Hist1h1e Syndrome
Summary
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 problems (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.
Diagnosis
No consensus clinical diagnostic criteria for HIST1H1E syndrome have been published.
Suggestive Findings
HIST1H1E syndrome should be considered in individuals with the following clinical findings [Tatton-Brown et al 2017, Duffney et al 2018, Takenouchi et al 2018, Burkardt et al 2019, Flex et al 2019].
Clinical findings include mild-to-profound developmental delay or intellectual disability AND a combination of the following features presenting in infancy or childhood:
- Generalized hypotonia of infancy
- Characteristic facial features including [Burkardt et al 2019, Figure 3]:
- In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
- In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
- Ectodermal abnormalities including thin and/or brittle, slow growing hair, reduced body hair, and thin nails
- Abnormal dentition including crumbling teeth, dental caries, and enamel hypoplasia
- Behavioral problems including anxiety disorder, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, and/or autism spectrum disorder
- Cryptorchidism in males
- Congenital cardiac anomalies, most frequently atrial septal defect
- Hypothyroidism
- Skeletal involvement including combinations of craniosynostosis, kypho/scoliosis, lower limb asymmetry, distal brachydactyly, camptodactyly, overlapping toes, and multiple fractures
Establishing the Diagnosis
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 (see Table 1).
Note: Identification of a heterozygous H1-4 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.
Molecular genetic testing approaches can include gene-targeted testing (single-gene testing and multigene panel) and/or comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of HIST1H1E syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic findings suggest the diagnosis of HIST1H1E syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of H1-4 is performed. Of note, the variants that have to date been shown to cause HIST1H1E syndrome are frameshift variants that cluster within the carboxy terminal domain. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, typically the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder.
- An intellectual disability multigene panel that includes H1-4 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of HIST1H1E syndrome has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene is likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in HIST1H1E Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| H1-4 | Sequence analysis 3 | 100% 4 |
| Gene-targeted deletion/duplication analysis 5 | None 4 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
To date all individuals reported with the recognizable pattern of findings characteristic of HIST1H1E syndrome have had frameshift variants in the carboxy terminal domain. No affected individuals with other sequence variants or gene dosage abnormalities have been reported.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
HIST1H1E syndrome is characterized by intellectual disability and a distinctive facial gestalt [Burkardt et al 2019, Figure 3].
To date, 47 individuals have been identified with a heterozygous pathogenic variant in H1-4 (formerly HIST1H1E). Table 2 provides data on the phenotypic features of 46 affected individuals in four studies and two case reports [Tatton-Brown et al 2017, Duffney et al 2018, Takenouchi et al 2018, Burkardt et al 2019, Flex et al 2019, Ciolfi et al 2020]. Because the earliest identified published report of an individual with a H1-4 pathogenic variant mentioned "Sotos syndrome-like features" and autism spectrum disorder, but no other clinical information [Helsmoortel et al 2015], it was not included in this tabulation.
Table 2.
Features of HIST1H1E Syndrome
| Feature | Proportion of Persons w/Feature | Comment |
|---|---|---|
| Cognition & motor development | 100% (46/46) | ID is highly variable, ranging from mild to severe. |
| Abnormal brain MRI | 92% (22/24) | Corpus callosal abnormalities are most frequent; 2 persons w/seizures |
| Cryptorchidism | 75% (15/20 males) | |
| Hypotonia | 67% (29/43) | |
| Behavioral issues | 59% (23/39) | Anxiety, phobias, obsessive behaviors, ADD, aggression, auditory hypersensitivity, & AS disorder/traits |
| Skeletal features | 54% (22/41) | A range of skeletal features are described. |
| Abnormal dentition | 51% (22/43) | Crumbling teeth, missing teeth (primary & adult) & multiple dental caries |
| Congenital cardiac anomalies / Abnormal echocardiogram | 40% (16/41) | Atrial septal defect is most frequent. |
| Hypothyroidism | 29% (6/21) |
ID = intellectual disability; ADD = attention-deficit disorder; AS = autism spectrum
Phenotypic Features
Cognition. All children have had some degree of intellectual disability (ID) ranging from mild to severe.
- Mild ID typically describes an individual who had delayed milestones but attended a mainstream school with additional help, and as an adult lived independently with support (5 individuals described to date).
- Moderate ID typically describes an individual who required high-level support in a mainstream school or had special educational needs schooling, and as an adult lived with support (most frequently characterized among individuals old enough for evaluation; 17 individuals described to date).
- Severe ID typically describes an individual who required special educational needs schooling, had limited speech, and did not live independently as an adult (4 individuals described in the literature).
Speech was significantly delayed in most individuals, with expressive language more severely affected than receptive language skills.
Motor milestones were notably delayed, with range of walking independently between ages 15 and 66 months (mean 31 months) [Flex et al 2019].
Behavioral problems included combinations of anxiety/phobias (4 individuals), obsessive behaviors (2 individuals), attention-deficit/hyperactivity disorder (3); autistic spectrum disorder/traits (4); head banging (2), auditory hypersensitivity (1), and aggression (1).
Sleep problems were reported in three individuals and mostly included restlessness / difficulty staying asleep.
Neurologic phenotype [Burkardt et al 2019, Flex et al 2019]
- Abnormal tone. Hypotonia in the neonatal period or early childhood was reported across studies. Increased tone was described in two neonates.
- Seizures. Two individuals had afebrile seizures: one with childhood focal seizures and one with recurrent status epilepticus necessitating antiepileptic medication. Febrile seizures in childhood were reported in six children. No specific EEG findings were reported among those studied.
- Brain MRI. The most frequent were abnormalities of the corpus callosum (most commonly slender or hypoplastic). Hydrocephalus (usually mild ventricular enlargement sometimes with relative macrocephaly) and arachnoid cysts were also reported (2 individuals) with mild inferior vermian hypoplasia noted in one individual and a "periventricular white matter abnormality" in another [Duffney et al 2018].
Ophthalmologic findings included strabismus (4 individuals) and astigmatism (5).
Cryptorchidism was either unilateral or bilateral. One male with cryptorchidism experienced urinary tract obstruction due to a kidney stone. No additional renal anomalies were reported in those who were imaged.
Skeletal involvement includes combinations of kypho/scoliosis (7 individuals), camptodactyly (4 individuals), lower-limb asymmetry (3), clinodactyly/contracture of fifth finger proximal interphalangeal joint (3), distal brachydactyly (7), multiple fractures related to osteopenia (3), overlapping toes (2), and craniosynostosis presenting as dolichocephaly, scaphocephaly or mild turricephaly (7 of 12 individuals evaluated).
Advanced bone age was identified in four of 20 individuals evaluated in early childhood [Duffney et al 2018, Burkardt et al 2019, Flex et al 2019]. Tall stature is not a common finding, in contrast to the authors' initial reports suggesting HIST1H1E syndrome was an overgrowth-intellectual disability syndrome [Tatton-Brown et al 2017]. In a study of 30 individuals the mean postnatal height was 0.4 SD (range -1.8 SD to 8.3 SD) [Burkardt et al 2019].
Additional findings [Burkardt et al 2019, Flex et al 2019]:
- Congenital cardiac anomalies included atrial septal defect (11 individuals), ventricular septal defect (2), patent foramen ovale (1), patent ductus arteriosus (1), and persistent superior vena cava.
- Hypothyroidism was a frequent (and possibly under-reported) finding. Ages of testing of thyroid function ranged from infancy to late childhood.
- Ectodermal abnormalities included thin and/or brittle, slow growing hair (11 individuals), reduced body hair (3), thin or dysplastic nails (7).
- Abnormal dentition included: a range from small, widely spaced teeth to missing variable numbers of permanent teeth and small, fragile teeth; thin enamel, with erosions / crumbling teeth: and multiple dental caries.
Other
Hearing loss (both sensorineural and/or conductive) was reported in seven individuals, three of whom had recurrent otitis media.
Ophthalmologic abnormalities among those evaluated included strabismus/amblyopia (9 individuals), astigmatism (7), myopia (3), and hypermetropia (1).
Note: Given that this is an ultra-rare disorder, it is uncertain if clinical features reported in one or two individuals are true associations or incidental findings.
Gestational/Neonatal Course
While the majority of pregnancies were uneventful and delivery was at term, two had complications. In one, there was ventriculomegaly with macrocephaly on ultrasound examination at 32 weeks' gestation and decreased fetal movement and fetal heart rate decelerations at 38 weeks' gestation; intubation and ventilatory support were required at birth. In the other, delivery at 34 weeks' gestation was followed by a three-week NICU stay.
Two other term neonates required postnatal NICU stays: one for four days of ventilatory support using positive end expiratory pressure; the other for hypoglycemia / feeding difficulties and jaundice [Flex et al 2019].
Prognosis
There is no evidence currently that life expectancy is reduced in HIST1H1E syndrome. The oldest reported individual is age 49 years [Flex et al 2019]. However, as many adults with disabilities do not have ready access to genetic testing, it is likely that adults with this condition are underrecognized and underreported.
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Penetrance
Data are currently insufficient to determine the penetrance of H1-4 germline pathogenic variants
Nomenclature
HIST1H1E neurodevelopmental syndrome (HNDS) has been proposed as an alternative name for HIST1H1E syndrome.
Prevalence
HIST1H1E syndrome was only recently described; data to date are insufficient to estimate prevalence.
Differential Diagnosis
All disorders with intellectual disability (ID) without other distinctive findings should be considered in the differential diagnosis of HIST1H1E syndrome. To date more than 180 such disorders have been identified. See OMIM Phenotypic Series: Autosomal dominant ID; Autosomal recessive ID; Nonsyndromic X-linked ID; and Syndromic X-linked ID.
While it has previously been suggested that HIST1H1E syndrome belongs to the family of overgrowth-intellectual disability syndromes [Tatton-Brown et al 2014], recent data suggest that most children with HIST1H1E syndrome do not have tall stature or macrocephaly [Burkardt et al 2019].
Management
No clinical practice guidelines for HIST1H1E syndrome have been published.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with HIST1H1E syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with HIST1H1E Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Development | Developmental assessment | To incl:
|
| Behavior | Neuropsychiatric eval | For persons age >12 mos: evaluate for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. |
| Neurologic | Neurologic eval |
|
| Genitourinary | Examine males for cryptorchidism. | If present, referral to pediatric urologist. |
| Cardiovascular | Echocardiogram | To evaluate for structural cardiac anomalies |
| Endocrine | TSH & T4 | To evaluate for hypothyroidism |
| Skeletal abnormalities | Assessment of head shape & for sutural ridging in infants | If abnormal, consider head CT w/3D reconstruction to assess for craniosynostosis. |
| Physical exam to assess for evidence of scoliosis | Consider spine radiographs if scoliosis is evident on physical exam. | |
| Inquire about history of fractures. | Consider referral to orthopedic specialist to evaluate bone mineral density in those w/frequent or unexplained fracture(s). | |
| Abnormal dentition | Dental eval to assess for caries, evidence of thin enamel, hypodontia | Panorex may be considered if hypodontia is suspected |
| Eyes | Ophthalmology eval | To assess for strabismus, refractive error |
| Genetic counseling | By genetics professionals 1 | To inform patients & their families re nature, MOI, & implications of HIST1H1E syndrome in order to facilitate medical & personal decision making |
| Family support/ resources | Assess:
|
3D = 3-dimensional; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI= mode of inheritance; TSH = thyroid stimulating hormone
- 1.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations
Following initial evaluation, treatment is symptomatic.
Management by multidisciplinary specialists is recommended, including (but not limited to) developmental pediatrics / behavioral psychology, neurosurgery/neurology, urology, cardiology, endocrinology, ophthalmology, orthopedics, and dentistry.
Table 4.
Treatment of Manifestations in Individuals with HIST1H1E Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Developmental delay / Intellectual disability | See Developmental Delay / Intellectual Disability Management Issues. | |
| Behavioral | Behavioral management strategies & consideration of medication to treat ADHD | In consultation w/developmental pediatrician or psychiatrist |
| Seizures | Standardized treatment w/AEDs by experienced neurologist | Education of parents/caregivers 1 |
| Cryptorchidism in males | Standard treatment per urologist | |
| Congenital heart defects | Standard treatment per cardiologist | |
| Hypothyroidism | Thyroid hormone replacement per endocrinologist | |
| Craniosynostosis | Standard treatment, ideally through a craniofacial center | Treating physicians may incl neurosurgeons & plastic surgeons. |
| Scoliosis | Standard treatment per orthopedist | |
| Decreased bone mineral density |
| |
| Abnormal dentition | By a pediatric dentist specializing in care of children w/neurodevelopmental disorders &/or enamel hypoplasia | When possible |
| Hearing loss | Hearing aids may be helpful; per otolaryngologist. | Community hearing services through early intervention or school district; if conductive hearing loss, pressure-equalizing tube placement could be considered. |
| Strabismus / Refractive error | Standard treatment per ophthalmologist | |
| Family/Community |
| Consider involvement in adaptive sports or Special Olympics. |
ADHD = attention-deficit/hyperactivity disorder; AED = antiepileptic drug;
- 1.
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Developmental Disability / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Communication Issues
Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases, can improve it.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
Table 5.
Recommended Surveillance for Individuals with HIST1H1E Syndrome