44-Year-Old Woman with Weakness and Malaise

THE CASE: Generalized weakness and malaise have bothered a 44-year-old woman for a few days. The patient has several large, flat fa- cial lesions (A) that have been pres- ent for years; she has never consult- ed 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 extremi- ties. 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 café 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 dis- order that is carried on chromo- some 17. Mutations of the NF1 gene result in loss of function of neurofi- bromin, a tumor-suppressor protein that belongs to the family of glu- tamyl transpeptidase-activating pro- teins involved in cell growth and regulation. Neurofibromin is found in the tissues of several organs, in- cluding the brain and kidneys.

A diagnosis of NF1 is made if the patient has 2 or more of the fol- lowing criteria: •Six or more café 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, includ- ing pseudoarthritis and bone dyspla- sia. Short stature and scoliosis are possible.

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

In addition to cutaneous mani- festations, NF1 may cause or be as- sociated with optic pathway gliomas, other CNS neoplasms, learning disabilities and cognitive defects, macrocephaly, peripheral neuropa- thy, and hypertension. In our pa- tient, the presenting symptoms of generalized weakness and malaise were unrelated to NF1.

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

McCune-Albright syndrome is at- tributable to post-zygotic mutation after fertilization; bone and skin in- volvement usually affects only one side of the body. The diagnostic triad consists of café au lait spots, poly- ostotic fibrous dysplasia of the long bones, and precocious puberty. Oth- er features may include multinodular goiter and hyperfunction of several glands that can lead to Cushing syn- drome, acromegaly, hyperthyroid- ism, or hyperparathyroidism. A vari- ety of nonendocrine disorders, such

as chronic liver disease, hypophos- phatemia, and tachycardia may also be associated with this condition.

Watson syndrome is an autoso- mal 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 macro- cephaly and Lisch nodules (which are found in most patients) and neu- rofibromatosis (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 le- sions that vary in color from light to dark brown. These lesions, which result from increased melanin con- tent within giant melanosomes, usu- ally develop in early infancy, var y in size and number, and are often the first manifestation of NF1. Soli- tary lesions in newborns are seen in 18% of blacks, 3% of Hispanics, and 0.3% of whites. Solitar y lesions in childhood are seen in 27% of blacks and 13% of whites.

Café au lait spots are consid- ered 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. Sus- pect a genetic disorder if a patient has multiple or large lesions. 

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