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JAMA Ophthalmology Clinical Challenge
February 2015

Retinal Findings Leading to a Change in Diagnosis in a Newborn Child

Author Affiliations
  • 1Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida
JAMA Ophthalmol. 2015;133(2):215-216. doi:10.1001/jamaophthalmol.2014.4770

Case

At birth, a full-term newborn was noted to have numerous hypopigmented skin macules on the trunk, scalp, neck, face, back, and limbs after an uncomplicated pregnancy (Figure 1A). The family history was negative for any dermatologic or genetic diseases. A shave biopsy specimen of the right leg was interpreted as papillomatous epidermal hyperplasia consistent with an epidermal nevus. Because of the constellation of findings, an initial diagnosis of linear epidermal nevus syndrome was made. At age 3 months, the patient was referred for ophthalmologic examination owing to a flat, hypopigmented lesion in the left temporal iris noted by the patient’s father. On examination, the patient fixed and followed with both eyes. Pupils, motility, and binocular alignment were normal. Dilated ophthalmoscopic examination revealed a well-demarcated hypopigmented lesion originating from the retinal nerve fiber layer and protruding into the vitreous cavity of the right eye (Figure 1B). A similar lesion was seen along the left inferotemporal arcade (Figure 1C). B-scan ultrasonography revealed a 4.0 × 2.9 × 2.2-mm lesion with no calcification, no retinal detachment, and no choroidal involvement (Figure 1D). Given the suspected iris hamartoma and retinal astrocytic hamartoma, a systemic workup was commenced.

Figure 1.  
A, Dermatologic manifestations. The patient had multiple hypopigmented macules on his scalp, face, neck, back, limbs, and torso (arrowheads). B, A lesion was discovered in the right eye consistent with a retinal astrocytic hamartoma. C, A similar smaller lesion was seen in the left eye. D, B-scan ultrasonography revealed an elevated lesion emanating from the retina with no calcification or choroidal involvement.

A, Dermatologic manifestations. The patient had multiple hypopigmented macules on his scalp, face, neck, back, limbs, and torso (arrowheads). B, A lesion was discovered in the right eye consistent with a retinal astrocytic hamartoma. C, A similar smaller lesion was seen in the left eye. D, B-scan ultrasonography revealed an elevated lesion emanating from the retina with no calcification or choroidal involvement.

Box Section Ref ID

What Would You Do Next?

  1. Renal ultrasonography and lumbar puncture

  2. Brain imaging and echocardiography

  3. Metastatic workup

  4. Fine-needle aspiration biopsy of ocular lesion

Read the Discussion

Discussion

Diagnosis

Tuberous sclerosis complex

What To Do Next

B. Brain imaging and echocardiography

Brain magnetic resonance imaging revealed cortical and subcortical tubers along with subependymal nodules (Figure 2). The echocardiogram revealed several ventricular masses, with the largest measuring 7 mm in the left ventricle, consistent with cardiac rhabdomyomas. The constellation of findings confirmed a diagnosis of tuberous sclerosis.

Figure 2.  
Brain magnetic resonance imaging revealed multiple lesions, including a tuber in the cortex and subcortical white matter (arrowhead) (A), hyperintense patches in the subcortical white matter and a tuber in the right temporal lobe (arrowhead) (B), and multiple subependymal nodules along the lateral ventricles (arrowheads) (C).

Brain magnetic resonance imaging revealed multiple lesions, including a tuber in the cortex and subcortical white matter (arrowhead) (A), hyperintense patches in the subcortical white matter and a tuber in the right temporal lobe (arrowhead) (B), and multiple subependymal nodules along the lateral ventricles (arrowheads) (C).

Discussion

Tuberous sclerosis complex (TSC) is a rare disorder affecting cellular proliferation and differentiation that leads to hamartomatous formation in multiple organs, including the brain (tubers and subependymal giant cell astrocytomas), heart (rhabdomyomas), kidney (angiomyolipomas and renal cell carcinoma), skin, and retina.1 Tuberous sclerosis complex exhibits an autosomal dominant inheritance pattern and has been mapped to 2 genetic loci—9q34 (TSC1 [OMIM 605284], which encodes protein hamartin) and 16p13 (TSC2 [OMIM 191092], which encodes protein tuberin)1—but has been attributed to a spontaneous mutation in the majority of cases.2 Most patients are diagnosed between ages 2 and 6 years.

Diagnosis of TSC depends on the presence of a certain number of major and minor criteria. Characteristic dermatologic lesions include angiofibromas (adenoma sebaceum), shagreen patches, and ash leaf macules. Ocular manifestations of TSC include iris hypopigmentation, inferior iris colobomas, and retinal astrocytic hamartomas, with the latter being the most common and occurring in approximately 50% of patients and bilaterally in half of these.3 Retinal astrocytic hamartomas manifest as sessile or elevated lesions of the retinal nerve fiber layer and often calcify with age. These types of retinal astrocytic hamartomas have been described: type 1 (semitransparent, flat, no calcification), type 2 (multinodular, calcified lesions with a mulberry-like appearance), and type 3 (combined).4 Less common ocular manifestations include iris hypopigmentation (as seen in this patient) and iris colobomas.3

Among patients in whom there is a suspicion of TSC, computed tomography or magnetic resonance imaging of the brain should be performed, along with renal ultrasonography, echocardiography, and ophthalmoscopic examination. Genetic testing can be helpful. Antiepileptic medications are the mainstay therapy for patients with TSC, although appropriate treatment for end-organ pathology is sometimes necessary.

A notable facet of this case is the initial diagnosis of linear epidermal nevus syndrome, a condition in which hamartomas are also present. Linear epidermal nevus syndrome is a rare neurocutaneous disorder that manifests with skin lesions, mental retardation, seizures, and movement disorders.5 Hafner et al6 reported that 42% of epidermal nevi are due to mutations in the upstream regulators of the TSC1 and TSC2 genes. Hence, and as this case demonstrates, there can be overlap of the clinical presentation and histopathological characteristics between epidermal nevi and TSC lesions, and care must be taken to differentiate between these diagnoses.7

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Article Information

Corresponding Author: Christina Y. Weng, MD, MBA, Department of Ophthalmology, Bascom Palmer Eye Institute, 900 NW 17th St, Miami, FL 33136 (c.weng@med.miami.edu).

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported.

Additional Contributions: Joseph Y. Young, MD (Department of Radiology, Massachusetts General Hospital, Boston), assisted with neuroimaging interpretation.

References
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Elam  AL, McCleskey  PE.  White epidermal nevi at birth in a patient with tuberous sclerosis.  Pediatr Dermatol. 2014;31(3):360-362.PubMedGoogle ScholarCrossref
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