Information on the following diseases can be found in the Related Disorders section of this report:

• Cleidocranial Dysplasia
• Mandibuloacral Dysplasia

Yunis-Varon syndrome is a multisystem disorder characterized by growth retardation prior to and after birth; defective growth of the bones of the skull along with complete or partial absence of the shoulder blades (cleidocranial dysplasia); characteristic facial features; and/or abnormalities of the fingers and/or toes.

In most cases, growth delays occur before birth (intrauterine growth retardation) and may result in low birth weight. In most cases, growth delays continue after birth (postnatally). 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 mild mental retardation. Failure to thrive results from feeding and respiratory problems. In some cases, feeding and respiratory difficulties may result in life-threatening complications.

Infants with Yunis-Varon syndrome exhibit a rare malformation known as "cleidocranial dysplasia." Cleidocranial dysplasia is characterized by the association of the three following features: absence or severe underdevelopment (hypoplasia) of one or both of the collarbones (clavicles); 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; and an abnormally large skull (macrocrania). 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. In some cases, affected children may also have an abnormal shoulder blade (scapula). In addition to delayed closure of the fontanels, separation of the sutures, and macrocrania, certain parts of the skull of an affected infant may fail to harden (ossify) properly (skull dysostosis). As a result of these cranial abnormalities, the head of an affected infant may appear abnormally long (dolichocephaly). Eventually, affected infants exhibit microcephaly, a condition that indicates that the head circumference is smaller than would be expected for an infant’s age and sex.

Infants with Yunis-Varon syndrome also exhibit characteristic facial features including an abnormally small jaw (micrognathia) and underdeveloped (hypoplastic) facial bones. Severe micrognathia may contribute to respiratory and feeding difficulties during early infancy that, in turn, may contribute to failure to thrive. Facial features may appear unusually small in comparison to an abnormally large skull. Other craniofacial features may include thin lips that appear drawn back (retracted); an abnormally short vertical groove (philtrum) on the upper lip; a small nose with nostrils that are flared forward (anteverted); low-set, malformed (dysplastic) ears with underdeveloped (hypoplastic) ear lobes; and/or upwardly slanted eyelid folds (palpebral fissures). In addition, the hair of the scalp, eyebrows, and/or eyelashes may be sparse or absent. In some cases, affected children may exhibit premature loss of their "baby" (deciduous) teeth.

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), 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, small, thin (tapered), and appear pointed toward the ends. 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).

In some cases, affected infants may exhibit additional skeletal abnormalities including deformity of the pelvis (pelvic dysplasia), dislocation of both (bilateral) hips, and/or lack of hardening of the breastbone (sternal ossification).

Additional findings that may be associated with Yunis-Varon syndrome include abnormalities of the heart such as abnormal enlargement of the heart (cardiomegaly), irregular heart rhythms (arrythmia), or other heart problems (cardiomyopathy). Heart abnormalities eventually may result in life-threatening cardio-respiratory failure.

In some cases, 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 clefting of the scrotum (bifid scrotum).

Additional findings have been reported in individual cases of Yunis-Varon syndrome.

Yunis-Varon syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective 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 normal genes from both parents and be genetically normal for that particular trait is 25%.

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 abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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. More research is necessary to determine whether defective lysosomal storage is involved in the development of Yunis-Varon syndrome.

Yunis-Varon syndrome is an extremely rare inherited disorder that affects males and females in equal numbers. Approximately 18 cases have been reported since the disorder’s initial description in the medical literature in 1980. The characteristic physical findings associated with this disorder are obvious at birth (congenital).

Symptoms of the following disorders can be similar to those of Yunis-Varon syndrome. Comparisons may be useful for a differential diagnosis:

Cleidocranial dysplasia is a rare genetic disorder characterized by the association of the three following features: absence or severe underdevelopment (hypoplasia) of one or both of the collar bones (clavicles); delayed closure of the two soft openings (fontanels) on an infants head with abnormal separation of the fibrous joints (sutures) that connect certain bones of the skull; and an abnormally large skull (macrocrania). Characteristic findings may include an unusually short, wide head (brachycephaly); dental abnormalities such as delayed growth (eruption) of both the "baby" and "adult" teeth; a short middle bone (phalanx) in the fifth fingers; abnormally short fingers (brachydactyly); and/or growth retardation, resulting in moderate short stature. Other physical findings may include a wide pelvic joint (pubic symphysis), and deformities of the spine such as abnormal side-to-side curvature of the spine (scoliosis), which may worsen (progress) with age. In some cases, affected infants may exhibit respiratory problems. Cleidocranial dysplasia is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Cleidocranial Dysplasia" as your search term in the Rare Disease Database.)

Mandibuloacral dysplasia is an extremely rare inherited disorder characterized by underdeveloped (hypoplastic) collarbones (clavicles); abnormally wide fibrous joints between certain bones of the skull (cranial sutures); joint stiffness; and an underdeveloped (hypoplastic) lower jaw (mandible) causing crowding of the teeth. Individuals with this disorder may also exhibit increased sensitivity to cold in the fingers as well as loss of bone tissue in the hands (acroosteolysis). In some cases, affected children may exhibit short stature, patchy loss of hair (alopecia), and/or degeneration (atrophy) of the skin on the hands and feet. Mandibuloacral dysplasia is thought to be inherited as an autosomal recessive trait.

Diagnosis
Certain findings that may suggest a diagnosis of Yunis-Varon syndrome (e.g., growth retardation and major bone deformities) may be identified before birth (prenatally) using ultrasonography. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus. Yunis-Varon syndrome may be diagnosed or confirmed after birth based upon a thorough clinical evaluation, the identification of characteristic findings (e.g., cleidocranial dysplasia, severe micrognathia, and abnormalities affecting the fingers and toes), and a variety of specialized tests, particularly advanced imaging techniques.

If affected individual has an enlarged heart, the condition may be detected by echocardiogram, a specialized imaging technique in which ultrasound vibrations are used to create a graphic outline (echocardiogram) of the heart. A physician may detect an irregular heart rhythm (arrhythmia) by listening to heart sounds with a stethoscope.

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 insertion of a tube through a surgical opening in the wind pipe (trachea) to assist breathing (tracheostomy) and the use of a special machine (ventilator) that supports breathing (artificial respiration).

Early intervention is important to ensure that children with Yunis-Varon syndrome reach their potential. 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 will be of benefit 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 website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

TEXTBOOKS
Walch E, Dame C. Yunis-Varon Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 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.

Buyce ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1806.

JOURNAL ARTICLES
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.

Dworzak F, et al. Generalized lysosomal storage in Yunis-Varon syndrome. Neuromuscul Disord. 1995;5:423-8.

Rabe H, et al. Yunis-Varon syndrome: the first case of German origin. Clin Dysmorphol. 1996;5:217-22.

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 (Jul 1980; 134(7)). Pp. 649-53.

FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:216340; Last Update:3/17/2004.
Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=216340 Accessed on: May 15, 2005.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:248370; Last Update:2/21/2005.
Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=248370 Accessed on: May 15, 2005.