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Congenital Tonic Pupils Associated With Congenital Central Hypoventilation Syndrome and Hirschsprung Disease

Mehta, Viraj J. MD, MBA; Ling, Joseph J. BA; Martinez, Elizabeth G. DO; Reddy, Anvesh C. MD; Donahue, Sean P. MD, PhD

doi: 10.1097/WNO.0000000000000405
Clinical Observation

Abstract: Autonomic dysfunction can be associated with pupillary abnormalities. We describe a rare association of tonic pupils, congenital central hypoventilation syndrome, and Hirschsprung disease in a newborn with a mutation in the PHOX2B gene, a key regulator of neural crest cells. Hirschsprung disease is characterized by the congenital absence of neural crest–derived intrinsic ganglion cells. Tonic pupils may result from an abnormality of the ciliary ganglion, another structure of neural crest origin. The close association of these conditions in this child suggests a common abnormality in neural crest migration and differentiation.

Department of Ophthalmology (VJM, AR, SD), Vanderbilt Eye Institute, Nashville, Tennessee; Morehouse School of Medicine (JL), Atlanta, Georgia; and Department of Pathology, Microbiology, and Immunology (EGM), Vanderbilt University Medical Center, Nashville, Tennessee.

Address correspondence to Sean Donahue, MD, PhD, Department of Ophthalmology, Vanderbilt Eye Institute, 2311 Pierce Avenue, Nashville, TN 37232; E-mail:

The authors report no conflicts of interest.

Pupillary abnormalities have been described in patients with autonomic dysfunction, including congenital central hypoventilation syndrome (CCHS) and Hirschsprung disease (1,2). The combination of both CCHS and Hirschsprung disease is a rare entity also known as Haddad syndrome. These disorders are known as neurocristopathies, which are characterized by dysfunctional neural crest migration and differentiation (3).

Tonic pupils are dilated due to parasympathetic denervation secondary to ciliary ganglion dysfunction. Dramatic pupillary constriction is seen with dilute pilocarpine from the resultant cholinergic hypersensitivity (4). CCHS is characterized by autonomic dysfunction in which there is hypoventilation despite hypoxemia and hypercarbia in the absence of primary lung, cardiac, or neuromuscular disease or identifiable brainstem abnormalities. The disease-defining gene is PHOX2B (5). Hirschsprung disease is a condition characterized by the absence of parasympathetic ganglion cells within the colon, resulting in a functional obstruction (3). In this report, we describe an infant with congenital tonic pupils associated with CCHS and Hirschsprung disease.

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Our patient was born at 39 weeks to a 42-year-old G3P3 Hispanic woman via cesarean section with a birth weight of 2,740 g. Her Apgar scores at 1 and 5 minutes were 5 and 8, respectively. She was noted to have copious amount of amniotic fluid in her mouth and nares requiring suction. Shortly thereafter, she was found to have prolonged apneas requiring continuous positive airway pressure (CPAP) to maintain oxygen saturations. Despite CPAP, the apneas worsened, necessitating intubation. Medical and family histories were unremarkable.

Physical examination was notable for hypoventilation requiring synchronized intermittent mandatory ventilation, dilated pupils with poor light response, and distended abdomen. While maternal and infant laboratory tests were negative for infection, including rapid plasma reagin, HIV, group B streptococcus, chlamydia, gonorrhea, and hepatitis, the infant was noted to have hypoxemia and hypercapnia on arterial blood gases.

An ophthalmic examination performed at 5 days of age was notable for 6.5 mm pupils with no light response (Fig. 1A). With the instillation of dilute 0.1% pilocarpine into each eye, the pupils constricted to 2 mm (Fig. 1B). The remainder of the examination was within normal limits.

FIG. 1

FIG. 1

Brain magnetic resonance imaging and renal ultrasound were unremarkable, while an abdominal x-ray showed a dilated intestinal tract. Rectal suction biopsy was negative for calretinin staining without identifiable ganglion cells, consistent with Hirschsprung disease (Fig. 2). Genetic testing was notable for a 38 base pair deletion mutation (c.722_759del38) in the PHOX2B gene causing a frameshift mutation. This mutation resulted in a nonfunctional protein product with 31 extra amino acids, consistent with CCHS. The patient ultimately received a tracheostomy and gastrostomy tube at 1 month of age.

FIG. 2

FIG. 2

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The pupil examination is a useful tool in the evaluation of autonomic nervous system function (6). Pupil size and reactivity are determined by tone in 2 opposing smooth muscles controlled by sympathetic and parasympathetic innervation (4). Tonic pupils with supersensitivity to dilute pilocarpine suggest a defect in parasympathetic innervation and can localize to the ciliary ganglion or short posterior ciliary nerves (1).

CCHS is defined by a mutation in the PHOX2B gene, which encodes a transcription factor involved in the regulation of neural crest cells (5). While Hirschsprung disease is most commonly associated with mutations of the RET gene, a cell surface transducer of signal for cell growth and differentiation, it has also been noted to be associated with PHOX2B mutations. This association suggests a common pathway for the 2 diseases. Croaker et al (7) estimated that nearly 50% of patients with CCHS may also develop Hirschsprung disease.

CCHS and Hirschsprung disease may be present within a spectrum of clinical severity. The CCHS phenotype may range from individuals who need only nocturnal ventilatory support to those who may require continuous support (5). The Hirschsprung disease phenotype varies from total colonic agangliosis to distal aganglionosis of the sigmoid colon or even milder involvement (7). Consequently, pupillary abnormalities may vary based on the severity of the disease. O'Connor et al (8) conducted pharmacologic pupillary testing in patients with Hirschsprung disease without any evidence of denervation hypersensitivity, although clinical pupillary abnormalities before pharmacologic testing were not noted. On the other hand, pupillary abnormalities have been described in children with CCHS, yet pharmacologic testing was not conducted (9). Lambert et al (2) described tonic pupils confirmed with dilute pilocarpine testing in 2 patients with CCHS, Hirschsprung disease, and neuroblastoma. Genetic testing was not reported.

The pupillary finding in our patient is most consistent with tonic pupils, given marked constriction to dilute pilocarpine, a pathognomonic finding for denervation supersensitivity. The tonic pupils were likely due to abnormalities in the neural crest–derived ciliary ganglion. Mouse models of PHOX2B mutations have demonstrated ciliary ganglion atrophy (10). As the colonic ganglion cells, the autonomic nervous system, and cells of the ciliary ganglion all arise from neural crest cells, a mutation in the PHOX2B gene may be the unifying mutation in our patient. Future studies with histopathological and genetic evaluation of the ciliary ganglion may help substantiate this connection.


Category 1: a. Conception and design, V. J. Mehta, A. Reddy, S. Donahue; b. Acquisition of data, V. J. Mehta, J. Ling, E. G. Martinez; c. Analysis and interpretation of data, V. J. Mehta, J. Ling, A. Reddy, S. Donahue. Category 2: a. Drafting the manuscript, V. J. Mehta, J. Ling, A. Reddy; b. Revising it for intellectual content, V. J. Mehta, E. G. Martinez, A. Reddy, S. Donahue. Category 3: a. Final approval of the completed manuscript, V. J. Mehta, J. Ling, E. G. Martinez, A. Reddy, S. Donahue.

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V. J. Mehta, MD, MBA, and S. Donahue, MD, PhD, had full access to the patient record and all the data, and take responsibility for the integrity of the data and the accuracy of the analysis.

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