A number sign (#) is used with this entry because of evidence that the Bain type of X-linked syndromic intellectual developmental disorder (MRXSB) is caused by heterozygous mutation in the HNRNPH2 gene (300610) on chromosome Xq22.

MRXSB is an X-linked neurodevelopmental disorder characterized by delayed psychomotor development, impaired intellectual development with behavioral abnormalities, and dysmorphic facial features. Additional variable features include musculoskeletal abnormalities, seizures, acquired microcephaly, and feeding problems with poor overall growth (summary by Bain et al., 2016).

Bain et al. (2016) reported 6 unrelated females, ranging in age from 2 to 34 years, with a complex neurodevelopmental disorder. All had delayed psychomotor development, intellectual disability, and poor or absent speech. Three patients showed developmental regression, suggesting an underlying neurodegenerative process. Most had behavioral or psychiatric abnormalities, including autism spectrum disorder, aggression, attention deficit-hyperactivity disorder, and self-injurious behavior. Additional neurologic features included hypotonia, hypertonia, and ataxic gait. Three had seizures and 2 had acquired microcephaly. Dysmorphic facial features included almond-shaped eyes, short palpebral fissures, short philtrum, full lower lip, long columella, hypoplastic alae nasi, and micrognathia. Musculoskeletal abnormalities included short stature, scoliosis, lordosis, pectus carinatum, pes planus, and joint laxity. More variable features included feeding difficulties, gastroesophageal reflux disease, and constipation. Later reports of MRXSB included affected males (e.g., Harmsen et al., 2019, Jepsen et al., 2019, and Somashekar et al., 2020).

Harmsen et al. (2019) reported a boy with MRXSB. He was born at term without complications and had a normal birth weight, length, and head circumference, but was noted to have hypotonia and profound developmental delay in the first year of life. He had progressive microcephaly, with a head circumference less than the 3rd centile at age 2 years. At age 3 years, he had profound hypotonia, inability to move independently, flexion contractures of the knees, and lack of speech development.

Jepsen et al. (2019) reported 2 boys with MRXSB. The first patient was noted to have developmental delay and unusual posturing of his extremities at age 3 months. At age 2 years, a G-tube was required for nutrition. At age 5 years, he had severe developmental delay and extreme hypotonia. He had no dysmorphic features. The second patient was an 8-year-old boy with global developmental delay, microcephaly, failure to thrive, intractable epilepsy, hypotonia, and cortical visual impairment. He had frequent athetoid movements of the upper extremities and dyskinetic movements of the face and tongue. He required G-tube placement for feeding problems.

Somashekar et al. (2020) reported a brother and sister, born to consanguineous Indian parents, with MRXSB. The boy was evaluated at 8 years of age for global developmental delay, intellectual disability, and seizures. He was small for gestational age at birth and required admission to the neonatal intensive care unit because of a delayed cry. His early developmental milestones were delayed, and he had onset of generalized tonic-clonic seizures at 18 months of age, after which he lost previously attained milestones. Myoclonic jerks were noted at 8 years of age. At age 8 years, he had growth delay, microcephaly, and dysmorphic features including hypertelorism, medial flaring of eyebrows, bilateral ptosis, thick vermilion of upper and lower lips, short philtrum, and high-arched palate. He also had mild scoliosis, bilateral fifth finger clinodactyly, hyperextensible skin, and joint hypermobility. In addition, he had flapping of hands, tremors, and generalized hypotonia. MRI of the brain and EEG were both normal. The sister had global developmental delay, impaired intellectual development, and neuroregression after 2 years of age. Her early milestones were delayed. No seizures were observed. On physical exam, she had growth delay, and her head circumference was -1 to -2 SD below the mean. She had no dysmorphic facial features but had long, slender fingers, skin hyperextensibility, and joint hypermobility. She also had generalized hypotonia and involuntary hand movements. MRI of the brain at age 3 years showed a hyperintense lesion in the inferior part of the splenium of the corpus callosum, suggestive of a lipoma.

In 5 unrelated female patients with MRXSB, Bain et al. (2016) identified 3 different de novo heterozygous missense mutations in the HNRNPH2 gene: 3 patients carried the same variant (R206W; 300610.0001), 1 carried a different mutation at the same residue (R206Q; 300610.0002), and 1 carried a mutation that was 3 amino acids away (P209L; 300610.0003). All mutations affected conserved residues in the nuclear localization sequence. The patients were from a large cohort of 2,030 females and 2,486 males with developmental delay and/or intellectual disability who underwent whole-exome sequencing. Bain et al. (2016) noted that a sixth female patient with the R206W mutation and a similar phenotype was identified by another laboratory. Functional studies of the variants and studies of patient cells were not performed; however, Bain et al. (2016) noted that all mutations affected highly conserved residues in the nuclear localization sequence, and postulated a toxic gain-of-function effect. The authors suggested that these variants may be lethal in males.

In a boy with MRXSB, Harmsen et al. (2019) identified a hemizygous de novo missense mutation in the HNRNPH2 gene (R206Q; 300610.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in his mother. The authors stated that this diagnosis should be considered in males with profound developmental delay, intellectual disability, and secondary microcephaly.

By whole-exome and Sanger sequencing in 2 boys with MRXSB, Jepsen et al. (2019) identified hemizygous mutations in the HNRNPH2 gene. The first boy had the previously identified R206W mutation (300610.0001) and the second boy had a novel R114W mutation mutation (300610.0004). In the second boy, exome sequencing revealed 7% reference reads and 93% variant reads, suggesting low-level mosaicism for the reference allele. These findings provided further support that this condition is not embryonically lethal in males.

In a brother and sister, born to consanguineous Indian parents, with MRXSB, Somashekar et al. (2020) identified the previously reported R206Q mutation in the HNRNPH2 gene in hemizygous and heterozygous state, respectively. Both parents were found to have the wildtype allele. Identification of a pathogenic variant in HNRNPH2 in another male patient confirmed that this X-linked condition is compatible with postnatal survival in boys. The authors proposed that maternal germline mosaicism was the most likely explanation for the occurrence in sibs.