Epilepsy & Seizures
Epileptic lesions due to malformation of cortical development
Sep. 06, 2023
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Yunis-Varon syndrome (“cleidocranial dysostosis”) is a rare, generally severe, and autosomal recessive condition manifested by numerous anomalies of the craniofacial complex (dolichocephaly, wide fontanelles, sparse hair, hypoplastic facial bones, thin lips, short philtrum, micrognathia, and variable changes of the CNS, including eyes), small/absent clavicles, small/absent thumbs and great toes, and other anomalies. Mutations in FIG4 have been identified in several unrelated or consanguineous families; a biallelic mutation in VAC14 has been identified in a single neonate with normal FIG4 sequencing. The syndrome continues to undergo phenotypic and molecular delineation.
• Major phenotypic changes in this rare congenital disorder involve the clavicles and head (cleidocranial dysostosis), mandible, and distal limbs.
• Craniocerebral anomalies include poor growth of cranial bones, macrocephaly, large fontanels, and cortical malformations (eg, polymicrogyria).
• Neurologic symptoms and craniofacial findings may include hypotonia and weakness, psychomotor delay, large, dysplastic ears, and cleft lip and palate. Seizures and psychiatric manifestations are recognized as well.
• Cardiorespiratory failure commonly leads to death in the neonatal period, although survival into the second decade has been reported.
• Familial recurrence, sometimes with a history of consanguinity, has suggested autosomal recessive inheritance in the past, and is supported by the finding of FIG4 mutations in several families.
In 1980, Yunis and Varon described an infant boy and 4 infant girls from 3 Colombian families; 1 family had a single affected infant, and the other 2 families each had 2 affected infants. The patients had multiple malformations, including cleidocranial dysostosis, severe micrognathism, and hypoplasia or aplasia of metatarsal bones, phalanges, or thumbs. Changes in the cranium consisted mainly of “skull dysostosis,” characterized by wide fontanelles and separated sutures, craniofacial disproportion, macrocrania, hypoplastic facial bones, and micrognathia. Clavicular changes included uniform absence of the right clavicle and hypoplasia or absence of the left clavicle. All died before the age of 10 weeks. In 2 of the families, consanguinity was reported. The authors postulated that this was a new recessively inherited syndrome (49). In 1983, Hughes and Partington reported a 4.25-year-old boy with the same pattern of malformations, shortness of stature, and mental retardation; they referred to the condition as “the syndrome of Yunis and Varon” (18).
Additional cases have been described with similar findings and some new features (33; 34; 17; 15; 01; 11; 36; 07; 47). Rabe and colleagues added a note that their patient had a sister with features of Yunis-Varon but did not describe her (36). The patient described by Partington had cardiomyopathy (33), and Ades and colleagues described a patient with congenital heart malformations (tetralogy of Fallot) (01). The patient reported by Dworzak and colleagues was a female with generalized lysosomal storage (11). A female baby of German origin had a severe hearing impairment between 1000 Hz and 8000 Hz, detected by auditory evoked potential studies (36). Christie and colleagues described a 28-year-old woman with multiple anomalies interpreted as Yunis-Varon syndrome (although the morphology of the clavicle was not described). By a variety of imaging techniques, the woman had atrophy of the left lobe of the liver and an anomalous dilated hepatic vessel at the junction of right and left lobes. Vascular compromise of the left lobe was suggested, but the patient was lost to follow-up before additional studies could be performed (07). Walch and colleagues reported a 15-week-old female infant with Yunis-Varon syndrome with microcephaly, hydrocephalus, and Dandy-Walker malformation; an additional case with associated Dandy-Walker malformation has been reported (39). Severe neurologic impairment associated with intraneuronal inclusions and vacuolar degeneration has been taken as evidence for a lysosomal storage disorder (47). However, the patient reported by Sumi and colleagues showed no evidence for such a disorder (42). Striatonigral degeneration has been associated with VAC14 mutations in a number of young patients (20; 28).
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