Hyperpigmented Macules and Soft, Flesh-Colored Masses

THE CASE: Generalized weakness and malaise have bothered a 44-year-old woman for a few days. The patient has several large, flat facial lesions (

A

) that have been present for years; she has never consulted a physician about them. They are not painful or pruritic and have not changed in size or color.

Examination of the skin reveals 16 hyperpigmented macules on the torso, back, and upper extremities. Freckling is present in the groin and axillary areas (B). Several soft, raised, nontender, flesh-colored masses are noted on the trunk (C), and a large, fleshy mass is present on the tongue.

Which of these conditions best explains the findings?

• McCune-Albright syndrome

• Watson syndrome

• von Recklinghausen disease

• Idiopathic caf au lait spots

(Answer and discussion on next page.)

DISCUSSION: The patient has

von Recklinghausen disease,

also known as neurofibromatosis type 1 (NF1), an autosomal dominant disorder that is carried on chromosome 17. Mutations of the

NF1

gene result in loss of function of neurofibromin, a tumor-suppressor protein that belongs to the family of glutamyl transpeptidase-activating proteins involved in cell growth and regulation. Neurofibromin is found in the tissues of several organs, including the brain and kidneys.

A diagnosis of NF1 is made if the patient has 2 or more of the following criteria:

• Six or more caf au lait macules larger than 5 mm in prepubertal children and larger than 15 mm in postpubertal persons.

• Two or more neurofibromas of any type or one plexiform neurofibroma.

• Freckling in the axillary or inguinal area.

• Two or more Lisch nodules (iris hamartomas).

• Optic glioma.

• Distinctive bony lesions, including pseudoarthritis and bone dysplasia. Short stature and scoliosis are possible.

• A first-degree relative with NF1 based on the above criteria.

In addition to cutaneous manifestations, NF1 may cause or be associated with optic pathway gliomas, other CNS neoplasms, learning disabilities and cognitive defects, macrocephaly, peripheral neuropathy, and hypertension. In our patient, the presenting symptoms of generalized weakness and malaise were unrelated to NF1.

Management is best undertaken by a multidisciplinary team that can provide anticipatory guidance as well as treatment for the expected complications, which most often involve invasion of neurofibromas into nerve sheaths and surrounding tissue. This results in the development of neoplasms, motor disability, and disfigurement.

McCune-Albright syndrome is attributable to post-zygotic mutation after fertilization; bone and skin involvement usually affects only one side of the body. The diagnostic triad consists of café au lait spots, polyostotic fibrous dysplasia of the long bones, and precocious puberty. Other features may include multinodular goiter and hyperfunction of several glands that can lead to Cushing syndrome, acromegaly, hyperthyroidism, or hyperparathyroidism. A variety of nonendocrine disorders, such as chronic liver disease, hypophosphatemia, and tachycardia may also be associated with this condition.

Watson syndrome is an autosomal dominant disorder that is carried on chromosome 17. It was originally thought to consist of pulmonary valvular stenosis, café au lait spots, axillary freckles, mental deficiency, and short stature. The criteria were later expanded to include macrocephaly and Lisch nodules (which are found in most patients) and neurofibromatosis (which is found in one third of patients). The characteristics of Watson syndrome overlap those of NF1 and Noonan syndrome.

Café au lait spots are macular lesions that vary in color from light to dark brown. These lesions, which result from increased melanin content within giant melanosomes, usually develop in early infancy, vary in size and number, and are often the first manifestation of NF1. Solitary lesions in newborns are seen in 18% of blacks, 3% of Hispanics, and 0.3% of whites. Solitary lesions in childhood are seen in 27% of blacks and 13% of whites.

Café au lait spots are considered significant (ie, not idiopathic) if there are 5 or more in children or 6 or more in adults, and if they are 5 mm or larger in children younger than 5 years and 15 mm or larger in persons older than 5 years. Suspect a genetic disorder if a patient has multiple or large lesions.

References:

FOR MORE INFORMATION:

• Albright F, Butler AM, Hampton AO. Syndrome characterized by osteitis fibrosa disseminata, area of pigmentation and endocrine dysfunction, with precocious puberty in females. N Engl J Med. 1937;216:727-747.
• Allanson JE, Watson GH. Watson syndrome. Nineteen years on. Proceedings of the Greenwood Genetic Center. Greenwood, SC. 1987;6:173.
• Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick's Dermatology in General Medicine. 6th ed. New York: McGraw-Hill; 2003.
• Plon SE, Blazo M. Neurofibromatosis type 1 (von Recklinghausen's disease). Up-to-Date 2005; version 13.2.