Clinical characteristics.

HOXA1-related disorders are characterized by ocular motility disorder (horizontal gaze palsy with or without Duane syndrome), bilateral sensorineural deafness, cerebrovascular malformations (predominantly involving the carotid arteries), motor delay, central hypoventilation, and intellectual disability. Additional common features include congenital heart disease, facial paresis, vocal cord paresis, and swallowing dysfunction. Some individuals have seizures.

Diagnosis/testing.

The diagnosis of a HOXA1-related disorder is established in a proband with suggestive findings and biallelic pathogenic variants in HOXA1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment of Duane syndrome or horizontal gaze palsy includes orthoptic exercises, botulinum toxin injection, and surgery in those with severe manifestations; hearing aids, cochlear implants, speech therapy, educational support, and accommodations for those with sensorineural deafness; management of cerebrovascular anomalies per cardiovascular specialist with medications or surgical interventions; physical therapy, occupational therapy, and early intervention services for motor delay; educational and developmental support; mechanical ventilation with aminophylline and continuous monitoring of respiratory function in those with central hypoventilation; treatment of congenital heart disease includes medications, surgical intervention, and cardiac rehabilitation; medications, botulinum toxin injection, and physical therapy for facial twitching or paresis; tracheostomy, gastrostomy tube feedings, and pharmacologic therapies for gastroesophageal reflux in those with vocal cord paresis and swallowing dysfunction; social work and family support.

Surveillance: Ophthalmologic examination every six to 12 months; assessment of visual acuity and ocular alignment and orthoptic and fundoscopic evaluation per ophthalmologist; audiology, speech, and auditory processing assessment annually or as needed; surveillance for cerebral vascular anomalies per neurologist and/or vascular surgeon; developmental and physical therapy evaluation annually; assess for need for early intervention services, educational support, and accommodations and for signs of intellectual disability annually; respiratory evaluation with pulmonary function tests and sleep studies annually; assess for central hypoventilation and respiratory manifestations annually; cardiac evaluation, EKG, and echocardiogram annually; neurologic examination for facial twitching, facial paresis, and seizures annually; brain MRI as clinically indicated; assess family needs at each visit.

Agents/circumstances to avoid: Avoid high altitude, especially among individuals with HOXA1-related Athabascan brainstem dysgenesis syndrome; avoid risk factors for stroke.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of surveillance and treatment.

Genetic counseling.

HOXA1-related disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a HOXA1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the HOXA1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

HOXA1-related disorders should be suspected in probands with the following clinical and imaging findings and family history.

Clinical findings

• Ocular motility disorder: horizontal gaze palsy with or without Duane syndrome (also referred to as Duane retraction syndrome)
• Bilateral sensorineural deafness
• Developmental delay
• Intellectual disability
• Central hypoventilation while awake or asleep requiring supplemental oxygen and/or mechanical ventilatory support
• Congenital heart malformations, cerebrovascular malformations
• Facial paresis, vocal cord paresis, and swallowing dysfunction leading to recurrent aspiration and pneumonia
• Seizure disorder
• Neurobehavioral/psychiatric manifestations

Imaging findings

• Bosley-Salih-Alorainy syndrome (See Figure 1.)
  • Cerebrovascular malformations often involving the carotid arteries
  • Abnormalities of inner ear structures
  • Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve)
  • Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves
• Athabascan brainstem dysgenesis syndrome
  • Generalized cerebral atrophy
  • Normal brainstem
  • Abnormalities of the cerebrovascular system
  • Abnormalities of inner ear structures
  • Variable absence of cranial nerves VI-XII

Figure 1

a-f. Brain and neck imaging of a female age 19 years with Bosley-Salih-Alorainy syndrome (BSAS). (a,b) Brain MRI: supratentorial and infratentorial axial T₂-weighted images show normal appearance of the cerebral and cerebellar hemispheres. (c) Time-of-flight (more...)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of a HOXA1-related disorder is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in HOXA1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic HOXA1 variants of uncertain significance (or of one known HOXA1 pathogenic variant and one HOXA1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

HOXA1-related disorders are characterized by ocular motility disorder (horizontal gaze palsy with or without Duane syndrome), bilateral sensorineural deafness, variable cerebrovascular malformations (predominantly involving the carotid arteries), motor developmental delay, central hypoventilation, and intellectual disability. To date, 34 individuals have been identified with biallelic pathogenic variants in HOXA1 [Holve et al 2003, Tischfield et al 2005, Bosley et al 2007, Bosley et al 2008, Higley et al 2011, Oystreck et al 2011, Ellsworth et al 2020, Patil et al 2020]. Two overlapping phenotypes have been described: Athabascan brainstem dysgenesis syndrome (ABDS) and Bosley-Salih-Alorainy syndrome (BSAS).

Ocular motility disorder. One of the most common clinical findings among affected individuals with ABDS and BSAS is horizontal gaze palsy with or without Duane syndrome due to underlying abducens nucleus / nerve abnormalities [Holve et al 2003, Tischfield et al 2005, Bosley et al 2007, Bosley et al 2008, Higley et al 2011, Oystreck et al 2011, Ellsworth et al 2020, Patil et al 2020]. Horizontal gaze palsy can be unilateral or bilateral and can be apparent from early infancy. Affected individuals have variable severity of abduction/adduction with or without refractive errors, nystagmus, vertical gaze involvement, strabismus (esotropia), and ptosis. Only two reported individuals with BSAS did not have the typical ocular motility disorder; one had mild ocular motility disorder and the other had normal ocular motility. Untreated eye complications can lead to amblyopia [Bosley et al 2008].

Inner ear anomalies / sensorineural deafness. Structural abnormalities within the inner ear accompanied by congenital profound sensorineural deafness are observed in most affected individuals (32/34 individuals). Structural abnormalities of the inner ear described in individuals with ABDS and BSAS can be unilateral or bilateral, including complete absence of the labyrinthine structure, common cavity deformity, and/or underdevelopment or absence of the cochlea [Holve et al 2003, Tischfield et al 2005, Bosley et al 2007, Bosley et al 2008, Higley et al 2011, Oystreck et al 2011, Ellsworth et al 2020, Patil et al 2020].

Cerebrovascular malformations. Cerebrovascular anomalies affecting the carotid arteries are frequently observed; the internal carotid arteries are most commonly involved [Bosley et al 2007, Bosley et al 2008]. These anomalies may be unilateral or bilateral, including carotid artery aplasia or hypoplasia, early branching of the common carotid artery, anterior cerebral artery aplasia, and duplication of the vertebral artery along with compensatory enlargement of the posterior communicating artery or the vestibulobasilar arterial system. Although a cerebrovascular malformation may increase the risk of stroke, in most individuals with ABDS and BSAS these vascular defects remain silent, except for two individuals. One individual with ABDS had a vertebral artery stroke and another individual with BSAS had a stroke following cardiac surgery [Holve et al 2003, Bosley et al 2008].

Developmental delay. Motor delay is noted in most affected individuals, which can be attributed to the absence of a vestibular system and congenital heart defects in individuals with BSAS rather than a widespread disturbance in the brain [Bosley et al 2008]. Most individuals with BSAS and motor delay achieved independent ambulation [Bosley et al 2008, Patil et al 2020]. However, in individuals with ABDS, unsteady and wide-based gait was reported in those who became ambulatory along with dysmetria possibly related to cerebellar dysfunction [Holve et al 2003].

Learning difficulties / intellectual disability. Cognitive dysfunction is seen in all affected individuals with ABDS and is believed to result from chronic brain oxygen deficiency due to a combination of central hypoventilation, cerebrovascular abnormalities, and the elevated altitude where the Athabascan community resides [Bosley et al 2008]. Two individuals of 14 with ABDS are reported to have relatively mild cognitive impairment, possibly because they were raised at lower altitude.

Individuals with BSAS are reported to have variable developmental abilities and cognitive function ranging from isolated motor delay, learning difficulties, or behavioral issues to global developmental delay and autism spectrum disorder. Often neurologic assessment is confounded by the presence of profound sensorineural deafness and speech issues. Normal neurologic function has been reported in seven of 20 individuals with BSAS [Bosely et al 2007, Bosely et al 2008].

Central hypoventilation is the distinguishing feature in individuals with ABDS. Most children with ABDS had clinical features of central hypoventilation identified in early infancy (age <6 months). All reported individuals required supplemental oxygen either through mechanical ventilation or nasal cannula and aminophylline. Weaning of supplemental oxygen was possible in those who survived beyond infancy with improved respiratory drive with age. Central hypoventilation has been reported to be more severe during sleep. Some individuals only required supplemental oxygen at night [Holve et al 2003, Bosley et al 2008, Ellsworth et al 2020].

None of the individuals with BSAS have central hypoventilation.

Congenital heart disease. The majority of children with ABDS have congenital heart disease commonly involving the cardiac outflow tract including tetralogy of Fallot, coarctation of aorta, double aortic arch, transverse hypoplastic arch, aortic valve stenosis, aberrant left subclavian artery, patent ductus arteriosus, bicuspid aortic valve, ventricular septal defect, and total anomalous pulmonary venous return.

Some individuals with BSAS also have congenital heart disease including double outlet left ventricle, tetralogy of Fallot, and ventricular septal defect. One individual with BSAS was reported to have apparently isolated congenital heart disease without ocular motility disorder or hearing impairment [Bosely et al 2008].

Facial paresis, vocal cord paresis, and swallowing dysfunction are manifestations of hypoplasia and/or aplasia of certain cranial nerves. Variable facial paresis or twitching/spasms (unilateral or bilateral) have been documented in individuals with ABDS and BSAS, which is attributed to hypoplasia or aplasia of cranial nerve VII [Holve et al 2003, Tischfield et al 2005, Bosley et al 2008, Higley et al 2011]. Vocal cord paresis (2/10 individuals) and swallowing dysfunction (6/10 individuals) have also been reported in individuals with ABDS. Often these complications lead to recurrent aspirations requiring hospitalization and gastrostomy tube feeding [Holve er al 2003].

Seizures were reported in two individuals with BSAS and four individuals with ABDS [Holve et al 2003, Bosley et al 2008]. To date, further information regarding type of seizures is not available, except in one individual with ABDS described as having generalized tonic-clonic seizures (onset at age 3 years) [Holve et al 2003].

Other variable, less common clinical features [Bosley et al 2007, Bosley et al 2008]:

• External ear minor malformations (e.g., flattened ear helix, low-set ears) in four individuals with BSAS
• Clubfoot in three individuals
• Chronic constipation in two individuals with BSAS
• Frequent grimacing in two individuals with BSAS
• Facial asymmetry in one individual with BSAS and one individual with ABDS
• Multiple lentigines, hypertrichosis, polydactyly, brachydactyly, and duplex ureteral system with urethral stricture (1 individual each)

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Central hypoventilation has only been reported in individuals with ABDS, and high altitude is a suspected contributing factor [Holve et al 2003, Bosley et al 2008].

Nomenclature

ABDS was previously referred to as "Navajo brainstem syndrome." Holve et al [2003] proposed the term "Athabascan brainstem dysgenesis syndrome."

Prevalence

To date, 34 individuals have been reported with biallelic variants in HOXA1.

ABDS is prevalent in individuals of Navajo and Apache descent due to the HOXA1 founder pathogenic variant c.76C>T (p.Arg26Ter). The incidence of ABDS was predicted to be 0.5-1:1,000 live births in the White River Apache Reservation and 1:3,000 live births in the Navajo population [Erickson et al 1999, Holve et al 2003].

BSAS has been reported in individuals from Middle Eastern populations including Saudi Arabia and Turkey due to the HOXA1 founder pathogenic variant c.175dupG (p.Val59Ter).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a HOXA1-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for HOXA1-related disorders. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

It seems prudent to avoid high altitude, especially among individuals with ABDS, based on a few case studies [Bosely et al 2008], but this needs further study and confirmation. In addition, practical limitations would make avoiding high altitude challenging.

Avoid risk factors leading to stroke (lifestyle and drugs).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of surveillance and treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

HOXA1-related disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a HOXA1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a HOXA1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a HOXA1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has a HOXA1-related disorder or is a carrier (see Family Planning), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in HOXA1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a HOXA1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the HOXA1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals affected with a HOXA1-related disorder and individuals known to be carriers of a HOXA1 pathogenic variant, particularly if consanguinity is likely and/or if both partners are of the same ethnic background (HOXA1 founder variants have been identified in individuals of Navajo and Apache ancestry and individuals from Saudi Arabia [see Table 7]).

Prenatal Testing and Preimplantation Genetic Testing

Once the HOXA1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Homeobox (HOX) genes occur in four clusters (A-D), located on different chromosomes. In each cluster, 3' HOX genes are expressed earlier and more anteriorly than 5' HOX genes [Lappin et al 2006]. HOX genes encode proteins that play an important role in specification of anterior-posterior patterning and lineage-specific cellular differentiation [De Kumar et al 2017]. Pathogenic variants in HOX genes result in malformations reflecting the pattern of developmental expression. Homozygous HOXA1 mutated mice show faulty development of hindbrain and associated structures [Mark et al 1993, Makki et al 2012].

To date, the reported biallelic pathogenic variants in HOXA1 in the majority of affected individuals lead to loss of all functional domains. In one reported individual, preservation of the PBX binding domain (almost resembling isoform 3) has been observed [Patil et al 2020].

Mechanism of disease causation. Loss of function

Author Notes

Dr Siddaramappa J Patil (moc.liamg@litapjsrd) is keen to identify more individuals with HOXA1-related disorders to better characterize the phenotype and genotype. He and Dr Prince Jacob (ni.ude.inussj@bocajecnirp) serve as moderators for the HOXA1 entry in the Human Disease Genes website series.

Dr Patil and Dr Jacob are actively involved in clinical research regarding individuals with HOXA1-related disorders. They would be happy to communicate with persons who have any questions regarding diagnosis of HOXA1-related disorders or other considerations.

Dr Patil is also interested in hearing from clinicians treating families affected by inherited cardiovascular malformations in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Patil and Dr Jacob to inquire about review of HOXA1 variants of uncertain significance.

Acknowledgments

We are thankful to Narayana Hrudayalaya Hospital / Mazumdar Shaw Medical Center and JSS Academy of Higher Research (JSSAHER) for providing the support and resources for conducting the study.

Revision History

• 14 November 2024 (sw) Review posted live
• 22 April 2024 (sp) Original submission

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