Cutaneous findings.

Over 80% of myofibromas present in the first 2 years of life, and 60% are apparent at birth or shortly thereafter.^3,4 Lesions may be superficial or deep, involving the skin, subcutaneous tissues, and muscle. They appear clinically as discrete, rubbery, firm to hard nodules measuring from 0.5 to 8 cm in diameter (Fig. 26.1). Cutaneous myofibromas may be skin-colored or have a prominent vascular appearance, resembling hemangioma. Sites of predilection for solitary lesions are the head, neck, trunk, and upper extremities. In the multicentric and generalized forms there are multiple and widespread myofibromas, numbering from a few to over 100 (Fig. 26.2).⁵ Skin and soft tissue lesions are asymptomatic and usually cause little morbidity. Rarely, a myofibroma presents with surface ulceration or an atrophic morphology (Fig. 26.3).^4,6 Joint contractures have been observed with extensive limb lesions.⁷

Extracutaneous findings.

In the multicentric form of the disease, myofibromas in the skin and soft tissues are associated with multiple lytic bone lesions. These may be extensive and can involve any bone.⁵ Progression in size and number has been observed during infancy.⁵ The bone tumors eventually stabilize, and spontaneous healing occurs with complete regression during the first few years of life. The development of sclerotic borders around lytic areas may be an early sign of regression.⁵ In most cases, there are no clinical signs or symptoms of bone disease. Pathologic fractures may occur rarely and usually heal without residual deformity.^5,8 Vertebral body collapse has been described, with residual loss of vertebral height in early childhood.⁵ There are reports of spinal cord compression resulting from solitary or multicentric lesions involving the spinal canal.⁹ Solitary infantile myofibroma may also occur in the orbit.¹⁰

The much rarer generalized form of infantile myofibromatosis is characterized by involvement of visceral organs in addition to skin, soft tissue, and bone tumors. The gastrointestinal tract, heart, and lungs are most frequently affected. Involvement of the central nervous system is rare. Myofibromatosis in visceral organs is locally invasive and may severely compromise organ function. Cardiopulmonary, gastrointestinal, and hepatobiliary complications can be fatal, particularly in the newborn period or early infancy.¹¹ There have been two reports of associated aneurismal dilatations of arteries as observed in fibromuscular dysplasia.¹²

Multiple skin and soft tissue tumors may occasionally occur in the absence of bone or visceral involvement.¹ Conversely, bone involvement has been observed in association with a single soft tissue lesion,¹¹ or in the absence of skin lesions.⁵

Etiology and pathogenesis.

The pathogenesis is unknown. Most cases are sporadic. Familial occurrence is associated with autosomal dominant inheritance.¹³

Diagnosis.

Myofibromatosis may be suspected by the presence of firm, cutaneous and subcutaneous nodules. A biopsy is required to confirm the diagnosis. All three forms of infantile myofibromatosis show interlacing fascicles of spindle-shaped fibroblasts.¹ Central vascular areas resembling hemangio­pericytoma are variably present. Focal necrosis, calcification, hyalinization, macrophages containing hemosiderin, and chronic inflammation may be seen.¹ A giant cell variant containing multiple multinucleated giant cells has also been described. There is positive immunoreactivity for vimentin and actin, consistent with the presumed myofibroblastic derivation of the tumor; desmin staining is variable. Electron microscopy shows cells with features of both fibroblasts and smooth muscle cells.

Infants with cutaneous myofibromas should be evaluated for bone and visceral involvement, particularly when there are multiple lesions. Recommended initial investigations include a skeletal survey, chest X-ray, echocardiogram, and abdominal imaging studies.¹¹

Differential diagnosis.

Infantile myofibromatosis can be distinguished from other pediatric soft tissue tumors by histopathologic examination of biopsy material. These include other forms of fibromatosis, as well as congenital fibrosarcoma, leiomyoma and leiomyosarcoma, neurofibroma, metastatic neuroblastoma, hemangioma, hemangiopericytoma, chondromatosis, stiff skin syndrome, and nodular fasciitis.¹

Treatment and prognosis.

The prognosis for infantile myofibromatosis is good in the absence of visceral involvement. Lesions in the skin and soft tissues show spontaneous involution during the first few years of life, sometimes leaving residual areas of skin atrophy or hyperpigmentation (Fig. 26.4). Bone lesions also regress spontaneously, usually without significant disability or residual radiologic change. They do not interfere with enchondral bone growth.⁵ The prognosis is grave for newborns with visceral disease, in whom a mortality rate of 76% has been documented.¹¹

Surgical excision may be necessary to obtain tissue for diagnosis. Otherwise, excision should be limited to lesions that result in functional impairment or severe cosmetic disability.^7,11 The role of chemotherapy or radiation for symptomatic, recurrent, or nonresectable disease is not established. Successful treatment of life-threatening generalized infantile myofibromatosis and multicentric disease using low-dose chemotherapy has been reported.¹⁴

Clinical findings.

Infantile desmoid-like or aggressive fibromatosis involves deep tissues and is generally extra-abdominal.¹ The usual clinical presentation is a slowly growing, nontender subcutaneous mass that has been present for weeks or months (Fig. 26.5). Sites of predilection in children are the head and neck, extremities, shoulder girdle, trunk, and hip regions. The abdomen, retroperitoneum, spermatic cord, and breast may also be involved. Rarely, there are multiple lesions. The tumor tends to be very locally aggressive, with infiltration of adjacent skeletal muscles, tendons, or periosteum, and erosion of bone.

Approximately 12% of pediatric patients with desmoid fibromatosis have other congenital abnormalities.¹ Adult-type intra-abdominal desmoid tumors are associated with familial adenomatous polyposis (FAP) and Gardner syndrome.^1,17 Although most tumors in children are sporadic, there are reported cases of associated Gardner syndrome in childhood, one of which presented in infancy.^18–20

Etiology and pathogenesis.

The finding of minor radiologic bone abnormalities in 80% of patients with desmoids and 48% of their relatives suggests an autosomal dominant mode of inheritance.¹ Antecedent trauma, including surgery or irradiation, is reported in 12–63% of patients with all forms of desmoid tumor.¹ It is postulated that desmoid tumors are associated with a familial defect in the regulation of connective tissue and may be precipitated by multiple factors.^1,17,21 Desmoid fibromas in adults and children can be associated with mutations in the adenomatosis polyposis coli (APC) or β-catenin CTNNB1 genes.²²

Diagnosis.

The tumor is composed of bundles of slender, uniform spindle cells surrounded by variable amounts of collagen. Cleft or slit-like blood vessels are variable in number and more abundant at the periphery. The fibrous proliferation may be indistinguishable from scar tissue, except that it infiltrates skeletal muscle and tendons. Cellularity is variable. Some childhood lesions have an increased number of mitoses and greater cellularity.¹ Immunohistochemical and ultrastructural studies show that the lesion is composed of fibroblasts and myofibroblasts. Immunohistochemistry and genotyping may help to distinguish sporadic from FAP cases.²²

Differential diagnosis.

Myofibromatosis and other juvenile fibromatoses should be considered in the differential diagnosis. Keloid scars are more superficial than desmoid tumors. Cellular variants must be distinguished histopathologically from fibrosarcoma.

Treatment and prognosis.

Local excision with wide margins, if possible, is the mainstay of treatment.^16–19,23 The recurrence rate varies from 30–80%.¹ Higher recurrence rates are associated with a young age at diagnosis, large lesions, intralesional or marginal excision, and intra-abdominal location. Microscopic features of high vascularity, myxoid foci, and abundant immature myofibroblasts are associated with a higher recurrence rate.¹ Treatment with combination chemotherapy and radiotherapy, or with tamoxifen and nonsteroidal anti-inflammatory agents, has been advocated for nonresectable, symptomatic or progressive disease.^19,24 Mortality from locally aggressive desmoids is less than 10%.¹

Clinical findings.

A hard, nontender, lobulated subcutaneous mass is palpable in the lower third of the sternocleidomastoid muscle. The trapezoid muscle is sometimes involved. Following an initial rapid period of growth, the tumor stabilizes in size. Torticollis and facial asymmetry are variable and may be transient. There is a right-sided predominance, and 2–3% of cases are bilateral.¹

Etiology and pathogenesis.

The pathogenesis is unknown. Birth trauma has been implicated in 50% of cases, with a history of complicated delivery; whether this is a cause or an effect of the tumor is not clear. Familial cases are rare.¹

Diagnosis.

Histopathologically, bands of fibroblasts with abundant collagen are intermingled with residual angulated skeletal muscle fibers. The diagnosis may be established by fine-needle aspiration, which shows benign spindle cells and degenerating skeletal muscle fibers. Ultrasound or magnetic resonance imaging may also be useful.²⁵

Differential diagnosis.

A combination of the typical location of the lesion in the neck and the characteristic histopathology is diagnostic. The clinical differential diagnosis of a neck swelling includes lymphatic malformation, hemangioma, and malignant neoplasms. The histopathologic features may resemble those of a desmoid tumor.¹

Treatment and prognosis.

The majority of lesions regress within the first year of life. Most resolve completely, but minor residual asymmetry or tightening of the sternocleidomastoid muscle is seen in 25% of cases.¹ Only 9% have persistence of the tumor and torticollis. Physiotherapy is the treatment of choice.²⁶ Surgery is rarely necessary unless the diagnosis is in doubt or the mass fails to resolve.

Cutaneous findings.

Almost all lesions are diagnosed in infancy, and one-third are present at birth. Both sexes are affected equally. The typical lesion is an asymptomatic, firm, smooth, pink nodule located on the lateral or dorsal aspect of the digit, measuring <3 cm in diameter (Fig. 26.6). Lesions are more common on the fingers than on the toes. The thumbs and great toes are spared. There is often deformity of the affected digit. There may be single or multiple nodules (Fig. 26.7). Rarely, more than one digit is involved or extradigital lesions are seen.²⁷

Extracutaneous findings.

Periosteal attachment is not unusual, but underlying bone erosion is rare.

Etiology and pathogenesis.

The pathogenesis is not known. Defective organization of actin filaments in myofibroblasts has been hypothesized.¹

Diagnosis.

Whorls and interdigitating sheets of uniform fibroblasts in a densely collagenous stroma are seen in the dermis or subcutis.¹ A unique feature is the presence of distinctive, eosinophilic, perinuclear cytoplasmic inclusions surrounded by a clear halo that stain red with a trichrome stain. Electron microscopy shows abundant cytoplasmic filaments that form whorled bodies; these are the ultrastructural correlate of the cytoplasmic inclusions. Immunostaining is positive for desmin, actin, vimentin, and keratin.

Differential diagnosis.

The digital location and the characteristic histopathology distinguish this lesion from other fibromatoses and pediatric soft tissue tumors.

Treatment and prognosis.

The local recurrence rate is 60–90% following surgical excision. Many tumors regress spontaneously within a few years.²⁷ Conservative management without surgery is appropriate, unless there is functional impairment.²⁷ Mohs micrographic surgery to debulk the tumor has been performed.²⁸ Successful treatment with intralesional fluorouracil injections has been reported in a 7-year-old child.²⁹

Cutaneous findings.

Fibrous hamartoma presents as a subcutaneous lesion located around the axillae, shoulders, and upper chest wall.³¹ It may involve other sites, such as the inguinal region, extremities, and head and neck. It is usually a solitary nodule, measuring 2–5 cm in diameter, that feels lumpy to palpation. There may be overlying hypertrichosis. Occasionally, these lesions are multifocal. There are no symptoms.

Extracutaneous findings.

There are no systemic associations.

Etiology and pathogenesis.

Fibrous hamartoma of infancy is believed to represent a hamartomatous process rather than a true neoplasm. It is not familial.

Diagnosis.

The hamartoma is located in the subcutaneous and musculoaponeurotic tissues.^30,31 Histopathologic examination reveals three characteristic elements: a fibrous component consisting of well-defined fascicles of fibroblasts or disorderly fibroblasts in a collagenous stroma; mature adipose tissue; and myxoid mesenchymal tissue in a basophilic matrix. Electron microscopy reveals the presence of both fibroblasts and myofibroblasts, primitive mesenchymal cells, small blood vessels, and mature adipocytes.¹

Differential diagnosis.

The clinical differential diagnosis of fibrous hamartoma of infancy includes a macrocystic lymphatic malformation, hemangioma, and other soft tissue tumors. Identification of the three histopathologic components of this lesion distinguishes it from other fibroblastic proliferations.³¹ A similar hamartoma with an admixture of fat and an absence of fibromyxoid tissue is described as lipofibromatosis.³²

Treatment and prognosis.

There is no tendency to spontaneous regression. The treatment of choice is surgical excision. The recurrence rate is low, even with incomplete excision.³¹

Cutaneous findings.

There is slowly progressive gingival enlargement that may cover the crowns of the teeth and result in difficulty in eating or speaking. It is associated with generalized hypertrichosis.

Extracutaneous findings.

Rarely there is associated mental retardation and epilepsy. The Zimmerman–Laband syndrome is characterized by gingival fibromatosis, hypertrichosis, intellectual disability, and absence and/or hypoplasia of the nails or terminal phalanges of the hands and feet as well as other anomalies.³³

Etiology and pathogenesis.

Inheritance is most commonly autosomal dominant and the disorder has been mapped to loci on chromosomes 2 and 5.^34,35 Autosomal recessive and sporadic cases are also reported.³⁶

Diagnosis.

Mucosal biopsy shows coarse, interlacing collagen bundles with sparse fibroblasts and myofibroblasts. There may be calcification, ossification, abundant amorphous extracellular material, and cellular fibroblastic proliferation.

Differential diagnosis.

The differential diagnosis includes phenytoin usage, chronic gingivitis, cherubism, juvenile hyaline fibromatosis, and other rare syndromes.

Treatment and prognosis.

Treatment options include repeated surgical debulking of the gums or dental extraction.

Cutaneous findings.

Cutaneous leiomyomas appear as discrete papules or nodules with a pink or brown discoloration of the overlying skin. They are usually solitary but may be multiple. Rarely, a leiomyoma may present as a pedunculated mass at birth or as a papular plaque in early infancy.^37–39 Leiomyomas are often painful, particularly on exposure to cold. Leiomyomas of the tongue are also reported.³⁸

Extracutaneous findings.

Most cutaneous leiomyomas are not associated with visceral disease. The multiple leiomyomas of the esophagus and tracheobronchial tree in Alport syndrome may be associated with female genital leiomyomas in older children and adults.⁴⁰ Leiomyomas that occur in immunocompromised children only rarely involve the skin or soft tissues.⁴¹

Etiology and pathogenesis.

Multiple cutaneous leiomyomas presenting in adolescence or adult life may be inherited as an autosomal dominant trait, but the etiology of other forms is unknown.

Diagnosis.

The diagnosis is made by skin biopsy, which demonstrates whorls and bundles of well-differentiated spindle cells with cigar-shaped nuclei in the dermis. There is a variable collagenous component. The smooth muscle stains red with the Masson trichrome stain. Immunochemistry is positive for muscle-specific actin and desmin reactivity.

Differential diagnosis.

Leiomyoma must be distinguished from the fibroblastic and myofibroblastic proliferations of infancy and childhood, as well as from other spindle cell tumors such as neurofibroma and leiomyosarcoma. Immunohistochemistry may be helpful, as myofibroblastic tumors express smooth muscle actin more than muscle-specific actin or desmin.³⁷ The circumscribed spindle cell appearance of leiomyoma differs from the smooth muscle bundles of congenital smooth muscle hamartoma.

Treatment and prognosis.

Excision is curative for solitary lesions.

Cutaneous findings.

The typical juvenile xanthogranuloma is an asymptomatic, firm, well-demarcated papule or nodule that measures from 1 mm to 2 cm in diameter. Early lesions are pink or red in color, later changing to a distinctive yellow or orange-brown (Fig. 26.9). There may be overlying telangiectasia with a purpuric appearance, and occasionally surface ulceration and bleeding with associated pruritus and discomfort. Solitary lesions with a hyperkeratotic surface, pedunculated or plaque-like morphology are also reported.⁴⁶ As many as 17% of juvenile xanthogranulomas are present at birth, and 70% develop within the first year of life.⁴⁶ The majority are solitary lesions. Multiple lesions may be few or number in the hundreds (Fig. 26.10A). They can be located at virtually any body site, but are most common on the head, neck, and upper trunk.

Juvenile xanthogranulomas may be classified as micronodular, measuring 2–5 mm, or macronodular, measuring 0.5–2 cm in diameter. An unusual variant is the giant juvenile xanthogranuloma, which measures from 2–10 cm in diameter (Fig. 26.10B).⁵² These lesions are congenital or appear in early infancy and may have a greater propensity to ulcerate. Rarely, numerous micronodular lesions may present as a generalized lichenoid eruption.⁵³

Extracutaneous findings.

Extracutaneous juvenile xanthogranuloma is rare, and less than 50% of these patients have associated cutaneous lesions.⁵⁴ The most frequent extracutaneous sites are the eye and orbit, central nervous system, liver/spleen, lung, oropharynx, and muscle. In contrast to cutaneous lesions, a systemic juvenile xanthogranuloma may produce symptoms related to a mass effect or infiltration of the involved organ. The incidence of ocular disease in patients with cutaneous lesions is 0.3–0.4%.⁵⁵ Eye lesions manifest as an asymptomatic mass on the iris, unilateral glaucoma, spontaneous hyphema, or color change of the iris. Risk factors for eye involvement include multiple lesions, age <2 years, and recently diagnosed disease.⁵⁵

Juvenile xanthogranulomas are seen with increased frequency in patients with NF-1. A triple association between juvenile chronic myeloid leukemia, juvenile xanthogranulomas, and NF-1 is recognized (Fig. 26.11).⁴⁷

Etiology.

The etiology of juvenile xanthogranuloma is unknown. The precursor cell of the histiocytic proliferation is believed to be the interstitial/dermal dendrocyte.⁵⁶ The observed occurrence in monozygotic twins may suggest a genetic predisposition.^57,58

Diagnosis.

The typical histopathologic appearance consists of a dense dermal infiltrate of foamy histiocytes with Touton giant cells. There is an admixture of other cell types, including lymphocytes, eosinophils, neutrophils, and foreign body giant cells, as well as infrequent mitoses. In early lesions, there may be few or absent foam cells or Touton giant cells, with a variable number of spindle cells and numerous mitotic figures.⁵⁹ Immunohistochemistry shows negative staining for S100 and CD1a, and positive staining for factor X111a, CD68, CD163, fascin and CD14.⁵⁶ There are no Birbeck granules visible on ultrastructural examination.

Differential diagnosis.

Distinguishing a small juvenile xanthogranuloma from clinically similar lesions such as xanthoma, mastocytoma, Spitz nevus, and other benign skin tumors may require a skin biopsy. Giant lesions may be mistaken for a hemangioma or malignant tumor. Early lesions that lack the characteristic lipid-laden histiocytes and Touton giant cells may resemble Langerhans’ cell histiocytosis on histopathologic examination.^56,59 The absence of Birbeck granules and negative staining for S100 is characteristic of juvenile xanthogranuloma.

Treatment and prognosis.

Most cutaneous lesions resolve spontaneously over months or years and do not require treatment. Ulcerating, symptomatic, or large unsightly lesions may require surgical excision. A residual area of hyperpigmentation or anetoderma-like atrophy may persist. Ocular and systemic lesions can be more problematic and involvement of the liver and bone marrow can be life-threatening.⁶⁰ Treatment options include observation, corticosteroids, surgical excision, radiation therapy, and chemotherapy.^46,60

Cutaneous findings.

Lesions first appear between the ages of 2 months and 2 years. The face is the site of predilection, but the scalp, neck, and ears can also be involved. Lesions may be scattered over the shoulders and upper arms. Typical lesions are slightly raised, asymptomatic papules measuring 2–3 mm in diameter that vary from erythematous to light-brown or yellowish in color (Fig. 26.12). The mucous membranes are not involved.

Extracutaneous findings.

Typically, extracutaneous disease is absent, but there has been one report of associated diabetes insipidus.⁶³

Diagnosis.

Histopathologically, a monomorphous histiocytic infiltrate is located in the upper and mid-dermis. There may also be a few lymphocytes and eosinophils. Foamy macrophages and Touton giant cells are typically absent. Staining for S100 protein is usually negative.⁶⁴ Electron microscopy reveals coated vesicles and comma- or worm-shaped bodies. Birbeck granules are absent.

Differential diagnosis.

The differential diagnosis includes juvenile xanthogranuloma, Langerhans’ cell histiocytosis, and cutaneous mastocytosis. The lesions of mastocytosis have a similar color but urticate when rubbed (Darier sign) and have a distinctive histology. Benign cephalic histiocytosis can be distinguished from Langerhans’ cell histiocytosis by immunohistochemical stains and the absence of Birbeck granules on electron microscopy.

Treatment and prognosis.

There is no effective treatment. The skin lesions regress spontaneously over months to years. There may be residual hyperpigmentation and anetoderma-like atrophy.

Cutaneous findings.

The nodule is firm and measures 3–10 mm in diameter. The surface may be warty in appearance, or smooth and dome-shaped. The color is chalky white or yellow. Surface ulceration and discharge of calcified material may occur spontaneously or as a result of trauma. There are usually no associated symptoms.

Extracutaneous findings.

Serum calcium and phosphate levels are normal. There are no systemic abnormalities.

Etiology and pathogenesis.

The pathogenesis of these lesions is not clear. Most authors believe they represent dystrophic calcification following dermal damage from some unknown source. Proposed hypotheses include derivation from milia, syringomas, other sweat gland hamartomas, nevi, trauma, and ischemic injury.^77,78

Diagnosis.

The diagnosis is often made on the clinical appearance. Histopathologically, amorphous and/or globular masses of calcified material are seen in the papillary dermis and may extend to the reticular dermis. Foreign body giant cells may be observed in association with the calcified masses. The overlying epidermis shows a warty architecture with variable amounts of pseudoepitheliomatous hyperplasia. Ulceration and transepidermal elimination of calcium may occur.

Differential diagnosis.

Clinically, calcified nodules may be misdiagnosed as viral warts, molluscum contagiosum, pilomatricomas, syringomas, and congenital inclusion cysts.

Treatment and prognosis.

If treatment is necessary, the nodule can be removed by curettage or excision. Calcified nodules sometimes recur following curettage or shave excision. Intralesional injection of triamcinolone at the time of shave excision has been suggested for recurrent lesions.⁷⁶

Cutaneous findings.

Tumoral calcinosis presents as progressively growing, lobulated masses in a juxta-articular location. The hip joints, shoulders, and elbows are most frequently affected in older children and adults. A predilection for the anterior aspect of the knee has been noted in three infants.⁸¹ Involvement of the buttock, axilla, and supraclavicular region has also been observed in infancy.⁸² Lesions may be multifocal and occasionally bilateral. Rarely, ulceration of the overlying skin with discharge of a chalky-white substance may occur.⁸⁰ Large lesions may interfere with joint or muscle function.

Extracutaneous findings.

One subtype of tumoral calcinosis is associated with idiopathic hyperphosphatemia. Transient and marginally elevated serum phosphate levels were found in an affected infant.⁸¹ Serum calcium levels are normal.

Etiology and pathogenesis.

Familial tumoral calcinosis with hyperphosphatemia has been linked to mutations in the GALNT3 gene on chromosome 2q24, to the KL gene, encoding Klotho, and to the fibroblast growth factor-23 (FGF-23) gene.⁸⁴ Normophosphatemic familial tumoral calcinosis is linked to SAMD9 mutations. Both subtypes have an autosomal recessive mode of inheritance.⁸⁴

Diagnosis.

Radiographs show discrete, sometimes lobulated, calcified areas. There is no joint involvement, and the underlying bones appear normal. Excisional biopsy specimens usually show a well-encapsulated calcified mass, but there may be invasion of the surrounding musculature. Histopathologic examination reveals calcification, central necrosis, a chronic inflammatory cell infiltrate including multinucleate giant cells, and fibrosis.^79,81

Treatment.

Excision is the treatment of choice, but there may be recurrence after excision. Spontaneous resolution was observed in one infant after incisional biopsy of a supraclavicular mass.⁸²

Cutaneous findings.

Osteoma cutis is present in up to 42% of patients with PHP1 and PPHP. Lesions are usually first noted in infancy or childhood. They may be located anywhere on the body and have a predilection for sites of friction or mild trauma. The characteristic lesions are blue-tinged, stone-hard papules, nodules, or plaques that range in size from pinpoint to 5 cm in diameter (Fig. 26.14). Early lesions may present as blue or erythematous macules (Fig. 26.15). Rarely, more extensive or deeper cutaneous ossification or POH may develop (Fig. 26.16). Ulceration occurs occasionally.

Extracutaneous findings.

The characteristic phenotype of AHO includes short stature, round face, obesity, and brachydactyly, in particular a shortened fourth metacarpal. Other manifestations include dental defects, short broad nails, cataracts, calcification of the basal ganglia, and variable degrees of mental retardation. These findings are easier to discern in late childhood and adulthood than in infancy. Hypocalcemia may result in seizures and tetany. Most patients with PHP1 have thyroid stimulating hormone (TSH) resistance and hypothyroidism may occasionally present in the neonatal period. Hypogonadism and growth hormone resistance may also occur.

Etiology and pathogenesis.

The metabolic changes in PHP result from a failure of receptors in renal and skeletal target tissues to respond to PTH. This resistance to the action of PTH is variable in PHP and absent in PPHP. End-organ resistance to PTH in PHP1 is associated with reduced expression or function of a guanine nucleotide stimulatory protein (Gs-α) that is required for activation of adenylate cyclase by the hormone-bound receptor.⁸⁷ This protein is encoded by the GNAS1 gene located on chromosome 20q13. Inheritance is by autosomal dominant transmission. AHO with hormone resistance (PHP1) occurs only with maternal transmission of the genetic defect, whereas paternal imprinting results in PPHP or POH.⁹¹ The reason for development of cutaneous ossification is unclear but may relate to differentiation of dermal mesenchymal cells into osteoblasts.⁹²

Diagnosis.

Skin histopathology shows bone formation in the dermis and subcutis. Osteoblasts, osteocytes, and osteoclasts are present within the spicules of bone. When ossification is severe and progressive, a proliferation of spindle cells, resembling fibroblasts, may be prominent.

In PHP there is hypocalcemia, hyperphosphatemia, and an elevated serum PTH. In PPHP there is no discernible abnormality of calcium and phosphate metabolism. Urinary excretion of cAMP in response to intravenous infusion of PTH is impaired in most cases of PHP1, but is normal in PPHP.

Radiologic abnormalities include ossification of the skin and subcutaneous tissues; shortening of the metacarpal, metatarsal, and phalangeal bones, notably the distal phalanx of the thumb and the fourth metacarpal; and cone epiphyses. Occasionally, there may be radiographic evidence of hyperparathyroidism or osteomalacia.

Differential diagnosis.

Hypocalcemia, hyperphosphatemia, and elevated levels of circulating PTH in the absence of renal disease, steatorrhea, and generalized osteomalacia are characteristic of PHP1. A diagnosis of PPHP may be difficult to establish in infancy, particularly when there is no family history of AHO. The differential diagnosis includes POH, congenital plate-like osteoma cutis, and familial osteoma cutis in families without evidence of AHO.⁹⁰

Treatment and prognosis.

Treatment of PHP is directed towards controlling hypocalcemia by careful administration and monitoring of calcium and vitamin D. Normocalcemic patients must be monitored closely and evaluated regularly for the development of cataracts or hypocalcemia. Mental retardation may be causally related to poorly-controlled or undetected hypocalcemia. Patients should also be screened for hypothyroidism. There is no effective treatment for osteoma cutis. Surgical excision may be considered for individual lesions that cause pain or cosmetic disfigurement.

Cutaneous findings.

The pilomatricoma presents clinically as a slowly enlarging, hard nodule that is fixed to the skin but freely mobile over the underlying tissues. The overlying skin may be white, skin-colored, or have a blue-red discoloration. The size varies from 0.1–6 cm in diameter, with an average of about 1 cm.⁹⁹ Ulceration of the overlying skin occurs rarely, with discharge of a white chalk-like material, and rapid enlargement due to bleeding within the lesion has been described.¹⁰² Pilomatricomas are seen most commonly on the head and neck (Figs 26.17, 26.18), but also appear on the trunk and extremities (Fig. 26.19). They are usually solitary, but multiple and recurrent pilomatricomas are well recognized and may be seen in otherwise healthy children. Multiple lesions are reported in myotonic dystrophy, Gardner syndrome and FAP, the Rubinstein–Taybi, Soto and Turner syndromes and in association with trisomy 9, gliomatosis cerebri and glioblastoma.^{98,101,103–105}

Extracutaneous findings.

Most patients with pilomatricoma have no extracutaneous findings. Myotonic dystrophy and a familial predisposition to adenomatous polyposis coli should be considered in children with multiple pilomatricomas.^101–105

Etiology and pathogenesis.

The tumor derives from cells in the hair matrix. Mutations in the β-catenin gene, a gene associated with colon cancer, have been demonstrated in pilomatricomas.¹⁰⁶ Mutations in APC causative for Gardner syndrome/FAP may result in pilomatricoma formation possibly by affecting a different part of the same Wnt signaling pathway.¹⁰¹

Diagnosis.

The histopathology of pilomatricoma is very characteristic, with two distinct types of cell, basophilic and shadow cells, located in the dermis or subcutis and surrounded by a fibrous capsule. The basophilic cells are seen at the periphery of the tumor and have rounded, darkly staining nuclei and scanty cytoplasm. The shadow cells are eosinophilic with a well-defined border and a central unstained area where the nucleus has been lost. Areas of keratinization may be seen, with foreign body giant cells and melanin pigmentation. Dystrophic calcification is a common finding and ossification occasionally occurs. Immunohistochemical staining typically shows nuclear β-catenin accumulation in the basaloid cellular component.¹⁰¹

Differential diagnosis.

The clinical differential diagnosis includes other skin tumors, dermoid cyst, or a calcified nodule. Dermoid cysts are attached to underlying tissues rather than to the skin. A calcified nodule is hard to palpation and has a white surface discoloration; it can be difficult to distinguish clinically from a calcified pilomatricoma. Ultrasound examination of pilomatricomas shows a mass with an echogenic center and a hyperechoic rim at the junction of the dermis and subcutaneous fat.¹⁰⁷

Presentation with multiple lesions or familial disease should raise the possibility of an underlying genetic disorder.¹⁰¹

Treatment and prognosis.

Surgical excision with narrow margins or through a small skin incision is the treatment of choice. In asymptomatic lesions without progressive growth or recurrent inflammation, this may be deferred until the child is older and able to cooperate with excision under local anesthesia. Very superficial lesions may be amenable to incision and curettage. Spontaneous resolution is occasionally observed.

Cutaneous findings.

The typical nevus sebaceus is a pink-yellow or yellow-orange plaque with a pebbly or velvety surface that is located on the scalp or face (Fig. 26.21). It varies in size from one to several centimeters and can be round, oval, or linear in shape. Lesions on the scalp present as a congenital area of circumscribed alopecia (Fig. 26.21B). There may be evolution from a slightly raised plaque at birth to a flat, almost macular lesion in infancy and childhood. A verrucous or cobblestone appearance develops in adolescence when the sebaceous and apocrine glands enlarge and proliferate.¹¹⁴ Some lesions present with an atypical cerebriform (Fig. 26.22) or papillomatous morphology (Fig. 26.23).

Extracutaneous findings.

Nevus sebaceus is usually an isolated lesion with no extracutaneous findings. Rarely, it is associated with other developmental abnormalities in the Schimmelpenning or linear nevus sebaceus syndrome.¹¹⁵ The nevus sebaceus can be of any size or shape but is often extensive and/or linear, with a distribution following the lines of Blaschko. Extracutaneous manifestations include mental retardation, seizures and other central nervous system abnormalities, skeletal developmental anomalies, and ocular lesions, including coloboma of the eyelid and lipodermoid of the conjunctiva.^{115,117,120–122} Vitamin D-resistant hypophosphatemic rickets is a less common but well-described association.^{115,117,123,124} Vascular anomalies are also reported.¹²⁵

A related syndrome in which an extensive nevus sebaceus is associated with a large speckled lentiginous nevus (which appears as an area of segmental hyperpigmentation in infancy) is termed phakomatosis pigmentokeratotica (PPK) (see Chapter 24). Hypophosphatemic rickets occurs more commonly in PPK whereas ocular lipodermoids and colobomas are apparently not found.¹¹⁵ Nevus sebaceus adjacent to an area of aplasia cutis congenita has been termed didymosis aplasticosebacea, or SCALP syndrome when the additional features of CNS abnormalities, limbal dermoid and pigmented melanocytic nevus are present.¹²⁶

Etiology and pathogenesis.

Nevus sebaceus is thought to be caused by a post-zygotic somatic gene mutation. Lesional mutations in HRAS, and less commonly KRAS, have been identified both in localized nevus sebaceus and in Schimmelpenning syndrome.^119,127 There have been rare reports of familial occurrence of nevus sebaceus.^128,129 The Schimmelpenning syndrome occurs sporadically, and an autosomal lethal mutation that survives by mosaicism is postulated.¹³⁰

Diagnosis.

The diagnosis of nevus sebaceus is usually made on clinical grounds except in atypical cases. In infancy and childhood the characteristic histopathologic changes are less developed than in adolescence and adulthood. Mature lesions show numerous hyperplastic sebaceous and apocrine glands in the dermis, with overlying epidermal hyperplasia. In infants the histopathologic findings are more subtle, with rudimentary hair follicles and immature glandular structures. Sebaceous hyperplasia may not be so evident in a linear nevus sebaceus localized outside the head and neck area.¹¹⁵

Differential diagnosis.

The differential diagnosis of a circumscribed area of alopecia on the scalp at birth includes aplasia cutis congenita and neural tube closure defects such as meningocele, encephalocele, and rests of heterotopic meningeal or brain tissue in the skin (see Chapter 9). Aplasia cutis congenita can be distinguished by the presence of atrophy and scarring, and in some cases ulceration of the skin at birth. Neural tube defects are located in or close to the midline at the vertex, nasal bridge, or lower occipital scalp. Both aplasia cutis congenita and neural tube closure defects may show a collarette of dark terminal hair in the newborn.¹³¹ Eczematous changes overlying a nevus sebaceus may sometimes cause diagnostic confusion.¹³²

Treatment and prognosis.

The nevus sebaceus has a propensity to develop neoplastic growths, most of which are benign appendageal tumors such as syringocystadenoma papilliferum, trichilemmoma, trichoblastoma, and apocrine cystadenoma. Malignant tumors include basal cell epithelioma, squamous cell carcinoma, and apocrine or sebaceous carcinoma. These tumors are unusual in childhood, are localized to the skin lesion and rarely metastasize, although they may be locally invasive.¹³³ The lifetime risk of developing a superimposed malignant tumor is uncertain, and previously high figures may be due to ascertainment bias.¹³³ More recent studies have found a lower incidence of malignant tumors and suggest that benign follicular neoplasms such as trichoblastoma may have been misinterpreted as basal cell carcinoma in the past.^134–136 Changes that should lead one to suspect a neoplastic growth include surface ulceration or the development of a nodule within the lesion.

The need for prophylactic excision of a nevus sebaceus is controversial.^134–136 Decisions regarding surgery should be individualized. Excision may be performed in infancy or postponed until later childhood or adolescence. Continued observation may be preferable to surgery for lesions that are difficult to excise with a good cosmetic result, particularly on the face.

Cutaneous findings.

The keratinocytic epidermal nevus presents at birth or during early childhood and may continue to extend for a variable period.¹¹⁷ Rarely, new lesions become apparent in adolescence or adult life. They vary in extent from a small cluster or linear arrangement of pigmented, warty papules to widespread linear and swirled areas of pigmentation following the lines of Blaschko (Fig. 26.24A,B). A linear keratinocytic nevus may involve an entire limb, half of the body in a unilateral distribution, or both sides of the trunk, limbs, and face in a symmetric pattern, with demarcation at the midline. Extensive bilateral lesions have been referred to historically as ‘systematized epidermal nevus’ or ‘ichthyosis hystrix,’ and unilateral lesions as ‘nevus unius lateris.’

Keratinocytic nevi may have a macerated appearance at birth because of prolonged contact with amniotic fluid (Fig. 26.24C). During childhood, the degree of verrucosity varies from subtle, almost flat pigmentation to a grossly elevated, warty appearance.¹¹⁷ They have a tendency to become more verrucous with age, particularly during puberty. Keratinocytic nevi involving the head and neck often exhibit the morphology of a nevus sebaceus. Scalp lesions may be associated with woolly hair nevus, and occasional epidermal nevi have overlying hypertrichosis.¹⁴³ A linear lesion that impinges on the nail matrix may cause dystrophy of the involved nail.

A number of patients with one or more small hyperkeratotic papules with a distinctive histopathologic appearance have been described as ‘papular epidermal nevus with skyline basal cell layer’ or PENS.¹⁴⁴ Somewhat similar epidermal nevi with a white color have been observed at birth as a presentation of tuberous sclerosis.¹⁴⁵

The linear inflammatory verrucous epidermal nevus (ILVEN) is an extremely pruritic, erythematous lesion that can occur at any site, but is most often seen on the limbs or perineum in girls (Fig. 26.25). It may simulate linear psoriasis or linear lichen planus. It is rarely present at birth, but may appear in the first months of life.

Extracutaneous findings.

Most keratinocytic nevi are isolated lesions with no evidence of extracutaneous disease. A number of syndromes are associated with non-epidermolytic keratinocytic nevi.^115,118 These include Proteus syndrome; CLOVES (congenital lipomatous overgrowth, vascular malformation, epidermal nevus and skeletal abnormalities) syndrome; type 2 segmental Cowden disease; FGFR3 epidermal nevus, and CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome.^115,118 In the Proteus syndrome, epidermal nevi occur in association with limb overgrowth, lipomatous lesions, cerebriform malformations of the feet, and cutaneous vascular anomalies.^106,117 The CHILD syndrome is characterized by verrucous lesions corresponding to the lines of Blaschko in conjunction with limb reduction defects.^117,130

Extracutaneous manifestations have also been described in association with PENS.^146,147

Diagnosis.

The most common histopathologic pattern is that of a benign papilloma, with acanthosis, elongation of rete ridges, hyperkeratosis, and papillomatosis. This histopathologic appearance may be shared by viral warts, seborrheic keratosis, or acanthosis nigricans. Histopathology of lesions from the scalp may reveal features of a nevus sebaceus, especially after puberty. A subset of keratinocytic nevi shows the histopathologic features of epidermolytic hyperkeratosis, characterized by perinuclear vacuolization of keratinocytes and increased numbers of enlarged keratohyalin granules with overlying hyperkeratosis. In a less common variant, there is acantholytic hyperkeratosis similar to that seen in Darier disease.¹⁴⁸ Another rare variant is linear Cowden nevus, described as having a soft, thick papillomatous appearance and associated with a PTEN mutation.¹¹⁵ In PENS, the basal cell nuclei have a characteristic palisaded pattern.¹⁴⁴ Histopathologic findings in ILVEN include psoriasiform epidermal hyperplasia and an inflammatory infiltrate in the upper dermis.¹¹⁷ The nevus of CHILD syndrome resembles ILVEN but may also have collections of foam cells in the upper dermis consistent with a verruciform xanthoma.¹¹⁷

Etiology and pathogenesis.

The distribution of lesions following the lines of Blaschko suggests somatic mosaicism. Chromosomal mosaicism has been demonstrated in a number of patients with linear keratinocytic nevi.^149,150 Keratin 1 and 10 gene mutations have been identified in epidermolytic keratinocytic nevi.¹⁵¹ Keratinocytic nevi are thought to represent a phenotypic expression of several genetic defects due to post-zygotic mutations, rather than a single disease. Whether the basic pathogenetic defect of nonepidermolytic lesions lies in the dermal fibroblast or in the keratinocyte is not known.

Differential diagnosis.

The differential diagnosis of a localized cluster of lesions includes viral warts, which do not commonly have a linear arrangement and regress spontaneously with time. Linear lesions at birth may be confused with the verrucous stage of incontinentia pigmenti. Linear keratinocytic nevi that develop during infancy and childhood differ in morphology, if not in distribution, from lichen striatus, a self-limiting disorder with an inflammatory, papular appearance and lichenoid histopathology. The differential diagnosis of ILVEN includes lichen simplex chronicus, linear psoriasis, and linear lichen planus, none of which is seen in the newborn period.

The CHILD syndrome, the CLOVE syndrome and Proteus syndrome have distinctive clinical features.

Treatment and prognosis.

Unlike nevus sebaceus, the linear keratinocytic nevus is rarely associated with the development of superimposed benign or malignant tumors in adult life. Patients with epidermal nevi should be evaluated clinically for manifestations of one of the epidermal nevus syndromes.^115,118 When histopathologic examination shows epidermolytic hyperkeratosis, the patient should receive counseling about the potential for genetic transmission of a keratinopathic ichthyosis via germline mutation although the actual risk of transmission is not known.

Treatment may be requested for cosmetically disfiguring lesions but is generally undertaken in later childhood or adolescence. Excision of small lesions or localized areas of larger lesions may be feasible. Treatment of extensive nevi is difficult. Various destructive modalities, including CO₂ laser ablation, dermabrasion, or liquid nitrogen cryotherapy, have been attempted, but there may be recurrence.¹¹⁷ The same is true for pharmacologic treatments such as topical or oral retinoids and 5-fluorouracil.¹⁵²

Cutaneous findings.

Groups of enlarged follicular openings containing pigmented, comedo-like keratin plugs may be localized or extensive (Fig 26.26). Most nevi are unilateral and located on the face or upper trunk. They frequently have a linear arrangement. Extensive lesions are distributed along the lines of Blaschko and are limited at the midline.^153,144 There may be associated white papules representing milia, closed comedones, or deeper follicular cystic structures. Interfollicular atrophy is often observed.¹¹⁵

Later in childhood or adolescence these lesions may develop painful, inflammatory cystic nodules and acneiform scarring (Fig. 26.26).¹⁵⁴ The coexistence of a nevus comedonicus and a keratinocytic epidermal nevus has been reported.¹⁵⁵ Comedo-like structures may also be seen within keratinocytic nevi.¹¹⁷

Extracutaneous findings.

In most cases, there are no extracutaneous manifestations. Rarely, a nevus comedonicus is associated with ipsilateral central nervous system, skeletal, and ocular abnormalities in the nevus comedonicus syndrome.¹¹⁵ Ipsilateral cataracts are a characteristic feature.¹¹⁵ Rarely, these extracutaneous anomalies may be localized contralaterally.¹¹⁵

Etiology and pathogenesis.

Nevus comedonicus is a sporadic disorder and is not inherited. The pathogenesis is believed to involve somatic mosaicism.^130,156 A mutation in the fibroblast growth factor receptor 2 (FGFR2) gene detected in an inflammatory acne nevus suggests that some cases of this type of nevus represent a mosaic form of Apert syndrome.¹⁵⁷

Diagnosis.

The diagnosis is made on the clinical appearance of the lesion. Histopathologic examination reveals hyperkeratosis and acanthosis of the epidermis with widely dilated, keratin-filled, cystic structures. Epidermolytic hyperkeratosis may be observed in the keratinocytes of the follicular epithelial wall.^153,154

Differential diagnosis.

The localized appearance of the lesion is very characteristic and unlikely to be mistaken for comedonal acne unless bilateral.¹⁵⁶

Porokeratotic eccrine nevus presents with comedo-like lesions on the palms and soles and has distinctive histopathologic features.

Inflammatory cysts may closely resemble cystic acne.

Nevus comedonicus syndrome should be distinguished from the Happle–Tinschert syndrome, in which multiple segmentally arranged basaloid follicular hamartomas are associated with ipsilateral osseous, dental and cerebral anomalies, and from a less well-defined syndrome with multiple trichilemmal cysts arranged along Blaschko’s lines.^115,118,158

Treatment and prognosis.

Recurrent inflammation and scarring can cause cosmetic disfigurement. Treatment is difficult. Excision of smaller lesions is curative,¹⁵⁹ but inflammatory acneiform cysts may recur if excision is incomplete. Pharmacologic agents such as oral or topical retinoids are of minimal benefit. Topical and systemic antibiotics have been used to treat inflammatory lesions, with variable success.¹⁵⁶

Cutaneous and extracutaneous findings.

Porokeratotic eccrine nevus is characterized clinically by grouped comedo-like keratotic papules or pits on a palm or sole.¹⁶¹ Lesions may be more widespread with a linear distribution following the lines of Blaschko.¹⁶² Keratotic papules and plaques located in sites other than the palms and soles may resemble a linear keratinocytic nevus or ILVEN.^162,163 Multiple erosions and atrophy have been reported in cases presenting in the newborn period.¹⁶⁰ Most cases are asymptomatic but pruritus has been reported.¹⁶⁰ Rare cases have associated anhidrosis, hair loss and nail dysplasia, psoriasis, palmar plantar keratoderma or ipsilateral breast hypoplasia.¹⁶⁰ Development of Bowen disease or squamous cell carcinoma within the lesional skin is an unusual complication.¹⁶⁰

Cases of generalized porokeratotic eccrine nevus associated with deafness and also with the keratitis-ichthyosis-deafness (KID) syndrome have been reported.^164–166

Etiology and pathogenesis.

The pathogenesis is believed to represent a circumscribed disorder of keratinization localized to the acrosyringium and follicular ostia.¹⁶² Somatic mutations in the GJB2 gene encoding the gap junction protein connexin 26, have been identified in patients with generalized porokeratotic eccrine nevus suggesting it might be a mosaic form of the KID syndrome.¹⁶⁶ These authors also report the observation of generalized lethal KID syndrome in an infant born to a mother with porokeratotic eccrine nevus.

Diagnosis.

Histopathologically, there are epidermal invaginations with parakeratotic plugs emerging from dilated eccrine ostia and follicular openings, surrounded by parakeratotic columns of cornoid lamellae.¹⁶⁰

Differential diagnosis.

The clinical differential diagnosis includes linear porokeratosis, nevus comedonicus, and linear keratinocytic nevus. Histopathologically, punctate porokeratosis and linear porokeratosis of Mibelli can be distinguished by the lack of epidermal invaginations. The histopathologic features can resemble those seen in KID syndrome.¹⁶⁶

Treatment and prognosis.

Treatment is unsatisfactory.¹⁶⁰ There are reports of successful treatment with the ultrapulsed CO₂ laser but recurrence has been noted.^160,162,167

Cutaneous findings.

The typical congenital smooth muscle hamartoma presents as a lightly pigmented plaque or patch with overlying hypertrichosis (Fig. 26.27). The trunk, in particular the lumbosacral area, is the site of predilection, but lesions may also occur on the proximal limbs. Perifollicular papules are sometimes evident.¹⁷³ The overlying hair is vellus in type. Hypertrichosis is not invariable, and the hamartoma may present as a plaque of perifollicular papules with little or no increase in hair growth.¹⁷⁴ Transient elevation or a rippling movement of the lesion due to contraction of the muscle bundles can sometimes be elicited by rubbing or stroking the surface. Rarely, a congenital smooth muscle hamartoma has a linear configuration, or presents with multiple lesions or diffuse involvement.^172,175,176

Extracutaneous findings.

There are no systemic findings with localized lesions. There may be associated growth and developmental abnormalities in children with extensive smooth muscle hamartoma as a manifestation of the ‘Michelin tire baby’ syndrome.^171,172 Unilateral hypoplasia of the breast and other cutaneous, muscular, or skeletal defects may be associated with smooth muscle hamartoma in the Becker nevus syndrome.¹⁷⁷

Etiology and pathogenesis.

Congenital smooth muscle hamartoma is believed to represent aberrant development of pilar smooth muscle during fetal life. It has been suggested that the hamartoma involves other structures, such as neural tissue and hair.¹⁷³ The hypertrichosis appears to result from increased hair length and diameter rather than an increase in hair density.¹⁷⁴

Diagnosis.

Light microscopic examination of a skin biopsy specimen will establish the diagnosis if the clinical appearance is atypical. Numerous well-defined and variably oriented bundles of smooth muscle are seen within the reticular dermis. They may or may not be associated with follicular structures. Increased epidermal pigmentation may be observed.

Differential diagnosis.

The differential diagnosis of congenital smooth muscle hamartoma includes Becker nevus, nevus pilosus, leiomyoma, connective tissue nevus, solitary mastocytoma, plexiform neurofibroma, and a congenital hairy melanocytic nevus. Smooth muscle may be observed in the dermis in Becker nevus, and a continuum between the two conditions has been proposed.¹⁷³ Unlike Becker nevus, the congenital smooth muscle hamartoma is always present at birth, does not show prominent epidermal changes, and may demonstrate abnormally whorled myofilaments on electron microscopy.¹⁷⁴

A nevus pilosus, or hairy patch, shows no alteration in skin texture or pigmentation, and the hair is usually terminal in type. A congenital melanocytic nevus is more deeply pigmented, and the overlying hypertrichosis is composed of terminal hair. Leiomyoma is a circumscribed spindle-cell tumor. Connective tissue nevi and mastocytoma may be distinguished by skin biopsy.¹⁷⁴

Prognosis.

This hamartoma has no malignant potential and the prognosis is excellent. There is a tendency for the pigmentation and hair growth to become less noticeable with age.¹⁶⁸ Treatment is unnecessary, unless there are cosmetic concerns in later life.

Cutaneous findings.

Connective tissue nevi present clinically as asymptomatic, firm, skin-colored to yellowish nodules or plaques located on the trunk or limbs (Fig. 26.29). The surface of the lesion may be smooth or have a ‘cobblestone,’ ‘leather-grain,’ or ‘peau d’orange’ appearance. They may be solitary or multiple. A linear or ‘zosteriform’ morphology is sometimes observed. A rare monomelic variant simulating linear scleroderma and causing functional impairment has been described in three children, with onset at birth or in early childhood.¹⁸⁹

Extracutaneous findings.

Osteopoikilosis is seen in association with elastic tissue nevi in the Buschke–Ollendorff syndrome.¹⁹⁰ The skin lesions in this condition may rarely be present at birth, but the distinctive bone changes are not reported in infancy. The collagenoma or ‘shagreen patch’ of tuberous sclerosis develops in later childhood, although other stigmata of the disease may be present at birth or in early infancy. Cardiomyopathy may occur in association with the multiple lesions of familial cutaneous collagenoma and with collagenomas and hypogonadism.¹⁸⁸ A cerebriform collagenoma on the sole of the foot may be an isolated phenomenon or a component of Proteus syndrome.¹⁹¹

Etiology and pathogenesis.

The pathogenesis is unknown. In familial cutaneous collagenoma, the skin lesions are inherited as an autosomal dominant trait. Tuberous sclerosis and Buschke–Ollendorff syndrome are also inherited by autosomal dominant transmission; mutations in the LEMD3 gene have been identified in Buschke–Ollendorff syndrome.¹⁸⁹ Somatic mosaicism may be postulated for sporadic lesions, particularly those with a linear distribution.

Diagnosis.

Histopathologic examination of connective tissue nevi shows an excess of collagen or elastic tissue, or both, in the dermis. This excess may not be apparent unless a specimen of normal adjacent skin is obtained for comparison. Thus biopsies of connective tissue nevi are often reported as ‘normal skin.’ Special elastic stains are necessary to demonstrate the increased numbers of elastic fibers in elastic tissue nevi. A more uncommon cellular histopathologic variant has recently been identified.¹⁸⁹ Congenital mucinous nevus may be a variant of connective tissue nevus in which deposition of mucin (proteoglycan) in the dermis is the predominant histopathologic finding.¹⁹²

Differential diagnosis.

The differential diagnosis includes other cutaneous hamartomas, such as neurofibroma, leiomyoma, smooth muscle hamartoma, and epidermal nevus. These entities may be distinguished by histopathologic examination of a skin biopsy specimen.

Treatment and prognosis.

Connective tissue nevi are permanent lesions. They grow in proportion to the child’s growth. There is no malignant potential and most do not require treatment. Surgical excision may occasionally be indicated for cosmetic reasons.