What is Yunis-Varon Syndrome?

Causes and symptoms
Case reports
Diagnosis and treatment
Further reading

Yunis-Varon Syndrome (YVS) is a rare genetic disorder with characteristic skeletal and ectodermal abnormalities. It is also known as cleidocranial dysplasia.

Yunis-Varon syndrome is a rare genetic disorder with characteristic skeletal and ectodermal abnormalities. Image Credit: Billion Photos/Shutterstock.com

The disorder comprises structural brain abnormalities, facial dysmorphisms, sparse and pale hair and follows the autosomal recessive pattern of inheritance. Neurons, muscles, and cartilage all have enlarged vacuoles.

Symptoms and signs are usually present from birth. Affected infants may be born small, have slowed growth and are difficult to feed. Mutations in the FIG4 gene cause Yunis-Varon syndrome.


Cleidocranial dysplasia (absent clavicles, macrocrania, diastasis of sutures), absent thumbs and distal phalanges of fingers, micrognathia, hypoplasia of the proximal phalanx were described by Yunis and Varon (1980) in 5 children of 3 families.

Other observed symptoms were the absence of the distal phalanx of the big toes, pelvic dysplasia, bilateral hip dislocation, and retracted and poorly delineated lips In two of the families, the parents were consanguineous. Yunis-Varon syndrome was coined by Hughes and Partington (1983).

Causes and symptoms

YVS is reported to be caused by mutations in the FIG4 gene. FIG4 protein (also known as SAC3), coded by the FIG4 gene, is a 50-phosphoinositide phosphatase that is required for endosome and lysosome activity. On early endosomal membranes, FIG4 forms a functional complex with Vac14 and Fab1. This complex mediates the conversion of endosomal phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol 3,5-biphosphate (PI(3,5)P2), which is required for protein sorting, trafficking late endosomes to the lysosomal degradation compartment, and regulating other endolysosomes/lysosomal functions such as ion channel activation and endolyso FIG4 deficiency results in a decrease in PI(3,5)P2, which causes endosome/endolysosome/lysosome dysfunction.

FIG4 is also known to be associated with other conditions like Charcot-Marie-Tooth Disease 4J, Amyotrophic Lateral Sclerosis 11, and bilateral Temporooccipital Polymicrogyria.

Yunis-Varon syndrome is a multisystem disorder comprising a wide range of orthopedic, cardiovascular, and endocrine abnormalities. A large proportion of patients experience aplasia of the distal phalanx of the hallux and aplasia of the distal phalanges of the hand along with a short proximal phalanx of the hallux.

Other frequent symptoms include agenesis of the corpus callosum, anteverted nares, arrhinencephaly, bilateral microphthalmos, cardiomegaly, cardiomyopathy, and abnormalities of the occipital, parietal, and pelvis bone.

Anomalies of the face comprise dolichocephaly, high, narrow palate, hypertelorism, high forehead, short chin, proptosis, sparse eyebrows, and eyelashes. Affected neonates may also experience syndactyly, thin vermilion border, short stature, reduced/lack of hair on the scalp, rocker-bottom feet, and sclerocornea. Neuronal loss in the central nervous system, pachygyria, and postnatal growth retardation are also common observations.

Supernumerary, retained, or misplaced teeth, insufficient cementum, or no secondary eruption are possible features related to the dental profile. Atrial septal defect, cerebellar hypoplasia, glossoptosis, cryptorchidism, clitoral hypertrophy, hearing impairment, polyhydramnios, hydrocephalus, renal artery stenosis, and flared metaphysis are present in less than 30% of the patients.


YVS is a rare disease with limited (less than 30) cases reported from across the world. The incidence of the syndrome and its prevalence in different ethnicities is yet to be investigated.

Case reports

Siddique et al., in 2019 described a newborn with classic clinical and radiologic symptoms of Yunis-Varon syndrome, as well as a complete cleft lip and palate, who was born to consanguineously married normal parents.

The newborn girl was born at 39 weeks of gestation in a tertiary care hospital in Lahore via lower segment Caesarean section, with Apgar scores of five and seven at one and five minutes, respectively. Absent clavicles bilaterally with winging of scapulae, syndactyly, hypoplastic nails, hypoplasia of distal phalanges of fingers, agenesis of thumbs and big toes, and bilateral developmental dysplasia of the hip joint were among the skeletal anomalies.

Biventricular hypertrophy was found on an echocardiogram, along with strong left ventricular function and a 60% ejection fraction.

The neonate was given oxygen via nasal prongs and a nasogastric tube was placed in his stomach, but he died on his ninth day of life due to respiratory difficulties. Two earlier babies in the family had comparable traits but died in infancy. This is the first case of Yunis-Varon syndrome to be documented in Pakistan.

Umair et al., in 2021 described a newborn with typical YVS clinical manifestations who was born to a consanguineous couple. They discovered a unique homozygous missense variant (c.968A>G; p.Gln323Arg) in the FIG4 gene using whole-exome sequencing.

This research broadens the molecular and genomic scope of FIG4-related alterations. This is the first time YVS has been documented in the Saudi population.

Diagnosis and treatment

After a thorough clinical evaluation and identification of typical features, Yunis-Varon syndrome can be diagnosed or confirmed after birth. FIG4 mutation testing can potentially be used to confirm a diagnosis.

Antenatal screening using ultrasonography can detect the syndrome in infants with skeletal or cardiac abnormalities. The image of the developing fetus is created using reflected sound waves in fetal ultrasonography.

Treatment is determined by the signs and symptoms that each individual exhibits as there is no cure for the condition. Bone and skeletal abnormalities can be diagnosed and treated by orthopedic specialists. Syndactyly can be treated with surgery to separate the digits. This can be done for either utilitarian or cosmetic purposes.

Standard techniques can successfully handle the varied indications of cardiovascular disease. When breathing problems are serious and life-threatening, additional measures, such as the use of a ventilator, may be required.

In Yunis-Varon syndrome, early intervention is critical. Special services that may be beneficial to children who have been affected are necessary. Affected individuals and their families may also benefit from sessions of genetic counseling.

Although the majority of patients with Yunis–Varon syndrome are expected to have a bad prognosis, given the wide range of phenotypic expression, survival into adulthood is feasible.


  • Yunis-Varon syndrome. [Online] NIH-GARD. Available at: https://rarediseases.info.nih.gov/diseases/331/yunis-varon-syndrome
  • YUNIS-VARON SYNDROME; YVS. [Online] OMIM. Available at: https://www.omim.org/entry/216340
  • Yunis Varon Syndrome. [Online] National Organization for Rare Disorders. Available at: https://rarediseases.org/rare-diseases/yunis-varon-syndrome/
  • FIG4 PHOSPHOINOSITIDE 5-PHOSPHATASE; FIG4. [Online] OMIM. Available at: https://www.omim.org/entry/609390#description
  • Nakajima J, Okamoto N, Shiraishi J, et al. (2013). Novel FIG4 mutations in Yunis-Varon syndrome. Journal of Human Genetics, 58(12), 822–824. doi:10.1038/jhg.2013.104
  • Campeau PM, Lenk GM, Lu J, et al. (2013). 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
  • Varghese P, Collins N, Warner G, et al. (2014). Yunis-Varon syndrome: further delineation of cardiovascular and endocrine outcome. American Journal of Medical Genetics. Part A, 164A(5), 1213–1217. doi:10.1002/ajmg.a.35741
  • Lines MA, Ito, Y, Kernohan K, et al. (2017). Yunis-Varón syndrome caused by biallelic VAC14 mutations. European Journal of Human Genetics: EJHG, 25(9), 1049–1054. doi:10.1038/ejhg.2017.99
  • Siddique AW, Ahmed Z, Haider A, et al. (2019). Yunis-Varon Syndrome. Journal of Ayub Medical College, Abbottabad: JAMC, 31(2), 290–292.
  • Yunis-Varon syndrome. Nursing Children and Young People (2014+); London Vol. 31, Iss. 3, (May 2019): 19-19. doi:10.7748/ncyp.31.3.19.s18. Available at: https://www.proquest.com/openview/0c95e7058199f043e2a288570e064406/1?pq-origsite=gscholar&cbl=2042233
  • Umair M, Alkharfy TM, Sajjad S, et al. (2021). FIG4-Associated Yunis-Varon Syndrome: Identification of a Novel Missense Variant. Molecular Syndromology, 12(6), 386–392. doi:10.1159/000516971

Further Reading

  • All Genetic Disorder Content
  • What are Genetic Disorders?
  • Genetic Disorder Comorbidities
  • Multifactorial And Polygenic (Complex) Genetic Disorder
  • Single Gene Genetic Disorder

Last Updated: Sep 18, 2023

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