Legius syndrome

Legius syndrome (neurofibromatosis type 1-like syndrome) is a recently identified autosomal dominant disorder caused by a mutation in the SPRED1 gene.¹⁷ The SPRED1 gene is responsible for making spred-1 protein which inhibits the Ras/MAPK pathway. Affected individuals typically have CALM and axillary freckling. However, neurofibromas, typical osseous lesions, Lisch nodules of the iris and central nervous system tumors are characteristically absent. Some patients with Legius syndrome have been described with macrocephaly, a Noonan-like facial appearance, learning disorders, developmental delay and/or attention deficit/hyperactivity disorder in childhood.^17,18 Several families with Legius syndrome have been described with lipomas as well.^17–19 Many individuals may meet the NIH diagnostic criteria for NF-1 but gene testing will be negative for mutations in the neurofibromin gene. It is uncertain if there is an increased risk of malignancies. However, some authors have proposed less stringent monitoring in Legius patients as compared to NF-1 patients.¹⁸ Screening for developmental delay and behavioral and learning problems is recommended as well as examination and counseling by a clinical geneticist familiar with Legius syndrome.

Familial (inherited) café-au-lait macules

Multiple familial CALM have been described in several families without the other stigmata of NF-1, including the absence of NF-1 gene mutation. SPRED1 had not been tested in these families.²⁰ This diagnosis should only be made in an older child without the other stigmata of NF-1 with a clear family history of multiple CALM without other signs of NF-1.⁴

McCune–Albright syndrome

The cardinal features of McCune–Albright syndrome (MAS) include polyostotic fibrous dysplasia, endocrinopathies and precocious puberty as well as CALM. MAS is a rare and sporadic disorder caused by a postzygotic mutation in the gene, GNAS1.^21–23 The GNAS1 gene encodes for the alpha subunit of the guanine nucleotide-binding protein, causing loss of GTPase activity and increased stimulation of the adenylate cyclase system, resulting in proliferation and autonomous hyperfunction of hormonally responsive cells.^24–26 This autosomal dominant mutation is only compatible with life when it occurs in individuals as a postzygotic somatic mutation with resulting mosaicism, which in turn results in marked phenotypic variability.

The CALM seen in MAS are often large, and segmental with favored distribution over the torso and buttocks. They may also follow the lines of Blaschko (Fig. 24.2).^27,28 The border of the CALM in MAS is often described as ‘jagged’ and irregular. These cutaneous findings may be present at birth or within the first few years of life and have been noted in approximately 53–98% of patients with MAS.^29,30 Melanotic macules of the oral mucosa have also been reported.^31,32

Extracutaneous findings in MAS include polyostotic fibrous dysplasia, where bone is replaced by fibrous tissue resulting in asymmetry, bony growths and pathologic fractures; this finding is rarely seen at birth and tends to manifest over time, usually within the first decade. In addition, endocrine abnormalities that may occur include precocious puberty, hyperthyroidism, Cushing syndrome, hyperparathyroidism, hyperprolactinemia, and hypersomatotropism.^25,33–35 Neonatal cholestasis, acholic stools and jaundice have been described as presenting symptoms in neonates with MAS.³⁵

Due to the variable clinical expression and segmental nature, diagnosis of MAS may be difficult in infancy. Cutaneous findings of MAS must be differentiated from NF-1. The CALM found in NF-1 tend to be smaller, lighter in color, and more scattered in distribution. Histologic studies would not be helpful in differentiating these disorders. Radiologic studies for MAS may not reveal bony abnormalities in the neonatal period and CALM often precede the development of bony changes by 3 months to 9 years.³⁶ When MAS is suspected, close observation for endocrine abnormalities is warranted. In those with known or suspected MAS, a referral to orthopedics and endocrinology is recommended. Prognosis for MAS is generally favorable and the development of malignancy is rare. Extensive osseous dysplasia early in life, however, portends a poorer prognosis.³⁶

Congenital dermal melanocytosis (Mongolian spots)

Mongolian spots are common birthmarks present in over 80% of black and Asian infants compared with only up to 10% of Caucasians infants.^37,38 They present at birth, or early infancy, as blue-gray, blue-green, or blue-black macules most often noted over the sacrum and gluteal regions (Fig. 24.3) and less often on extensor extremities and the posterior shoulder. Size can range from a few millimeters to over 10 cm and single or multiple lesions may be present. The borders of Mongolian spots are ill-defined and tend to fade gradually into the surrounding skin color. The coloration will often stabilize in infancy and fade during the first decade of life. Only a small number of lesions persist (3–4%) after adolescence and it has been suggested that these are likely not distinct entities but analogous to Nevus of Ota or Ito.^37,39–41 Clinically, these persistent lesions are often blue-black homogenous or speckled patches present in a segmental distribution.

In the Mongolian spot, elongated, slender and slightly wavy dendritic cells containing melanin granules are found in the mid and deep dermis.⁴² These dendritic melanocytes are present in low numbers and scattered between collagen bundles, both of which are orientated parallel to the skin surface. There is an absence of melanophages. The reason for regression of Mongolian spots and failure of regression of other dermal melanocytic lesions such as nevus of Ito or Ota with age is currently unknown.

Mongolian spots are common, and associated abnormalities are rare. Dermal melanocytosis may be associated with certain lysosomal storage diseases, including gangliosidosis type 1 (GM1), Niemann–Pick disease, Hunter syndrome, α-mannosidosis syndrome, and Hurler syndrome.⁴³ Dermal melanocytosis is generally extensive in distribution often involving the ventral and dorsal aspects of the trunk in addition to the sacrum and extremities.^44–50 Mongolian spots may also co-exist within CALM in NF-1.^51,52 Dermal melanocytosis is part of the criteria for a subgroup of neurocristopathies labeled ‘phakomatosis pigmentovascularis’ (PPV), in which vascular malformations of the skin, pigmented nevi and Mongolian spots occur together in the same patient (see below). Cleft lip malformation has been associated with adjacent dermal melanocytosis although the significance of the association is unknown.^53,54

Nevus of Ota (nevus fuscoceruleus ophthalmomaxillaris, oculodermal melanocytosis)

Bluish hyperpigmentation of the skin along the ophthalmic and maxillary branches of the trigeminal nerve is known as Nevus of Ota (Fig. 24.4). These patches can be brown, blue-gray or blue-black, gray or purple and have a speckled or mottled appearance with poorly-demarcated borders. Nodular areas similar to blue nevi can be present.^58–61 Nevus of Ota often affects one side of the face and bilateral involvement is described in only 5–10% of patients.^62,58,63 Distribution of Nevus of Ota most commonly involves the ophthalmic and maxillary branches with involvement of all three branches of the trigeminal nerve being the least common distribution.^41,60,63 This condition is more commonly seen in Asians and has a female preponderance. They may be present at birth or appear within the first year of life, or later between the ages of 11–20 years; mid-childhood onset is rare. Spontaneous resolution does not occur as seen in Mongolian spots. Pathology of cutaneous lesions shows a greater concentration of elongated, dendritic dermal melanocytes scattered within the collagen bundles in the upper dermis (compared with Mongolian spots).

In addition to cutaneous involvement, Nevus of Ota involving the ocular sclera can be seen in two-thirds of patients.⁶⁴ Pigmentation of the sclera, conjunctiva, cornea, iris and choroid, and less commonly, the optic nerve, retrobulbar fat, orbital periosteum and extraocular muscles can occur. Oral mucosal pigmentation and pigmentation of the tympanic membrane can occur as well.

Most Nevi of Ota pose a potential cosmetic concern but few may be associated with complications. Open-angle glaucoma occurs in approximately 10% of patients due to proliferation of melanocytes in the anterior chamber angle.^65,66 The most concerning complication is the development of melanoma within pigmented areas. Malignant degeneration has been reported and may include the eye (choroid, iris, or orbit), skin, and brain.^67–69 Sturge–Weber syndrome, Klippel–Trenaunay syndrome, neurofibromatosis, inflammatory vascular disease, cerebral arteriovenous malformation, multiple hemangiomas, and spinocerebellar degeneration have been described occurring in association with Nevus of Ota.^70–75 Rare occurrences of ipsilateral hearing loss with Nevus of Ota have been reported.^76,77 Nevus of Ota occurring with nevus flammeus is seen in variants of phakomatosis pigmentovascularis. Leptomeningeal melanosis and Nevus of Ota can occur concurrently as well.^{68,69,75,78,79}

Nevus of Ito (nevus fuscoceruleus acromiodeltoideus)

The Nevus of Ito is an analogous lesion to Nevus of Ota with a distribution over the posterior supraclavicular and lateral cutaneous branchial nerves. These blue-gray poorly-demarcated patches may present over the shoulder, supraclavicular neck, upper arm, scapular and deltoid areas (Fig. 24.5). Bilateral nevus of Ito has been reported in a patient with a speckled lentiginous nevus,⁸⁵ and bilateral Nevus of Ota with a unilateral Nevus of Ito has been noted.⁸⁶ Cutaneous melanoma and malignant cellular blue nevus have been rarely reported in Nevus of Ito and extracutaneous findings are not seen.^87–89

Blue nevi

Blue nevi are dermal melanocytomas that represent benign proliferations of pigment producing dendritic dermal melanocytes (Fig. 24.6). Dermoscopy of common blue nevi reveals uniform blue coloration. Blue nevi are rarely seen at birth, but congenital forms have been described.^90–92 Most are acquired, with onset in childhood or adolescence, with predilection for the scalp and face, dorsal aspects of the distal extremities and sacral area. Three types of blue nevi have been described: (1) cellular blue nevus, (2) common blue nevus, and (3) the combined nevus.

Cellular blue nevi seen at birth are rare and have a predilection for the scalp, sacrococcygeal area and buttocks. They present with blue-gray or blue-black nodules or plaques with a smooth or irregular surface texture. Although most congenital cellular blue nevi are small in size (1–3 cm), larger and ‘giant’ lesions can be seen, most commonly on the scalp.⁹³ Melanoma has been described particularly in larger lesions on the scalp.^92–104 Multiple satellite blue nevi in association with a large congenital cellular blue nevus have also been reported.^93,105 Other related variants of congenital blue nevi include the pauci-melanotic cellular blue nevi, epithelioid blue nevi (also known as pigmented epithelioid melanocytoma), congenital plaque-type blue nevi and neurocristic hamartomas. Multiple blue nevi may be seen in Carney complex (see below) or without associated abnormalities. A rare, congenital, plaque-like type of blue nevus, showing a circumscribed area with numerous macules and papules has been described.¹⁰⁶ Blue nevi may arise within speckled lentiginous nevi as well as within other dermal melanocytoses such as Nevus of Ota.^58,107,108

Blue-black nodules, papules and plaques seen at birth or infancy are suggestive of blue nevi. A biopsy may be needed to confirm the diagnosis and differentiate lesions from melanoma. Common blue nevi will show pigmented dendritic melanocytes singly or in small aggregations in the reticular dermis, surrounded by thickened collagen. Histopathology of cellular blue nevi, in contrast, shows cellular islands of large spindle-shaped or epithelioid cells with little or no melanin, in addition to pigmented dermal dendritic melanocytes. Lesions may penetrate deep into the subcutaneous fat.⁴²

Chimerism

A chimera refers to an individual with cells derived from two separate zygotes that can be demonstrated by molecular analysis. Human chimerism is rare. Nevoid hyperpigmentation patterns described in human chimeras have included a flag-like rectangular pattern, a pattern of rounded units (café-au-lait-like patches) and a striated pattern.¹¹⁵

Linear and whorled nevoid hypermelanosis

The term ‘linear and whorled nevoid hypermelanosis’ (LWNH) is generally used to describe a sporadic disorder of hyperpigmentation in swirls and streaks following a Blaschkoid distribution. Classically, the hyperpigmentation consists of homogenous 1–5 mm macules forming a reticulated configuration and sparing the palms, soles, mucous membranes and eyes.¹¹⁶ Segmental, linear or swirled hyperpigmentation or a combination of these with a sharp midline demarcation is seen over the trunk and less commonly involving the extremities (Fig. 24.7).¹¹⁷ LWNH appears at birth or during the first few weeks to months of life without any preceding inflammatory eruption. The pigmentation may progress for the first 1–2 years of life and then stabilize, possibly becoming less prominent over time. Biopsy of the hyperpigmented macules shows basilar hyperpigmentation with no pigment incontinence or dermal melanophages.¹¹⁶

Systemic abnormalities seen in association with LWNH include neurologic, developmental, musculoskeletal, and cardiac abnormalities that often arise early in life;^117–119 LWNH has been described as akin to hypomelanosis of Ito (HI) with cutaneous hyperpigmentation instead of hypopigmentation. No large study exists to define the incidence of systemic features in patients with LWNH. However, systemic comorbidities are described much less frequently in association with LWNH as compared with HI.^119,117

LWNH is believed to result from somatic mosaicism of neuroectodermal cells deriving from neural crest, with normal and hyperpigmented skin a result of two distinct populations of cells.^116,120 Chromosomal mosaicism has also been described.^{114,121–126} Although thought to be a sporadic disorder, rare familial occurrences of LWNH have been reported, suggesting an undescribed gene abnormality.¹²⁷

LWNH is usually diagnosed clinically and should be distinguished from other conditions with Blaschkoid hyperpigmentation (Box 24.1). With diffuse skin disease, it can be difficult to deem which coloration represents the patient’s normal skin and whether the affected areas are represented by hyper- or hypopigmentation. Skin biopsy will enable differentiation from some conditions such as incontinentia pigmenti (IP) and early (macular) epidermal nevus.

Incontinentia pigmenti

Incontinentia pigmenti (IP; see also Chapter 29) is an X-linked dominant hereditary disorder found predominantly in females, manifesting with characteristic skin findings, various tooth, eye and nail abnormalities, and neurologic and immunologic impairment. Incontinentia pigmenti is due to a mutation in the IKK-gamma (NEMO) gene.¹²⁸

The cutaneous findings of the IP syndrome are evident at birth or shortly thereafter and have been classically defined by four stages: (1) vesiculobullous, (2) verrucous, (3) hyperpigmented and (4) hypopigmented.¹²⁹ However, all four stages may not be seen over time, or they may overlap throughout life. The first inflammatory vesiculobullous stage presents with streaks of eosinophil-filled epidermal vesicles in a geometric fashion, mainly on the extremities, followed by verrucous or lichenoid lesions, and papules and pustules within 2–6 weeks (Fig. 24.8). This stage may persist for several months. Once resolved, widely disseminated hyperpigmentation in a whirled or linear fashion arises, mainly on the trunk. The third stage generally resolves over years and may completely disappear. A fourth stage of atrophy and hypopigmentation, commonly over the lower extremities, may replace the hyperpigmented areas. This stage may be subtle and faint and can be easily overlooked in adult females.¹³⁰

The differential diagnosis of the hyperpigmented stage of IP includes linear and whorled nevoid hypermelanosis, macular epidermal nevi and other disorders with Blaschkoid pigmentation.

Phakomatosis pigmentovascularis

Phakomatosis pigmentovascularis (PPV) is defined by the presence of a widespread vascular malformation, in particular a capillary malformation (port-wine stain), with cutaneous pigmented lesions such as dermal melanocytosis (usually slate-gray or blue melanosis or Mongolian spot-like) or nevus spilus with various other cutaneous nevi (nevus anemicus, epidermal nevus, cutis marmorata telangiectatica) and possible extracutaneous alterations. Pigmentation in PPV is often diffuse (>50% of the skin) and persistent and does not correlate with the typical locations for Mongolian spots (Fig. 24.9).¹³¹

A classification system based upon dominant pigmentary anomalies and subdivisions with extracutaneous findings categorizes four prominent types of PPV (Table 24.3), with type II the most common. The pathogenesis of PPV has been proposed as a phenomenon called ‘twin spotting’.¹³²

Numerous extracutaneous abnormalities may be seen, the most common being an overlap with Sturge–Weber syndrome, as well as Klippel–Trenaunay syndrome and melanosis oculi.^133–138

The differential diagnosis of PPV includes capillary malformation-macrocephaly syndrome and Beckwith–Wiedemann syndrome. Proteus syndrome may also be considered and is distinguished by the presence of overgrowth, asymmetry and gigantism. Treatment for certain birthmarks, with the aim of improving aesthetics, such as the port wine stain and dermal melanocytosis, can be accomplished with laser therapy.

Phakomatosis pigmentokeratotica

Phakomatosis pigmentokeratotica (PPK) describes the sporadic concurrence of a Blaschkoid epidermal nevus (organoid or sebaceous differentiation) with a cutaneous pigmentary anomaly such as nevus spilus.¹³⁹ The name rightly suggests an analogy with PPV and may occur due to the twin spotting genetic mechanism, and/or multilineage somatic mosaicism. In neonates and infants, the speckled lentiginous nevus may appear as a large CALM, prior to the development of ‘speckles’ and papules. Extracutaneous findings are usually present, including neurologic abnormalities (seizures, mental deficiency, hemiparesis and muscular weakness, dysesthesias), skeletal problems (including vitamin D-resistant rickets), and ophthalmologic alterations.^139,140 Basal cell carcinoma and melanoma have been reported to arise in the nevus sebaceus and nevus spilus, respectively, and emphasizes the importance for long-term surveillance in these patients.¹⁴¹

Naegeli–Franceschetti–Jadassohn syndrome

Naegeli–Franceschetti–Jadassohn syndrome is an autosomal dominant subtype of ectodermal dysplasia syndrome characterized by the development of brown-gray reticulated pigmentation in early childhood without preceding inflammation.¹⁴² Pigmentation is localized on the abdomen in most cases but may be periorbital or perioral, or on the neck, flexures, groin or proximal extremities in some cases. Pigmentation gradually increases over the first decade of life and begins to fade after puberty. Sweating is markedly decreased in affected individuals, dermatoglyphics are often absent, and keratoderma of the palms and soles and dental anomalies can be seen. The syndrome is due to a mutation in the KRT14 gene located on 17q11.2-q21 and is allelic to dermatopathia pigmentosa reticularis.¹⁴³

Striated hyperpigmentation of the torso

Horizontal thin stripes of hyperpigmentation (see Chapter 7) over the creases of the abdomen and extremities can be observed in the neonatal period.¹⁴⁴ This finding is typically transient and likely to result from shedding of hyperkeratotic skin after birth.

Congenital curvilinear palpable hyperpigmentation (sock-line bands, sock-line hyperpigmentation)

Congenital curvilinear palpable hyperpigmentation is a relatively recently described clinical finding on the posterior legs (usually bilateral posterior calves) of infants (see Fig. 8.27).¹⁴⁵ Involvement of the arms (‘mitten-line hyperpigmentation’) and heels (‘heel-line hyperpigmentation’) has also been described.^146–148 The hyperpigmented to slightly erythematous plaques are often symmetric, palpable, curvilinear and semicircumferential. Macular hyperpigmentation is also common. The etiology of these lesions is unknown but trauma from tight socks or mittens has been proposed. The pigmentation resolves spontaneously over months to years. Because of the strikingly linear configuration of the lesions, this disorder can be confused with child abuse.

Treatment and care.

Management of individuals with XP involves genetic counseling, strict UV exposure avoidance, protective clothing and long hairstyles, sunscreen, sunglasses, protective window coatings and vitamin D supplementation. Skin examinations by the patient/family and dermatologist should be frequent so that malignancy and pre-malignant changes can be caught and treated early. Surgery techniques typically undertaken in normal individuals with skin cancer, such as cryotherapy, simple excision, electrodissection and curettage, Mohs micrographic surgery and the use of topical chemotherapeutic agents, are appropriate. The use of high-dose oral isotretinoin and acitretin has been reported to reduce certain types of new skin cancer formation in XP patients but use is often limited by side-effects, especially in children.^158,159 Topical liposome-encapsulated endonuclease has also been reported to decrease the formation of actinic keratoses and basal cell carcinomas in XP patients.¹⁶⁰ Radiation therapy has been used successfully in treatment of aggressive skin cancers in patients with XP, as these patients tend to have a normal cellular and clinical response to ionizing radiation.¹⁶¹ Death may occur in individuals with XP due to cutaneous or internal malignancy or neurologic degeneration.

Treatment and care.

In patients with lentigines noted at birth or during the neonatal period, evaluation should include a complete physical examination for associated extracutaneous findings, electrocardiogram (ECG), hearing evaluation, and other studies prompted by signs and symptoms. Abnormalities should be monitored by the appropriate specialist and genetic counseling should be provided. Treatment of lentigines has been attempted with cryotherapy and various lasers in some patients. The end results of these treatments are quite variable. It is generally not recommended in early childhood.^186–189

Carney complex (NAME/LAMB syndrome)

Several previous descriptions of the syndromes now consolidated under the term Carney complex represent various manifestations of this complex. These include NAME syndrome (nevi, atrial myxoma, myxoid neurofibromata, ephelides) and LAMB syndrome (lentigines, atrial myxoma, myxoid tumors, blue nevi).^190–192 Carney complex is an autosomal dominant multiple endocrine neoplasia disorder characterized by lentigines, endocrine hyperactivity, cardiac myxomas and schwannomas.

The cutaneous findings in Carney complex include lentigines, café-au-lait macules, and blue nevi. Lentigines occur shortly after birth and are concentrated over the central facial area and can involve the mucosa. They can also extend to the neck, trunk, extremities and genitalia. Associated nevi can be congenital or arise later in infancy. Nontender dermal nodules, or cutaneous myxomas, do not often develop until the second decade of life and are typically located on the head and neck. Associated noncutaneous findings in Carney complex include cardiac myxoma, endocrine diseases and tumors (Cushing syndrome, acromegaly), testicular tumors (in particular, Sertoli cell tumor), psammomatous melanotic schwannomas and possibly other benign and malignant neoplasms such as ductal adenoma of the breast.

Carney complex is due to a mutation in the PRKAR1A gene on chromosome 17q23.¹⁹³ This gene encodes the regulatory subunit of protein kinase A and functions as a tumor-suppressor gene. Linkage to the short arm of chromosome 2 has also been described in 11 kindreds with clinical findings of Carney complex, indicating genetic heterogeneity.¹⁹⁴

Other multiple lentigines syndromes need to be differentiated from Carney complex, including LEOPARD and Peutz–Jeghers syndromes. If a neonate has skin findings suggestive of Carney complex, evaluation by cardiology, endocrinology, and urology is warranted, and genetic counseling should be offered.¹⁹⁴

Centrofacial lentiginosis

Lentigines with involvement of the central face without further extension to other areas of the skin or mucosa have been termed ‘centrofacial lentiginosis’. Onset is usually in infancy and autosomal dominant inheritance is suggested. In adulthood, the lentigines often fade. Centrofacial lentiginosis may be associated with skeletal and bony abnormalities, neurologic manifestations, developmental and psychiatric symptoms and endocrine dysfunction.¹⁹⁵

Segmental lentiginosis (partial unilateral lentiginosis, lentiginous mosaicism)

Asymmetric segmental distribution of lentigines in large numbers usually designated to one side of the body has been termed segmental lentiginosis (also reported as partial lentiginosis, unilateral lentigines or agminated lentiginosis).¹⁹⁶ It has been suggested that some of these cases may actually represent a speckled lentiginous nevi, epidermal nevus or LWNH.^197,198

Another term, ‘partial unilateral lentiginosis’ (PUL), has been coined to describe small clustered hyperpigmented macules distributed in a unilateral limited area of the body (sometimes in a segmental pattern), usually involving the face, neck, and upper trunk.¹⁹⁹ These macules overlie normal skin and they have a sharp midline demarcation. Histologically lesions show features of lentigo simplex without nevus cells being present, although small nests of melanocytes have been described at the tips of the rete ridges, forming a ‘jentigo’ pattern.^200,201 Lesions appear in childhood, as early as one year of age, but are rarely seen at birth. PUL has been associated rarely with central nervous system diseases (epilepsy, mental retardation, intracranial vascular malformations).^202–204 Familial inheritance has not been described.

Segmental lentiginosis should be differentiated from other segmental disorders including speckled lentiginous nevus, segmental NF and agminated Spitz nevi. Wood’s light examination and skin biopsy may be helpful in these cases. Destruction of lentigines via laser or cryotherapy can be performed if desired.¹⁸⁹

Peutz–Jeghers syndrome

Peutz–Jeghers syndrome (PJS) is one of the most well-known familial lentiginosis syndromes. It is dominantly inherited and caries a risk of solid tumor malignancy.^205,206 A key cutaneous diagnostic feature of PJS is dark brown-blue macules on the oral mucosa (buccal mucosa, palate, gingival), border of the lips (Fig. 24.13), and palms/soles, eyes, nares and perianal region.^207,208 Pigmented bands in the nail plates can also be seen. The macules typically appear in childhood but can be present at birth and may fade in late adulthood. Mucosal lentigines tend not to fade. In addition, patients with PJS can have pigmented macules of the bowel mucosa, intestinal hamartomatous and adenomatous polyps (found in the jejunum, ileum, colon, rectum, stomach and duodenum). There is also an increased susceptibility to benign and malignant tumors including benign ovarian sex cord tumors, calcifying Sertoli tumors of the testes, cervical, breast, pancreatic, endometrial and gastrointestinal cancer.

PJS is mainly due to a heterozygous mutation in the serine threonine kinase STK11/LKB1 gene, a tumor suppressor gene.^209,210 Disease manifestations are triggered by the loss of the functional copy of the gene in somatic cells.

Histopathology of the cutaneous pigmented macules is typical for lentigines (see above). Abdominal pain, melena, or intussusception may be the presenting sign in individuals with intestinal involvement. The differential diagnosis of neonatal lentigines includes LEOPARD syndrome, Carney complex, and generalized lentiginosis. For patients with PJS, hematocrit and stool guaiacs are recommended in childhood and polyps may require surgical intervention for symptom relief. Referral to gastroenterology is needed for continued surveillance for malignancy of the GI tract, and medical screening with interval history and physical examinations of other associated organs to monitor for malignancy should be undertaken.

Bannayan–Riley–Ruvalcaba syndrome

Bannayan–Riley–Ruvalcaba (Riley–Smith, Bannayan–Zonana, and Ruvalcaba–Myhre–Smith syndromes) is an autosomal dominant phenotypically variable disorder under the heading of ‘PTEN hamartoma tumor syndromes’ due to the discovery of mutation in the tumor suppressor gene PTEN in up to 60% of patients.²¹¹ Mutations in this gene are also described in Cowden syndrome and other related hamartoma syndromes.^209,210 Vascular anomalies and intestinal hamartomatous polyps have also been described.

Lentigines, 2–6 mm in size commonly occur on the glans and shaft of the penis or on the vulva of females. These may be present at birth or infancy, or develop during childhood and adolescence.^212,213 Other cutaneous findings may include single or multiple café-au-lait macules, subcutaneous lipomas, vascular anomalies, facial papules (displaying features of trichilemmomas and verrucae),²¹⁴ oral and perianal papillomas, acrochordons, acral keratoses and acanthosis nigricans.

Noncutaneous findings in BRRS include the common findings of macrocephaly (without ventricular enlargement) that may be noted at birth or infancy. About half of the patients will have neurologic abnormalities including hypotonia, delayed psychomotor development, mental deficiency and seizures.²¹⁴ Visceral lipomas, hamartomatous intestinal polyps (45% of patients),²¹⁵ skeletal abnormalities and joint hyperextensibility may also be seen. Retinal abnormalities such as prominent Schwalbe lines and corneal nerves may be noted in 35% of patients as well as pseudopapilledema.^216,217 A myopathic process described in BRRS has shown a lipid storage myopathy on muscle biopsy, predominantly in enlarged type 1 skeletal muscle fibers.^218,219 Thyroiditis and thyroid neoplasms have been reported.²¹⁵

BRRS is allelic to Cowden syndrome with many overlapping cutaneous and systemic features; however, Cowden syndrome has a later age of onset, usually in adulthood. Patients with Peutz–Jeghers syndrome do not have the genital distribution of lentigines as in BRRS. Proteus syndrome, another multiple hamartoma syndrome, presents with pigmented lesions consistent with epidermal nevi and Blaschkoid nevoid hypermelanosis, which should be easily distinguishable from BRRS. Genital lentigines in BRRS may be subtle and easily overlooked. Recognition of the disorder should prompt referrals for management of associated systemic conditions.

Pigmentary demarcation lines

Pigmentary demarcation lines are natural pigmentary boundaries mostly described and seen in black and Asian patients. These lines have been categorized into five groups, designated A–E.²²⁵ Group A (anterior brachial) designates lines along the upper limb with variable trans-pectoral extension;²²⁶ group B lines are along the medial lower limbs; group C lines are paired lines in median or paramedian courses on the chest with midline abdominal extension; group D lines describe a posteromedian demarcation, and group E are bilaterally symmetric, obliquely orientated hypopigmented macules on the chest/periareolar region.

Groups A and C are most commonly described and distinct. Group A lines were described in 20%, 29%, and 37% of examined black patients by Futcher, Vollum, and Selmanowitz, respectively, and 6% of Japanese patients.^225–227 The degree of overall skin pigmentation did not seem to correlate with incidence of A lines. Lines tended to be more apparent in the older population. Group C lines were noted in more than 30% of black patients.^228,229 Group E lines have been described more often in children (69%) and seem to become less noticeable over time.²³⁰

Small and medium congenital melanocytic nevi

Small and medium CMN are often tan to brown in color and oval-shaped with well-demarcated borders (Fig. 24.15). Lesions may develop a mammillated surface and hypertrichosis over time (Figs 24.15, 24.16). The risk of melanoma development in small and medium CMN is thought to be less than 1% over a lifetime and these melanomas generally develop well after puberty (Table 24.7).^245–259 Melanomas arising in small and medium CMN tend to develop at the dermoepidermal junction and at the peripheral or leading edge of the CMN, making them more readily recognized by patients and clinicians.²⁶⁰ Although rare prepubertal cases of melanoma arising in medium CMN have been described, no cases of melanoma in medium-sized CMN were described in four large prospective and retrospective studies with significant patient follow-up.^{253–255,257}

Large congenital melanocytic nevi

Large CMN occur in 1 in 20 000 individuals and are obvious at birth, most commonly covering an aspect of the trunk and less common on the head, neck and extremities.⁹³ Affected areas of large CMN have been designated as a ‘cape’, ‘bathing trunk’ or ‘garment’ CMN due to their distribution, respectively. Lesions may have irregular or geographic borders. In about 75% of cases, multiple small CMN will accompany the large CMN; these additional CMN noted at birth and which may gradually increase in number over time have been historically termed ‘satellite nevi’. These additional multiple CMN should be noted in both size and number as a larger number of satellite nevi have been correlated with neurological anomalies.

At birth or within the first few weeks of life, transient erosions or ulcerations may develop over large CMN due to increased skin fragility during this period (Fig. 24.17).^261,262 Healing usually occurs over days to weeks. Also notable during the infantile period are rapidly growing ‘proliferative nodules’ within the CMN that mimic melanoma but show benign histological features.^263,264 Evaluation of these specimens by a dermatopathologist with expertise in pigmented lesions is re­commended to avoid a misdiagnosis of melanoma.²⁶⁰ The use of comparative genomic hybridization (CGH) has been used to support the benign nature of these proliferative nodules and this can be performed on paraffin-embedded specimens.^265,266 Significant lightening of pigmentation in large CMN can also been seen in the first few years of life.²⁶⁷ Over time, areas of large CMN may undergo neurotization, which may present as soft, plexiform neurofibroma-like plaques and nodules, especially around the lower back, flanks, and buttocks and groin (Fig. 24.18). Neurotized scalp nevi can be associated with alopecia and cerebriform folds that resemble cutis verticis gyrata. Over time, several large CMN on the scalp have been reported to spontaneously lighten and regress;^268,269 however, further histologic studies on these scalp nevi showed the presence of nevus cells within the deep dermis and around adnexal structures.²⁶⁹ The halo phenomenon and vitiligo-like changes can also occur in large CMN.^270–272 A ‘desmoplastic hairless hypopigmented’ type CMN is a rare variant of CMN and is characterized by a woody induration, alopecia, progressive loss of pigmentation and associated intense pruritus.^273,274

The absolute risk of melanoma development (cutaneous or extracutaneous) in large CMN is approximately 2–5% over one’s lifetime, considering prospective and retrospective cohort studies with significant follow-up.²⁵⁴ About 50% of these melanomas occur in the first 5 years of life.^246,247,275 Cutaneous melanomas tend to arise deep in the dermis or subcutaneous tissues of a large CMN, making early detection difficult. Cutaneous melanomas reported over the past decades in patients with large CMN were seen more commonly in those over the trunk, as compared to the head/neck and extremities.^{247,248,257,276} However, this difference may be attributable entirely on the melanocytic burden since CMN on the torso are usually larger (>40 cm PAS) and bulkier than CMN on other sites. The number of satellite nevi does not portend a higher risk for developing cutaneous melanoma but having >20 satellite lesions does increase the risk for neurocutaneous melanocytosis (NCM) and central nervous system melanoma. Other malignancies such as liposarcomas, rhabdomyosarcomas, and malignant peripheral nerve sheath tumors have been described in association with large CMN.²⁷⁷ No reliable case of melanoma arising within a satellite nevus has been reported.

Magnetic resonance imaging (MRI) with contrast of the brain and spine is recommended for any individual with multiple CMN, or a large CMN with >20 satellite nevi, as those with ≥20 satellite nevi are five times more likely to have neurocutaneous melanocytosis (see below) than those with fewer.²⁷⁸ Individuals with large CMN, >40 cm adult size, or those with a CMN over the posterior axis (in select studies) may also be at increased risk for NCM.^267,278 In addition, CMN overlying the lower back/sacrum area may be associated with the tethered cord syndrome, which can be detected via MRI scanning. It is estimated that about 4% of these ‘high-risk’ CMN individuals will develop symptomatic NCM and prognosis is generally poor even without melanoma development.^247,279,280 Ideally, MRI should be done in the first 4–6 months of life, prior to myelinization of the brain, which may make it more difficult to observe the melanin signal. The typical radiologic appearance of melanocytic deposits is T1 hyperintensity and/or T2 hypointensity, overlying the cerebellum, leptomeninges, amygdala and temporal lobes.^{250,267,281,282} Other CNS tumors and malformations found during brain and spine imaging of CMN patients have included Dandy–Walker malformations, Chiari I malformations, posterior fossa cysts, spinal lipomas, arachnoid cysts and tethered spinal cord.^{250,267,283–286}

Recently, facial morphology analysis found that patients with CMN had a characteristic facies, with 74% of the children in the series having at least three typical features: wide or prominent forehead, apparent hypertelorism, eyebrow variants, periorbital fullness, small/short nose, narrow nasal bridge, broad nasal tip, broad or round face, full cheeks, prominent pre-maxilla, prominent/long philtrum and everted lower lip.²⁸⁷ Thus, the term congenital melanocytic nevus syndrome was recommended to describe these associations.²⁸⁸

Large CMN

Neonatal and infantile erosions or ulceration overlying a large CMN are often treated successfully with conservative wound care. Pruritus and overlying eczematous changes in these nevi may be treated with topical corticosteroids, bland emollients and oral antihistamines when appropriate. Intractable pruritus over localized areas may also be relieved by surgical excision of limited areas.

Absolute indications for removal of large CMN include the development of malignancy and metastatic melanoma with an unknown primary. Relative indication for treatment include: (1) to decrease melanocytic burden, especially in those lesions that are thick, rugous, and heterogeneous in color; (2) lesions present in covered areas that may be clinically difficult to follow; (3) improvement in cosmesis and psychosocial benefits, and (4) symptoms such as intractable pruritus or functional impairment.

Removal of large CMN is often desired in attempts to prevent melanoma development within the lesion. There are no studies to date that clearly support the notion that early removal of a large CMN will prevent melanoma development. Also, complete removal of all nevus cells is often impossible as these cells often involve deeper structures such as fascia and muscle. In addition, removal of the main nevus would not prevent melanoma development in noncutaneous sites, such as the CNS. The use of skin grafts and development of hypertrophic scars may also obscure the detection of melanoma underneath the defect when nevus cells still remain. However, excision of those nevi that are symptomatic, bulky and cumbersome, psychologically distressing and/or functionally limiting may be beneficial despite the risks of surgery.

Elective surgical procedures are often initiated during the first 2 years of life due to the increased elasticity of the skin and the lower risk of abnormal scarring.^260,290 It is not uncommon for subsequent repigmentation to occur within or around the resultant surgical scar, as the full extent of the CMN is often not apparent until after this age.^257,260,291 Numerous surgical treatment choices are available for excision and reconstruction of CMN: staged excision with tissue expansion and flap reconstruction, excision with skin grafting, cultured epithelial grafts or artificial skin substitutes.^291,292 Surgical excision of CMN of the scalp, in particular, should be debated as there is a low risk of malignant transformation at this location and the possibility of regression or significant lightening in the first few years of life may supersede any cosmetic concerns in this area.²⁶⁸

Dermabrasion is a procedure performed early in life to remove the epidermis and superficial dermis resulting in a decreased density in hair and lightening in pigmentation. This procedure runs the risk of hypertrophic scarring and resultant skin fragility and does not eliminate the risk of melanoma, as nevus cells in deeper tissues are still present. Curettage done during the first few weeks of life takes advantage of a natural cleavage plane between normal dermis and dermis containing nevomelanocytes, leaving a sclerotic and dense connective tissue. The risks of anesthesia this early in life as well as potential abnormal scarring, skin fragility and difficulty in monitoring for melanoma due to the resultant scar should be taken into consideration with this technique.

A number of ablative (carbon dioxide) and non-ablative pigment-specific lasers (ruby, alexandrite, Nd : YAG) have been used in attempts to destroy nevus cells and melanosomes (Q-switched), lighten pigmentation and remove excessive hair from nevi that are not amenable to surgical resection.^10,293,294 Repigmentation, scarring and the need for numerous treatments (often with general anesthesia) are common. An increased incidence of melanoma in those patients treated with laser therapy has not been reported.

Parents should be counseled to perform skin examinations to monitor for focal worrisome changes. Serial clinical photographs, dermoscopy and palpation of these lesions may be beneficial for clinicians following patients with any size CMN. With large CMN, lifelong monitoring is mandatory, both with parent (then self-skin) examinations and by an experienced dermatologist. In addition to physical examination and photography, examination of lymph nodes and a thorough review of systems may aid physicians in early detection of melanoma.

Differential diagnosis

The differential diagnosis of small and medium CMN includes smooth muscle hamartoma or Becker’s nevus, mastocytoma, variant of dermal melanocytosis, and café-au-lait macules. Large CMN may be confused with a plexiform neurofibroma in neurofibromatosis type 1 syndrome.²⁹⁶ Histologic evaluation, dermoscopy and the development of typical CMN features over time may clarify the diagnosis.

Treatment and care

The management of patients with SLN, is similar to CMN and should consist of clinical long-term follow-up, especially during adulthood, even though the risk of melanoma is low. Any concerning changes or atypical features should be biopsied.

Treatment and care

The management of pediatric Spitz nevi is surrounded by controversy and there is no clear consensus. It is generally accepted that classic Spitz nevi (those with typical clinical and dermoscopic features and history) are benign; however, as their natural history is not well described, many lesions concerning for Spitz nevi are biopsied to confirm the diagnosis. Those Spitz nevi with classic and unconcerning features, if not completely excised, have a small chance of recurrence, making long-term follow-up difficult. Thus conservative re-excision with 1–2 mm margins should be considered.³²⁹ A minority of clinicians will monitor clinically apparent Spitz and find that many nevi regress over time.^330,331 However, long-term observation, perhaps starting in infancy, may cause significant anxiety for the family and relies on compliance of the patient and family and the comfort of the clinician in monitoring these lesions. Those lesions with the so-called diagnosis of atypical Spitzoid nevus/tumor or STUMP, should be conservatively excised to diminish the risk of recurrence. CGH and additional histochemical studies now available may favor a more benign diagnosis, which is reassuring, as Spitz nevi have been found to have different molecular alterations in comparison to melanoma.³³² Those lesions deemed as pediatric Spitzoid melanomas are often treated as adult melanomas with wide excision based on the lesion depth, and evaluation of the draining lymph node basis by sentinel lymph node biopsy when indicated. Long-term follow-up of these patients with incompletely excised Spitz nevi and those with atypical and Spitzoid melanoma lesions should be carried out.

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