Yunis-Varon Syndrome

A number sign (#) is used with this entry because Yunis-Varon syndrome (YVS) is caused by homozygous or compound heterozygous mutation in the FIG4 gene (609390) on chromosome 6q21.

Description

Yunis-Varon syndrome is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy (summary by Campeau et al., 2013).

Clinical Features

Yunis and Varon (1980) described 5 children in 3 families with cleidocranial dysplasia (absent clavicles, macrocrania, diastasis of sutures), micrognathia, absent thumbs and distal phalanges of fingers, hypoplasia of proximal phalanx and absence of distal phalanx of the big toes, pelvic dysplasia, bilateral hip dislocation, and retracted and poorly delineated lips. The parents were consanguineous in 2 of the families. Hughes and Partington (1983) proposed the designation Yunis-Varon syndrome.

Pfeiffer et al. (1988) described a Yunis-Varon syndrome patient with consanguineous parents and emphasized aplasia of the thumbs and great toes as the outstanding feature. Hennekam and Vermeulen-Meiners (1989) described an affected boy who was the offspring of consanguineous parents.

Garrett et al. (1990) described 2 male sibs affected in 1 family and 2 female sibs in a second, both with normal parents. All died before 10 weeks of age.

Ades et al. (1993) described a male infant with Yunis-Varon syndrome who had tetralogy of Fallot. They reviewed 12 previous cases. Absent or hypoplastic thumbs, short pointed fingers, nail hypoplasia or agenesis, absent/hypoplastic halluces, and short pointed toes were present in all or almost all cases. Anteverted nostrils and short upper lip were frequent. By Sanger sequencing, Campeau et al. (2013) excluded mutations in the FIG4 gene sequencing in the patient reported by Ades et al. (1993), and suggested that this patient had some features that differed from those usually seen in YVS.

Dworzak et al. (1995) reported a girl, born of unrelated Italian parents, with Yunis-Varon syndrome. She was noted to have dysmorphic features at birth, including soft skull with large fontanels, high forehead, prominent eyes, large ears, low nasal bridge, anteverted nostrils, short philtrum, high-arched palate, micrognathia, and sparse hair with absent eyebrows and eyelashes. The thumbs and halluces were absent, there was agenesis of the first metacarpals and metatarsals, agenesis of the distal phalanges, and absent nails. She was hypotonic with poor breathing and absent suck and was barely responsive. Other abnormalities that developed over time included cardiac hypertrophy, enlarged liver, and abnormal EEG. She died at age 15 weeks. Postmortem examination showed intracytoplasmic vacuoles in neurons from various brain regions and in muscle, heart, cartilage, and fibroblasts, suggestive of a lysosomal storage disease. Electron microscopy of muscle showed that the vacuoles were mostly membrane-bound and contained granular, amorphous, or degenerated membranous material. Studies of lysosomal hydrolases were normal, but urine sample showed some abnormal oligosaccharide bands.

Rabe et al. (1996) reported 2 affected sisters from a German family. One sister had severe hearing impairment and pyloric stenosis, features not previously described in this syndrome.

Walch et al. (2000) described a female infant with features of Yunis-Varon syndrome, including absent thumbs and halluces, aphalangia of fingers and toes, hypoplastic clavicles, severely undermineralized skeleton, and microcephaly. The patient also had Dandy-Walker malformation (220200), hydrocephalus, and hypertension, features not previously reported in this condition. Qualitatively abnormal bands for oligosaccharides and neuraminic acid were seen on urinalysis by thin-layer chromatography. The patient died at age 3 months of severe neurologic impairment. Autopsy showed prominent intraneuronal inclusions with vacuolar degeneration, mainly in the thalamic nuclei, dentate nuclei, cerebellar cortex, and inferior olivary nuclei. No storage phenomena were observed in other tissues. Walch et al. (2000) suggested that Yunis-Varon syndrome may be due to a defect in lysosomal storage.

Basel-Vanagaite et al. (2008) described a female infant with features of Yunis-Varon syndrome, including reduced ossification of the skull, hypoplastic phalanges, and hypotrichosis. Previously undescribed features included fetal hydrops detected on prenatal ultrasound and primary pulmonary hypertension. Vacuolated macrophages were found in bone marrow and pericardial fluid; PAS and alcian blue staining revealed diffuse staining of the cytoplasm but no staining of the vacuoles. The parents declined further investigation, including autopsy.

Corona-Rivera et al. (2011) reported 2 Mexican sisters, born of consanguineous parents, with Yunis-Varon syndrome. The older sister presented at birth with microcephaly, hypotonia, irritability, sparse scalp hair, eyebrows, and eyelashes, hypertelorism, protruding ears, hypoplastic earlobes with cup-shaped right ear, anteverted nares, thin upper lip, narrow-arched palate, broad secondary alveolar ridge, labio-gingival retraction, micrognathia, and loose nuchal skin. She had multiple skeletal anomalies, including wide cranial sutures, hypoplastic thumbs and phalanges, absent halluces, short toes, hypoplastic clavicles, absent ossification of the inferior sternal segment, anterior concavity on vertebral bodies, flattened acetabuli, and iliac hypoplasia. Many nails were hypoplastic or missing. Brain MRI showed hypoplasia of the frontal lobes with pachygyria, corpus callosum hypoplasia, and hypoplasia of the cerebellar vermis. She also had a ventricular septal defect, severe developmental delay, feeding difficulties, and hearing loss. Ophthalmologic evaluation showed papillomacular atrophic chorioretinopathy and reduced visual evoked potential, a finding that had not been reported in this syndrome. The younger sister had a similar phenotype, with the addition of microtia and absence of the clavicles. Ophthalmologic study showed similar findings as in her sister, suggesting that atrophic chorioretinopathy may be part of the phenotype of Yunis-Varon syndrome.

Clinical Variability

Reutter et al. (2012) reported a German girl, born of unrelated parents, with a phenotype reminiscent of Yunis-Varon syndrome. Prenatal studies showed polyhydramnios, increased nuchal translucency, and bilateral hydrothoraces. At birth, she had dysmorphic facial features, such as slight microphthalmia, a flat and deep-set nasal root, dysplastic low-set ears, a small mouth, and sparse hair. She also had inverted nipples, retinal hypopigmentation, hypotonia, and several digital defects of the feet, but halluces, fingers, and fingernails were normal. Cardiac septal defects and primary pulmonary hypertension were present. She had severe developmental delay. Brain imaging revealed hypoplasia of the corpus callosum and cerebellar vermis, and dilated ventricles. Reutter et al. (2012) suggested that this child may have YVS with pulmonary hypertension or a novel YVS-like entity. By Sanger sequencing, Campeau et al. (2013) excluded mutations in the FIG4 gene in the patient reported by Reutter et al. (2012).

Inheritance

Parental consanguinity (e.g., Yunis and Varon, 1980) and affected sibs (e.g., Garrett et al., 1990) suggest autosomal recessive inheritance of Yunis-Varon syndrome.

Molecular Genetics

In 5 patients from 3 unrelated families with Yunis-Varon syndrome, Campeau et al. (2013) identified homozygous or compound heterozygous mutations in the FIG4 gene (609390.0009-609390.0012). The families had previously been reported by Garrett et al. (1990), Dworzak et al. (1995), and Corona-Rivera et al. (2011). All the mutations, which were found by exome sequencing, resulted in complete loss of protein function. Sanger sequencing excluded FIG4 mutations in the families reported by Ades et al. (1993) and Reutter et al. (2012), suggesting that these patients had a different disorder or that Yunis-Varon syndrome is genetically heterogeneous. The report demonstrated that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies, which suggested a role for PI(3,5)P2 signaling in skeletal development and maintenance.

Animal Model

Chow et al. (2007) found that Fig4-null mice ('pale tremor') have a multiorgan disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy, and diluted pigmentation. The cytoplasm of fibroblasts from pale tremor mice was filled with large vacuoles that were immunoreactive for Lamp2 (309060), consistent with dysfunction of the late endosome-lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia was followed by loss of neurons from layers 4 and 5 of the cortex, deep cerebellar nuclei, and other localized brain regions. The sciatic nerve exhibited reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity, and reduced amplitude of compound muscle action potentials.

In mouse tissue, Campeau et al. (2013) found that Fig4 expression in calvaria, osteoblasts, and bone marrow cells was comparable to expression in brain. Fig4-null mice showed a smaller skeleton than wildtype mice at day P21, with smaller long bones, clavicles, and pelvic bones. Although the shapes of the bones were similar to wildtype, Fig4-null mouse bones had significantly lower (50%) trabecular and cortical density, bone volume fraction, bone surface, trabecular number, and connectivity density, consistent with abnormal ossification. Cultures of isolated osteoblasts from calvarial tissue showed extensive vacuolization. Fig4-null mice did not exhibit aplasia or hypoplasia of digits on the front or rear limbs.