Multiple pterygium syndrome

Multiple pterygium syndrome is a condition that is evident before birth with webbing of the skin (pterygium) at the joints and a lack of muscle movement (akinesia) before birth. Akinesia frequently results in muscle weakness and joint deformities called contractures that restrict the movement of joints (arthrogryposis). As a result, multiple pterygium syndrome can lead to further problems with movement such as arms and legs that cannot fully extend.

The two forms of multiple pterygium syndrome are differentiated by the severity of their symptoms. Multiple pterygium syndrome, Escobar type (sometimes referred to as Escobar syndrome) is the milder of the two types. Lethal multiple pterygium syndrome is fatal before birth or very soon after birth.

In people with multiple pterygium syndrome, Escobar type, the webbing typically affects the skin of the neck, fingers, forearms, inner thighs, and backs of the knee. People with this type may also have arthrogryposis. A side-to-side curvature of the spine (scoliosis) is sometimes seen. Affected individuals may also have respiratory distress at birth due to underdeveloped lungs (lung hypoplasia). People with multiple pterygium syndrome, Escobar type usually have distinctive facial features including droopy eyelids (ptosis), outside corners of the eyes that point downward (downslanting palpebral fissures), skin folds covering the inner corner of the eyes (epicanthal folds), a small jaw, and low-set ears. Males with this condition can have undescended testes (cryptorchidism). This condition does not worsen after birth, and affected individuals typically do not have muscle weakness later in life.

Lethal multiple pterygium syndrome has many of the same signs and symptoms as the Escobar type. In addition, affected fetuses may develop a buildup of excess fluid in the body (hydrops fetalis) or a fluid-filled sac typically found on the back of the neck (cystic hygroma). Individuals with this type have severe arthrogryposis. Lethal multiple pterygium syndrome is associated with abnormalities such as underdevelopment (hypoplasia) of the heart, lung, or brain; twisting of the intestines (intestinal malrotation); kidney abnormalities; an opening in the roof of the mouth (a cleft palate); and an unusually small head size (microcephaly). Affected individuals may also develop a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), a condition called a congenital diaphragmatic hernia. Lethal multiple pterygium syndrome is typically fatal in the second or third trimester of pregnancy.

The prevalence of multiple pterygium syndrome is unknown.

Mutations in the CHRNG gene cause most cases of multiple pterygium syndrome, Escobar type and a smaller percentage of cases of lethal multiple pterygium syndrome. The CHRNG gene provides instructions for making the gamma (γ) protein component (subunit) of the acetylcholine receptor (AChR) protein. The AChR protein is found in the membrane of skeletal muscle cells and is critical for signaling between nerve and muscle cells. Signaling between these cells is necessary for movement. The AChR protein consists of five subunits. The γ subunit is found only in the fetal AChR protein. At about the thirty-third week of pregnancy, the γ subunit is replaced by another subunit to form adult AChR protein. The replacement of fetal AChR by adult AChR is the reason most people with multiple pterygium syndrome, Escobar type do not have problems with muscle movement after birth.

CHRNG gene mutations result in an impaired or missing γ subunit. The severity of the CHRNG gene mutation influences the severity of the condition. Typically, mutations that prevent the production of any γ subunit will result in the lethal type, while mutations that allow the production of some γ subunit will lead to the Escobar type. Without a functional γ subunit, the fetal AChR protein cannot be assembled or properly placed in the muscle cell membrane. As a result, the fetal AChR protein cannot function and the communication between nerve cells and muscle cells in the developing fetus is impaired. A lack of signaling between nerve and muscle cells leads to akinesia and pterygium before birth, and may result in many of the other signs and symptoms of multiple pterygium syndrome.

Mutations in other genes, most providing instructions for other AChR protein subunits, have been found to cause multiple pterygium syndrome. Changes in these genes can cause both the lethal and Escobar types of this condition, although they account for only a small number of cases. Some people with multiple pterygium syndrome do not have an identified mutation in any of the known genes associated with this condition. The cause of the disease in these individuals is unknown.

Genetic Testing Information

• Genetic Testing Registry: Autosomal recessive multiple pterygium syndrome
• Genetic Testing Registry: Lethal multiple pterygium syndrome

Genetic and Rare Diseases Information Center

• Autosomal recessive multiple pterygium syndrome
• Lethal multiple pterygium syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• MULTIPLE PTERYGIUM SYNDROME, LETHAL TYPE; LMPS
• MULTIPLE PTERYGIUM SYNDROME, ESCOBAR VARIANT; EVMPS

Scientific Articles on PubMed

• PubMed

• Cox PM, Brueton LA, Bjelogrlic P, Pomroy P, Sewry CA. Diversity of neuromuscular pathology in lethal multiple pterygium syndrome. Pediatr Dev Pathol. 2003 Jan-Feb;6(1):59-68. doi: 10.1007/s10024-002-0042-9. Epub 2002 Nov 7. Citation on PubMed
• Hoffmann K, Muller JS, Stricker S, Megarbane A, Rajab A, Lindner TH, Cohen M, Chouery E, Adaimy L, Ghanem I, Delague V, Boltshauser E, Talim B, Horvath R, Robinson PN, Lochmuller H, Hubner C, Mundlos S. Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am J Hum Genet. 2006 Aug;79(2):303-12. doi: 10.1086/506257. Epub 2006 Jun 20. Citation on PubMed or Free article on PubMed Central
• Michalk A, Stricker S, Becker J, Rupps R, Pantzar T, Miertus J, Botta G, Naretto VG, Janetzki C, Yaqoob N, Ott CE, Seelow D, Wieczorek D, Fiebig B, Wirth B, Hoopmann M, Walther M, Korber F, Blankenburg M, Mundlos S, Heller R, Hoffmann K. Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet. 2008 Feb;82(2):464-76. doi: 10.1016/j.ajhg.2007.11.006. Citation on PubMed or Free article on PubMed Central
• Morgan NV, Brueton LA, Cox P, Greally MT, Tolmie J, Pasha S, Aligianis IA, van Bokhoven H, Marton T, Al-Gazali L, Morton JE, Oley C, Johnson CA, Trembath RC, Brunner HG, Maher ER. Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome. Am J Hum Genet. 2006 Aug;79(2):390-5. doi: 10.1086/506256. Epub 2006 Jun 20. Citation on PubMed or Free article on PubMed Central
• Parashar SY, Anderson PJ, McLean N, Djohansjah M, David DJ. Spectrum of features in pterygium syndrome. Asian J Surg. 2006 Apr;29(2):104-8. doi: 10.1016/S1015-9584(09)60118-4. Citation on PubMed
• Vogt J, Harrison BJ, Spearman H, Cossins J, Vermeer S, ten Cate LN, Morgan NV, Beeson D, Maher ER. Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Am J Hum Genet. 2008 Jan;82(1):222-7. doi: 10.1016/j.ajhg.2007.09.016. Citation on PubMed or Free article on PubMed Central