Mental Retardation, X-Linked, Syndromic, Cabezas Type

A number sign (#) is used with this entry because of evidence that the Cabezas type of X-linked syndromic mental retardation (MRXSC) is caused by mutation in the CUL4B gene (300304) on chromosome Xq23.

Description

This form of syndromic X-linked mental retardation is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor (Cabezas et al., 2000).

Clinical Features

In a population survey for common hereditary diseases conducted in China in 1990, Wei et al. (1993) identified a family with X-linked mental retardation in 5 affected males in 4 sibships. The distinguishing manifestations were short stature, patulous lips, difficulty in speech, short thumbs and little fingers with adduction, hypotonia at age less than 10 years, and later hypertonia, restlessness, and seizures. Other features included pes planus, and 2 had small testes, with delayed sex development in 1. IQ ranged from 40 through 57. Obligate carrier females were clinically normal except for rather large hands with deep palmar and finger creases with rhagades. The disorder was initially classified as Smith-Fineman-Myers syndrome (SFMS; 309580), based on mild facial dysmorphisms, such as microcephaly, hypertelorism, micrognathia, and macrostomia. However, on reexamination of this family, Zou et al. (2007) noted that no remarkable facial features were present; in particular, the small palpebral fissures, flat nasal bridge, micrognathia, and hypertelorism characteristic of SFMS were not obvious. However, several other physical features were distinct, including short stature, brachydactyly, macroglossia, and a unique gait, with toes pointing inwards.

Cabezas et al. (2000) reported a large family in which 7 males with mental retardation were identified, with transmission from 5 normal or minimally affected female carriers and an absence of male-to-male transmission. Characteristic clinical features included short stature, prominent lower lip, small testes, muscle wasting in lower legs, kyphosis, joint hyperextensibility, abnormal gait, tremor, and decreased fine motor coordination. Affected subjects had impaired speech and decreased attention span. For the 3 individuals for whom IQ data were available, scores ranged from 29 to 54; affected males were described as being retarded by clinical examination and history. One female carrier was examined and had normal growth and development but had been evaluated for Tourette syndrome (137580) and had several tics, memory problems, and learning difficulties. On examination at age 12 years, she had a thin habitus and a mild tremor in the upper extremities.

Vitale et al. (2001) described a large family in Sardinia, Italy, with X-linked mental retardation. The phenotype observed in the 8 affected males included severe mental retardation, lack of speech, coarse face, distinctive skeletal features with short stature, brachydactyly, small downslanting palpebral fissures, large bulbous nose, hypoplastic earlobes, and macrostomia. Carrier females were not mentally retarded, although some of them had mild dysmorphic features such as minor earlobe abnormalities, as well as language and learning problems. Levels of growth hormone were normal. Vitale et al. (2001) distinguished the disorder in this family from that reported by Hamel et al. (1996), in which affected males had panhypopituitarism and mental retardation (300123).

Tarpey et al. (2007) discussed the clinical features of the family described by Cabezas et al. (2000) and 7 additional families. During the adolescence of affected subjects, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. Seven families were white, and 1 was of Asian descent.

Ravn et al. (2012) described a Danish monozygotic twin pair concordant for X-linked mental retardation resulting from a deletion encompassing most of the CUL4B gene. Ravn et al. (2012) found that the twins shared many of the features in patients previously reported with mutation in the CUL4B gene, including moderate mental retardation with pronounced language deficit, short stature, truncal obesity, relative macrocephaly, characteristic facial dysmorphisms, tremor, and seizures. In addition, twin A exhibited intrauterine growth retardation, and twin B had scaphocephaly due to premature fusion of the sagittal suture.

Vulto-van Silfhout et al. (2015) reported 24 patients from 10 families with MRXSC caused by mutation in the CUL4B gene. The phenotype was similar to that reported previously. All patients had intellectual disability with severe speech impairment. Other variable neurologic features included behavioral problems (59%), gait abnormalities (48%), tremor (45%), and seizures (32%). Additional prominent features included hypogonadism (85%), short stature (77%), small hands (74%), kyphosis (35%), gynecomastia (33%), and macrocephaly (32%). Dysmorphic facial features included high forehead (76%), prominent lower lip (78%), and malformed and/or abnormally positioned ears (89%) The facial phenotype changed with age: younger patients tended to have a depressed nasal bridge with a bulbous tip (55%), while older patients had more coarse facial features with hyperplastic supraorbital ridges (77%) and prognathia (68%). Variable neuroimaging abnormalities were noted in 10 of 12 patients who underwent imaging studies. The most severe changes included severe ventriculomegaly with bilateral persylvian polymicrogyria or a simplified gyral pattern, and a cortical dysplasia. More subtle changes observed in some patients included mildly diminished white matter volume, white matter hyperintensities, thin corpus callosum, and cerebellar vermis atrophy.

Mapping

Cabezas et al. (2000) performed linkage analysis on their family with syndromic X-linked mental retardation and achieved a maximum lod score of 2.80 at marker DXS1212 and 2.76 at DXS425, within a region defined by markers DXS424 and DXS1047 (Xq24-q25).

Using linkage analysis, Gong et al. (1999) mapped the phenotype in the family reported by Wei et al. (1993) to a 20-Mb interval between DXS8064 and DXS8050 on chromosome Xq25. Liu et al. (2002) excluded linkage of the ATRX gene (300032) at Xq13 to the disorder in this family, confirming locus heterogeneity for the disorder. Liu et al. (2004) narrowed the candidate interval to a 10.18-Mb region between XSTR3 and XSTR4.

By linkage analysis in a large Italian family segregating a syndromic form of mental retardation, Vitale et al. (2001) obtained a maximum lod score of 3.61 with marker DXS1001 on Xq24. Recombination observed with flanking markers identified a region of 16 cM for further study.

Pathogenesis

Kerzendorfer et al. (2010) showed that cells from patients with mental retardation, macrocephaly, tremor, peripheral neuropathy, and CUL4B mutations exhibited sensitivity to camptothecin (CPT), impaired CPT-induced topoisomerase I (TOP1; 126420) degradation and ubiquitination, suggesting that TOP1 may be a novel CUL4-dependent substrate. These cells exhibited increased levels of CPT-induced DNA breaks, as well as overexpression of the known CUL4-dependent substrates CDT1 (605525) and p21 (CDKN1A; 116899).

Molecular Genetics

By a systematic mutational screen of the X chromosome in 250 families with multiple members with X-linked mental retardation, Tarpey et al. (2007) found 8 families who carried mutations in the CUL4B gene (see, e.g., 300304.0001-300304.0003) on Xq24. One of these was the family reported by Cabezas et al. (2000). CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biologic processes, and CUL4B was the first identified XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series (8/250) indicated that it is one of the most commonly mutated genes underlying XLMR and suggested that its introduction into clinical diagnostics should be a high priority.

In the family reported by Wei et al. (1993), Zou et al. (2007) detected a nonsense mutation in the CUL4B gene (R388X; 300304.0002) that rendered the peptide completely devoid of the C-terminal domain. Mutant mRNA underwent nonsense-mediated decay (NMD). In peripheral leukocytes of obligate carriers a strong selection against cells expressing the mutant allele resulted in an extremely skewed X chromosome inactivation pattern. These findings pointed to the functional significance of CUL4B in cognition and in other aspects of human development.

Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation. They identified 5 nonrecurrent mutations in the CUL4B gene that segregated completely with mental retardation in the families and were not identified in unaffected family members. In addition to mental retardation, affected family members had relative macrocephaly, hypogonadism, central obesity, and tremor.

In affected members of the family with X-linked mental retardation and short stature originally reported by Vitale et al. (2001), Londin et al. (2014) identified a hemizygous splice site mutation in the CUL4B gene (300304.0004). The mutation, which was found by exome sequencing of the X chromosome, was predicted to result in either aberrant or no splicing of intron 7, but functional studies or studies of patient cells were not performed. Exome sequencing also identified a T-to-G transversion in the 3-prime UTR of the KAISO gene (ZBTB33; 300329) that segregated with the phenotype, but functional studies did not show a significant effect on gene expression. Londin et al. (2014) concluded that the phenotype resulted primarily from the CUL4B mutation, but noted that the KAISO variant may be a contributing factor.

By massive parallel sequencing of 407 families with X-linked mental retardation, Vulto-van Silfhout et al. (2015) identified CUL4B mutations in affected members of 8 families (2.0%). Subsequent screening of 29 patients with malformations of cortical development identified CUL4B mutations in 3 patients from 2 families. Ten different mutations were identified in the 10 families, including 5 truncating mutations, 2 splice site variants, an in-frame deletion, an in-frame duplication, and a missense variant (see, e.g., 300304.0005 and 300304.0006). Some of the patients were found to have variable malformations of cerebral development, suggesting that CUL4B has a role in this process.

Cytogenetics

In a patient with X-linked mental retardation with relative macrocephaly, short stature, lack of speech development, hypogonadism, and abnormal gait, Isidor et al. (2010) identified a 60-kb de novo deletion at chromosome Xq24 that encompassed the 3-prime region of the CUL4B gene and the MCTS1 gene (300587). Isidor et al. (2010) concluded that the deletion would result in premature termination and nonsense-mediated mRNA decay of CUL4B.

In a monozygotic twin pair with X-linked mental retardation, Ravn et al. (2012) identified a 28-kb deletion on the X chromosome, which partially encompassed the CUL4B gene and which was inherited from the unaffected mother. Using quantitative PCR, Ravn et al. (2012) mapped the proximal breakpoint within intron 4 of CUL4B and the distal breakpoint 1,000 bp downstream of the 3-prime UTR. X-inactivation studies in the unaffected mother revealed an extremely skewed X-inactivation pattern, consistent with her being an unaffected carrier.