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Yunis–Varon syndrome

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Yunis–Varon syndrome (YVS), also called cleidocranial dysplasia with micrognathia or absent thumbs and distal aphalangia,[1][2] is an extremely rare[3] autosomal recessive[4] multisystem congenital disorder[5] which affects the skeletal system, ectodermal tissue, heart and respiratory system. It was first described by Emilio Yunis and Humberto Váron from the National University of Colombia.

Yunis–Varon syndrome
Other namesCleidocranial dysplasia with micrognathia, absent thumbs and distal aphalangia
Yunis–Varon syndrome has an autosomal recessive pattern of inheritance.
SpecialtyMedical genetics Edit this on Wikidata

Signs and symptoms

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Genetics

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This syndrome is inherited in an autosomal recessive manner.[4][6] Several mutations in the FIG4-encoding gene were found to cause Yunis–Varon syndrome. Some of these mutations result in complete loss of protein function; others involve amino-acid replacements at highly conserved residues. Not all mutations in the FIG4 gene result Yunis–Varon syndrome. Some mutations lead to various forms of Charcot–Marie–Tooth disease, Amyotrophic lateral sclerosis 11, and bilateral temporooccipital polymicrogyria.[7][8][9][10]

Patients affected with Yunis–Varon syndrome are homozygous, compound homozygous, or compound heterozygous for deleterious mutations in FIG4.[11][12][13][14][15][16][excessive citations]

Animal model

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Spongiform degeneration of mouse brains caused by altering PI3P to PI(3,5)P2 conversion is associated with human Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS) by accumulation of Lc3II, p62, and LAMP2 proteins, which also contributes to inclusion body disease.[17] Manipulation of this signaling lipid involves culturing fibroblasts obtained by insertion of ETn2-beta(early transposon 2-beta) into intron 18 of FIG4 gene in vacuolar membrane of mice labeled pale tremor (plt). These fibroblasts fill with immunoreactive large vacuoles; but more importantly their abnormal concentration of PI(3,5)P2 demonstrates conserved function of mammalian FIG4 and late endosome-lysosome axis failure responsible for lack of apoptosis of neurons and Schwann cells (but large motor axons are still lost while demyelination still happens).[18][19][20] In contrast, homozygous FIG4 defective (FIG4-/-) mice have a reduction of myelin, especially in optic nerves; but this detriment is rescued by an overexpression of human FIG4 I41T at low-level function.[21] While FIG4-null adult mice have macroscopically normal brains with increments in apoptosis and neuronal density with delayed cell maturation, neonatal mice maintain all neurologic defects.[22][23] FIG4 expression in mouse brain cells is also comparable to that of calvaria, osteoblasts, and bone marrow cells.[24]

Pathophysiology

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The mechanism of mutation in FIG4 causing Yunis–Varon syndrome involves altering conversion of phosphatidylinositol 3-phosphate (PI3P) to signaling lipid phosphatidylinositol 3,5-bisphosphate(PI(3,5)P2). Because this conversion in endosomal membranes changes dynamically with fission and fusion events to create/absorb intracellular transport vesicles, enlarged cytoplasmic vacuoles have been found in patient neurons, muscle, and cartilage.[25][26] These have been identified as intracytoplasmic vacuoles(fluid sacs inside cellular cytoplasm) causing excessive build-up of vacuolated macrophages in bone marrow and pericardial fluid in the heart.[27][28] Fluids may also accumulate in a choroid spaces under the retina, causing central serous retinopathy or chorioretinopathy and possibly vision loss.[29] Paradoxically, overexpression of FIG4 does not yield obvious morphologic phenotype of these fluids accumulating, but alters PI(3,5)P2 levels making cells prone to expansion through dilation of intracellular membranes. Under expression, on the other hand, enhances endosome carrier and formation of vesicles/multivesicular bodies.[30] Central nervous system dysfunction and extensive skeletal anomalies suggest a role for Phosphatidylinositol 3,5-bisphosphate, or PI(3,5)P2, signaling in skeletal development and maintenance.[31]

Diagnosis

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Features of Yunis–Varon syndrome include growth retardation before and after birth, defective growth of the bones of the skull along with complete or partial absence of the shoulder blades and characteristic facial features.[3][32][33] Additional symptoms may include abnormalities of the fingers and/or toes including missing nails/fingers.[32][34] In most cases, infants with this disorder experience severe feeding problems and respiratory difficulties. In addition, affected infants may have heart defects. Osteodysplasties or bone abnormalities may be severe enough to become fatal in as little as 10 weeks of age, making lethality extremely common during infancy.[35][36]

Skeletal

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Defects include cleidocranial dysplasia as abnormal bone development through hypoplastic (absent) clavicles, induced macrocrania (abnormal increase of skull), and diastasis (separation) of sutures.[37] Yunis–Varon syndrome also causes digital anomalies as most patients show aplasia (absence) of thumbs as well as distal phalanges or hypoplasia (underdevelopment) of proximal phalanx with absence and/or agenesis of halluces' (big toes') distal phalanxes sometimes with absent.[38][39][40] Pelvic dysplasia may also be present, causing hips to be retracted and delineated through bilateral dislocation. These deformities in addition to microcephaly and reduced ossification from the disease might be partially due to the affected individual's under-mineralized skeleton.[37][41]

Neurologic

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Intraneural inclusions (bodies within neural cells) with vacuolar degeneration are prominent mostly in the patient's thalamic nuclei, dentante nuclei, cerebellar cortex, and inferior olivary nuclei.[42] Hypoplasia of frontal lobes, corpus callosum, cerebellar vermis connecting the two brain hemispheres along with polymicrogyria causing excessive folding leading to an abnormally thick cortex are also phenotypes of this disorder.[43]

Facial

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Obvious signs of Yunis–Varon syndrome include soft and large fontanelles, high forehead, prominent eyes, large ears with hypoplastic lobes, low nasal bridge, anteverted nostrils, short philtrum above the lip, high-arched palate at the roof of the mouth, micrognathia or small jaw, and sparse hair (Hypotrichosis) with absent eyebrows and eyelashes.[44][41][45]

Treatment

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Early intervention is considered important. For infants, breathing and feeding difficulties, are monitored. Therapies used are "symptomatic and supportive."[46]

Epidemiology

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Yunis–Varon syndrome has been described relatively recently in the 1980s and since then less than 15 cases have been reported around the world. Many of the infants did not survive beyond one year of age.[34][6]

References

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  1. ^ Online Mendelian Inheritance in Man (OMIM): 216340
  2. ^ Kulkarni ML, Vani HN, Nagendra K, Mahesh TK, Kumar A, Haneef S, et al. (April 2006). "Yunis Varon syndrome" (PDF). Indian Journal of Pediatrics. 73 (4): 353–5. doi:10.1007/BF02825832. PMID 16816498. S2CID 21944556. Archived from the original (PDF) on 2019-08-19. Retrieved 2007-04-22.
  3. ^ a b Christie J, Sacks S, Decorato D, Bergasa NV (September 1999). "Atrophy of the left lobe of the liver and anomalous hepatic vessel in a patient with Yunis-Varon syndrome". Journal of Clinical Gastroenterology. 29 (2): 210–1. doi:10.1097/00004836-199909000-00025. PMID 10478891.
  4. ^ a b Basel-Vanagaite L, Kornreich L, Schiller O, Yacobovich J, Merlob P (February 2008). "Yunis-Varon syndrome: further delineation of the phenotype". American Journal of Medical Genetics. Part A. 146A (4): 532–7. doi:10.1002/ajmg.a.32135. PMID 18203163. S2CID 26679823.
  5. ^ "Yunis Varon Syndrome". Archived from the original on 2016-06-23. Retrieved 2007-04-22.
  6. ^ a b Yunis E, Varón H (July 1980). "Cleidocranial dysostosis, severe micrognathism, bilateral absence of thumbs and first metatarsal bone, and distal aphalangia: a new genetic syndrome" (Free full text). American Journal of Diseases of Children. 134 (7): 649–53. doi:10.1001/archpedi.1980.02130190017005. PMID 7395825.
  7. ^ Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, et al. (May 2013). "Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase". American Journal of Human Genetics. 92 (5): 781–91. doi:10.1016/j.ajhg.2013.03.020. PMC 3644641. PMID 23623387.
  8. ^ Lenk, Guy M.; Ferguson, Cole J.; Chow, Clement Y.; Jin, Natsuko; Jones, Julie M.; Grant, Adrienne E.; Zolov, Sergey N.; Winters, Jesse J.; Giger, Roman J.; Dowling, James J.; Weisman, Lois S. (June 2011). "Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J". PLOS Genetics. 7 (6): e1002104. doi:10.1371/journal.pgen.1002104. ISSN 1553-7404. PMC 3107197. PMID 21655088.
  9. ^ Chow, Clement Y.; Landers, John E.; Bergren, Sarah K.; Sapp, Peter C.; Grant, Adrienne E.; Jones, Julie M.; Everett, Lesley; Lenk, Guy M.; McKenna-Yasek, Diane M.; Weisman, Lois S.; Figlewicz, Denise (January 2009). "Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS". American Journal of Human Genetics. 84 (1): 85–88. doi:10.1016/j.ajhg.2008.12.010. ISSN 1537-6605. PMC 2668033. PMID 19118816.
  10. ^ Ouled Amar Ben Cheikh, Bouchra; Baulac, Stéphanie; Lahjouji, Fatiha; Bouhouche, Ahmed; Couarch, Philippe; Khalili, Naima; Regragui, Wafae; Lehericy, Stéphane; Ruberg, Merle; Benomar, Ali; Heath, Simon (2008-08-29). "A locus for bilateral occipital polymicrogyria maps to chromosome 6q16–q22". Neurogenetics. 10 (1): 35–42. doi:10.1007/s10048-008-0143-3. ISSN 1364-6745. PMID 18758830. S2CID 43539025.
  11. ^ Garrett C, Berry AC, Simpson RH, Hall CM (February 1990). "Yunis-Varon syndrome with severe osteodysplasty". Journal of Medical Genetics. 27 (2): 114–21. doi:10.1136/jmg.27.2.114. PMC 1016932. PMID 2319578.
  12. ^ Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, et al. (May 2013). "Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase". American Journal of Human Genetics. 92 (5): 781–91. doi:10.1016/j.ajhg.2013.03.020. PMC 3644641. PMID 23623387.
  13. ^ Corona-Rivera JR, Romo-Huerta CO, López-Marure E, Ramos FJ, Estrada-Padilla SA, Zepeda-Romero LC (January 2011). "New ocular findings in two sisters with Yunis-Varón syndrome and literature review". European Journal of Medical Genetics. 54 (1): 76–81. doi:10.1016/j.ejmg.2010.09.013. PMID 20932945.
  14. ^ Dworzak F, Mora M, Borroni C, Cornelio F, Blasevich F, Cappellini A, et al. (September 1995). "Generalized lysosomal storage in Yunis Varón syndrome". Neuromuscular Disorders. 5 (5): 423–8. doi:10.1016/0960-8966(94)00089-r. PMID 7496176. S2CID 30559290.
  15. ^ Campeau, Philippe M.; Lenk, Guy M.; Lu, James T.; Bae, Yangjin; Burrage, Lindsay; Turnpenny, Peter; Román Corona-Rivera, Jorge; Morandi, Lucia; Mora, Marina; Reutter, Heiko; Vulto-van Silfhout, Anneke T. (2013-05-02). "Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase". American Journal of Human Genetics. 92 (5): 781–791. doi:10.1016/j.ajhg.2013.03.020. ISSN 1537-6605. PMC 3644641. PMID 23623387.
  16. ^ Corona-Rivera, J. Román; Romo-Huerta, Carmen O.; López-Marure, Eloy; Ramos, Feliciano J.; Estrada-Padilla, Sara A.; Zepeda-Romero, Luz Consuelo (January 2011). "New ocular findings in two sisters with Yunis-Varón syndrome and literature review". European Journal of Medical Genetics. 54 (1): 76–81. doi:10.1016/j.ejmg.2010.09.013. ISSN 1878-0849. PMID 20932945.
  17. ^ Ferguson CJ, Lenk GM, Meisler MH (December 2009). "Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2". Human Molecular Genetics. 18 (24): 4868–78. doi:10.1093/hmg/ddp460. PMC 2778378. PMID 19793721.
  18. ^ Chow CY, Zhang Y, Dowling JJ, Jin N, Adamska M, Shiga K, et al. (July 2007). "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J". Nature. 448 (7149): 68–72. Bibcode:2007Natur.448...68C. doi:10.1038/nature05876. PMC 2271033. PMID 17572665.
  19. ^ Sharma S, Carmona A, Skowronek A, Yu F, Collins MO, Naik S, et al. (July 2019). "Apoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95". Nature Communications. 10 (1): 3105. Bibcode:2019NatCo..10.3105S. doi:10.1038/s41467-019-11025-y. PMC 6629679. PMID 31308371.
  20. ^ Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J (August 2008). "Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration". Brain. 131 (Pt 8): 1990–2001. doi:10.1093/brain/awn114. PMC 2724900. PMID 18556664.
  21. ^ Winters JJ, Ferguson CJ, Lenk GM, Giger-Mateeva VI, Shrager P, Meisler MH, Giger RJ (November 2011). "Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P(2) phosphatase Fig4". The Journal of Neuroscience. 31 (48): 17736–51. doi:10.1523/JNEUROSCI.1482-11.2011. PMC 3711465. PMID 22131434.
  22. ^ Baulac S, Lenk GM, Dufresnois B, Ouled Amar Bencheikh B, Couarch P, Renard J, et al. (March 2014). "Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria". Neurology. 82 (12): 1068–75. doi:10.1212/WNL.0000000000000241. PMC 3962989. PMID 24598713.
  23. ^ Mironova YA, Lin JP, Kalinski AL, Huffman LD, Lenk GM, Havton LA, et al. (July 2018). "Protective role of the lipid phosphatase Fig4 in the adult nervous system". Human Molecular Genetics. 27 (14): 2443–2453. doi:10.1093/hmg/ddy145. PMC 6030899. PMID 29688489.
  24. ^ Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, et al. (May 2013). "Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase". American Journal of Human Genetics. 92 (5): 781–91. doi:10.1016/j.ajhg.2013.03.020. PMC 3644641. PMID 23623387.
  25. ^ Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A (August 2007). "Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex". The Journal of Biological Chemistry. 282 (33): 23878–91. doi:10.1074/jbc.M611678200. PMID 17556371.
  26. ^ Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, et al. (May 2013). "Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase". American Journal of Human Genetics. 92 (5): 781–91. doi:10.1016/j.ajhg.2013.03.020. PMC 3644641. PMID 23623387.
  27. ^ Walch E, Schmidt M, Brenner RE, Emons D, Dame C, Pontz B, et al. (November 2000). "Yunis-Varon syndrome: evidence for a lysosomal storage disease". American Journal of Medical Genetics. 95 (2): 157–60. doi:10.1002/1096-8628(20001113)95:2<157::AID-AJMG12>3.0.CO;2-E. PMID 11078567.
  28. ^ Basel-Vanagaite L, Kornreich L, Schiller O, Yacobovich J, Merlob P (February 2008). "Yunis-Varon syndrome: further delineation of the phenotype". American Journal of Medical Genetics. Part A. 146A (4): 532–7. doi:10.1002/ajmg.a.32135. PMID 18203163. S2CID 26679823.
  29. ^ Corona-Rivera JR, Romo-Huerta CO, López-Marure E, Ramos FJ, Estrada-Padilla SA, Zepeda-Romero LC (January 2011). "New ocular findings in two sisters with Yunis-Varón syndrome and literature review". European Journal of Medical Genetics. 54 (1): 76–81. doi:10.1016/j.ejmg.2010.09.013. PMID 20932945.
  30. ^ Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A (August 2007). "Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex". The Journal of Biological Chemistry. 282 (33): 23878–91. doi:10.1074/jbc.M611678200. PMID 17556371.
  31. ^ Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, et al. (May 2013). "Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase". American Journal of Human Genetics. 92 (5): 781–91. doi:10.1016/j.ajhg.2013.03.020. PMC 3644641. PMID 23623387.
  32. ^ a b "Yunis-Varon syndrome". Disease Information from NORD, National Organization for Rare Disorders, Inc.
  33. ^ Corona-Rivera JR, Romo-Huerta CO, López-Marure E, Ramos FJ, Estrada-Padilla SA, Zepeda-Romero LC (January 2011). "New ocular findings in two sisters with Yunis-Varón syndrome and literature review". European Journal of Medical Genetics. 54 (1): 76–81. doi:10.1016/j.ejmg.2010.09.013. PMID 20932945.
  34. ^ a b Bhatia S, Holla RG (April 2005). "Yunis-Varon syndrome" (PDF). Indian Pediatrics. 42 (4): 373–5. PMID 15876600.
  35. ^ Garrett C, Berry AC, Simpson RH, Hall CM (February 1990). "Yunis-Varon syndrome with severe osteodysplasty". Journal of Medical Genetics. 27 (2): 114–21. doi:10.1136/jmg.27.2.114. PMC 1016932. PMID 2319578.
  36. ^ Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, et al. (May 2013). "Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase". American Journal of Human Genetics. 92 (5): 781–91. doi:10.1016/j.ajhg.2013.03.020. PMC 3644641. PMID 23623387.
  37. ^ a b Walch E, Schmidt M, Brenner RE, Emons D, Dame C, Pontz B, et al. (November 2000). "Yunis-Varon syndrome: evidence for a lysosomal storage disease". American Journal of Medical Genetics. 95 (2): 157–60. doi:10.1002/1096-8628(20001113)95:2<157::AID-AJMG12>3.0.CO;2-E. PMID 11078567.
  38. ^ Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, et al. (May 2013). "Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase". American Journal of Human Genetics. 92 (5): 781–91. doi:10.1016/j.ajhg.2013.03.020. PMC 3644641. PMID 23623387.
  39. ^ Pfeiffer RA, Diekmann L, Stock HJ (1988). "Aplasia of the thumbs and great toes as the outstanding feature of Yunis and Varon syndrome. A new entity. A new observation". Annales de Génétique. 31 (4): 241–3. PMID 3265308.
  40. ^ Adès LC, Morris LL, Richardson M, Pearson C, Haan EA (September 1993). "Congenital heart malformation in Yunis-Varón syndrome". Journal of Medical Genetics. 30 (9): 788–92. doi:10.1136/jmg.30.9.788. PMC 1016540. PMID 8411078.
  41. ^ a b Basel-Vanagaite L, Kornreich L, Schiller O, Yacobovich J, Merlob P (February 2008). "Yunis-Varon syndrome: further delineation of the phenotype". American Journal of Medical Genetics. Part A. 146A (4): 532–7. doi:10.1002/ajmg.a.32135. PMID 18203163. S2CID 26679823.
  42. ^ Walch E, Schmidt M, Brenner RE, Emons D, Dame C, Pontz B, et al. (November 2000). "Yunis-Varon syndrome: evidence for a lysosomal storage disease". American Journal of Medical Genetics. 95 (2): 157–60. doi:10.1002/1096-8628(20001113)95:2<157::AID-AJMG12>3.0.CO;2-E. PMID 11078567.
  43. ^ Corona-Rivera JR, Romo-Huerta CO, López-Marure E, Ramos FJ, Estrada-Padilla SA, Zepeda-Romero LC (January 2011). "New ocular findings in two sisters with Yunis-Varón syndrome and literature review". European Journal of Medical Genetics. 54 (1): 76–81. doi:10.1016/j.ejmg.2010.09.013. PMID 20932945.
  44. ^ Dworzak F, Mora M, Borroni C, Cornelio F, Blasevich F, Cappellini A, et al. (September 1995). "Generalized lysosomal storage in Yunis Varón syndrome". Neuromuscular Disorders. 5 (5): 423–8. doi:10.1016/0960-8966(94)00089-r. PMID 7496176. S2CID 30559290.
  45. ^ Corona-Rivera JR, Romo-Huerta CO, López-Marure E, Ramos FJ, Estrada-Padilla SA, Zepeda-Romero LC (January 2011). "New ocular findings in two sisters with Yunis-Varón syndrome and literature review". European Journal of Medical Genetics. 54 (1): 76–81. doi:10.1016/j.ejmg.2010.09.013. PMID 20932945.
  46. ^ "Yunis Varon Syndrome". NORD (National Organization for Rare Disorders). Retrieved 2016-03-01.
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