Section 11. Genodermatoses

This is a generalized condition in which elastic fibers are degenerative. Clinical signs of the phenomenon can be recognized in the skin and eyes. In the skin, patches of yellowish discoloration and general laxness or redundancy develop on the neck (“chicken skin”), in the axillae, and in other places, such as the fossae of limbs and the inguinal folds, where considerable movement of skin is normal. In the eye, the so-called angioid streaks can be seen. They represent the result of faulty elastic fibers in Bruch's membrane and generally precede the cutaneous changes. These eye changes frequently result in the loss of central vision and sometimes result in almost complete peripheral vision is maintained blindness.

Gastrointestinal hemorrhage is the most serious acute consequence, but slower structural damage in various organs may result in hypertension, coronary artery occlusion, diabetes mellitus, thyroid dyscrasia, or ectopic calcinosis. The disease may be inherited in autosomal recessive or autosomal dominant fashion. This entity is caused by mutations in the ABCC6 gene mapped to chromosome 16p13.1.

In this condition, elastic fibers are decreased in number by an unknown mechanism. As seen in this patient, the skin hangs in folds and produces an appearance of premature aging. Because elastic fibers are affected in all organ systems, intestinal and urinary bladder diverticulae, rectal prolapse, inguinal hernias, and pulmonary emphysema occur frequently. The last of these is associated with significant mortality. The most common and severe form is inherited in autosomal recessive fashion.

This syndrome is actually a collection of ten major genetic types with the common features of hyperextensible skin and joints, easy bruising, defective wound healing, and blood vessel fragility. Distinct abnormalities in collagen synthesis have been identified in some of the varieties of Ehlers-Danlos syndrome. The result of the anomaly is extreme stretchability but unimpaired elasticity (i.e., the ability to return to normal after stretching). The figures illustrate the phenomenon; Fig. 11-5 shows skin of the neck and Fig. 11-6 shows skin of the elbow extended several times more than normal skin can be pulled out.

In these illustrations, more of the hyperextensible phenomena and the consequences of functional abnormality of elastic fibers and collagen are shown. Figure 11-7 shows hyperextensibility of joints, from which it may be inferred that skin, ligament, tendon, and to some extent bone are also abnormally stretchable. Another way in which softness of muscle and related structures can be appreciated is in the feel of a handshake with a patient who has Ehlers-Danlos syndrome. No matter how hard one presses, there is a feeling that one is not quite through with the handshake; so compressible is the hand. Figures 11-8 and 11-9 illustrate the result of incisions and shearing trauma in the skin of a patient with Ehlers-Danlos syndrome. The result is hemorrhage, failure of healing by primary intention, and finally broad, friable scars.

Small “pseudotumors” on the elbows (Fig. 11-10) and knees are actually calcified herniations of fat through the dermis. Depending on the type, inheritance may be autosomal dominant, autosomal recessive, or X-linked recessive. Gastrointestinal perforation and rupture of a large artery are the most severe complications of some forms of this syndrome. Premature birth (probably due to fragility of the fetal membranes) is a common event in patients with Ehlers-Danlos syndrome.

This is a combination of disordered structure of ectodermal and mesenchymal tissues of both skin and bone. The syndrome is transmitted in an X-linked dominant fashion. The most common cutaneous lesions are linear or reticulate areas of hypoplasia with telangiectasia, atrophy, and abnormal pigmentation. Figure 11-11 shows some such patches as well as the nodular fat tumors that are typically present.

This figure shows the whorled nature of the lesions on the trunk following the lines of Blaschko. Ulcers may be present initially in the areas of congenital absence of skin and heal with atrophy. The range of clinical presentation varies from a minor process on the limbs to extensive distortion of the skin and bony skeleton.

When bone is involved, syndactyly, polydactyly, oligodactyly with lobster claw deformity (as seen in this figure), skeletal asymmetry, and scoliosis may occur. Ocular abnormalities include colobomas, microphthalmia, and strabismus.

This figure illustrates the frequent involvement of the perioral skin and teeth. Patients may present with hypodontia, oligodontia, or small teeth with dysplastic enamel. Papillomas may be present on the lips or in the axillae, periumbilical area, or perineum.

This figure shows skin and eye defects that may occur in this syndrome. Note the atrophy on the forehead, the ocular defect in the right eye, and the papillomatous changes on the chin.

This rare condition is characterized by linear and whorled lesions and a wide variety of systemic manifestations. Incontinentia pigmenti is inherited as an X-linked dominant trait linked to the NEMO gene and is seen almost exclusively in girls. The cutaneous eruption is usually present at birth and evolves through three stages. Lesions typical of the first two stages, vesicular and verrucous, are seen in these figures. The vesicular phase of incontinentia pigmenti can be quite extensive and lasts for about 2 weeks. The verrucous phase lasts for about 6 weeks, although it may go on for many months or even for years in rare cases.

Over several months the raised areas flatten, and the patient develops whorled, or “marble-cake,” hyperpigmentation, as pictured here. In turn, the lesions of this third, hyperpigmented stage fade over a period of several years. A fourth, hypopigmented stage can develop in the second and third decade. The disorder may also result in scarring alopecia of the scalp, dystrophic nails, and abnormalities of the teeth.

This illustration is a good representation of how extensive the dyschromia of incontinentia pigmenti can be. Central nervous system and ocular abnormalities are the most serious aspects of this disease. One-third of patients will develop seizures, mental retardation, or spastic paralysis. Eye involvement may include the presence of a retrolental mass, retinal detachment, cataracts, and optic atrophy. Skeletal anomalies are sometimes seen.

The most common extracutaneous abnormality in incontinentia pigmenti involves teeth and occurs in about two-thirds of patients. There may be a marked delay in the eruption of deciduous teeth. Dental defects such as partial or complete absence of teeth as well as conical teeth may be seen.

This is another severe immunologic defect with X-linked recessive inheritance. The classic symptoms of this disease, which occurs only in males, are thrombocytopenia, recurrent infection, and a generalized eczematous or exfoliative dermatitis. Children with this disorder have impaired humoral and cell-mediated immunity, with deficient IgM and elevated IgA, and are at risk for sepsis and hemorrhage. The figure shows the kind of petechiae that are evidence of the persistent thrombocytopenia.

This autosomal recessive disorder affects the skin and the immunologic and central nervous systems. The onset of the disease, during early childhood, is characterized by the combination of progressive cerebellar ataxia and telangiectasias. The earliest site of telangiectasia is usually the bulbar conjunctiva, as pictured in Fig. 11-22. These vascular lesions also involve the neck, upper chest, face, and, as illustrated in Fig. 11-23, the pinna of the ear. Later cutaneous changes include blotchy hyper- and hypopigmentation, café-au-lait spots, hirsutism, a generalized eczematous dermatitis, and granulomatous skin lesions. There may be premature graying of the hair. The immunologic abnormalities include decreased levels of IgA and IgE and defective cell-mediated immunity. Children with ataxia telangiectasia suffer from recurrent sinopulmonary infection and may die from bronchiectasis and respiratory failure. Lymphoreticular malignancies are an additional complication.

The principal cutaneous manifestations of this autosomal recessive syndrome are erythema and telangiectasias of the cheeks and photosensitivity. Café-au-lait spots and acanthosis nigricans may also be present. Children with Bloom's syndrome are small at birth and have severe growth retardation throughout life. They also have recurrent respiratory infections and a strong tendency to develop malignancy. This rare disease is due to chromosomal abnormalities and defects in DNA repair. The syndrome is caused by mutation in the gene designated BLM, traced to band 15q26.1.

This rare autosomal recessive disorder is attributed to mutations of the RECQL4 helicase gene on chromosome 8q24. The condition begins during infancy with typically progressive skin changes. Erythema and edema of the facial skin are rapidly followed by the development of atrophy and telangiectasia. The same process occurs on the buttocks and extremities. Cataracts develop in many patients, and these often become apparent during infancy or early childhood. Skeletal deformities and short stature are other occasional features of this disease.

This is another rare autosomal recessive condition characterized by skin changes and dwarfism. During the second year of life, patients develop a scaly photoeruption on the face and upper neck. This resolves with hyperpigmentation. The scaling photodermatitis and typical bird-like facies of this syndrome are illustrated in Fig. 11-26. In addition to dwarfism (Fig. 11-27), affected individuals may demonstrate sensorineural deafness, microcephaly, and severe mental retardation. Optic atrophy and retinal degeneration may also be present. Characteristic intracranial calcifications are a feature of Cockayne's syndrome that may aid in confirmation of the diagnosis. The disorder has been attributed to a defect in DNA repair.

Embryonic underdevelopment of the ectoderm is seen in two syndromes: anhidrotic and hidrotic ectodermal dysplasia. Figure 11-28 shows the faulty dentition and pathognomonic facies in the more severe anhidrotic type. This syndrome, which occurs almost exclusively in boys, may include alopecia, nail dystrophy, stunted growth, and severe mental retardation. During warm weather, severe hyperthermia is the result of the absence of normal perspiration, and therapy should be aimed at regulation of environmental temperature, decreased exercise, and cool clothing. The hidrotic type affects males and females equally and is generally less severe. There is no abnormal sweating. Dystrophic nails, which may be distorted in size, shape, color, or consistency, are the hallmark of the syndrome. Patients tend to have sparse body and scalp hair. The nail dystrophy may be accompanied by severe hyperkeratosis of the palms and soles, as seen in Fig. 11-29. Topical keratolytics are of some help to affected individuals.

Most infants with this autosomal dominant disorder are born with generalized erythematous and scaly skin. Other common features include the presence of ankyloblepharon (small strands of skin between the eyelids) at birth, and cleft lip and palate. Many patients with this syndrome have persistent problems with an erosive scalp dermatitis, with frequent secondary infection and excessive granulation tissue. The hair on other parts of the scalp tends to be wiry and coarse.

This condition results from mutations in the genes encoding epidermal keratinocyte keratins, causing severe dyskeratinization of a special sort that especially affects nails, palms and soles, and the mucous membranes of the lips and mouth. The nail changes are distinctive in their discoloration, hardness, excessive growth, and attachment to hyperkeratotic nail beds. These figures show such nails in which scleronychia and binding to the nail beds can be appreciated. Not shown is a hyperkeratotic process on palms and soles that can be as bad as in nails. Also not shown is leukokeratosis of lips and tongue, a condition that severely disturbs function and is cosmetically distressing.

On the expanse of the body, especially on the buttocks and extremities, the dyskeratinization of pachyonychia congenita may take the form of what might be considered to be keratosis pilaris, except that forcible removal of the follicular keratotic plugs leaves cavities that have a tendency to bleed. This phenomenon is pictured in Fig. 11-33. More serious than follicular keratosis is a tendency to bulla formation on the lower part of the legs in a form that suggests epidermolysis bullosa. Figure 11-34 shows how severe this part of the syndrome can be. In the most severe instances of distortion of the nails, extirpation of the nail beds, may be required in order to achieve some degree of adequate function of the fingers.

This is another rare congenital and primarily X-linked recessive condition due to a mutation in the DKC1 gene located at Xq28. It is characterized by skin changes in the form of atrophy and dyschromia, atrophic dysplasia of nails, and a kind of leukoplakia. In Fig. 11-35, those skin changes are shown as mottled or retiform poikiloderma. The face, neck, and upper part of the body are characteristically involved. The process goes on to fine atrophy and hypo- and hyperpigmentation until the poikilodermatous character of the changes becomes established. The kind of process that occurs on mucous membranes is shown in Fig. 11-36. There are two lesions on the tongue that are gray and hypertrophic. The buccal mucosa and the mucosa of the urethra and anus may also be affected. Aside from the cutaneous and mucosal effects, abnormalities such as those seen in Fanconi's syndrome may be associated with this condition.

Here are more possible cutaneous changes in dyskeratosis congenita: Fig. 11-37 shows hypoplastic nail changes that are characteristic. Note how different they are from those of pachyonychia congenita (Figs. 11-31 and 11-32). Instead of overgrowth, there is underdevelopment. Details of the cutaneous changes on glabrous skin in and around the groin are shown in Fig. 11-38. Note how similar they are to those on the neck and face. In addition to what has been illustrated, hyperhidrosis of palms and soles, conjunctivitis, esophageal strictures, intestinal diverticula, mental retardation, and anemia may be part of the syndrome. Malignant degeneration in the leukoplakia of the mucous membranes is a possibility. Treatment of symptoms to whatever extent possible and observation for supervention of malignancy and its treatment are required.

This autosomal dominant disorder includes a number of distinctive cutaneous findings and a wide variety of neurologic manifestations. Figure 11-39 shows a café-au-lait spot. Solitary lesions of this type are common in normal individuals; most patients with neurofibromatosis have more than a single macule. The presence of more than six lesions that are larger than 0.5cm in diameter in prepubescent children and 1.5 cm in diameter in adults is considered one of the major diagnostic criteria for this disease. In Fig. 11-40, there are several macules of hyperpigmentation in the axilla. Axillary freckling, also called Crowe's sign, is a unique finding in neurofibromatosis. Pigmented hamartomas of the iris, termed Lisch nodules, are also present in almost all patients with this condition. Optic gliomas may also be seen. The inheritance of neurofibromatosis is complicated by a highly variable range of expression among those affected. A single family may include some individuals with only cutaneous involvement and others with numerous neurofibromas or severe neurologic disease. Spontaneous mutations are also common.

These are more illustrations of the pigmentary anomalies and tumors in the skin of patients with neurofibromatosis. Figure 11-41 shows several café-au-lait spots and small tumors. Figure 11-42 shows a large café-au-lait spot on the left and a barely discernible tumor on the right. Neurofibromas have variable consistency. The soft lesions can be pushed into the surrounding skin, a process called “buttonholing.” Neurofibromas usually begin to develop during puberty and may cause severe cosmetic disfigurement. Pruritus of the skin that overlies the neurofibroma is a common complaint, and the itching is aggravated by exertion or a warm environment. Malignant degeneration of a benign neurofibroma is a constant concern. In addition, patients with the disease are prone to developing neurofibrosarcomas or malignant schwannomas de novo. Selective surgical removal of neurofibromas, in order to improve either appearance or function, is feasible.

Figure 11-43 shows three café-au-lait spots and a small, soft neurofibroma. The enlargement in Fig. 11-44 was found to be due to a neurofibroma in the palm and along the length of the digits. Intellectual handicap, speech impediment, and seizures are frequent manifestations of classic, or von Recklinghausen, neurofibromatosis. Although this form of neurofibromatosis tends to be progressive, it is entirely unpredictable. There is no single aspect of the clinical course that allows the physician to foresee the evolution of other features.

These subcutaneous tumors are congenital and are pathognomonic for neurofibromatosis type I. Plexiform neurofibromas may sometimes be subtle, initially presenting only as a patch of hyperpigmentation and/or hypertrichosis. With time, they can grow quite large.

Larger lesions are described as having a “bag of worms” consistency and may be cosmetically disabling. Plexiform neurofibromas may also present as firm nodules attached to the nerves. Tumors around nerves may cause pain, muscle weakness, or atrophy.

Lisch nodules are melanocytic hamartomas occurring on the iris. They can be seen on routine examination of the eye, but a slit lamp is required to distinguish these lesions from nevi. Lisch nodules are brown and dome-shaped and measure up to 2 mm in diameter. The majority of patients with NF1 develop this finding during childhood, and the nodules are present in the vast majority of adolescents and adults with the disorder. The nodules do not cause any ophthalmologic complication.

The presence of numerous small neuromas of the lips, tongue, and oral mucosa is a marker for a unique autosomal dominant condition. This syndrome, now termed multiple endocrine neoplasia type 2B, carries a very high risk for malignancy. Eighty percent of affected individuals will develop medullary thyroid carcinoma. Pheochromocytoma may also occur. This patient developed both tumors and had the marfanoid habitus that is frequently seen in patients with the disorder.

This is an autosomal dominant disease with widely variable penetrance; its main effects are on the skin, central nervous system, eye, kidney, and heart. These figures illustrate adenoma sebaceum, one of the most common cutaneous manifestations.. The pink-to-red dome-shaped papules usually appear between the ages of 2 and 6 years. The lesions of adenoma sebaceum may be symmetrically distributed over the entire face but are usually most concentrated on the cheeks. Histologically, the individual papules are angiofibromas. The extent of cutaneous involvement is not generally predictive of the severity of the disease. Patients who are severely affected suffer from seizure disorders and mental retardation. Other findings of tuberous sclerosis include retinal and renal hamartomas, cerebral nodules and calcifications, and cardiac rhabdomyomas.

Two cutaneous manifestations of the syndrome are shown in Fig. 11-51. Above and to the right is a hypopigmented macule, which sometimes takes the shape of an ash leaf. Hypopigmented macules may occur in healthy infants, but the appearance of several such lesions should prompt a search for other manifestations of tuberous sclerosis in the patient and family members. The so-called ash-leaf spots are the earliest cutaneous manifestation of the syndrome; they are either present at birth or evolve during infancy. Wood's light examination may sometimes reveal hypopigmented macules whose presence is otherwise not obvious. In the midline in the same figure is a shagreen patch, an area of cutaneous thickening with a pebbled surface. Histologically, this lesion, which is frequently seen in children with tuberous sclerosis, is a form of connective tissue nevus. In Fig. 11-52 there are subungual and periungual fibromas. These firm lesions arise from the nail beds, usually after puberty.

Another cutaneous finding in tuberous sclerosis is firm fibrous plaques that are located on the forehead, scalp, and cheeks. These lesions, which may be present at birth, are different from angiofibromas in that there is no vascular dilatation associated with the dermal fibrosis.

This autosomal dominant syndrome is characterized by the presence of connective tissue nevi of the skin and a radiologic abnormality known as osteopoikilosis. The connective tissue nevi are yellowish plaques that tend to appear before puberty and are present on the trunk, buttocks, and arms. Osteopoikilosis is an asymptomatic bony abnormality that presents as round opacities within the carpal and tarsal bones, the phalanges, the epiphyses and metaphyses of the long bones, and the pelvis.

Patients with this autosomal dominant syndrome develop multiple basal cell carcinomas and cysts within the mandible. Additional findings include hypertelorism, a variety of other skeletal abnormalities, and calcification of the falx cerebri. Shown in this figure is an example of multiple small basaloid proliferations.

Most patients with this syndrome have more conventional basal cell carcinomas in the form of pearly telangiectatic nodules, sometimes with ulceration, as is shown in this figure. Basal cell carcinomas usually develop in these patients after puberty, although they may occur in childhood.

This figure shows the palmar pitting that appears during puberty in individuals with this syndrome. Rapidly enlarging basal cell carcinomas must be treated early on with the conventional surgical modalities in order to minimize disfigurement and avoid loss of function. Patients with this syndrome are also at risk for medulloblastoma. This grave complication tends to occur in early childhood.

This rare autosomal recessive disease is caused by an inability to repair DNA that has been damaged by ultraviolet light. There are at least eight different molecular defects. Freckling develops on sun-exposed skin at a very early age along with xerosis, scaling, and telangiectasia. Speckled hypo- and hyperpigmentation are also typical, as seen in Figs. 11-58, 11-59, 11-60.

Patients with this disease also tend to develop hyperkeratoses and changes consistent with actinic keratoses. In early childhood, patients with xeroderma pigmentosum begin to develop cutaneous malignancies: basal cell and squamous cell carcinomas and, less commonly, melanomas. The mortality from this disease is caused by destructive local growth of tumors and by metastases. In addition, patients may suffer from severe neurologic dysfunction, including mental retardation. Although no treatment is available, individuals with this disease benefit from a lifestyle that allows minimal exposure to sunlight.