, speech difficulties, vision problems, epilepsy and global developmental delay. An affected individual can have the full range of symptoms or only a few of them.

There is currently no cure or effective treatment for this rare condition. Current treatments consist mainly of different supportive therapies, medical interventions and medications when necessary, to improve the independence and quality of life of patients suffering from ZC4H2 Deficiency.

*The expression of ZC4H2 mutations is referred by some as “Wieacker-Wolff Syndrome”  (in other publications appearing as “Miles-Carpenter Syndrome” ). These nomenclatures describe the phenotypes observed in some individuals with a mutation in the ZC4H2 gene but they do not accurately define the highly variable clinical presentations seen among the affected males and females. Therefore we prefer referring to the condition by its cause, as “ZC4H2 Deficiency”.


Note: We thank Dr. Vera Kalscheuer for her contribution to this text.

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