HOXA1-Related Disorders

Excerpt

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 brain stem 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.