Alternative titles; symbols
SNOMEDCT: 721875000, 725912001; ORPHA: 528084, 85328; DO: 0060811;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.22 | Intellectual developmental disorder, X-linked syndromic, Turner type | 309590 | X-linked | 3 | HUWE1 | 300697 |
A number sign (#) is used with this entry because of evidence that the Turner type of X-linked syndromic intellectual developmental disorder (MRXST) is caused by mutation in the HUWE1 gene (300697) on chromosome Xp11.
A nonsyndromic form of X-linked intellectual developmental disorder (300705), designated MRX17 or MRX31, is caused by microduplications of chromosome Xp11.22, which include the HUWE1 and HSD17B10 (300256) genes.
Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder with a highly variable phenotype. Some affected families show X-linked recessive inheritance, with only males being affected and carrier females having no abnormal findings. In other affected families, males are severely affected, and female mutation carriers show milder cognitive abnormalities or dysmorphic features. In addition, there are female patients with de novo mutations who show the full phenotype, despite skewed X-chromosome inactivation. Affected individuals show global developmental delay from infancy, with variably impaired intellectual development and poor or absent speech, often with delayed walking. Dysmorphic features are common and can include macrocephaly, microcephaly, deep-set eyes, hypotelorism, small palpebral fissures, dysplastic, large, or low-set ears, long face, bitemporal narrowing, high-arched palate, thin upper lip, and scoliosis or mild distal skeletal anomalies, such as brachydactyly or tapered fingers. Males tend to have cryptorchidism. Other features, such as hypotonia, seizures, and delayed bone age, are more variable (summary by Moortgat et al., 2018).
The phenotype represented in this entry is termed 'X-linked syndromic mental retardation, Turner type' because the first mutation in the HUWE1 gene was found in the large affected family originally reported by Turner et al. (1994). Subsequently, HUWE1 mutations were found in patients with several other similar X-linked disorders, including Juberg-Marsidi syndrome and Brooks-Wisniewski-Brown syndrome, as well as nonspecific syndromic X-linked neurologic disorders with impaired intellectual development and additional features, thus indicating that they are all represent the same disorder.
Juberg and Marsidi (1980) reported a family in which 3 males, a 4-year-old boy (the proband) and his 2 uncles, had global developmental delay and impaired intellectual development associated with other abnormalities. All had low growth parameters at birth, including head circumference, delayed bone age, and similar dysmorphic facial features, including high forehead, large dysplastic low-set ears, hypotelorism, small palpebral fissures, pale retina, flat nasal bridge, high-arched palate, esotropia, and epicanthal folds. They also had hearing impairment and rudimentary scrotum with small penis and cryptorchidism. One uncle died at age 9 years and the second uncle at age 10 months. Friez et al. (2016) reported follow-up of the family (family K9149) originally reported by Juberg and Marsidi (1980). The only surviving patient from the first report was 27 years of age. He had severe intellectual disability (IQ less than 20), no speech, and notable dysmorphic features, including facial asymmetry, bifrontal narrowing with sunken midface, prominent brow, hypotelorism, upslanting palpebral fissures, prominent nose, long philtrum, and thin lips. Additional features included brachydactyly, foot deformities, muscle atrophy of the lower legs, scoliosis, and hyperextensible joints. His hearing loss was believed to be related to recurrent otitis media. Another affected male family member had been born since the original report. He had low growth parameters at birth and showed hypotelorism, small-appearing eyes, flat nasal bridge, right cleft lip and palate, aortic stenosis, small hands and feet, externally rotated feet, and undescended testes. He failed the newborn hearing test. Females in the family, including those shown to be mutation carriers, were unaffected; all mutation carriers showed markedly skewed X inactivation, presumably of the chromosome harboring the mutation.
Renier et al. (1982) described a kindred in which 3 brothers and 2 of their maternal uncles had microcephaly with severe mental retardation, spasticity, epilepsy, and deafness. Some heterozygous women had subnormal intelligence and microcephaly. Renier et al. (1982) concluded that the features in their family were similar to those in the family of Juberg and Marsidi (1980).
Turner et al. (1994) reported a large 5-generation family in which several males had moderate to profound mental retardation consistent with X-linked inheritance. Several carrier females had mild mental retardation. Affected hemizygous males and heterozygous females had macrocephaly. Variable features included limited extension of the elbows and tapering fingers. There were 2 cases of holoprosencephaly in male infants.
Brooks et al. (1994) reported 2 brothers and their nephew with a mental retardation syndrome characterized by a distinct facial appearance and intrauterine and postnatal growth retardation. Facial features included triangular face, bifrontal narrowness, malar flatness, blepharophimosis, deeply set eyes, epicanthus inversus, bulbous nose, low hairline, low-set and protruding ears, short philtrum, and thin tented upper lip. Large joint contractures and pectus excavatum developed with age. Other features included optic atrophy, esotropia, nystagmus, and spastic diplegia. The patients were self-abusive, hyperactive, and poorly coordinated. Friez et al. (2016) reported follow-up of the family (family K9223) reported by Brooks et al. (1994). As adults, the patients had poor or absent speech and hearing loss believed to be related to recurrent otitis media. Brain imaging showed cerebral atrophy with enlarged ventricles. Three carrier females were unaffected; 2 who were tested showed markedly skewed X inactivation.
Tsukahara et al. (1995) reported a 2-year-old boy with mental retardation, short stature, micropenis, and cryptorchidism. His Leydig cells responded to administration of human chorionic gonadotropin, and there were positive responses to luteinizing hormone (152780) and follicle-stimulating hormone (136530) with the administration of luteinizing hormone-releasing hormone (152760). He showed normal weight gain and head circumference, which had not been described previously. Hematologic and molecular studies of the patient excluded the thalassemia trait or Hb H disease. Tsukahara et al. (1995) diagnosed the boy clinically with Juberg-Marsidi syndrome.
Morava et al. (1996) reported 3 brothers with growth and mental retardation, bifrontal narrowness, short palpebral fissures, deeply set eyes, and spastic paraplegia. The authors noted similarities to the patients reported by Brooks et al. (1994).
Johnson et al. (1998) reported a large family in which 10 males spanning 2 generations had moderate mental retardation. Two female sibs of affected males were described as 'slow.' Four of 6 males studied had macroorchidism, and 5 had macrocephaly, but 1 affected male had normal testes. Two unaffected males also had macroorchidism and macrocephaly, suggesting that these traits may have segregated independently in this family.
Morava et al. (2006) reported 3 additional male patients with a similar phenotype. One was born of nonconsanguineous parents; the other 2 were brothers born of consanguineous Turkish parents. All had severe mental and growth retardation with characteristic facies, decreased muscle mass with spastic diplegia, optic atrophy, and behavioral problems. One patient had seizures, and the other 2 showed EEG abnormalities. Two of the children showed developmental regression after age 2 years. Laboratory tests showed increased serum lactate, and biochemical tests of muscle specimens indicated decreased oxidative phosphorylation suggesting a mitochondrial defect.
Froyen et al. (2008) reported 2 additional affected families. In 1 family (UK444), 3 males presented with moderate mental retardation. One was able to work in a sheltered environment and learned to read. As a child he had speech and language delay and clumsy motor skills. He was not dysmorphic, but had a long face and pointed chin without macrocephaly. His affected male cousin had a similar phenotype. An unrelated family (UK106) demonstrated severe to profound mental retardation. Two brothers had no speech or language. One had flexion deformity of the knees, but was able to walk. An affected uncle lived in a residential home and had severe knee contractures. None had macrocephaly.
Friez et al. (2016) reported a family (family 3) in which 2 brothers, 10 and 13 years of age, had severe intellectual disability, delayed walking after age 2, and poor language skills. Both had early-onset growth failure with short stature (-4 SD) and postnatal microbrachycephaly. Dysmorphic features included deep-set eyes, broad nasal bridge and tip, wide mouth, thin upper lip, prognathism, and cupped ears. They also had delayed bone age, but genitalia were normal, as was hearing. One had an ataxic gait associated with tight Achilles tendons. Female mutation carriers in the family were presumably unaffected.
Gauthier-Vasserot et al. (2017) reported a 4.5-year-old boy, born of unrelated Caucasian parents, with MRXST. He had neonatal hypotonia, global developmental delay with walking at age 54 months, impaired intellectual development, and postnatal short stature with microcephaly. Dysmorphic features included microphthalmia, deep-set eyes with downslanting palpebral fissures, broad nasal root, bulbous nose, short philtrum, tapering fingers, and kyphoscoliosis. He also had retinopathy, a short corpus callosum, and intermittent mild neutropenia without recurrent infections. Exome sequencing identified a de novo hemizygous missense mutation in the HUWE1 gene (M1328V); functional studies of the variant were not performed.
Moortgat et al. (2018) reported 21 patients with a neurodevelopmental disorder associated with mutations in the HUWE1 gene. There were 14 unrelated females, all with de novo mutations, 3 unrelated males with de novo mutations, and 2 pairs of brothers (P13, P14 and P20, P21) from 2 different families with maternally inherited mutations. Several of the patients had previously been reported (Taylor et al., 2015, Gauthier-Vasserot et al., 2017, Verloes et al., 2006). The phenotype was highly variable. All patients had variable degrees of intellectual disability, most often severe to profound, and all had severe speech delay or absent speech (13 patients). The mean age of walking was 2.5 years, although 3 patients never achieved walking, and many had hypotonia. About half (7 of 18) had childhood-onset seizures. Many (11 patients) had microcephaly (-2.5 to -7 SD), usually with postnatal onset, short stature (15 patients), and small hands and feet (12 patients) with brachydactyly and tapering fingers. More variable features included low birth weight, overlapping toes, craniosynostosis, scoliosis, knee contractures, hearing loss, hyperpilosity, sleep disorder, cryptorchidism, and hyperactivity/autistic/stereotypic features. Dysmorphic features were common, including long face, broad nasal tip, short philtrum with thin upper lip and full lower lip, low-set or posteriorly rotated ears, deep-set eyes, epicanthal folds, blepharophimosis, strabismus, and hypermetropia or astigmatism. Most females tested had a skewed X-inactivation ratio, with variable expression of the mutant or wildtype allele. However, even females with skewed X inactivation with preferential inactivation of the mutant chromosome had a severe phenotype, suggesting tissue-specific expression.
Muthusamy et al. (2020) reported 15- and 21-year-old brothers, born of unrelated Indian parents, with moderately to severely impaired intellectual development, trigonocephaly, delayed walking after age 4, and absent speech. Both had strikingly similar dysmorphic features, including flat occiput, elongated triangular face with frontal narrowing and malar hypoplasia, hypotelorism, ptosis, blepharophimosis, strabismus, low-set ears, wide nasal bridge, small pointed nose, narrow mouth, micrognathia, tented upper lip and high-arched palate. Other notable features included short neck, camptodactyly, elongated thumb, clinodactyly, pectus excavatum, hypospadias, and pes planus. Behaviorally, both affected individuals were diagnosed with autism spectrum disorder. The parents and sister were unaffected, although a remote maternal male relative was reportedly affected. In addition, there was a history of 3 neonatal deaths in the family, all males. The initial clinical diagnosis was compatible with Say-Meyer syndrome (314320), although these patients were not part of the original family with that disorder.
The transmission pattern of MRXST is consistent with X-linked recessive inheritance in some families and with X-linked dominant inheritance in others (Moortgat et al., 2018).
In their family with syndromic MRX, Turner et al. (1994) found linkage to the pericentromeric region of the X chromosome, with a maximum lod score of 3.31 at MAOB (309860) on Xp11.23, DXS991, and AR (313700) on Xq11-q12. The candidate region spanned from DXS1068 to DXS1125.
By linkage analysis in a large family in which 10 males had moderate mental retardation, Johnson et al. (1998) identified a 30-Mb region on chromosome Xp11.2-q21.31 between markers DXS991 and DXS1002 (maximum lod score of 2.96 at DXS1111, DXS566, and DXS986). The region overlapped that identified by Turner et al. (1994).
In affected individuals of the family reported by Turner et al. (1994), Froyen et al. (2008) identified a missense mutation in the HUWE1 gene (R4013W; 300697.0001). Affected individuals in 2 additional families were also found to have missense mutations in the HUWE1 gene (R2981H; 300697.0002; R4187C; 300697.0003).
In affected members of the families reported by Juberg and Marsidi (1980) and Brooks et al. (1994), Friez et al. (2016) identified the same hemizygous missense mutation in the HUWE1 gene (G4310R; 300697.0004). The mutation, which was found by a combination of linkage analysis and exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in both families. Affected males in a third family with a similar disorder reported by Friez et al. (2016) were found to carry a different hemizygous missense mutation in the HUWE1 gene (R4063Q; 300967.0005). Friez et al. (2016) concluded that the location of the mutations in the reported cases does not explain the phenotypic variability observed in this disorder. However, they noted that carrier females in families with less severe phenotypic expression in the males may have mild features of the disorder, not being protected by skewed X inactivation of their affected X chromosome.
In 21 patients with MRXST, Moortgat et al. (2018) identified 16 different heterozygous or hemizygous mutations in the HUWE1 gene (see, e.g., 300967.0007-300967.0010). The mutations were found by exome sequencing and confirmed by Sanger sequencing. There were 14 unrelated females, all with de novo mutations, 3 unrelated males with de novo mutations, and 2 pairs of brothers (P13, P14 and P20, P21) from 2 different families with maternally inherited mutations. All mutations except 1 were missense mutations affecting highly conserved residues, with about half affecting the catalytic HECT domain. None were present in control databases, but functional studies of the variants were not performed. The majority of female patients tested had a skewed X-inactivation pattern, most often favoring the wildtype allele, although these results were variable, consistent with differential tissue expression. Three unrelated girls with the same mutation (R110Q; 300967.0007) had preferential expression of the mutant allele, suggesting a unique situation (see GENOTYPE/PHENOTYPE CORRELATIONS). Otherwise, there were no clear genotype/phenotype correlations.
In 2 brothers, born of unrelated Indian parents, with MRXST, Muthusamy et al. (2020) identified a hemizygous splice site mutation in the HUWE1 gene (300967.0011). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was found in the unaffected mother. Analysis of patient cells confirmed that the mutation resulted in aberrant splicing and a 6-nucleotide deletion in exon 6, causing an in-frame deletion of 2 conserved residues in the N terminus (cys49_glu50del). Additional functional studies were not performed. The patients initially had a clinical diagnosis compatible with Say-Meyer syndrome (314320), but were not part of the original family with that disorder.
Taylor et al. (2015) identified a de novo heterozygous missense mutation in the HUWE1 gene (R110Q; 300697.0007) in a girl with MRXST with craniosynostosis and learning difficulties. X-chromosome inactivation studies showed exclusive expression only of the mutant allele in blood and fibroblasts. She had synostosis of all sutures noted in utero, as well as microcephaly, tall skull, and dysmorphic features, such as upslanting palpebral fissures, arched eyebrows, high-arched palate, and thin upper lip. She had impaired intellectual development with decreased attention and concentration and severe language disability (Muthusamy et al., 2020). Another de novo hemizygous mutation affecting the same residue (R110W; 300697.0006) was found in a boy with craniosynostosis with premature fusion of metopic sutures and moderate to severe intellectual disability. Additional features included flat midface, facial asymmetry, downslanting palpebral fissures, low-set ears, retracted premaxilla, right choanal stenosis, micrognathia, malpositioned teeth, pectus excavatum, scoliosis, slight digital shortening, mild 4/5 syndactyly of the toes, and Chiari malformation (Miller et al., 2017, Muthusamy et al., 2020).
Moortgat et al. (2018) reported 3 unrelated girls with the R110Q HUWE1 mutation (300697.0007), including the girl previously reported by Taylor et al. (2015). All 3 had a similar phenotype, including craniosynostosis and oligodontia; 1 had a Chiari malformation. X-chromosome inactivation studies showed that all had preferential expression of the mutant allele, suggesting a unique situation.
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