Case report: is there a link between morning glory syndrome and TANGO2 mutation disease, or is this an unusual association?

Introduction

Congenital anomalies of the optic nerve are a rare but significant cause of visual deficits.¹ In 1970, Peter Kindler described for the first time a sporadic congenital anomaly of the optic nerve whose cause was not fully understood; involvement was predominantly unilateral, and characterised by an abnormally large optic disc, large excavation, presence of glial tissue remnants, and a radial peripapillary microvascular network. He named the condition morning glory syndrome. Most of these cases manifest during childhood or adolescence, predominantly affecting girls, presenting with symptoms of visual deficit and strabismus.²

Case report

Our patient was a 32-year-old woman, born to first-degree consanguineous parents and with history of psychomotor retardation, moderate intellectual disability, non-autoimmune hypothyroidism, and bilateral sensorineural hearing loss. She was being followed up by the neurology department due to episodes of disorientation.

The examination revealed generalised hyperreflexia with increased reflexogenic zone, absence of clonus, and bilateral positive Hoffman sign. The ophthalmological examination revealed exotropia of the right eye. Direct ophthalmoscopy showed right optic disc pallor, and indirect ophthalmoscopy revealed increased size and excavation of the right optic disc. The papilla was surrounded by an abnormally pigmented chorioretinal ring with marked peripapillary atrophy and a radial layout of blood vessels. The centre of the optic disc was covered by whitish glial tissue remnants. The peripheral retina and fovea of the right eye were normal. An A- and B-mode ultrasound study ruled out serous retinal detachment, which is described in up to 30% of cases of morning glory syndrome (Fig. 1).^3,4

Figure 1.

Retinography. Left: eye fundus examination of the right eye with abnormally large optic disc and increased excavation. The papilla is surrounded by an abnormally pigmented chorioretinal ring. Peripapillary atrophy. Right: eye fundus examination of the left eye, with normal findings.

An MRI study revealed a discontinuity of the uveoscleral coat at the most posterior margin of the right eye, at the entry point of the optic nerve (Fig. 2).

Figure 2.

Magnetic resonance imaging study revealing discontinuity of the uveoscleral coat at the most posterior margin of the right eye, at the entry point of the optic nerve.

Microarray-based comparative genomic hybridisation of the patient and her parents found that both parents were heterozygous for a pathogenic copy number variation of the TANGO2 gene (heterozygous deletion of exons 3–9), located on chromosome 22q11.21; the patient inherited the mutation in homozygosis.

Discussion

Morning glory syndrome is a congenital anomaly of the optic nerve, with a very low incidence rate. It is more frequent among women and in white populations, and usually manifests unilaterally.^5,6 Its pathophysiology is believed to be due to failed closure of the terminal optic stalk.¹ It may be suspected when the physical examination reveals strabismus, nystagmus, amblyopia, or leukocoria. Ophthalmological alterations are consistent with those described by other authors: abnormally large optic disc, with deep conical excavation, peripapillary pigmentation, and radial microvascular network. Diagnosis is based on fundus examination, with the most outstanding pathognomonic signs being the funnel-shaped morphology of the optic nerve and abnormal discontinuity of the uveoscleral coat at the level of optic nerve insertion.¹

Up to 45% of patients present associated cerebrovascular anomalies. Endocrine, respiratory, and renal alterations may also appear. It is associated with a mutation of the PAX6 gene and such other syndromes as the XYY syndrome, neurofibromatosis type 2, and CHARGE syndrome.

A surprising finding in our patient is her moderate psychomotor delay, as the initial genetic study (karyotyping, metabolic and mitochondrial disease study) yielded normal results.

However, the complementary molecular study showed a mutation of the TANGO2 gene in homozygosis (both parents presented the mutation in heterozygosis). A review of the literature identified different clinical findings associated with this mutation, including recurrent acute metabolic crises, ataxia, disorientation, coma, dysphagia, cardiac arrhythmia, developmental delay, intellectual disability, dysarthria, and seizures, as well as laboratory findings including hypoglycaemia, hyperlactacidaemia, hyperammonaemia, hypertransaminasaemia, and hypothyroidism.

From an ophthalmological perspective, the literature includes reports of exotropia, and some patients have been diagnosed with optic atrophy; otorhinolaryngological findings include sensorineural hearing loss in association with this mutation.⁷ These findings are compatible with the phenotype and clinical symptoms of our patient.

The literature does not report any association between morning glory syndrome and the TANGO2 mutation disease; therefore, we do not know whether this is a coincidental finding or a real association that has not previously been described.