Liebenberg syndrome

Liebenberg syndrome is a condition that involves abnormal development of the arms, resulting in characteristic arm malformations that can vary in severity. In people with this condition, bones and other tissues in the elbows, forearms, wrists, and hands have characteristics of related structures in the lower limbs. For example, bones in the elbows are abnormally shaped, which affects mobility of the joints. The stiff elbows function more like knees, unable to rotate as freely as elbows normally do. Bones in the wrists are joined together (fused), forming structures that resemble those in the ankles and heels and causing permanent bending of the hand toward the thumb (radial deviation). The bones in the hands (metacarpals) are longer than normal, and the fingers are short (brachydactyly), similar to the proportions of bones found in the feet. In addition, muscles and tendons that are typically found only in the hands and not in the feet are missing in people with Liebenberg syndrome. Affected individuals also have joint deformities (contractures) that limit movement of the elbows, wrists, and hands. Development of the lower limbs is normal in people with this condition.

Individuals with Liebenberg syndrome have no other health problems related to this condition, and life expectancy is normal.

Liebenberg syndrome is a rare condition. Fewer than 10 affected families have been described in the medical literature.

Liebenberg syndrome is caused by genetic changes near the PITX1 gene. The protein produced from this gene plays a critical role in lower limb development by controlling the activity of other genes involved in limb development, directing the shape and structure of bones and other tissues in the legs and feet.

The genetic changes involved in Liebenberg syndrome delete, insert, or rearrange genetic material near the PITX1 gene. These changes affect regions of DNA known as regulatory elements, which help turn on or turn off genes (known as enhancers or repressors, respectively). They control when and where certain genes are active. The mutations that cause Liebenberg syndrome are thought to relocate enhancers that normally promote the activity of genes involved in upper limb development to be near the PITX1 gene, where they can promote its activity. Alternatively, the mutations may remove repressors that normally turn off the PITX1 gene during upper limb development. As a result, the PITX1 gene is abnormally active during development of the upper limbs. Because the PITX1 protein normally directs lower limb structure, bones, muscles, and tendons in the arms and hands develop more like those in the legs and feet, leading to the features of Liebenberg syndrome.

Genetic Testing Information

• Genetic Testing Registry: Brachydactyly-elbow wrist dysplasia syndrome

Genetic and Rare Diseases Information Center

• Brachydactyly-elbow wrist dysplasia syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• LIEBENBERG SYNDROME; LBNBG

Scientific Articles on PubMed

• PubMed

• Al-Qattan MM, Al-Thunayan A, Alabdulkareem I, Al Balwi M. Liebenberg syndrome is caused by a deletion upstream to the PITX1 gene resulting in transformation of the upper limbs to reflect lower limb characteristics. Gene. 2013 Jul 15;524(1):65-71. doi: 10.1016/j.gene.2013.03.120. Epub 2013 Apr 12. Citation on PubMed
• DeLaurier A, Schweitzer R, Logan M. Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb. Dev Biol. 2006 Nov 1;299(1):22-34. doi: 10.1016/j.ydbio.2006.06.055. Epub 2006 Jul 14. Citation on PubMed
• Duboc V, Logan MP. Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control. Development. 2011 Dec;138(24):5301-9. doi: 10.1242/dev.074153. Epub 2011 Nov 9. Citation on PubMed or Free article on PubMed Central
• Seoighe DM, Gadancheva V, Regan R, McDaid J, Brenner C, Ennis S, Betts DR, Eadie PA, Lynch SA. A chromosomal 5q31.1 gain involving PITX1 causes Liebenberg syndrome. Am J Med Genet A. 2014 Nov;164A(11):2958-60. doi: 10.1002/ajmg.a.36712. Epub 2014 Aug 14. No abstract available. Citation on PubMed
• Spielmann M, Brancati F, Krawitz PM, Robinson PN, Ibrahim DM, Franke M, Hecht J, Lohan S, Dathe K, Nardone AM, Ferrari P, Landi A, Wittler L, Timmermann B, Chan D, Mennen U, Klopocki E, Mundlos S. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am J Hum Genet. 2012 Oct 5;91(4):629-35. doi: 10.1016/j.ajhg.2012.08.014. Epub 2012 Sep 27. Citation on PubMed or Free article on PubMed Central