12-year-old girl presents with worsening vision

On exam, bilateral cataracts and optic atrophy were noted.

Catherine A. Cox

Jordana F. Goren

A 12-year-old girl was referred to our office for decreased vision, which was presumed to be due to progressing cataracts.

She had been diagnosed with sensorineural hearing loss early in life, leading to suspicion for a hereditary condition and regular ophthalmologic examinations since the age of 2 years. She was prescribed glasses at 7 years for distance correction, and bilateral cataracts were diagnosed at 8 years. She had no history of strabismus or amblyopia. Her medical history was significant for insulin-dependent diabetes mellitus and hypothyroidism.

Examination

On examination, the patient’s best corrected visual acuity was 20/100 in the right eye and 20/80 in the left eye. This was decreased from a baseline of 20/40 to 20/50, per the referring physician. Her pupils were reactive with no relative afferent pupillary defect, her extraocular movements were full, and IOPs were normal in both eyes.

On color vision testing with Ishihara plates, the patient was able to read only 1/11 plates with each eye (test plate only). Her anterior segment examination was significant for bilateral posterior subcapsular cataracts with scattered cortical opacities (Figure 1). On dilated fundus examination, optic atrophy was present in both eyes with prominent temporal pallor (Figure 2). No pigmentary retinopathy was noted. Optical coherence tomography showed significant nerve fiber layer atrophy in both eyes.

Figure 1. Retroillumination of the left eye highlights a central posterior subcapsular cataract (left). Cortical opacities are also present. Both of these findings were present bilaterally (right). Images: Liang MC, Strominger MB

Figure 2. Bilateral optic atrophy with temporal pallor. No pigmentary retinopathy was noted in either eye.

What is your diagnosis?

Bilateral optic atrophy

The differential diagnosis of bilateral optic atrophy includes many inherited and acquired diseases. Inherited causes include autosomal dominant optic atrophy — specifically a variant known as optic atrophy 3 — as well as Leber’s hereditary optic atrophy and Wolfram syndrome. Acquired causes include nutritional and toxic optic neuropathies, compressive tumors, and bilateral optic neuritis from inflammatory or demyelinating diseases.

The presence of cataracts in addition to bilateral optic atrophy should lead to consideration of other less likely etiologies, such as thiamine-responsive megaloblastic anemia, Refsum disease and Friedreich’s ataxia. These latter conditions can present with varying degrees of optic atrophy, hearing loss and diabetes with subsequent cataract formation. Given our patient’s clinical presentation, our differential was narrowed to include either Wolfram syndrome or autosomal dominant optic atrophy 3.

A head CT was performed to rule out a possible compressive lesion; it was found to be negative. MRI of the brain and orbits showed generalized atrophy of both the optic nerves and posterior hypothalamus. VEP and ERG testing were found to be abnormal. Due to her multisystem disease, the patient was sent for genetic testing. No mitochondrial disease was found; however, she was found to be positive for one allele of the WFS1 gene, thus confirming a diagnosis of Wolfram syndrome.

Discussion

Wolfram syndrome is a rare, hereditary, neurodegenerative disease. Clinical characteristics include diabetes insipidus, diabetes mellitus, optic atrophy and deafness, giving it the better known acronym of DIDMOAD. It usually follows an autosomal recessive inheritance pattern, although both autosomal dominant and mitochondrial forms have been reported. The common form, Wolfram syndrome 1, is due to a mutation on chromosome 4 encoding for the protein wolframin. While the exact function of wolframin is unknown, it is postulated to assist with protein folding and cellular transport. It can be found in the cellular endoplasmic reticulum in various tissues throughout the body, including the heart, brain, inner ear and pancreas.

Clinically, Wolfram syndrome is diagnosed by the presence of both insulin-dependent diabetes mellitus and optic atrophy before the age of 15 years. The optic atrophy is always progressive, with legal blindness occurring within 8 years of initial diagnosis. Approximately two-thirds of patients will also suffer from sensorineural hearing loss. Other ocular findings may include cataracts, pigmentary retinopathy and/or nystagmus. Hormonal imbalances and neurological abnormalities are also common, such as hypogonadism, hypothyroidism, growth retardation, truncal or gait ataxia, dementia and/or psychiatric illnesses. The median age of death is around 30 years, which has been reported to be due to hypoglycemic coma, end-stage renal disease, suicide or central respiratory failure from brain stem atrophy. Treatment is symptomatic with a goal to improve the patient’s quality of life.

Since diagnosis, our patient has been followed for cataracts and was given low vision tools to help with reading. At last follow-up, her vision was 20/70 in the right eye and 20/60 in the left eye, with an improvement of one to two lines with potential acuity meter testing. Due to trouble seeing the blackboard at school, she has been scheduled to undergo cataract surgery in the right eye.

References:

• Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome. J Med Genet. 1997;34(10):838-841.
• Barrett TG, Bundey SE, Macleod AF. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346(8988):1458-1463.
• Kinsley BT, Swift M, Dumont RH, Swift RJ. Morbidity and mortality in the Wolfram syndrome. Diabetes Care. 1995;18(12):1566-1570.
• Mets RB, Emery SB, Lesperance MM, Mets MB. Congenital cataracts in two siblings with Wolfram syndrome. Ophthalmic Genet. 2010;31(4):227-229.
• Viswanathan V, Medempudi S, Kadiri M. Wolfram syndrome. J Assoc Physicians India. 2008;56:197-199.
• Wolfram syndrome 1; WFS1. OMIM. http://omim.org/entry/222300. Updated Oct. 19, 2011.

• Michelle C. Liang, MD, and Mitchell B. Strominger, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; website: www.neec.com.
• Edited by Catherine A. Cox, MD, and Jordana F. Goren, MD, MS. Drs. Cox and Goren can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; website: www.neec.com.