Warsaw breakage syndrome

Warsaw breakage syndrome is a rare genetic condition. Fewer than 10 cases have been reported by 2018. Its clinical manifestations affect several organ systems, and includes microcephaly and severe growth retardation among others.

Signs and symptoms

The signs and symptoms of Warsaw breakage syndrome include:

Severe pre- and postnatal growth retardation
Microcephaly
Intellectual disability
Dysmorphic features
* Small and elongated face
* Narrow bifrontal diameter
* Prominent cheeks
* Small nares
* Flat philtrum
* Relatively large mouth
* Bilateral epicanthal folds
* High-arched palate
* Microretrognathism
* Coloboma of the optic disc
* Strabismus
* Cup-shaped ears
* Sensorineural deafness
* Short neck
* Jugular hypoplasia
Cardiac features
* Ventricular septal defect
* Tetralogy of Fallot
Sketelal features
* Clinodactyly of the fifth fingers
* Syndactyly of the second and third toes
* Small thumbs
* Small fibulae
Others
* Abnormal skin pigmentation
* Single palmar crease

The Israeli Health Ministry describes the condition manifestation as "characterized by smaller than average head circumference as early as the embryonic stage, intrauterine growth restriction as well as postnatal growth restriction. Furthermore, patients born with this condition experience hearing impairments, moderate to significant developmental delays, skeletal disorders, and heart disorders, as well as disorders of various body systems such as the renal and urogenital systems. In some patients, blood tests indicate increased chromosome fragility. Some fetuses die in utero."

Genetics

This condition is caused by mutations in the DDX11 gene.
DDX11 mutation that causes WABS is described at US National Library of Medicine:

The DDX11 gene provides instructions for making an enzyme called ChlR1. This enzyme functions as a helicase. Helicases are enzymes that attach to DNA and temporarily unwind the two spiral strands of the DNA molecule. This unwinding is necessary for copying DNA in preparation for cell division, and for repairing damaged DNA and any errors that are made when DNA is copied. In addition, after DNA is copied, ChlR1 plays a role in ensuring proper separation of each chromosome during cell division. By helping repair errors in DNA and ensuring proper DNA replication, the ChlR1 enzyme is involved in maintaining the stability of a cell's genetic information.
DDX11 gene mutations severely reduce or completely eliminate ChlR1 enzyme activity. As a result, the enzyme cannot bind to DNA and cannot unwind the DNA strands to help with DNA replication and repair. A lack of functional ChlR1 impairs cell division and leads to an accumulation of DNA damage. This DNA damage can appear as breaks in the DNA, giving the condition its name. It is unclear how these problems in DNA maintenance lead to the specific abnormalities characteristic of Warsaw breakage syndrome.

This gene encodes an iron-sulfur containing DNA helicase that belongs to the Fe–S DNA helicases. This protein interacts with the 9-1-1 checkpoint complex protein.
The inheritance pattern is autosomal recessive. Condition is very rare, but its prevalence in Ashkenazi Jews population is about 1/50.

Differential diagnosis

The DDX should be based on the following:

Treatment

There is no known curative treatment for this condition presently. Management is supportive.

History

This condition was first described in 2010.