Yunis–Varon syndrome

Yunis–Varon syndrome
Other names	Cleidocranial dysplasia with micrognathia, absent thumbs and distal aphalangia
Yunis–Varon syndrome has an autosomal recessive pattern of inheritance.
Specialty	Medical genetics

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.

Genetics

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]}

Pathophysiology

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

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]

Treatment

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

Epidemiology

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

External links

• Yunis-Varon syndrome; Cleidocranial dysplasia, micrognathia, absent thumbs, & distal aphalangia at NIH's Office of Rare Diseases