A Case of Athabaskan Brainstem Dysgenesis Syndrome and RSV Respiratory Failure

Tanner Ellsworth

Nahid Hiermandi DO

Diana Hu MD

Lisa M. Grimaldi MD

Cardiovascular Intensive Care Unit

Phoenix Children’s Hospital

Phoenix, Arizona USA

Abstract

Athabaskan Brainstem Dysgenesis Syndrome (ABDS) is a nonlethal, homozygous HOXA1 mutation typically marked by central hypoventilation, sensorineural deafness, horizontal gaze palsy, and developmental delay. In this report, we present a case of a 27-month-old Navajo female with a new diagnosis of ABDS after multiple failed attempts at extubation following anesthesia in the setting of respiratory syncytial virus (RSV) bronchiolitis. Her case is significant because she lacks sensorineural hearing loss, a defining feature of previously documented cases thereby underscoring the challenges of diagnosing this disease. This case expands the ever-growing spectrum of homozygous HOXA1 mutations and demonstrates unique junctions for diagnosis of ABDS in the critical care setting in patients lacking key features of the disease.

Introduction

Athabaskan Brainstem Dysgenesis Syndrome (ABDS) is an autosomal recessive, nonlethal, homozygous HOXA1 mutation. Though globally rare, incidence in Southwest Athabaskan (Navajo and Apache) populations spans 1/1000 to 1/3000 births (1)(2). This can be compared to Congenital Central Hypoventilation Syndrome (CCHS) with an estimated incidence of 1/200,000 births worldwide (3).

ABDS is marked by central hypoventilation, sensorineural deafness, horizontal gaze palsy, and developmental delay (2). Other features include cardiac outflow tract anomalies, swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, hypotonia, and cerebrovascular maldevelopment (4)(5). Affected individuals span a broad spectrum with many asymptomatic cases. Similar syndromes include Moebius syndrome and Bosley-Salih-Alorainy Syndrome, though both lack central hypoventilation (5). Central hypoventilation in children should include consideration for primary neuromuscular, lung, or cardiac disease, along with brainstem lesions, CCHS, asphyxia, infection, trauma, tumor, and infarction (6). As more Athabaskan individuals leave reservations, medical professionals must gain familiarity with the spectrum of HOXA1 mutations to prevent avoidable complications and expedite appropriate therapies.

We present a 27-month-old Navajo female with a new diagnosis of ABDS after several failed attempts at extubation following anesthesia in the setting of respiratory syncytial virus (RSV) bronchiolitis.

Case Description

A 27-month-old Navajo female with global developmental delay, patent ductus arteriosus (PDA), and sleep apnea presented with an acute, febrile respiratory illness confirmed as RSV bronchiolitis. She was admitted to a rural hospital for supportive care including supplemental oxygen and methylprednisolone.

Birth and developmental history were significant for transient poor feeding, poor visual tracking since birth, three failed newborn hearing exams with a subsequent pass, and global developmental delay, evidenced by inability to ambulate independently or speak more than two words.

At the rural hospital, persistent hypoxemia prompted a cardiac evaluation with echocardiography that revealed left ventricular hypertrophy, a tortuous aortic arch with moderate obstruction, and a small PDA with left-to-right shunting. Considering these findings, she was transferred to a tertiary pediatric hospital for further workup and management.

On the pediatric floor, blood gas analyses showed hypercarbia with metabolic compensation, suspicious for chronic hypoventilation. She consistently demonstrated generalized hypotonia and inconsistent tracking, specifically restricted lateral eye movements. Persistent hypoxemia and abnormal echocardiogram prompted further cardiac evaluation. On hospital day (HD) 3, a cardiac CT under general endotracheal anesthesia confirmed coarctation of the aorta and hypoplastic transverse arch. She was unable to be extubated due to persistent hypoxia and hypercarbia and was transferred to the cardiovascular intensive care unit.

Extubation attempts were initially deferred due to Moraxella tracheitis, treated with antibiotics and airway clearance. She weaned ventilator settings and was extubated to non-invasive support with bilevel positive airway pressure (BiPAP) on HD7. Within hours, she developed hypercarbia due to hypoventilation with a blood pH of 6.98 requiring reintubation.

Persistent central hypoventilation, hypercarbia, and cardiac outflow tract anomaly prompted investigation for ABDS. Brain MRI showed diffuse parenchymal volume loss with no brainstem abnormalities. Brainstem Auditory Evoked Response (BAER) testing showed no evidence of sensorineural hearing loss. Chromosome microarray testing confirmed homozygous HOXA1 mutation, consistent with ABDS.

Ventilator settings were again weaned, caffeine therapy initiated, and sedation medications discontinued for several days to avoid exacerbation of central hypoventilation. Unfortunately, repeat extubation failed due to stridor and hypoventilation, so she was reintubated and underwent an airway evaluation that revealed posterior vocal fold granulomas, which were debrided.

On HD33, the patient was successfully extubated to BiPAP. She weaned to room air during the day and BiPAP at night which she continued after discharge on HD57.

Discussion

In the critical care setting, familiarity with ABDS is important because patients can present with severe symptomatology out of proportion to their underlying disease. Minor respiratory illnesses or anesthesia can greatly exacerbate central hypoventilation and potentially lead to prolonged endotracheal intubation, mechanical ventilation, and associated complications such as ventilator-associated pneumonia, airway trauma, and habituation to sedation medications (2). Patients like this, who lack certain key features of ABDS—namely sensorineural deafness—are particularly challenging since diagnosis can be delayed (2). This case further illuminates the spectrum of homozygous HOXA1 mutations and emphasizes the importance of maintaining a high index of suspicion for ABDS in Athabaskan patients to anticipate the illness course and provide tailored medical care.

Conclusion

Overall, as Athabaskan individuals spread geographically, this case underscores the importance of widespread familiarity with ABDS for physicians. Basic knowledge of the features of ABDS will help identify individuals who may present with events such as infection or anesthesia that unmask an underlying abnormality, and their care can be directed at the unique challenges they present.

References

1. Erickson RP. Southwestern Athabaskan (Navajo and Apache) genetic diseases. Genet Med. 1999 May-Jun;1(4):151-7. [CrossRef] [PubMed]
2. Holve S, Friedman B, Hoyme HE, Tarby TJ, Johnstone SJ, Erickson RP, Clericuzio CL, Cunniff C. Athabascan brainstem dysgenesis syndrome. Am J Med Genet A. 2003 Jul 15;120A(2):169-73. [CrossRef] [PubMed]
3. Bardanzellu F, Pintus MC, Fanos V, Marcialis MA. Neonatal Congenital Central Hypoventilation Syndrome: Why We Should not Sleep on it. Literature Review of Forty-two Neonatal Onset Cases. Curr Pediatr Rev. 2019;15(3):139-153. [CrossRef] [PubMed]
4. Bosley TM, Alorainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, Tischfield MA, Engle EC, Erickson RP. The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet A. 2008 May 15;146A(10):1235-40. [CrossRef] [PubMed]
5. Erickson RP. Autosomal recessive diseases among the Athabaskans of the southwestern United States: recent advances and implications for the future. Am J Med Genet A. 2009 Nov;149A(11):2602-11. [CrossRef] [PubMed]
6. Weese-Mayer, DE, Marazita, ML, Rand, CM, et al. Congenital central hypoventilation syndrome. 2004 Jan 28. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1427/

Cite as: Ellsworth T, Hiermandi N, Hu D, Grimaldi LM. A Case of Athabaskan Brainstem Dysgenesis Syndrome and RSV Respiratory Failure. Southwest J Pulm Crit Care. 2020;21(5):124-6. doi: https://doi.org/10.13175/swjpcc053-20 PDF 

November 2016 Critical Care Case of the Month

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

History of Present Illness

A 45-year-old Iraqi War Veteran was seen in the outpatient clinic after referral for COPD based on abnormal blood gases. He denies any dyspnea or cough.

PMH, SH and FH

He has a history of a lower back injury and uses a motorized wheelchair. His pain is managed with morphine sulfate ER 60 mg daily and morphine sulfate 10 mg every 4 hours as needed for breakthrough pain.

He does not smoke cigarettes but does use marijuana for pain. He denies alcohol abuse.

Physical Examination

Physical examination shows a lethargic man in a wheelchair who intermittently falls asleep during questioning and examination. When aroused he is oriented to time, place and person and frequently mentions that his pain is a 10. His vital signs are normal expect his SpO2 is 75% on room air. His lungs were clear and his heart had a regular rhythm without murmur. His pupil size is approximately 2 mm bilaterally and muscle strength is difficult to determine due to his inability to remain alert or fully cooperate.

Radiography

A chest x-ray had been performed about a week previously (Figure 1).

Figure 1. Initial chest x-ray.

Spirometry had been performed earlier in the day (Figure 2).

Figure 2. Spirometry.

Which of the following are indicated at this time? (Click on the correct answer to proceed to the second of four pages)

1. Arterial blood gases (ABGs)
2. Immediate intubation
3. Intensive care unit (ICU) admission
4. 1 and 3
5. All of the above

Cite as: Robbins Ra. November 2016 critical care case of the month. Southwest J Pulm Crit Care. 2016;13(5):196-201. doi: http://dx.doi.org/10.13175/swjpcc103-16 PDF