A number sign (#) is used with this entry because of evidence that the Snijders Blok type of X-linked syndromic intellectual developmental disorder (MRXSSB) is caused by heterozygous or hemizygous mutation in the DDX3X gene (300160) on Xp11.

Syndromic X-linked intellectual developmental disorder of the Snijders Blok type (MRXSSB), which occurs predominantly in females, is characterized by mildly to severely impaired intellectual development with variable other features including brain abnormalities, microcephaly, hypotonia, movement disorder and/or spasticity, ventricular enlargement, hypoplasia, and behavioral problems (Snijders Blok et al., 2015; Nicola et al., 2019).

Snijders Blok et al. (2015) reported 38 females with mildly to severely impaired intellectual development and variable neurologic features, including hypotonia in 12 (76%), movement disorders comprising dyskinesia, spasticity, and stiff-legged or wide-based gait in 17 (45%), microcephaly in 12 (32%), behavioral problems such as autism spectrum disorder, hyperactivity, and aggression in 20 (53%), and epilepsy in 6 (16%). Additional variable nonneurologic features included joint hyperlaxity, skin pigmentary abnormalities, cleft lip and/or palate, hearing and visual impairment, and precocious puberty. Some patients had abnormal brain imaging findings, such as corpus callosum hypoplasia (35%), ventricular enlargement (35%), and evidence of cortical dysplasia (4 patients). Although common dysmorphic facial features were noted, there was no consistent recognizable phenotype. Five males from 3 additional, unrelated families also had MRXSSB. Features included mild to severe intellectual disability, movement disorders, such as spasticity, behavior problems, and variable dysmorphic features. Carrier females in these 3 families were unaffected.

Kellaris et al. (2018) described 2 brothers with mildly to moderately impaired intellectual development, macrocephaly, and progressive spasticity. The eldest brother had dysarthria and progressive spastic paraparesis. He lost the ability to ambulate independently at age 21. The younger brother had a progressive spastic paraparesis and tremor with a learning disability/mixed expressive-receptive language disorder. Both showed similar brain MRI findings: prominent lateral ventricles and cortical sulci and symmetric, confluent periventricular T2-hyperintensity in the supratentorial white matter suggesting central white matter loss.

Nicola et al. (2019) studied 3 unrelated boys with impaired intellectual development requiring special education support. The first patient was a 9-year-old boy with mildly to moderately impaired intellectual development. A prenatal ultrasound revealed nuchal thickening. He had a history of atrial septal defect (ASD), patent ductus arteriosus (PDA), and feeding problems as an infant. The second patient was an 8-year-old boy with moderately impaired intellectual development and hyperactive, aggressive behavior. He was diagnosed with cyanotic heart disease (pulmonary atresia, ventral septal defect, and confluent branch pulmonary arteries) as a neonate and required a modified Blalock-Taussig shunt. The third patient was a 16-year-old boy with severely impaired intellectual development and pulmonary stenosis. All had involuntary movements, although this had resolved in patient 1. Two patients had hearing issues (recurrent otitis or conductive hearing loss) and ophthalmologic issues (cataracts, myopia). Nicola et al. (2019) recommended screening for cardiac anomalies as well as ophthalmologic and hearing surveillance in males identified with DDX3X variants.

Scala et al. (2019) described 3 unrelated females with severely impaired intellectual development, dysmorphic features, and central nervous system malformations. Patient 1 was an 11-year-old girl with a history of global developmental delay, absent speech, spastic tetraparesis, and severe scoliosis. She was incidentally diagnosed with a pilocytic astrocytoma at age 8. Patient 2 was a 2-year-old girl with a prenatal history of intrauterine growth retardation (IUGR), increased nuchal translucency, ventriculomegaly, and oligohydramnios. Postnatally, she had diffuse hypotonia, feeding problems, sensorineural hearing loss, microcephaly, and severe developmental delay. Patient 3 was a 10-year-old nonverbal girl with a history of IUGR, akinetic seizures, hand stereotypies, and microcephaly. Brain MRI studies revealed similar malformations in all 3 girls. The findings were characterized by bilateral frontal polymicrogyria (patients 1 and 3), variable degrees of corpus callosal hypodysgenesis, dysmorphic basal ganglia, small olfactory bulbs, and pontine and inferior vermis hypoplasia. White matter was globally reduced with consequent enlargement of the lateral ventricles.

Beal et al. (2019) analyzed 6 females from 5 unrelated families with impaired intellectual development. Common facial dysmorphisms in this cohort included short palpebral fissures, micrognathia, bulbous nasal tip, protruding ears, high-arched palate, thin upper vermilion, and smooth philtrum. Novel clinical features included dystonia in one patient and cyclical vomiting syndrome in another. Patient 6 was reported to have cutaneous mastocytosis; the authors noted that although this diagnosis may be unrelated to DDX3X, the Wnt-beta catenin (see 116806) pathway is known to be impaired in DDX3X and plays a role in the maintenance and differentiation of mast cells.

Chanes et al. (2019) described a 10-year-old girl born at 25 weeks' gestation following an emergency cesarian section for severe preeclampsia. She was referred for a genetics evaluation at age 19.5 months with a diagnosis of cerebral palsy. Physical examination was notable for microcephaly, dolichocephaly, epicanthal folds, telecanthus, large ears, and hypopigmented spots on the chest and abdomen. At age 6, she was diagnosed with global cognitive delays, attention deficit-hyperactivity disorder, and possible autism. Follow-up examination at age 10 revealed a normal head circumference, dolichostenomelic appearance, joint hypermobility, and a long face with broad nasal bridge, anteverted nares, and telecanthus. Pigmentary abnormalities were still present on her chest and abdomen. MRI revealed a thin corpus callosum, prominent prepontine cistern, vertical clivus, and prominent ventricles.

The transmission pattern of MRXSSB in 38 females from 35 families reported by Snijders Blok et al. (2015) was consistent with X-linked dominant inheritance. All reported DDX3X mutations in females have occurred de novo (Nicola et al., 2019).

The transmission pattern of MRXSSB in males in 3 families reported by Snijders Blok et al. (2015) was consistent with X-linked recessive inheritance. Carrier females in these families were unaffected. DDX3X mutations in some males have been reported to occur de novo (Nicola et al., 2019).

Snijders Blok et al. (2015) identified 35 different de novo heterozygous mutations in the DDX3X gene (see, e.g., 300160.0001-300160.0004) in 38 girls with MRXSSB. The mutations were found by whole-exome sequencing of 3 large cohorts of patients referred for testing (including the Deciphering Developmental Disorders Study, 2015); DDX3X mutations were found in 1 to 3% of these patient cohorts, rendering it one of the most common causes of intellectual disability in females. Nineteen of the mutations were predicted to cause complete loss of function, resulting in haploinsufficiency in the female patients. In vitro cellular functional expression studies and in vivo studies in zebrafish of some of the identified missense mutations showed that they caused a loss of function in the canonical WNT signaling pathway with a disruption of beta-catenin signaling. There was no evidence for a dominant-negative effect; Snijders Blok et al. (2015) postulated haploinsufficiency as the disease mechanism. De novo variants were not found in any male patients who were part of the cohorts, but affected males in 3 families were found to carry hemizygous missense mutations in the DDX3X gene (see, e.g., 300160.0005) that were inherited from an unaffected mother. Functional studies revealed no differences of the male mutant alleles from wildtype, but Snijders Blok et al. (2015) speculated that they were pathogenic and that the effect of the mutant alleles was beyond the detection range of the assays. The results were consistent with the hypothesis that DDX3X is dosage sensitive and may have differential activity in females than in males.

By whole-exome sequencing, Kellaris et al. (2018) identified a maternally inherited missense mutation (R79K; 300160.0006) in the DDX3X gene in 2 brothers with MRXSSB. Functional testing of DDX3X activity in zebrafish embryos showed that the allele causes a partial loss of DDX3X function, indicating a hypomorphic variant.

In 3 unrelated males with MRXSSB, Nicola et al. (2019) identified hemizygous missense mutations in the DDX3X gene (see, e.g., R376H, 300160.0007 and V496M, 300160.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in 2 of the patients. Nicola et al. (2019) proposed that de novo DDX3X mutations are not necessarily male lethal and therefore should be considered as a cause of syndromic impaired intellectual development in both males and females.

Scala et al. (2019) identified 3 different de novo heterozygous mutations in the DDX3X in 3 unrelated females with MRXSSB (300160.0009-300160.0011). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing.

By whole-exome sequencing, Beal et al. (2019) identified 5 novel heterozygous DDX3X mutations (4 frameshifts and 1 splice site) in 6 females with MRXSSB from 5 unrelated families. Two sibs had the same frameshift mutation (300160.0012); parental testing for the mutation was negative, suggesting germline mosaicism. Although both girls had impaired intellectual development, the older sister was more severely affected.

By exome sequencing, Chanes et al. (2019) identified a de novo heterozygous frameshift mutation (300160.0013) in the DDX3X gene in a 10-year-old girl with MRXSSB.