Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology, Seventh Edition


Genetic Diseases


Pseudoxanthoma Elasticum ICD-9: 757.39 image ICD-10: Q82.810 image

image Pseudoxanthoma elasticum (PXE) is a serious hereditary disorder of connective tissue that involves the elastic tissue in the skin, blood vessels, and eyes. Autosomal recessive (most common) and autosomal dominant. Incidence: 1:40,000 to 1:100,000.

image Etiology and Pathogenesis: Pathogenic mutation in the ABCC6 gene, which encodes MRP6, a member of the ATPase-dependent transmembrane transporter family of proteins. MRP6 can serve as an efflux pump transporting small-molecular-weight glutathione conjugates, which may facilitate calcification of elastic fibers.

image The principal skin manifestations are a distinctive peau d’ orange surface pattern resulting from closely grouped clusters of yellow (chamois-colored) papules in a reticular pattern on the neck, axillae, and other body folds (Fig. 16-1).

image The effects on the vascular system include GI hemorrhage, hypertension occurring in young persons and resulting from involvement of renal arteries, and claudication.

image Ocular manifestations (“angioid” streaks and retinal hemorrhages) can lead to blindness.

image Dermatopathology: Biopsy of a scar can detect characteristic changes of PXE before typical skin changes are apparent. Swelling and irregular clumping and basophilic staining of elastic fibers, elastic fibers appear curled and “chopped up,” with calcium deposition.

image Imaging: X-ray—extensive calcification of the peripheral arteries of the lower extremities. Arteriography of symptomatic vessels.

image The course is inexorably progressive. Gastric artery hemorrhage → hematemesis. Peripheral vascular disease → cerebrovascular accidents, atherosclerosis obliterans, or bowel angina. Pregnancies are complicated by miscarriage, cardiovascular complications. Blindness. Life span is often shortened due to myocardial infarction or massive GI hemorrhage.

image Management: Genetic counseling. Evaluate family members for PXE. Regular reevaluation by primary care physician and ophthalmologist is mandatory.

image Support organization: PXE International,


Figure 16-1. Pseudoxanthoma elasticum Multiple, confluent, chamois-colored or yellow papules (pseudoxanthomatous) create a large, circumferential, pebbled plaque on the neck of a 32-year-old woman. Changes in the connective tissue in this condition lead to excessive folds on the lateral neck.

Tuberous Sclerosis (TS) ICD-9: 759.5 image ICD-10: Q85.1 image

image Tuberous sclerosis is an autosomal-dominant disease arising from a genetically programmed hyperplasia of ectodermal and mesodermal cells and manifested by a variety of lesions in the skin, CNS (hamartomas), heart, kidney, and other organs.

image The principal early manifestations are the triad of seizures, mental retardation, and congenital white spots.

image Facial angiofibromata are pathognomonic but do not appear until the third or fourth year.


Incidence. In mental institutions, 1:100 to 1:300; in general population, 1:20,000 to 1:100,000.

Age of Onset. Infancy.

Sex. Equal incidence.

Race. All races.

Heredity. Autosomal dominant. TS is caused by mutations in a tumor-suppressor gene, either TSCS1 or TSCS2. TSCS1 maps to chromosome 9q34. TSCS2 maps to 16p13.3.


Genetic alterations of ectodermal and mesodermal cells with hyperplasia, with a disturbance in embryonic cellular differentiation.

Clinical Manifestation

White macules are present at birth or appear in infancy (>80% occur by 1 year of age, 100% appear by 2 years); >20% of angiofibromata are present at 1 year of age, 50% occur by 3 years. Seizures (infantile spasms) occur in 86%; the earlier the onset of seizures, the worse the mental retardation. Mental retardation (49%).

Skin Lesions. 96% incidence.

Hypomelanotic Macules. “Off-white”; one or many, usually more than three. Polygonal or “thumbprint,” 0.5–2 cm; lance ovate or “ash-leaf” spots (Fig. 16-2), 3–4 cm (up to 12 cm); tiny white “confetti” macules, 1–2 mm (Fig. 16-3). White macules occur on trunk (>), lower extremities (>), upper extremities (7%), head and neck (5%). White macules shine up with Wood light (Fig. 16-2B)


Figure 16-2. Tuberous sclerosis: ash-leaflet hypopigmented macules (A) Three well-demarcated, elongated (ash-leaflet shaped), hypomelanotic macules on the lower leg of a child with tan skin. (B) Ash-leaflet hypomelanotic macules in pale skin are better visualized under Wood light where they light up.


Figure 16-3. Tuberous sclerosis: “confetti” macules Multiple, discrete, small, confetti-like, hypopigmented macules of variable size on the leg. These lesions are pathognomonic.

Angiofibromas. 0.1–0.5 cm, dome-shaped and smooth, exhibiting red or skin color (Fig. 16-4). Occur in the center of the face. They are firm and disseminated but may coalesce; termed adenoma sebaceumbut represent angiofibromas (present in 70%).


Figure 16-4. Tuberous sclerosis: angiofibromas Confluent, small, angiomatous (erythematous, glistening) papules on the cheek and nose. These lesions were not present during the first few years of life; appeared only after the age of 4 years.

Plaques. Represent connective tissue nevi (“shagreen” patch), present in 40%; skin colored; occur on the back and buttocks (Fig. 16-5B).


Figure 16-5. Tuberous sclerosis: (A) Periungual fibroma (Koenen tumor). (B) Shagreen patch, slightly elevated, skin colored. This represents a connective tissue nevus.

Periungual Papules or Nodules. Ungual fibromas (Koenen tumors) present in 22%, arise late in childhood, and have the same pathology (angiofibroma) as the facial papules (Fig. 16-5A).

Associated Systems

CNS (tumors producing seizures), eye (gray or yellow retinal plaques, 50%), heart (benign rhabdomyomas), hamartomas of mixed cell type (kidney, liver, thyroid, testes, and GI system).

Laboratory Examinations

Dermatopathology. White Macules. Decreased number of melanocytes, decreased melano-some size, decreased melanin in melanocytes and keratinocytes.

Angiofibromata. Proliferation of fibroblasts, increased collagen, angioneogenesis, capillary dilatation, absence of elastic tissue.

Brain Pathology. “Tubers” are gliomas.

Imaging. Skull X-Ray. Multiple calcific densities.

CT Scan. Ventricular deformity and tumor deposits along the striothalamic borders.

MRI. Subependymal nodules.

Electroencephalography. Abnormal.

Renal Ultrasound. Reveals renal hamartoma.


More than five ash leaf macules (Fig. 16-2) in an infant are highly suggestive. Confetti spots (Fig. 16-2) are virtually pathognomonic. Evaluate the patient with a study of the family members and by obtaining various types of imaging as well as electroencephalography. Mental retardation and seizures may be absent.

Differential Diagnosis

White Spots. Focal vitiligo, nevus anemicus, tinea versicolor, nevus depigmentosus, postinflammatory hypomelanosis.

Angiofibromas. Tricholemmoma, syringoma, skin-colored papules on the face, dermal nevi.

Note: angiofibromata of the face (Fig. 16-4) have been mistaken for and treated as acne vulgaris or rosacea.

Periungual Fibromas. Verruca vulgaris.

Course and Prognosis

A serious autosomal disorder that causes major problems in behavior, because of mental retardation, and in therapy, to control the serious seizure problem present in many patients.

In severe cases, 30% die before the fifth year of life, and 50–75% die before reaching adult age. Malignant gliomas are not uncommon. Genetic counseling is imperative.


Prevention. Counseling.

Treatment. Laser surgery for angiofibromas.

Support organization:

Neurofibromatosis (NF) ICD-9: 237.7 image ICD-10: Q85.0 image

image NF is an autosomal-dominant trait manifested by changes in the skin, nervous system, bones, and endocrine glands. These changes include a variety of congenital abnormalities, tumors, and hamartomas.

image Two major forms of NF are recognized: (1) classic von Recklinghausen NF, termed NF1, and (2) central or acoustic NF, termed NF2.

image Both types have café-au-lait macules and neurofibromas, but only NF2 has bilateral acoustic neuromas (unilateral acoustic neuromas are a variable feature of NF1).

image An important diagnostic sign present only in NF1 is pigmented hamartomas of the iris (Lisch nodules).

image Synonym: von Recklinghausen disease.


Incidence. NF1: 1:4000; NF2: 1:50,000.

Race. All races.

Sex. Males slightly more than females.

Heredity. Autosomal dominant; the gene for NF1 is on chromosome 17 (q1.2) and the gene codes for a protein named neurofibromin. The gene for NF2 is on chromosome 22 and codes for a protein called merlin.


Action of an abnormal gene on cellular elements derived from the neural crest: melanocytes, Schwann cells, endoneurial fibroblasts.

Clinical Manifestation

Café-au-lait (CAL) macules are not usually present at birth but appear during the first 3 years; neurofibromata appear during late adolescence. Clinical manifestations in various organs are related to pathology: hypertensive headaches (pheochromocytomas), pathologic fractures (bone cysts), mental retardation, brain tumor (astrocytoma), short stature, precocious puberty (early menses, clitoral hypertrophy).

Skin Lesions. CAL Macules. Light or dark brown uniform melanin pigmentation with sharp margination. Lesions vary in size from multiple “freckle-like” tiny macules <2 mm (Fig. 16-6, “axillary freckling” is pathognomonic) to large brown macules >20 cm (Fig. 16-7). CAL macules also vary in number, from a few to hundreds.


Figure 16-6. Neurofibromatosis (NF1) Several larger (>1 cm) café-au-lait macules on the upper chest and multiple small macules on the axillae (axillary “freckling”) in a brown-skinned female. Myriads of early, small, pink-tan neurofibromas on the chest, breasts, and neck.


Figure 16-7. Neurofibromatosis (NF1) Skin-colored and pink-tan, soft papules and nodules on the back are neurofibromas. The lesions first appeared during late childhood. One large café-au-lait macule on the back. The large, soft, ill-defined, subcutaneous nodule on the right lower back and on the right posterior axillary line are plexiform neuromas.

Papules/Nodules (Neurofibromas). Skin-colored, pink, or brown (Fig. 16-7); flat, dome shaped or pedunculated (Fig. 16-8); soft or firm, sometimes tender; “buttonhole sign”—invagination with the tip of the index finger is pathognomonic.


Figure 16-8. Neurofibromatosis (NF1) An excessively large number of small and large, pedunculated neurofibromas on the chest of a 56-year-old woman who also had a severely distorted face due to multiple neurofibromas and plexiform neuromas.

Plexiform Neuromas. Drooping, soft (Figs. 16-7 and 16-9), doughy; may be massive, involving entire extremity, the head, or a portion of the trunk.


Figure 16-9. Neurofibromatosis (NF1) Plexiform neuroma on the sole of the foot of a child. This ill-defined subcutaneous mass is soft and asymptomatic. The patient has café-au-lait macules and multiple neurofibromas.

Distribution. Randomly distributed but may be localized to one region (segmental NF1). The segmental type may be heritable or a sporadic hamartoma.

Other Physical Findings. Eyes. Pigmented hamartomas of the iris (Lisch nodules) begin to appear at the age of 5 and are present in 20% of children with NF before age 6 but can be found in 95% of patients with NF1 in adolescence (Fig. 6-10). They do not correlate with the severity of the disease. They are not present in NF2.


Figure 16-10. Lisch nodules are visible only by slit-lamp examination and appear as “glossy” transient dome-shaped yellow to brown papules of up to 2 mm.

Musculoskeletal. Cervicothoracic kyphoscoliosis, segmental hypertrophy.

Adrenal Pheochromocytoma. Elevated blood pressure and episodic flushing.

Peripheral Nervous System. Elephantiasis neuromatosa (gross disfigurement from NF of the nerve trunks).

Central Nervous System. Optic glioma, acoustic neuroma (rare in NF1 and unilateral, but common and bilateral in NF2), astrocytoma, meningioma, neurofibroma.

Laboratory Examinations

Wood Lamp Examination. In white persons with pale skin, the CAL macules are more easily visualized with Wood lamp examination.

Diagnosis and Differential Diagnosis

Two of the following criteria:

1. Multiple CAL macules—more than six lesions with a diameter of 1.5 cm in adults and more than five lesions with a diameter of 0.5 cm or more in children younger than 5 years.

2. Multiple freckles in the axillary and inguinal regions.

3. Based on clinical and histologic grounds, two or more neurofibromas of any type, or one plexiform neurofibroma.

4. Sphenoid wing dysplasia or congenital bowing or thinning of long bone cortex, with or without pseudoarthrosis.

5. Bilateral optic nerve gliomas.

6. Two or more Lisch nodules on slit-lamp examination.

7. First-degree relative (parent, sibling, or child) with NF1 by the preceding criteria.

Differential Diagnosis. Brown CAL-type macules: Albright syndrome (polyostotic fibroma, dysplasia, and precocious puberty); note: a few CAL macules (three or less) may be present in 10–20% of normal population.

Course and Prognosis

There is variable involvement of the organs affected over time, from only a few pigmented macules to marked disfigurement with thousands of nodules, segmental hypertrophy, and plexiform neuromas. The mortality rate is higher than in the normal population, principally because of the development of neurofibrosarcoma during adult life. Other serious complications are relatively infrequent.


Cosmetic Counseling. NF support groups help with social adjustment in severely affected persons.

An orthopedic physician should manage the two major bone problems: kyphoscoliosis and tibial bowing. A plastic surgeon can do reconstructive surgery on the facial asymmetry. The language disorders and learning disabilities should be evaluated by a psychologist. Close follow-up annually should be mandatory to detect sarcomas that may arise within plexiform neuromas.

Surgical removal of pheochromocytoma.

Support Group:

Hereditary Hemorrhagic Telangiectasia

ICD-9: 448.0 image ICD-10: I78.0 image

image Hereditary hemorrhagic telangiectasia is an autosomal-dominant condition affecting blood vessels, especially in the mucous membranes of the mouth and the GI tract.

image The disease is frequently heralded by recurrent epistaxis that appears often in childhood.

image The diagnostic lesions are small, pulsating, macular and papular, usually punctate, telangiectases (Figs. 16-11A and B) on the lips, tongue, face, palms/soles, fingers/toes, nail beds, tongue, conjunctivae, nasopharynx, and throughout the GI and genitourinary tracts. In the 18-year-old male, shown in Fig. 16-11A, there had been repeated epistaxis, but the telangiectasias had gone unnoticed until the patient was evaluated for anemia. Careful history revealed that the patient’s father had a minor form of the same condition.

image Pulmonary arteriovenous fistulas may occur.

image Chronic blood loss results in anemia.

image Electrocautery and pulse dye laser are used to destroy cutaneous and accessible mucosal lesions. Estrogens have been used to treat recalcitrant bleeding.

image Synonym: Osler–Weber–Rendu syndrome.


Figure 16-11. Hereditary hemorrhagic telangiectasia (A) Multiple 1–2 mm, discrete, red macular and papular telangiectases on the lower lip and tongue. (B) Multiple pinpoint telangiectases on the index finger of another patient. Using dermatoscopy or a glass slide, the lesions can be shown to pulsate.