Abstract
Purpose: To describe a case of periungual masses probably related to tuberous sclerosis and to review the literature regarding tuberous sclerosis, including the historical, clinical, and diagnostic aspects. Also discussed is the long-term follow-up of the disease.
Methods: Report of a case of periungual masses secondary to tuberous sclerosis and review of the literature from 1999 to 2009, with the use of MEDLINE (National Library of Medicine).
Results: I describe a case of periungual masses occurring as a result of tuberous sclerosis. A literature review confirms periungual masses associated with tuberous sclerosis in most cases. Also, the observance of cutaneous manifestations is most helpful in the diagnosis of this disorder.
Conclusion: Tuberous sclerosis is an uncommon disorder, which has a variable clinical presentation. Tuberous sclerosis is associated with seizures and mental retardation. In the absence of these 2 signs/symptoms, physicians should still consider the diagnosis when presented with varied dermatologic conditions.
INTRODUCTION
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome. It is characterized by a widely variable phenotype and the development of multiple hamartomas distributed at various sites throughout the body, especially the brain, skin, retina, kidney, heart, and lung.1–4 The prevalence is not well defined, with reported incidence of from 1∶6,000 to more than 1∶100,000.1–13 This is perhaps due to undiagnosed or mildly affected symptomatic individuals.1 There appear to be 2 major loci where mutations can cause TSC: TSC1 9q34 and TSC2 at 16p13.3.5,7,14 Also, 50% to 84% of cases are sporadic as new mutations.4–7 Although the classic triad of TSC is seizures, mental retardation, and angiofibromas, this triad occurs in only 29% of patients.1,14 However, skin involvement is cardinal for suspecting the diagnosis of TSC.5,8,9 In the following case, periungual fibromas are a major criterion for diagnosing TSC.
CASE
A 56-year-old white woman presented with multiple growths on every digit of both feet. She related a history of having had them since her early twenties. The mass on the second toe of the right foot impeded her wearing shoes comfortably. She had not shown these masses to anyone, including her primary physician. She related a past history of seizures as a very young child for which she continues to receive medication. She also has had 3 miscarriages, which were associated with a “malfunctioning kidney.” No records were attainable for review. The rest of the history was negative, and she appeared to have normal cognitive function. There was no family history of tuberous sclerosis.
The examination revealed pedal digits displaying multiple lobulated fibromas. The largest mass measured 3 × 2.5 cm (Figure 1).
Clinical appearance of periungual fibromas. Left: right foot; right: left foot.
Results from the neurovascular examination of the lower extremity were normal. The orthopedic examination demonstrated bilateral hallux abductovalgus deformities. Radiographs revealed bone cysts in multiple digits. Surgical intervention with sharp excision was performed owing to the size and severity of the lesions.
The lesions were histologically identified as consistent with tuberous sclerosis by both Ochsner Clinic Foundation and Mayo Clinic (Figure 2).
Photomicrograph showing histopathology of the lesions.
The postoperative period was uneventful. The patient developed a small reoccurrence of the lesion on 1 digit of her left foot 4 months postoperatively. She is pain free and able to wear shoes.
DISCUSSION
Tuberous sclerosis syndrome has been referred to in the literature as Bourneville disease, Pringle disease, and epiloia.15 These all refer to the entity of TSC that is highly variable even within families.14 To aid with the diagnosis of this disorder, criteria for major and minor features have been devised. A definite diagnosis requires 2 major features or 1 major and 2 minor features.4 A probable diagnosis of TSC requires 1 major and 1 minor feature.1
Major features:
Facial angiofibromas or forehead plaque
Nontraumatic ungual or periungual fibroma
Hypomelanotic macule (3 or more)
Shagreen patch (connective tissue nevus)
Multiple retinal nodular hamartomas
Cortical tuber
Subependymal nodule
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma, single or multiple
Lymphangiomyomatosis
Renal angiomyolipoma
Minor features:
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
DNA testing is useful for diagnosis and for determining the causative mutation. However, approximately 30% of patients with TSC have negative results for genetic testing of TSC1 and TSC2.3 Therefore, a careful skin examination for patients at risk for TSC is the easiest and most accessible method to establish a diagnosis. One must be aware that all diagnostic features are age dependent.1,3
The most common skin lesions are hypomelanotic macules (ash-leaf spots) that occur in more than 90% of patients with TSC. They are best visualized by Wood light.1,3 Other cutaneous clinical features include forehead plaques, shagreen patch, and facial angiofibromas.5,16 Koenen fibromas develop in up to 50% of cases of TSC, with onset occurring around puberty.1,4,5,17,18 These tumors range in size and can involve every digit. The feet are more commonly involved than the hands. The nodules are usually skin colored or reddish, arising from the nail bed. Histologically, they are fibromas or angiofibromas similar to fibrous forehead plaques and facial anigiofibromas.1,3,17 The presence of periungual fibromas is a major criterion in the diagnosis of TSC and, as in facial angiofibromas, it is nearly always pathognomonic for TSC (Table).
Cutaneous Manifestations of Tuberous Sclerosis
TSC has many extracutaneous manifestations. Neurologic manifestations are the leading cause of morbidity and mortality in TSC. Brain hamartomas are often responsible for intractable seizures most commonly seen as infantile spasms. Approximately 90% to 96% of patients with TSC suffer from seizures.1 Many patients with TSC experience mental retardation, autism, and increased intracranial pressure.3 Renal and pulmonary manifestations are strongly associated with TSC. Angiomyolipoma is the most common renal lesion (up to 80%) found in patients with TSC. Pulmonary involvement is relatively rare. Cardiovascular features are often the earliest diagnostic finding.1 The lesions are usually asymptomatic unless they cause obstruction of flow.3 Ocular findings of TSC are retinal hamartomas and occur in 40% to 50% of patients.1 These most often do not cause visual dysfunction. Numerous other findings include tooth pitting and radiographic abnormalities. TSC often presents with bone abnormalities that do not limit motion. All bones may show osteoclastic lesions; the characteristic changes are patches of osteosclerosis. The bones of the hand and feet may show cystlike areas, particularly in the distal phalanges.19 However, these rarely attract medical attention.1,3
With the variable expression of TSC, it is often difficult to diagnose this entity. As in the case presented, all the pieces of the puzzle may not come together until later in life. A diagnostic work-up should include a careful history and skin examination. If infantile spasms or autism are present, magnetic resonance imaging (MRI) of the brain is indicated. If these investigations are inadequate for diagnosis of TSC, an ophthalmologic examination for retinal hamartomas or renal ultrasonography may provide confirmatory evidence. Echocardiography is usually not helpful beyond the age of 2 years because cardiac rhabdomyomas regress with advancing age.3
Follow-up testing after the diagnosis puts focus on treatment or prevention of problems. If there are no seizures, an electroencephalogram is not needed. Neurodevelopment testing is done upon school entry. Giant cell astrocytomas of the brain typically do not grow after the second decade of life, whereas renal angiomyolipomas often enlarge during early adulthood. Therefore, MRI of the brain is repeated every 1 to 3 years during childhood and adolescence. Renal ultrasonography is repeated every 1 to 3 years.3
TREATMENT
The cutaneous lesions, as identified in this case, were sharply excised as demonstrated (Figure 3).
Procedure for excision of lesions.
Treatment options included using a CO2 laser, which provides efficient and bloodless extraction of the lesions,4,8 or phenolization that allows for a better cosmetic result.5,8,9,15 However, in this case, the severity and penetration of the lesion into bone led to the decision to perform a sharp excision of the mass. The nail bed was not salvageable. The reoccurrence rate of Koenen tumors is high. Complete excision is required to achieve a permanent cure.20
Recent discoveries have led to the use of oral rapamycin to induce regression of tumors associated with TSC. This may represent a major advance in therapy.1,20–22
CONCLUSION
TSC is a multisystem disorder with variable clinical manifestations. To decrease the morbidity from seizures, an early diagnosis of TSC is essential. The appropriate diagnosis requires a multidisciplinary approach to properly treat affected individuals. This case met the criteria, set forth in this article, for diagnosis as tuberous sclerosis. It demonstrates the need for awareness of the cutaneous manifestations of the disease and of the correlation of these manifestations with other body systems.
- Academic Division of Ochsner Clinic Foundation
