Dermatology Quiz and Case Discussion
From The Child's Doctor, Spring 2012
- Brandi M. Kenner-Bell, MD
- Attending Physician, Dermatology, Ann & Robert H. Lurie Children's Hospital of Chicago; Assistant Professor of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. Kenner-Bell has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.
- Antoinette Chateau, BSc, MBCHB, DCH, FCDerm (SA)
- Fellow, Pediatric Dermatology, Children's Memorial Hospital
- Disclosure: has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.
Other Disclosure Information
At the conclusion of this activity, participants will be able to:
- Recognize the disorder described in the vignette and shown in the photograph
- Describe the clinical features and causes of the condition
- Discuss the management approaches
A 15-month-old female presents with hypopigmented macules measuring approximately 2 cm on the back and thighs since birth and increasing in number over time (Figures 1, 2). She was otherwise a healthy, thriving baby with no systemic or other cutaneous signs on examination.
1. What is the most likely diagnosis?
a. Pityriasis alba
b. Post inflammatory hypopigmentation
d. Tuberous sclerosis
2. What is the most common complication?
Answers: 1d, 2c
Our patient’s MRI brain scan showed white matter foci of increased T1 signal consistent with cortical tubers. ECHO showed echogenicity of the apex of the left ventricle, which may represent rhabdomyomas. A renal ultrasound and EKG were normal. Ophthalmology examination revealed a single hypopigmented spot on the retina. Genetics testing confirmed a mutation in the TSC2 gene.
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystemic neurocutaneous syndrome with variable expressivity, characterized by the development of hamartomas in the skin and vital organs. Vogt’s classic diagnostic triad of symptoms – seizures, mental retardation and cutaneous angiofibromas – is present in 29% of patients while 6% of patients have none of these findings. There is no sexual predilection and the syndrome occurs in up to 1:6000 persons.
TSC is caused by mutations in the TSC1 and TSC2 genes, which encode for hamartin and tuberin, proteins which form complexes that suppress cell growth through the regulation of several signaling pathways. Mutations in these genes result in hamartoma formation. Eighty percent of patients with TSC have mutations in 1 of these genes. Of patients with known mutations, 70% are sporadic.
A suspected diagnosis of TSC is based on a series of clinical criteria. Definite TSC is defined as 2 major features or 1 major and 2 minor features.
Major features include: facial angiofibromas or forehead plaque; nontraumatic ungual or periungual fibroma; hypomelanotic macules (3 or more); shagreen patch (connective tissue nevus); multiple retinal nodular hamartomas; cortical tubers; subependymal nodule; subependymal giant cell astrocytoma; cardiac rhabdomyoma, single or multiple; lymphangiomyomatosis; renal angiomyolipoma.
Minor features include: multiple, randomly distributed pits in dental enamel; hamartomatous rectal polyps; bone cysts; cerebral white matter radial migration lines; gingival fibromas; nonrenal hamartomas; retinal achromic patch; “confetti” skin lesions; multiple renal cysts.
The cutaneous manifestations of TSC are pathognomonic. Hypomelanotic or ash-leaf macules are usually the earliest sign of TSC, noted in 90% of patients. They are usually present at birth or may be evident after a few months of age. The macules may be ovate or linear, often resembling a thumbprint, located mainly on the trunk and buttocks. Confetti macules of TSC are 1-3 mm macules noted on the extremities around the second decade of life.
Facial angiofibromas are erythematous to pink papules symmetrically distributed over the face mainly on the nasolabial folds, cheeks and chin. They occur between the second and fifth decade of life and become more prominent with advancing age. Facial angiofibromas are also seen in multiple endocrine neoplasia (MEN 1) and in neurofibromatosis; the clinical features and genetic testing help to differentiate these syndromes.
Connective tissue hamartomas are common in TSC. The shagreen patch is a yellowish or erythematous plaque over the lumbosacral region, usually present in childhood and can increase in size and number with age. The forehead fibrous plaque is a yellow-brown or skin colored plaque on the forehead or scalp, which is usually present at birth or in early infancy. Periungual fibromas or Koenen’s tumors are erythematous or skin colored papules arising from the nail bed of the fingers and toes that occur in early adolescence.
The morbidity and mortality of TSC stem from the many systemic manifestations of the disease. Brain hamartomas in the form of cortical tubers, subependymal nodules and subependymal astrocytomas are responsible for the seizures that affect 90% of patients with TSC. Behavioral and cognitive dysfunction, including mental retardation and autism, are present in 40%-50% of children with TSC. Eighty percent of patients with TSC have renal involvement by the end of the first decade of life; they present with renal cysts resembling polycystic renal disease and angiomyolipomas, which may present with hypertension or hemorrhage. A late sequela of TSC is lymphangiomyomatosis, seen in affected women in the third decade of life who present with cystic lung lesions and pneumothorax.
One of the earliest manifestations of TSC are cardiac rhabdomyomas, which can often be detected in utero. Rhabdomyomas are only present in 47%-60% of patients with TSC, but 80%-95% of patients with rhabdomyoma have TSC. They are usually benign and asymptomatic, but may rarely present with Woolf Parkinson White syndrome, cardiac failure and sudden death. However, the majority of rhabdomyoma cases resolve spontaneously. Retinal hamartomas are noted in 40%-50% of patients with TSC; they are relatively asymptomatic and remain stable over time.
Diagnosis of TSC relies heavily on recognizing the cutaneous manifestations. Confirmatory testing may include MRI, echocardiogram, opthalmology exam and renal ultrasound. EEG, EKG, chest x-ray, and CT scans are considered based on any concerning signs or symptoms, such as seizures.
Management of TSC is directed at treatment of the individual manifestations. Seizures are controlled with novel antiepileptics such as vigabatrin, thus decreasing the risk of developmental delay and mental retardation. It should be noted that phenytoin, often used to control seizures, may enhance the growth of gingival fibromas. Treatment of cutaneous angiofibromas is difficult with a high percentage of recurrence after treatment. Traditional treatments include destructive lasers, curettage, dermabrasion and excision.
Rapamycin, an inhibitor of mTOR signaling, is a novel therapeutic option with promising results. Systemic rapamycin has been shown to regress renal angiomyolipomas, pulmonary lymphangiomyomas, facial angiofibromas and cerebral astrocytomas. Topical rapamycin has been used to treat facial angiofibromas with some success.
A multidisciplinary approach is essential for early, accurate diagnosis and appropriate management of affected patients to alleviate morbidity and mortality associated with this syndrome. The prognosis of tuberous sclerosis is guarded and depends on disease expressivity/severity.
For Further Reading
[1.] Paller A, Mancini A, eds. Hurwitz Clinical Pediatric Dermatology. 4th ed. London: Elsevier; 2011:244-246.
[2.] Schwartz R, et al. Tuberous sclerosis complex: advances in diagnosis, genetics and management. J Am Acad Dermatol 2007;57:189-202.