HIST1H1E Syndrome

Excerpt

Clinical characteristics: The name HIST1H1E syndrome has been proposed as a mnemonic for the characteristic features of this emerging, recognizable phenotype: hypotonia; intellectual disability with behavioral issues; skeletal; testes (undescended) and thyroid; heart anomalies (most commonly atrial septal defect); and ectodermal issues (including sparse hair, thin nails, and abnormal dentition). In the 47 affected individuals reported to date, predominant findings were intellectual disability (ranging from mild to profound) and behavioral issues (combinations of anxiety/phobias, obsessive behaviors, attention-deficit/hyperactivity disorder, and autistic spectrum disorder/traits among others). Skeletal involvement can include scoliosis and decreased bone mineral density. Other findings in some include seizures, craniosynostosis, and hearing loss. Life expectancy does not appear to be reduced in HIST1H1E syndrome.

Diagnosis/testing: The diagnosis of HIST1H1E syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in H1-4 (formerly HIST1H1E) identified by molecular genetic testing.

Management: Treatment of manifestations: Management by multidisciplinary specialists is recommended, including but not limited to developmental pediatrics/behavioral psychology, neurosurgery/neurology, urology, cardiology, endocrinology, ophthalmology, orthopedics, and dentistry.

Surveillance: Routine periodic assessment of significant issues as per multidisciplinary specialists.

Genetic counseling: HIST1H1E syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. To date, all probands reported with HIST1H1E syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a de novo H1-4 pathogenic variant. If the H1-4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism. Once the H1-4 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.