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'''Warsaw breakage syndrome''' is a rare genetic condition. Fewer than 10 cases have been reported by 2018.<ref name=Alkhunaizi2018>Alkhunaizi E, Shaheen R, Bharti SK, Joseph-George AM, Chong K, Abdel-Salam GMH, Alowain M, Blaser SI, Papsin BC, Butt M, Hashem M, Martin N, Godoy R, Brosh RM Jr, Alkuraya FS, Chitayat D (2018) Warsaw breakage syndrome: Further clinical and genetic delineation. Am J Med Genet A doi: 10.1002/ajmg.a.40482</ref> Its clinical manifestations affect several organ systems.
'''Warsaw breakage syndrome''' ('''Warsaw syndrome''', '''WABS''') is a rare genetic condition. Fewer than 10 cases have been reported by 2018.<ref name=Alkhunaizi2018>{{cite journal |last1=Alkhunaizi |first1=Ebba |last2=Shaheen |first2=Ranad |last3=Bharti |first3=Sanjay Kumar |last4=Joseph-George |first4=Ann M. |last5=Chong |first5=Karen |last6=Abdel-Salam |first6=Ghada M. H. |last7=Alowain |first7=Mohammed |last8=Blaser |first8=Susan I. |last9=Papsin |first9=Blake C. |last10=Butt |first10=Mohammed |last11=Hashem |first11=Mais |last12=Martin |first12=Nicole |last13=Godoy |first13=Ruth |last14=Brosh |first14=Robert M. |last15=Alkuraya |first15=Fowzan S. |last16=Chitayat |first16=David |title=Warsaw breakage syndrome: Further clinical and genetic delineation |journal=American Journal of Medical Genetics Part A |date=November 2018 |volume=176 |issue=11 |pages=2404–2418 |doi=10.1002/ajmg.a.40482 |display-authors=3}}</ref> Its clinical manifestations affect several organ systems, and includes microcephaly and severe growth retardation among others.


==Presentation==
==Presentation==
Presentation include:<ref name=Pisani2019>{{cite journal |last1=Pisani |first1=Francesca M. |title=Spotlight on Warsaw Breakage Syndrome |journal=The Application of Clinical Genetics |date=5 December 2019 |volume=12 |pages=239–248 |doi=10.2147/TACG.S186476 |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901054/ |access-date=9 April 2023}}</ref><ref name=GeneReviews>{{cite journal |last1=Alkhunaizi |first1=Ebba |last2=Brosh |first2=Robert M. |last3=Alkuraya |first3=Fowzan S. |last4=Chitayat |first4=David |title=Warsaw Syndrome |journal=GeneReviews® |date=1993 |url=https://www.ncbi.nlm.nih.gov/books/NBK541972/ |access-date=9 April 2023 |publisher=University of Washington, Seattle}}</ref>

These include<ref name=Pisani2019>Pisani FM (2019) Spotlight on Warsaw Breakage Syndrome. Appl Clin Genet 12:239-248</ref>
* Severe pre- and postnatal growth retardation
* Severe pre- and postnatal growth retardation
* Microcephaly
* Microcephaly
Line 48: Line 47:
** Abnormal skin pigmentation
** Abnormal skin pigmentation
** Single palmar crease
** Single palmar crease

Israeli Health Ministry describes the condition manifestation as "characterized by smaller than average head circumference (microcephaly) as early as the embryonic stage, intrauterine growth restriction (IUGR) as well as postnatal growth restriction (dwarfism). Furthermore, patients born with this condition experience hearing impairments, moderate to significant developmental delays, skeletal disorders and heart disorders (40%), as well as disorders to various body systems such as the renal and urogenital systems. In some patients, blood tests indicate increased chromosome fragility. Some fetuses die in utero (intrauterine fetal demise)."<ref name=israel/>


==Genetics==
==Genetics==


This condition is caused by mutations in the [[DDX11]] gene which is located on the short arm of [[chromosome 12]] (12p11).{{cn|date=October 2020}}
This condition is caused by mutations in the [[DDX11]] gene.<ref name=GeneReviews/><ref>{{cite web |title=DDX11 gene: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/gene/ddx11/ |website=medlineplus.gov |access-date=9 April 2023 |language=en}}</ref>

⚫
This gene encodes an [[iron]]-[[sulfur]] containing DNA [[helicase]] that belongs to the superfamily 2 of helicases. This protein interacts with the 9-1-1 checkpoint complex protein.{{cn|date=October 2020}}
DDX11 mutation that causes WABS is described at US [[National Library of Medicine]]:<ref name=medlineplus>{{cite web |title=Warsaw breakage syndrome: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/warsaw-breakage-syndrome |website=medlineplus.gov |access-date=9 April 2023 |language=en}} {{PD-notice}}</ref>
<blockquote>The DDX11 gene provides instructions for making an enzyme called ChlR1. This enzyme functions as a helicase. Helicases are enzymes that attach (bind) to DNA and temporarily unwind the two spiral strands (double helix) of the DNA molecule. This unwinding is necessary for copying (replicating) 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.</blockquote>


⚫
This gene encodes an [[iron]]-[[sulfur]] containing DNA [[helicase]] that belongs to the Fe–S DNA helicases.<ref name=Pisani2019/> This protein interacts with the 9-1-1 checkpoint complex protein.{{cn|date=October 2020}}
The inheritance pattern is autosomal recessive.<ref name=Alkhunaizi2018/>


The inheritance pattern is autosomal recessive.<ref name=Alkhunaizi2018/><ref name=israel/> Condition is very rare, but its prevalence in [[Ashkenazi Jew]]s population is about 1/50.<ref name=israel>{{cite web |title=Warsaw Breakage Syndrome |url=https://www.gov.il/en/departments/general/disease-genetic-warsaw-breakage-syndrome |website=GOV.IL |access-date=9 April 2023 |language=en}}</ref><ref name=medlineplus/>
==Diagnosis==


The diagnosis may be suspected on clinical grounds and can be confirmed by sequencing the DDX11 gene.{{cn|date=October 2020}}
===Differential diagnosis===
===Differential diagnosis===
The DDX should be based on the following:{{cn|date=October 2020}}
The DDX should be based on the following:{{cn|date=October 2020}}
Line 69: Line 73:


==Treatment==
==Treatment==
⚫
There is no known curative treatment for this condition presently. Management is supportive.<ref name=GeneReviews/>

⚫
There is no known curative treatment for this condition presently. Management is supportive.{{cn|date=October 2020}}


==History==
==History==
This condition was first described in 2010.<ref name=vanderLelij2010>{{cite journal |last1=van der Lelij |first1=Petra |last2=Chrzanowska |first2=Krystyna H. |last3=Godthelp |first3=Barbara C. |last4=Rooimans |first4=Martin A. |last5=Oostra |first5=Anneke B. |last6=Stumm |first6=Markus |last7=Zdzienicka |first7=Małgorzata Z. |last8=Joenje |first8=Hans |last9=de Winter |first9=Johan P. |title=Warsaw Breakage Syndrome, a Cohesinopathy Associated with Mutations in the XPD Helicase Family Member DDX11/ChlR1 |journal=The American Journal of Human Genetics |date=February 2010 |volume=86 |issue=2 |pages=262–266 |doi=10.1016/j.ajhg.2010.01.008}}</ref>

This condition was first described in 2010.<ref name=vanderLelij2010>van der Lelij P, Chrzanowska KH, Godthelp BC, Rooimans MA, Oostra AB, Stumm M, Zdzienicka MZ, Joenje H, de Winter JP (2010) Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am J Hum Genet 86(2):262-6. doi: 10.1016/j.ajhg.2010.01.008</ref>


==References==
==References==

Revision as of 18:00, 9 April 2023

Warsaw breakage syndrome
Other namesWABS[1]

Warsaw breakage syndrome (Warsaw syndrome, WABS) is a rare genetic condition. Fewer than 10 cases have been reported by 2018.[2] Its clinical manifestations affect several organ systems, and includes microcephaly and severe growth retardation among others.

Presentation

Presentation include:[3][4]

  • 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

Israeli Health Ministry describes the condition manifestation as "characterized by smaller than average head circumference (microcephaly) as early as the embryonic stage, intrauterine growth restriction (IUGR) as well as postnatal growth restriction (dwarfism). Furthermore, patients born with this condition experience hearing impairments, moderate to significant developmental delays, skeletal disorders and heart disorders (40%), as well as disorders to various body systems such as the renal and urogenital systems. In some patients, blood tests indicate increased chromosome fragility. Some fetuses die in utero (intrauterine fetal demise)."[5]

Genetics

This condition is caused by mutations in the DDX11 gene.[4][6]

DDX11 mutation that causes WABS is described at US National Library of Medicine:[7]

The DDX11 gene provides instructions for making an enzyme called ChlR1. This enzyme functions as a helicase. Helicases are enzymes that attach (bind) to DNA and temporarily unwind the two spiral strands (double helix) of the DNA molecule. This unwinding is necessary for copying (replicating) 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.[3] This protein interacts with the 9-1-1 checkpoint complex protein.[citation needed]

The inheritance pattern is autosomal recessive.[2][5] Condition is very rare, but its prevalence in Ashkenazi Jews population is about 1/50.[5][7]

Differential diagnosis

The DDX should be based on the following:[citation needed]

Treatment

There is no known curative treatment for this condition presently. Management is supportive.[4]

History

This condition was first described in 2010.[8]

References

  1. ^ "OMIM Entry - # 613398 - WARSAW BREAKAGE SYNDROME; WABS". omim.org. Retrieved 29 October 2019.
  2. ^ a b Alkhunaizi, Ebba; Shaheen, Ranad; Bharti, Sanjay Kumar; et al. (November 2018). "Warsaw breakage syndrome: Further clinical and genetic delineation". American Journal of Medical Genetics Part A. 176 (11): 2404–2418. doi:10.1002/ajmg.a.40482.
  3. ^ a b Pisani, Francesca M. (5 December 2019). "Spotlight on Warsaw Breakage Syndrome". The Application of Clinical Genetics. 12: 239–248. doi:10.2147/TACG.S186476. Retrieved 9 April 2023.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ a b c Alkhunaizi, Ebba; Brosh, Robert M.; Alkuraya, Fowzan S.; Chitayat, David (1993). "Warsaw Syndrome". GeneReviews®. University of Washington, Seattle. Retrieved 9 April 2023.
  5. ^ a b c "Warsaw Breakage Syndrome". GOV.IL. Retrieved 9 April 2023.
  6. ^ "DDX11 gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 9 April 2023.
  7. ^ a b "Warsaw breakage syndrome: MedlinePlus Genetics". medlineplus.gov. Retrieved 9 April 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ van der Lelij, Petra; Chrzanowska, Krystyna H.; Godthelp, Barbara C.; Rooimans, Martin A.; Oostra, Anneke B.; Stumm, Markus; Zdzienicka, Małgorzata Z.; Joenje, Hans; de Winter, Johan P. (February 2010). "Warsaw Breakage Syndrome, a Cohesinopathy Associated with Mutations in the XPD Helicase Family Member DDX11/ChlR1". The American Journal of Human Genetics. 86 (2): 262–266. doi:10.1016/j.ajhg.2010.01.008.
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