Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

Abstract

Objective: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals.

Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.

Results: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.

Conclusions: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Participant Genotypes and Predicted Pathogenicity

Regions of HNRNPH2 gene with plot of all the variants (A) and predicted pathogenicity and allele frequencies of HNRNPH2 variants (B).

Figure 2. Participant Face and Extremity Findings

Participant 1 at 5 years (A), participant 2 at 4 years (B), participant 3 at 17 years (C), participant 4 at 21 years (D), participant 5 at 10 years (E), participant 6 at 37 years (F), participant 7 at 11 years (G), participant 8 at 5 years (H), participant 9 at 3 years (I), participant 10 at 3 years (J), participant 11 at 4 years (K), participant 12 at 7 years (L), participant 13 at 13 years (M), participant 14 at 18 years (N), participant 15 at 2 years (O), participant 17 at 8 years (P), participant 18 at 16 years (Q), participant 19 at 23 years (R), participant 20 at 4 years (S), participant 21 at 6 years (T), participant 22 at 19 years (U), and participant 23 at 9 years (V). (W.a) Dorsal view of thumb hypoplasia in participant 5 at 3 years. (W.b) Palmar view of thumb hypoplasia in participant 20 at 5 years. (W.c) Dorsal view of arachnodactyly in participant 16 at 17 years. (W.d) Curvature of the fifth finger toward the adjacent fourth finger (clinodactyly) in participant 11 at 12 years. (X.a) Frontal view; sandal gap left hallux; right foot clubbing in participant 5 at 2 years. (X.b) Bilateral brachydactyly in participant 29 at 3 years. (X.c) Medial view of calcaneal adduction with navicular bone drop in participant 9 at 18 years. (X.d) Frontal view of sandal gap (right) with varus deviation in participant 17 at 21 years.

Figure 3. Remarkable Brain MRIs

Sagittal T1-weighted image demonstrates a vertical configuration of the posterior body/splenium of the corpus callosum (A and C, arrows) as well as thinning of the corpus callosum (C) (participant 27). Coronal T2-weighted image demonstrates prominence of the extra-axial spaces (arrows) in this child age 1 year 5 months (B) (participant 14). Axial T2-weighted image demonstrates delayed myelination of the anterior limbs of the internal capsule (arrow) in this patient age 10.5 months (D) (participant 1). Axial diffusion-weighted (E) and apparent diffusion coefficient (F) images demonstrate restricted diffusion involving the tegmental tracts (arrows, participant 1).

Figure 4. Parent-Reported Sensory Processing of Participants Carrying Variants in HNRNPH2

(A) Radar plot depicting sensory processing domains of Toddler Sensory Profile 2, where scores of 1 represent much less than others, 2 represents less than others, 3 represents just like the majority of others, 4 represents more than others, and 5 represents much more than others (n = 2). (B) Radar plot depicting sensory processing domains of Child Sensory Profile 2, where scores of 1 represent much less than others, 2 represents less than others, 3 represents just like the majority of others, 4 represents more than others, and 5 represents much more than others. Dotted lines represent participants with a parent reported ASD diagnosis (n = 7). (C) Radar plot depicting sensory processing quadrants for all Toddler, Child and Adolescent Sensory Profile 2, where scores of 1 represent much less than others, 2 represents less than others, 3 represents just like the majority of others, 4 represents more than others, and 5 represents much more than others. Dotted lines represent participants with an ASD diagnosis (n = 10). (D) Domain scores behavioral and emotional concerns were measured using the Behavior Assessment System for Children, third edition. ASD = autism spectrum disorder.

Figure 5. Parent-Reported Standardized Social, Adaptive, and Motor Skills Testing of Participants Carrying Variants in HNRNPH2

(A) Social Communication Questionnaire (SCQ) with elevated scores more than 15 suggestive of autism spectrum disorder (ASD) diagnosis. (B) Social Responsiveness Scale (SRS) with elevated T scores more than 60 suggestive of ASD diagnosis. (C) Standard scores for 19 affected individuals are shown for the Vineland Adaptive Behavior Scale, third edition (VABS-III), Parent or Caregiver form. Scores include the overall Adaptive Behavior Composite (ABC) Score as well as individual scores for each domain (communication, daily living skills, socialization, and motor skills). The motor skills domain is only calculated for individuals aged 9 years or younger (n = 8). Scores are norm-referenced to individual of the same age, with normed scores standardized with a mean of 100 and a SD of 15. The horizontal line at 70 represents 2 SDs below the mean.