What Is Yunis Varon Syndrome?

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Yunis Varon Syndrome

It is possible that the main title of the report Yunis Varon Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report. Yunis-Varon syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate  metabolism.

FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment.

Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns P2 effector TRPML1.

The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varon syndrome.

Description, Causes and Risk Factors:

Yunis-Varon syndrome is an extremely rare genetic multisystem disorder with defects affecting the skeletal system, ectodermal tissue (hair and teeth); and cardiorespiratory (i.e., heart and lungs) systems. 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. In most cases, infants with this disorder experience severe feeding problems and respiratory difficulties.

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 trait.

Yunis Varon Syndrome occurs in approximately 1 per million individuals worldwide.

The cause of the condition in these individuals is unknown. Reserchers beleive RUNX2 gene provides instructions for making a protein that is involved in bone and cartilage development and maintenance. This protein is a transcription factor, which means it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Researchers believe that the RUNX2 protein acts as a “master switch,” regulating a number of other genes involved in the development of cells that build bones (osteoblasts).

Some mutations change one protein building block (amino acid) in the RUNX2 protein. Other mutations introduce a premature stop signal that results in an abnormally short protein. Occasionally, the entire gene is missing.

These genetic changes reduce or eliminate the activity of the protein produced from one copy of the RUNX2 gene in each cell, decreasing the total amount of functional RUNX2 protein. This shortage of functional RUNX2 protein interferes with normal bone and cartilage development, resulting in the signs and symptoms of Yunis Varon Syndrome. In rare cases, affected individuals may experience additional, unusual symptoms resulting from the loss of other genes near RUNX2.

In about one-third of individuals with Yunis Varon Syndrome, no mutation in the RUNX2 gene has been found.

Discussion

Yunis-Varon syndrome is an extremely rare genetic multisystem disorder with defects affecting the skeletal system, ectodermal tissue (hair and teeth); and cardiorespiratory (i.e., heart and lungs) systems. 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.

 In most cases, infants with this disorder experience severe feeding problems and respiratory difficulties. 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 trait.

Causes

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.

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.

Symptoms

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.

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO). The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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).

In some cases, 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.

Affected individuals may be 3 to 6 inches shorter than other members of their family, and may have:

Short, tapered fingers and broad thumbs.

  • Short forearms.
  • Flat feet.
  • Knock knees.
  • An abnormal curvature of the spine .
  • Characteristic facial features may include.
  • A wide, short skull (brachycephaly).
  • A prominent forehead.
  • Wide-set eyes (hypertelorism).
  • Flat nose.
  • Small upper jaw.

Characteristics

Features of YVS 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. Additional symptoms may include abnormalities of the fingers and/or toes. In most cases, infants with this disorder experience severe feeding problems and respiratory difficulties. In addition, affected infants may have heart defects.

Diagnosis

Differential diagnoses may include hypophosphatasia (perinatal and infantile forms), congenital pseudarthrosis of the clavicle, osteogenesis imperfecta congenita (type 1) and Yunis-Varon syndrome.

Most cases of Yunis Varon Syndrome are diagnosed during childhood or adolescence. So far, there have been few reports of an early diagnosis or even neonatal cases revealing the whole characteristic of this skeletal dysplasia. In case of a positive family history, prenatal ultrasound can help establishing an early diagnosis by showing an abnormal growth of the clavicles or for example hypomineralization of the skull bones.

The fontanelles may remain open until adulthood but the sutures often close with interposition of wormian bones. More than 100 additional anomalies have been reported and because of the variable clinical expression the diagnosis of Yunis Varon Syndrome can be misjudged even after careful assessment. Hypoplastic clavicles in association with further skeletal abnormalities are suggestive of Yunis Varon Syndrome, but still have to be reviewed in context with other findings.

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. 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.

Affected Populations

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.

Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.

Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.

Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

PubMed is a searchable database of medical literature and lists journal articles that discuss Yunis-Varon syndrome. Click on the link to view a sample search on this topic.

Treatment

Treatment options cut down to symptomatic measures such as corrective dental and orthopedic surgery, depending on the extent of accompanying abnormalities. It is stated that medical evaluation for consequences of delayed craniofacial development should further include evaluation for obstructive sleep apnea, medical and surgical therapy for upper airway obstruction, and medical and surgical therapy for recurrent and chronic sinusitis and otitis.

As most reports focus on accompanying craniofacial and dental abnormalities, we would like to point out the possibility of respiratory distress and the need for an adequate and early treatment in newborn infants presenting with Yunis Varon Syndrome. Especially the obstetrician and the pediatrician looking after the newborn as well as the radiologist reading the first exams have to be aware of this possible condition.

Early intervention is considered important. For infants, breathing and feeding difficulties, are monitored. Therapies used are “symptomatic and supportive.”

Standard Therapies

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 will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.

Investigational Therapies

All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

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