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Last updated:
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NORD gratefully acknowledges Philippe Campeau, MD, FCCMG, Clinical Assistant Professor, Department of Pediatrics, University of Montreal, for assistance in the preparation of this report.
Yunis-Varon syndrome is a rare genetic multisystem disorder with defects affecting mostly the skeletal system, the nervous system, and ectodermal tissue (hair and teeth). It is characterized by large fontanelles, clavicular hypoplasia, characteristic facial features and/or abnormalities of fingers and toes. Characteristic features may include microcephaly, ear abnormalities, anteverted nares, midfacial hypoplasia, tented upper lip and small jaw (micrognathia), sparse or absent eyebrows and/or eyelashes. Abnormalities of the fingers and toes may include absence (aplasia) or underdevelopment (hypoplasia) of the fingers and toes. Most infants with this disorder experience severe feeding problems and respiratory difficulties. Some of these difficulties are related to the severe involvement of the central nervous system, with malformations of the brain affecting half of the children and hypotonia (low tone) affecting all of them. In addition, affected infants may have heart defects (e.g., abnormal enlargement of the heart muscle [hypertrophic cardiomyopathy]). Frequently, feeding problems, respiratory difficulties, and/or heart defects may result in life-threatening complications during infancy. Yunis-Varon syndrome is inherited as an autosomal recessive condition.
Yunis-Varon syndrome is a rare genetic multisystem disorder characterized by large fontanelles, clavicular hypoplasia, characteristic facial features and/or abnormalities of fingers and toes. Characteristic features may include microcephaly, ear abnormalities, anteverted nares, midfacial hypoplasia, tented upper lip and small jaw (micrognathia), sparse or absent eyebrows and/or eyelashes.
As infants with Yunis-Varon syndrome mature, they may also exhibit failure to gain weight or grow at the expected rate (failure to thrive), severe developmental delays, and/or intellectual disability.
Infants with Yunis-Varon syndrome exhibit absence or severe underdevelopment (hypoplasia) of one or both of the collarbones (clavicles) and delayed closure of the two soft membraned-covered openings (fontanels) on an infant’s head, with abnormal separation of the fibrous joints (sutures) that connect certain bones of the skull. Children without collarbones or with underdeveloped collarbones may have “droopy” shoulders or, in extreme cases, may be able to bring their shoulders together in front of their bodies.
Infants with Yunis-Varon syndrome also have abnormalities of the fingers and toes (digits). The thumbs and the bones at the ends of the fingers and the great toes (distal phalanges) may be absent (aplastic) or underdeveloped (hypoplastic). In some cases, other bones may be underdeveloped including the bones between the wrists and the fingers (metacarpals), the bones between the knuckles of the fingers (middle phalanges), the bones of the great toes nearest to the feet (proximal phalanges) or other toes, and/or the bones between the ankles and the toes (metatarsals). As a result of these abnormalities, the fingers and toes may be unusually short. In addition, some affected infants may exhibit absence or underdevelopment of the fingernails and/or toenails and/or webbing between the fingers and/or toes (syndactyly).
Some affected infants may exhibit additional skeletal abnormalities including deformity of the pelvis (pelvic dysplasia), dislocation of both (bilateral) hips, lack of sternal ossification, slender ribs or bone fractures.
Additional findings that may be associated with Yunis-Varon syndrome include abnormalities of the heart such as cardiomyopathy or congenital heart defects.
In some children, urinary tract abnormalities may occur, including abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), failure of the testes to descend into the scrotum (cryptorchidism) and micropenis.
Additional findings have been reported in individuals with Yunis-Varon syndrome including central nervous system abnormalities and hypodontia.
Yunis-Varon syndrome is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a changed gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Some cases of Yunis-Varon syndrome have occurred among children who had parents who were related by blood (consanguineous). All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, which increases the risk to have children with a recessive genetic disorder.
The gene causing Yunis-Varon syndrome in some families was identified as FIG4. FIG4 codes for a protein regulating the transport of vesicles inside cells by modifying molecules called phosphoinositides. Different mutations in FIG4 can also cause Charcot-Marie-Tooth disease, a condition where the peripheral nerves lose their proper function, and polymicrogyria, a condition with brain malformations. Some researchers thought that mutations in FIG4 could also predispose mutation carriers to ALS (amyotrophic lateral sclerosis) but subsequent larger studies did not support this finding.
Some researchers have speculated that Yunis-Varon syndrome may occur as a result of defects in lysosomal storage. Lysosomal storage diseases comprise a group of metabolic disorders characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. These disorders affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. FIG4 is involved in regulating the transport of various vesicles, including lysosomes, which could help explain the findings suggestive of abnormal lysosomal function.
Mutations in the VAC14 gene have also been found to be associated with Yunis-Varon syndrome.
Yunis-Varon syndrome is an extremely rare inherited disorder that affects males and females in equal numbers. 25 cases from 19 families have been reported since the disorder’s initial description in the medical literature in 1980.
Yunis-Varon syndrome may be diagnosed or confirmed after birth based upon a thorough clinical evaluation, the identification of characteristic findings (e.g., hypoplastic claviculae, limb abnormalities, sparse hair, characteristic facial features). Genetic testing for mutations in FIG4 can also confirm a diagnosis. Certain findings that may suggest a diagnosis of Yunis-Varon syndrome (e.g. limb and bone abnormalities or congenital heart defect) may be identified before birth (prenatally) using ultrasonography. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus.
Treatment
Specific therapies for individuals with Yunis-Varon syndrome are symptomatic and supportive. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedists), physical therapists, physicians who specialize in diagnosing and treating disorders of the heart (cardiologists), and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Physicians should closely monitor infants with Yunis-Varon syndrome to promptly detect any feeding or breathing difficulties associated with the disorder. Physicians may recommend preventive measures and/or institute immediate appropriate therapy. Treatment for feeding difficulties may include artificial feeding methods such as tube feeding, which administers food through a tube directly into the infant’s stomach, or intravenous feeding, in which essential nutrients are administered into a vein using a tube. Breathing difficulties, when severe and life-threatening, may require special measures such as the use of a special machine (ventilator) that supports breathing (artificial respiration).
Early intervention is important in Yunis-Varon syndrome. Special services that may be beneficial to affected children may include special remedial education, special social support, physical therapy, and other medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., respiratory and heart problems, skeletal dysplasia, craniofacial deformities, etc.].)
TEXTBOOKS
Walch E, Dame C. Yunis-Varon Syndrome. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:275.
Jones KL., ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co; 1997:410.
Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:253-4.
Buyse ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1806.
JOURNAL ARTICLES
Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera, J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H. Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. Am. J. Hum. Genet. 2013; 92: 781-791.
Corona-Rivera JR, Romo-Huerta CO, López-Marure E, Ramos FJ, Estrada-Padilla SA, Zepeda-Romero LC. New ocular findings in two sisters with Yunis-Varón syndrome and literature review. Eur J Med Genet. 2011;54(1):76-81.
Basel-Vanagaite L, Kornreich L, Schiller O, Yacobovich J, Merlob P. Yunis-Varon syndrome: further delineation of the phenotype. Am J Med Genet A. 2008;146A(4):532-7.
Walch E, et al. Yunis-Varon syndrome: evidence for a lysosomal storage disease. Am J Med Genet. 2000;95:157-60.
Christie J, et al. Atrophy of the left lobe of the liver and anomalous hepatic vessel in a patient with Yunis-Varon syndrome. J Clin Gastroenterol. 1999;29:210-1.
Rabe H, et al. Yunis-Varon syndrome: the first case of German origin. Clin Dysmorphol. 1996;5:217-22.
Dworzak F, et al. Generalized lysosomal storage in Yunis-Varon syndrome. Neuromuscul Disord. 1995;5:423-8.
Ades LC, et al. Congenital heart malformation in Yunis-Varon syndrome. J Med Genet. 1993;30:788-92.
Lapeer GL, et al. Hypodontia, impacted permanent teeth, spinal defects, and cardiomegaly in a previously diagnosed case of the Yunis-Varon syndrome. Oral Surg Oral Med Oral Pathol. 1992;73:456-60.
Garrett C, et al. Yunis-Varon syndrome with severe osteodysplasty. C. Garrett et al.; J Med Genet. 1990;27:114-21.
Hennekam RC, et al. Further delineation of the Yunis-Varon syndrome. J Med Genet. 1989;26:55-8.
Pfeiffer RA, et al. Aplasia of the thumbs and great toes as the outstanding feature of Yunis and Varon syndrome. A new entity. A new observation. Ann Genet. 1988;31:241-3.
Yunis E, Varon H. Cleidocranial dysostosis, severe micrognathism, bilateral absence of thumbs and first metatarsal bone, and distal aphalangia: a new genetic syndrome. Am J Dis Child. 1980;134(7):649-53.
INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University.Yunis-Varon Syndrome. Entry No: 216340. Last Edited 08/09/2016. Available at: https://omim.org/entry/216340 Accessed December 18, 2018.
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