See Ash Leaf Macules, Think Tuberous Sclerosis

PORTLAND, ORE. — If an infant presents with at least three hypopigmented macules, think tuberous sclerosis.

Tuberous sclerosis is described as a triad of neurologic impairment, multisystem hamartomas, and skin findings (such as ash leaf macules and facial angiofibromas). The disease is of autosomal dominant inheritance, with an incidence of 1:6,000 to 1:10,000. Spontaneous mutation occurs in 50%-75% of cases.

Ash leaf spots or hypopigmented macules occur in 90% of patients with the disease, Dr. Dawn Siegel said at the annual meeting of the Pacific Dermatologic Association. They can range in size from 1 to 12 cm in diameter and “are rounded at one end and tapered at the other, resembling the leaf of an ash tree. They can vary quite a bit in their presentation. In some cases, they present as confetti macules, which are only 1–2 mm in diameter,” she said.

If an infant presents with more than three hypopigmented macules, she recommends screening evaluations, which could include a renal ultrasound, an eye exam, and a cardiac echocardiogram. “I usually reserve head MRI or CT for babies who are developing seizures, or who have a positive finding on one of the other screening tests, or if I have a high clinical suspicion,” said Dr. Siegel, assistant professor of dermatology and pediatrics at Oregon Health and Science University, Portland.

Infantile spasms, the most common presenting neurologic sign, tend to develop by 4–5 months of age in about 70% of patients.

Establishing a definitive diagnosis of tuberous sclerosis requires the presence of two major clinical diagnostic criteria or one major and two minor criteria.

Major criteria include facial angiofibromas or forehead plaque, nontraumatic ungual fibroma, three or more hypomelanotic macules, shagreen patch (most commonly on the torso and chest), multiple retinal nodular hamartomas, cortical tuber, subependymal nodule, subependymal giant cell astrocytoma, single or multiple cardiac rhabdomyoma, renal angiomyolipoma, and pulmonary lymphangiomyomatosis, said Dr. Siegel.

Minor clinical criteria include multiple randomly distributed pits in dental enamel, hamartomatous rectal polyps, bone cysts, cerebral white matter radial migration lines, gingival fibromas, nonrenal hamartoma, retinal achromic patch, “confetti” skin lesions, and multiple renal cysts.

Current treatments for the facial angiofibromas include pulsed dye laser and pulsed KTP (532 nm) laser. “Some people use a CO₂ laser or the erbium: YAG laser to try and flatten down the lesions,” Dr. Siegel said.

Studies of oral and topical rapamycin are underway after a published case report demonstrated that the agent significantly improved angiofibroma lesions in a patient with tuberous sclerosis complex who took rapamycin after undergoing renal transplantation (Br. J. Dermatol. 2008;159:473–5).

“This would be exciting, because angiofibromas are so disfiguring and treatment has been frustrating,” she said.

Incontinentia Pigmenti

Dr. Siegel went on to discuss incontinentia pigmenti, which is caused by a genomic rearrangement of the gene for nuclear factor kappa B essential modulator and has an incidence of 1:40,000. The skin disorder is marked by four stages that occur in most patients.

In stage I, vesicles in linear streaks follow the lines of Blaschko. These lesions are present at birth in 50% of cases and wax and wane for up to 1 year. In stage II, verrucous-hyperkeratotic streaks usually appear at 2–6 months of age. Stage III is marked by hyperpigmentation in streaks along the lines of Blaschko in a so-called “marble-cake pattern,” she said.

Cutaneous findings in stage IV typically involve atrophy and hypopigmentation that may be subtle. Affected infants may have a lack of hair along the lines of Blaschko.

Recurrence of the vesicular phase may occur, but this typically lasts only 1–2 weeks and is often preceded by a viral illness. “Sometimes these lesions are mistaken for herpes zoster,” Dr. Siegel noted.

Additional findings of incontinentia pigmenti may include scarring alopecia, most commonly on the vertex; conical or peg-shaped teeth; absence of teeth; nail dystrophy; and abnormal sweating.

“The management of incontinentia pigmenti in the newborn period should focus on skin care with emollients and monitoring for skin infection,” she said.

“Topical steroids can sometimes be beneficial for symptomatic relief in the verrucous phase. Referral to an ophthalmologist for a retinal exam is important. If neurologic symptoms are present, then evaluation includes an EEG and an MRI,” she added.

Neurofibromatosis Type 1

Dr. Siegel concluded her presentation by discussing neurofibromatosis type 1 (NF1), a multisystem disorder caused by a mutation of a gene on the long arm of chromosome 17 that occurs in about 1 in 4,000 births.

According to the 1988 National Institutes of Health Consensus Development Conference, a diagnosis of NF1 requires two or more of the following clinical features: six or more café-au-lait macules, two or more neurofibromas or one or more plexiform neurofibromas, freckling in the axilla and inguinal region (Crowe's sign), tumor of the optic nerve pathway, two or more Lisch nodules (iris hamartomas), and distinctive osseous lesions.