Splenic-flexure syndrome

Genodermatoses are inherited disorders with dermatologic manifestations. Many of these disorders are autosomal dominant, and most are quite rare. Some are associated with subsequent disease-related malignancy (Table 1). Physicians need to maintain a high index of suspicion for the development of cancer in patients who have genodermatoses with malignant potential.

Nevoid Basal Cell Carcinoma Syndrome

Since the first description of nevoid basal cell carcinoma syndrome, also known as basal cell nevus syndrome and Gorlin's syndrome, more than 300 case reports have been published. Major manifestations of the syndrome include multiple basal cell carcinomas (Figure 1), odontogenic keratocysts of the jaws, skeletal anomalies (most commonly involving the ribs and vertebrae), ectopic calcification with lamellar calcification of the falx cerebri, and pits of the palms and soles (Figure 2).

Basal cell carcinomas, palmoplantar pits, epithelial cysts, milia, fibromas, lipomas, care au lait spots and dermal calcinosis are the cutaneous findings that may be present in patients with nevoid basal cell carcinoma syndrome. In addition to rib anomalies (bifid, splaying and synostoses) and vertebral anomalies (scoliosis and spina bifida), associated skeletal abnormalities include jaw cysts, sellar bridging, cystic changes of the long bones and phalanges, brachymetacarpia, frontal bossing, defective dentition and prognathism (Figure 3). Gonadal, neurologic and ophthalmologic lesions may also be present. (1)

Patients with nevoid basal cell carcinoma syndrome continue to develop numerous basal cell carcinomas throughout their lives. Clinically, these lesions may appear as benign pigmented nevi (Figure 4 ). Noncutaneous neoplasms that have been observed in patients with the syndrome include medulloblastomas, meningiomas, neoplasms arising from the jaw cysts (squamous cell carcinomas, ameloblastomas, spindle cell carcinomas and fibrosarcomas), Hodgkin's disease, nasopharyngeal rhabdomyosarcoma and ovarian adenocarcinoma.(2)

Cowden's Disease

Cowden's disease, or multiple hamarroma syndrome, is characterized by multiple wart-like facial papules called trichilemmomas, gingival papillomas, acral keratoses, palmoplantar keratoses and other hamartomatous lesions. The incidence of breast and thyroid carcinoma is high in patients with this disease. In addition to the cutaneous manifestations of Cowden's disease, benign noncutaneous lesions may involve the thyroid gland, the female and male breasts or genitourinary tract, the gastrointestinal tract, the skeletal system, the nervous system and/or the eye.

Breast and thyroid carcinomas are the most commonly reported neoplasms in Cowden's disease. Breast cancer, usually a ductal adenocarcinoma, is so common that prophylactic mastectomy has been recommended for patients with Cowden's disease.3 Other malignancies associated with the disease include genitourinary cancer (cervix, uterus, ovary and bladder), mucocutaneous cancer (melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin and tongue), hematologic cancer (acute myelogenous leukemia and non-Hodgkin's lymphoma), colon cancer, lung cancer and liposarcoma.(4)

Gardner's Syndrome

Gardner's syndrome is characterized by the presence of colonic polyposis in patients with multiple epidermoid cysts, osteomas, fibromas and/or desmoid tumors. Although the epidermal inclusion cysts are most commonly located on the head and neck, they can also be found on the chest, back and extremities (Figures 5). Other associated features of Gardner's syndrome include dental anomalies, pigmentation of the fundi, and polyps of the stomach and small intestine.s

Bleeding and intestinal obstruction are symptoms of polyposis. Eventually, carcinomatous degeneration of colonic polyps occurs in all patients with Gardner's syndrome. Since malignant transformation usually begins between the ages of 20 and 30 years, early prophylactic colectomy is recommended?

Muir-Torre Syndrome

Muir-Torre syndrome is characterized by sebaceous tumors and associated internal malignancy. Patients with this syndrome often have multiple, low-grade primary neoplasms and prolonged survival after the diagnosis of their initial cancer. Colorectal carcinomas have been observed in 51 percent of these patients. In contrast to colorectal Cancer in the general population, tumors in patients with Muir-Torre syndrome are frequently located proximal to the splenic flexure. Genitourinary malignancies are observed in 25 percent of patients. Colonic polyps are found in more than 25 percent of patients with the syndrome and are especially prevalent in patients with colorectal carcinoma. (7,8)

Cutaneous tumors associated with MuirTorre syndrome include sebaceous adenomas, epitheliomas and carcinomas (Figure 6). The tumors are most commonly located on the face and may appear as yellow papules or nodules. These skin lesions are uncommon or rare; therefore, the detection of even a single sebaceous tumor associated with Muir-Torre syndrome warrants initial and periodic evaluations for cancer. Diagnosis of these sebaceous tumors is important, because they occur before or concurrent with cancer in at least 64 percent of patients with the syndrome. Keratoacanthomas have also been noted in at least 20 percent of patients with Muir-Torre syndrome.(8)

Multiple Endocrine

Neoplasia Syndromes

Patients with multiple endocrine neoplasia (MEN) type lIB or III, also known as mucosal neuroma syndrome, have medullary carcinoma of the thyroid, pheochromocytoma, a distinctive phenotype, mucosal neuromas, intestinal ganglio| neuromatosis and certain neurologic findings. These individuals have a slim, asthenic, marfanoid habitus with some degree of muscle wasting. Skeletal deformities, such as kyphoscoliosis, pes cavus, genu valgum and increased joint mobility, may also be present. Thickening and eversion of the eyelids and linear, yellowish elevations and infiltrations of the conjunctiva result from neuromas of the eyelids, conjunctiva and cornea. The enlarged corneal nerves can be visualized on slit-lamp examination?

Mucocutaneous manifestations of MEN lIB are always present. Skin lesions may include care au lait spots, cutaneous neuromas, circumoral or midfacial lentiginosis (freckling), and diffuse pigmentation of the hands and feet. Mucosal neuromas of the lips, tongue and eyes result in generalized or localized thickening of these features. The neuromas may be present from birth and are localized in the submucosa of virtually all organs and spinal nerve roots.(9)

The gastrointestinal and neurologic systems also have syndrome-associated findings. Diffuse gastrointestinal ganglioneuromatosis can result in diverticu| losis, persistent diarrhea or constipation with megacolon. Somatic and autonomic nervous system involvement, weakness of the ankle and intrinsic foot muscles, and chronic neurologic atrophy may also be present .(10)

The two characteristic endocrine neoplasms are pheochromocytoma and medullary carcinoma of the thyroid. The latter arises from parafollicular or "C" cells, which are derived from the neural crest. In contrast to patients with sporadic medullary carcinoma of the thyroid, which typically appears at around 50 years of age, the average age of onset for medullary carcinoma of the thyroid is 20 years in patients with MEN lIB. (10)

Neurofibromatosis

The diagnosis of type 1 neurofibromatosis, or von Recklinghausen's disease, is based on the presence of two or more of the following features (Figures 7, 8 and 9): (1) six or more care au lait macules that measure over 5 mm in greatest diameter in a prepubertal patient or six or more care au lait macules that measure over 15 mm in greatest diameter in a postpubertal patient (care au lait macules are present in over 99 percent of patients with type 1 neurofibromatosis), (2) two or more neurofibromas of any type or one plexiform neurofibroma, (3) "freckling" (care au lait spots) in the axillary or inguinal regions, termed Crowe's sign, (4) optic glioma, (5) two or more Lisch nodules (pigmented iris hamartomas are present in 94 percent of patients with type 1 neurofibromatosis who are over six years of age), (6) a distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis, and (7) a first-degree relative (parent, sibling or offspring) with type 1 neurofibromatosis as defined by the preceding criteria .(11)

The diagnosis of type 2 neurofibromatosis, also referred to as bilateral acoustic neurofibromatosis, is based on the presence of (1) bilateral masses of the eighth cranial nerve or (2) a first-degree relative with type 2 neurofibromatosis and either a unilateral mass of the eighth cranial nerve or two of the following conditions: neurofibroma, meningioma, glioma, schwannoma or juvenile posterior subcapsular lenticular opacity. (11)

Malignancies in patients with neurofibromatosis include both neural neoplasms and neoplasms of other systems. In addition to acoustic neuromas, optic neuromas, andneuromas of the fifth cranial nerve and spinal nerve roots, neural malignancies include ependymomas, meningiomas and, rarely, medulloblastomas. Nonneural malignancies include those of presumed neural-crest origin (neuroblastoma, pheochromocytoma, medullary thyroid carcinoma and melanoma) and those of nonneuralcrest origin (Wilms' tumor, rhabdomyosarcoma and leukemia). (12)

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is characterized by polyposis of the gastrointestinal tract and macular hyperpigmentation (most frequently perioral). Patients with polyps of the stomach, colon and rectum may present with symptoms of bleeding and anemia, while patients with polyps of the small intestine may present with recurrent intussusception. The polyps in Peutz-Jeghers syndrome are pedunculated nonneoplastic hamartomas with a low malignant potential. However, the risk of colon cancer is higher in patients with this syndrome than in the general population.(13)

The cutaneous stigmata of Peutz-Jeghers syndrome are pigmented (melanin) macules on the lips, gums, buccal mucosa, hard palate, face and acral skin. Pigmentation may be present at birth or may begin in childhood. Although the facial pigmenration may fade with age, the mucosal pigmentation persists. (14)

Nongastrointestinal malignancies, primarily of the reproductive organs, have also been observed in patients with PeutzJeghers syndrome. These malignancies include cervical cancer and granulosacell-derived tumors of the ovary and testicIe. Breast carcinoma has also been reported as an associated neoplasm in these patients.(14)

Porphyria Cutanea Tarda

Porphyria cutanea tarda results from a partial deficiency of the enzyme uroporphyrinogen decarboxylase. In the inherited familial form, the activity of this enzyme is deficient in both erythrocytes and hepatocytes. In contrast, patients with acquired porphyria cutanea tarda only have diminished enzyme activity in their liver cells. (15)

The cutaneous lesions of porphyria cutanea tarda predominantly develop. in sun-exposed areas, such as the face and the dorsal aspect of the hands. Early skin features are vesicles and bullae (Figure 10), increased skin fragility, facial hypertrichosiS (Figure 11) and hyperpigmentation (mimicking melasma). Late cutaneous features consist of scarring, milia, sclerodermoid changes, dystrophic calcifications with ulcerations, and alopecia. (15)

The diagnosis of porphyria cutanea tarda may be suspected on the basis of clinical features. Often, unaltered urine from patients with the disorder will fluoresce reddish brown on examination with a Wood's light. Laboratory confirmation of the disorder is based on elevated urine and plasma porphyrin levels, with the rise in uroporphyrin being greater than that of coproporphyrin. The stool contains a greater excess of coproporphyrin than uroporphyrin, as well as an increased level of isocoproporphyrin. (15)

Patients with porphyria cutanea tarda are at increased risk for primary hepatocellular carcinoma. Therefore, evaluation to rule out a hepatic tumor is recommended in patients with an unexplained exacerbation of previously longstanding porphyria cutanea tarda, atypical urinary porphyrins and/or disease onset at over 60 years of age. Evaluation is also recommended for patients who have the nonfamilial form of porphyria cutanea tarda without the usual precipitating factors.(15,16)

Final Comment

A patient who has the dermatologic manifestations of a genodermatosis with malignant potential should be evaluated to confirm the suspected diagnosis. Once the diagnosis has been established, the patient should be appropriately screened and followed for disease-associated neoplasm. The patient should also receive genetic counseling, and the patient's family members should be evaluated for the genodermatosis.

REFERENCES

1. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine 1987;66:98-113.

2. Gutierrez MM, Mora RG. Nevoid basal cell carcinoma syndrome. A review and case report of a patient with unilateral basal cell nevus syndrome. J Am Acad Dermatol 1986; 15(5 Pt 1):1023-30.

3. Shapiro SD, Lambert WC, Schwartz RA. Cowden's disease. A marker for malignancy. Int J Dermatol 1988;27:232-7.

4. Barax CN, Lebwohl M, Phelps RG. Multiple hamartoma syndrome. J Am Acad Dermatol 1987;17(2 Pt 2):342-6.

5. Traboulsi El, Krush AJ, Gardner EJ, et al. Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome. N Engl J Med 1987;316:661-7.

6. Sanchez MA, Zali MR, Khalil AA, Ponce R, Font RG. Be aware of Gardner's syndrome. A review of the literature. Am J Gastroenterol 1979; 71:68-73.

7. Cohen PR. Muir-Torre syndrome in patients with hematologic malignancies. Am J Hematol 1992;40:64-5.

8. Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med 1991;90:606-13.

9. Fryns JP, Chrzanowska K. Mucosal neuromata syndrome (MEN type lib [III]). J Med Genet 1988;25:703-6.

10. Van Zyl JA, Muller GS, Rossouw DJ, Van Velden DJ. Multiple endocrine neoplasia type lib: a clinicopathological report. J Surg Oncol 1990;45:282-8.

11. Mulvihill Jl, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer MI, Eldridge R. NIH Conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Ann Intern Med 1990; 113:39-52.

12. Hope DG, Mulvihill JJ. Malignancy in neurofibromatosis. Adv Neurol 1981;29:33-56.

13. Perzin KH, Bridge MF. Adenomatous and carcinomatous changes in hamartomatous polyps of the small intestine (Peutz-Jeghers syndrome): report of a case and review of the literature. Cancer 1982;49:971-83.

14. Coen P, Kulin H, Ballantine T, et al. An aromatase-producing sex-cord tumor resulting in prepubertal gynecomastia. N Engl J Med 1991; 324:317-22.

15. Cohen PR, DeLeo VA. Disorders of porphyrin metabolism. In: Alper JC, ed. Genetic disorders of the skin. St. Louis: Mosby, 1991: 79-104.

16. Grossman ME, Bickers DR. Porphyria cutanea tarda. A rare cutaneous manifestation of hepatic tumors. Cutis 1978;21:782-4.

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