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FG SYNDROME 4; FGS4

FG SYNDROME 4; FGS4

Other entities represented in this entry:INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH OR WITHOUT NYSTAGMUS, INCLUDEDMENTAL RETARDATION, X-LINKED, WITH OR ...

Other entities represented in this entry:

  • INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH OR WITHOUT NYSTAGMUS, INCLUDED
  • MENTAL RETARDATION, X-LINKED, WITH OR WITHOUT NYSTAGMUS, INCLUDED

▼ Description

FG syndrome-4 (FGS4) is an X-linked recessive intellectual developmental disorder characterized by congenital hypotonia, constipation, behavioral disturbances, and dysmorphic features (summary by Piluso et al., 2003).

For a general phenotypic description and a discussion of genetic heterogeneity of FG syndrome, see FGS1 (305450).

▼ Nomenclature

The name 'FG' derives from the first description of the disorder (FGS1; 305450) by Opitz and Kaveggia (1974), who named it 'FG syndrome' according to the Opitz system of using initials of patients' surnames.

▼ Clinical Features

Piluso et al. (2003) identified and clinically characterized an Italian family with FG syndrome, including 31 members with 3 affected males in 2 generations and 2 obligate carriers. At the age of 2 years, the propositus showed marked mental retardation with hyperactive behavior and occasional aggressive outbursts. Relative macrocephaly with prominent forehead and frontal upsweep of hair, hypertelorism, saddled root of the nose with a long philtrum and half-open mouth, micrognathia, congenital hypotonia with joint hyperlaxity, and severe constipation were observed. The mother had mild mental retardation with hypertelorism and long nasal philtrum. She suffered from absence attacks. A 34-year-old maternal uncle of the propositus had been institutionalized since the age of 2 years because of profound mental retardation and aggressive behavior. He also had prominent forehead, hypertelorism, and broad long philtrum. Hypotonia was present in infancy. He had a record of severe constipation and recurrent seizures. EEG was abnormal. His 16-year-old brother likewise showed mental retardation with hyperactive behavior, short stature, and similar facial appearance. Bilateral sensorineural deafness was present. He also suffered from severe constipation.

In 4 families with X-linked mental retardation, Tarpey et al. (2009) identified mutations in the CASK gene. In 2 of the families, nystagmus segregated with mental retardation. Mental retardation was mild to moderate. Hackett et al. (2010) provided clinical details on the families reported by Tarpey et al. (2009), as well on as 2 additional families with the disorder. The phenotype was variable, ranging from nonsyndromic mental retardation to severe MR with microcephaly, brain malformations, and facial dysmorphism. About half of mutation carriers had nystagmus, and some had reduced visual acuity and/or strabismus. Other less common neurologic features included tremor (21%), unsteady gait (16%), and seizures (21%). Only 1 of 3 patients with brain imaging had cerebellar hypoplasia and pachygyria. Affected individuals in 2 families had variable dysmorphic features, including flat midface, open mouth, flat nasal bridge, upslanting palpebral fissures, and short neck. Two female carriers were more mildly affected, but most were phenotypically normal.

▼ Mapping

Piluso et al. (2003) excluded linkage to the known FGS loci in the Italian family with FG syndrome that they reported. An extensive study of the whole X chromosome yielded a maximum lod score of 2.66 (recombination fraction of 0) for markers between DXS8113 and sWXD805. This novel locus for FG syndrome, designated FGS4, corresponds to a region of approximately 4.6 Mb on chromosome Xp11.4-p11.3.

▼ Molecular Genetics

FG Syndrome 4

In affected members of the Italian family with FG syndrome originally reported by Piluso et al. (2003), Piluso et al. (2009) identified a missense mutation in the CASK gene (300172.0003), resulting in exon skipping due to improper recognition of an exonic splicing enhancer (ESE) motif. The mutation segregated fully with the phenotype and was not found in 1,000 ethnically matched control X chromosomes.

Mental Retardation with or without Nystagmus

Tarpey et al. (2009) found 4 missense mutations in the CASK gene (300172.0004-300172.0007) that segregated with X-linked mental retardation in 4 independent families. In 2 of these families, the X-linked mental retardation segregated with nystagmus. Mental retardation was mild to moderate. Tarpey et al. (2009) considered their results and the results of Najm et al. (2008) consistent with the likelihood of missense variants in CASK being less deleterious than truncating variants (see 300749).

In 2 additional families with X-linked mental retardation and nystagmus, Hackett et al. (2010) identified 2 different mutations in the CASK gene (300172.0008 and 300172.0009, respectively). In conjunction with the report of Tarpey et al. (2009), CASK mutations were found in 1.5% of individuals with XLMR who were screened. Families with mutations in the C-terminal part of the gene had nystagmus, suggesting a possible genotype/phenotype correlation.

Tags: Xp11.4