III.17 Syndromes Involving Melanocytic Lesions

III.17

III.17.1 Introduction

Many congenital syndromes are diagnosed with the aid of cutaneous findings. Certain medical conditions are detected early based on the ap- pearance of premature, numerous, or abnormal skin lesions. The association of melanocytic nevi with specific syndromes is prominent with certain conditions and less consistent with oth- ers. Melanocytic nevi are fairly prevalent in the general population and often exhibit familial clustering; therefore, close attention must be paid to all associated findings in order to recog- nize the pattern of various syndromes and fa- cilitate counseling and timely intervention.

This chapter describes syndromes associated with melanocytic nevi.

III.17.2 Neurocutaneous Melanosis Neurocutaneous melanosis is a rare non-heredi- tary condition characterized by large and or multiple (greater than three) congenital mela- nocytic nevi associated with melanocytic tu- mors (benign and/or malignant) of the lepto- meninges [39].

III.17.2.1 Clinical Features

Main diagnostic features of neurocutaneous melanosis have been reviewed and formulated by Kadonaga and Frieden in 1991 to include me- lanocytic proliferations of the central nervous system (benign and/or malignant) in associa- tion with a large congenital melanocytic nevi (LCMN) or 3 or more smaller melanocytic nevi (satellite nevi) [6]. A LCMN is defined as a ne- Chapter III.17

Syndromes Involving Melanocytic Lesions

Cheryl G. Aber, Elizabeth Alvarez Connelly, Lawrence A. Schachner

III.17

Contents

III.17.1 Introduction . . . .164

III.17.2 Neurocutaneous Melanosis . . . .164

III.17.2.1 Clinical Features . . . .164

III.17.2.2 Diagnostic Investigation . . . .165

III.17.2.3 Management and Prognosis . . . .165

III.17.3 Xeroderma Pigmentosum . . . .166

III.17.3.1 Clinical Features . . . .166

III.17.3.2 Diagnostic Investigation . . . .166

III.17.3.3 Management and Prognosis . . . .167

III.17.4 Neurofibromatosis Type I . . . .167

III.17.4.1 Clinical Features . . . .167

III.17.4.2 Diagnostic Investigation . . . .168

III.17.4.3 Management and Prognosis . . . .168

III.17.5 Familial Atypical Multiple Mole and Melanoma Syndrome . . . .168

III.17.5.1 Clinical Features . . . .168

III.17.5.2 Diagnosis . . . .168

III.17.5.3 Management and Prognosis . . . .169

III.17.6 Carney/LAMB/NAME Syndromes . . . . .169

III.17.6.1 Clinical Features . . . .169

III.17.6.2 Diagnosis . . . .169

III.17.6.3 Management . . . .170

III.17.7 Occult Spinal Dysraphism/ Tethered Cord . . . .170

III.17.7.1 Management . . . .170

References . . . .170

Syndromes Involving Melanocytic Lesions

Cheryl G. Aber, Elizabeth Alvarez Connelly, Lawrence A. Schachner

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vus that is or can be expected to measure 20cm in largest diameter in adulthood. This corre- sponds to a nevi measuring 6cm on an infant‘s body or 9cm on an infant‘s head. Most patients with neurocutaneous melanosis present with nevi on their trunk (typically posterior midline) or head and neck (Fig. III.17.1) [22]. Approxi- mately two-thirds of the patients demonstrate large or giant congenital melanocytic nevi, whereas the remaining third have multiple nevi.

These pigmented nevi can be macular or raised and are typically circumscribed with irregular borders. Studies done by Marghoob et al dem- onstrate that the presence of many satellite nevi (>20) significantly increases the relative risk of NCM. Reference 44.

Those affected with neurocutaneous mela- nosis may be subdivided between symptomatic and asymptomatic depending on the presenta- tion of neurological symptoms such as head- aches, seizures, hydrocephalus, tremors, devel- opmental/motor delay, or focal neurological

deficits on exam [20]. These symptoms may re- sult from a malignant primary central nervous melanoma or non-malignant proliferation of melanocytes in the CNS (CNS melanocytosis) [41]. Neurological symptoms typically present before 2 years of age, and usually manifest by the first year of life [35]. Although neurological symptoms vary, almost two-thirds of patients with symptomatic neurocutaneous melanosis develop hydrocephalus usually due to obstruc- tion of cerebrospinal fluid flow, decreased ab- sorption by the leptomeninges or associated Dandy–Walker complex (up to 10% of cases) [35]. Neurocutaneous melanosis has been asso- ciated with additional neurocutaneous syn- dromes as well including neurofibromatosis or Sturge–Weber syndrome.

III.17.2.2 Diagnostic Investigation Brain magnetic resonance imaging (MRI) with gadolinium is the preferred screening modality in potentially affected patients to detect lepto- meningeal melanosis, melanomas, and posteri- or fossa malformations. Ideally, the MRI should be performed between 4 and 6 months of age before normal myelination of the brain.

III.17.2.3 Management and Prognosis Those patients with symptomatic neurocutane- ous melanosis carry a poor prognosis irrespec- tive of the presence of a malignancy [30]. No therapy has demonstrated improved clinical outcome in these patients. Patients with truncal large congenital nevi demonstrate a higher inci- dence of symptomatic neurocutaneous melano- sis and mortality vs those with head or extrem- ity large congenital nevi [2]. One large study demonstrated a 34% mortality rate in patients with symptomatic neurocutaneous melanosis and truncal nevi. In contrast, those with a large congenital nevi on the head or neck exhibit a significantly lower rate of symptomatic of neu- rocutaneous melanosis and death. In addition, the association of neurocutaneous melanosis with Dandy–Walker complex has demonstrated an even poorer prognosis with patients experi-

Fig. III.17.1.  Patients with neurocutaneous melanosis

demonstrate large or giant congenital melanocytic nevi

often associated with multiple satellite nevi

166 C.G. Aber, E.A. Connelly, L.A. Schachner

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encing neurological decompensation and death by 4 years of age [29]. Any patient with neuro- logical symptoms requires neurosurgical refer- ral. To date, there are no published reports of melanomas arising in satellite nevi associated with a large congenital melanocytic nevi; how- ever, the presence of multiple satellite nevi with- out a large nevus portends the highest risk of developing symptomatic neurocutaneous mela- nosis and death [2].

Treatment of cutaneous large melanocytic nevi remains controversial. Given the 5–15%

chance of malignant transformation, many der- matologists recommend prophylactic surgical removal [6]; however, removal of cutaneous nevi is a secondary concern in those patients with neurological symptoms.

III.17.3 Xeroderma Pigmentosum Xeroderma pigmentosum is an autosomal-reces- sive syndrome characterized by a group of de- generative disorders resulting from defective DNA nucleotide excision repair mechanisms.

The main features of this disorder include exqui- site photosensitivity to UV radiation, early onset of cutaneous malignancies (including melano- mas), ocular complications, and in certain sub- types, progressive neurological degeneration.

III.17.3.1 Clinical Features

At birth the skin is normal. Cutaneous symp- toms typically appear at 1–2 years of age. Ini- tially, patients develop a severe prolonged ery- thematous reaction to minimal sun exposure (severe abnormal sunburn) and photodistribut- ed solar lentigines that remain. At an early age, signs of premature aging (dermatoheliosis) be- come apparent such as increased pigmented macules, epidermal thinning, telangiectasias, and patchy hyper/hypopigmentation, collec- tively termed poikiloderma [16]. Skin malignan- cies, such as melanomas, basal cell carcinomas, and squamous cell carcinomas, start presenting at an early age primarily in photodistributed ar- eas and often result in significant disfigurement of facial features (Fig. III.17.2). Lentigo maligna

melanomas, a common type of cutaneous can- cer in xeroderma pigmentosum, develop at a median age of 17.5 years [36]. Compared with age-matched controls, affected xeroderma pig- mentosum patients are 2000 times more likely to develop a cutaneous skin malignancy [17].

Patients with xeroderma pigmentosum have a 10–20 times increased risk of developing an internal malignancies compared with age- matched controls, with an increased incidence of lung, breast, pancreatic, stomach, brain, and testicular cancer, as well as leukemia. Ocular findings are usually confined to the anterior portion of the eye (eyelids, cornea, conjunctiva), which is vulnerable to greatest exposure of UV radiation. Complications at this site include photophobia, conjunctivitis, keratitis, ectropi- an, corneal vascularization, basal cell carcino- mas, squamous cell carcinomas, and melano- mas. In addition, neurological degeneration, including mental deterioration, sensorineural hearing loss, ataxia, and spasticity, occur more frequently in certain complementation groups (group A and group D) [16].

III.17.3.2 Diagnostic Investigation Cell fusion technique has elucidated more than seven different xeroderma pigmentosum com- plementation groups (A–G) with impaired exci-

Fig. III.17.2.  Skin malignancies, such as melanomas,

present at an early age primarily in photodistributed ar-

eas. They often result in significant disfigurement of facial

features

sion repair type and one xeroderma pigmento- sum variant form with deficient post-replication repair. Each complementation group corre- sponds to different gene defects which, in turn, codes for different enzymes involved in the DNA nucleotide excision repair process [7]. Spe- cialized laboratories performing UV sensitivity and unscheduled DNA repair testing substanti- ate the diagnosis. Once the affected xeroderma pigmentosum gene is identified, direct muta- tion analysis allows for carrier detection and prenatal diagnosis of family members [3].

III.17.3.3 Management and Prognosis Counseling xeroderma pigmentosum patients must include a rigorous protection program against UV light from infancy. Sun avoidance, physical block sunscreens, wide-brimmed hats, appropriate long-sleeved clothing, and UV blocking sunglasses with side shields are some measures that require adherence. Dermatologi- cal cancer screenings should occur every 3 months, with prompt removal of suspicious lesions. Pre-malignant lesions can be treated with cryosurgery, topical 5-fluorouracil, or im- iquimod. Neoplasms should be removed by ex- cision, chemosurgery, cryosurgery, or intrale- sional IFN-a. Topical use of a prokaryotic DNA repair enzyme, T4 endonuclease V, has been shown to initiate repair of UV-induced DNA damage, thereby preventing the development of skin cancers [7, 36]. Certain xeroderma pigmen- tosum patients may benefit from oral isotreti- noin, which plays a role in the prevention of new skin cancers. Appropriate referral to ophthal- mology and neurology are recommended. Over- all the lifespan of those affected with xeroderma pigmentosum is shortened almost 30 years de- pending on the severity of the genetic defect and lifelong exposure to UV radiation.

III.17.4 Neurofibromatosis Type I

Neurofibromatosis type I (NF-1; also known as von Recklinghausen’s disease) is an autosomal- dominant syndrome characterized by six or more café-au-lait macules, neurofibromas, axillary/in-

guinal freckling, and Lisch nodules (Fig. III.17.3).

Although controversial, the association between congenital melanocytic nevi and NF-1 has been reported in 1–15% of patients [4, 5, 10]. A muta- tion in the NF-I gene located in the 17q11.2 gene locus is responsible for the phenotypic features of this disease. NF-1 has an incidence of 1 in 3500 individuals worldwide [9].

III.17.4.1 Clinical Features

Diagnostic skin findings include six or more café-au-lait macules measuring at least 5 mm before puberty and 15 mm or more after puber- ty. Although occasionally seen at birth, café-au- lait macules typically appear during the initial weeks to months of life and subsequently darken during the early years of life [36]. The hallmark lesion of this syndrome are neurofibromas which represent nerve sheath growths either at a

Fig. III.17.3.  Café-au-lait macules and skin fold freck-

ling (axillary/inguinal) are features of NF-1

168 C.G. Aber, E.A. Connelly, L.A. Schachner

III.17

focal site of the nerve (discrete neurofibroma) or along the nerve length (plexiform neurofibro- mas). Neurofibromas typically manifest in the preadolescent years and may occur superficially above the skin surface or deeper within the der- mal–subdermal layer. Additional features in- clude skin fold freckling (axillary/inguinal) ap- pearing between 3 and 5 years of age.

Previous studies have reported an increased incidence of giant congenital melanocytic nevi in patients with NF-1 [12]. A recent study by Ball and Kho analyzed the association of mela- nocytic nevi and neurofibromas in patients with NF-1 vs patients with sporadic neurofibromas [4]. Melanocytic nevi were identified in 11% of patients with NF-1 compared with none of the patients with sporadic neurofibromas. Neurofi- brin, the protein product of the NF-1 gene, af- fects the ras signal transduction pathway which has been associated with the development of melanocytic nevi [38] and melanomas [24].

Ocular findings associated with NF-1 include Lisch nodules (melanocytic pigmented iris hamartomas), orbital plexiform neurofibromas, and optic gliomas. Skeletal dysplasias, learning disabilities, vascular dysplasias, macrocephaly, short stature, and hypertension are additional features of the syndrome.

III.17.4.2 Diagnostic Investigation The diagnostic criteria are the presence of two of the following features: (a)six or more café-au- lait macules; (b) skin fold freckling; (c) two or more neurofibromas or (d) one plexiform neu- rofibroma; (e) two or more iris Lisch nodules; (f) optic nerve glioma; (g) skeletal dysplasia; or (h) an affected first-degree relative.

III.17.4.3 Management and Prognosis The care for an individual with suspected NF-1 requires a multidisciplinary approach involving dermatology, genetics, neurology, and ophthal- mology. Given the autosomal-dominant inheri- tance pattern, genetic and prenatal counseling is highly recommended. Careful neurological and developmental assessment, including evalu-

ation of learning disabilities, is imperative. Ra- diological imaging can aid diagnosis of skeletal or vascular dysplasias or central nervous system tumors (astrocytomas). Treatment of NF-1 is symptom driven. Transformation of neurofi- bromas to malignant peripheral nerve sheath tumors carries a lifetime 10% risk with a poor prognosis [34]. Pain or sudden growth of a neu- rofibroma may portend malignant transforma- tion and should prompt an excisional biopsy.

III.17.5 Familial Atypical Multiple Mole and Melanoma Syndrome Familial Atypical Multiple Mole and Melanoma syndrome (FAMMM), also known as Dysplastic Nevus syndrome, represents a group of disor- ders characterized by multiple cutaneous mela- nomas and atypical melanocytic nevi associated with a probable polygenic inheritance pattern.

III.17.5.1 Clinical Features

Hallmark features of FAMMM are early cutane- ous melanomas in the setting of multiple atypical melanocytic nevi (often exceeding 100). These nevi are typically greater than 5 mm exhibiting border and pigment irregularities. Individuals with FAMMM develop a higher rate of melano- mas at earlier ages of onset with an increased risk of developing multiple primary melanomas com- pared with the general population [26].

Earlier studies suggest a link between famil- ial melanoma and pancreatic cancer. Goldstein et al. reported a 22-fold increased risk of pan- creatic cancer in melanoma-prone families with defective CDKN2A [28]. Some reports of squa- mous cell carcinomas of the head and neck have also been described in patients with FAMMM.

III.17.5.2 Diagnosis

Clinical diagnosis of atypical nevi and melano-

mas with a family history of melanoma contrib-

utes to the diagnosis of FAMMM. Genetic CD-

KN2A testing, although commercially available,

is usually performed in academic settings. In-

heritance of FAMMM is complex and most like- ly of polygenic etiology. The prevalence of FAMMM is difficult to assess due to an absence of standardized diagnostic criteria and a lack of a reproducible clinical patterns [43]. Identifica- tion of the affected gene loci was localized to chromosome 9p21 [21]. Germline mutations of CDKN2A were demonstrated by Hussussian et al. [27] in 92% of melanoma-prone patients with linkage to the 9p21 chromosome; however, only 30% of persons with dysplastic nevi had muta- tions in the CDKN2A region, suggesting a re- lated but diverse etiology.

III.17.5.3 Management and Prognosis Regular dermatological screening exams with emphasis on sun avoidance and sunscreen use are fundamental components of care in indi- viduals with FAMMM. Total-body photography using dermoscopy and digital imaging every 6 months is strongly recommended. Using this technology to investigate and follow any new or changing moles is essential in making an early diagnosis of skin cancer. Genetic screening or therapeutic interventions are currently not rec- ommended for relatives of affected family mem- bers at this time. Although a lower tolerance for removal of suspicious lesions is warranted.

Studies demonstrate approximately a 50% risk of developing a cutaneous melanoma by 50 years of age among individuals with a positive family history of melanoma [23]. Specific therapeutic care of atypical nevi and melanomas are dis- cussed elsewhere in this book.

III.17.6 Carney/LAMB/

NAME Syndromes

Carney syndrome is a cardiocutaneous syn- drome whose features include: (a) pigmented skin lesions; (b) atrial myxomas; (c) endocrine overactivity; and (d) psammomatous melanotic schwannomas [1]. Linkage analysis has mapped the diseased gene to chromosome 2p16 and 17q2 [31].

Two previously described syndromes that fall under the umbrella of Carney complex [33] are

LAMB (lentigines, atrial myxomas, mucocuta- neous myxomas, and blue nevi) [32] and NAME (nevi, atrial myxomas, myxoid neurofibroma- tosis, ephelides, or endocrine overactivity) [11].

III.17.6.1 Clinical Features

Cutaneous pigmented lesions typically appear at birth and increase at puberty. These skin findings include congenital melanocytic nevi [13, 14, 15], congenital blue nevi, lentigines [19], perioral/buccal pigmented macules and macu- lar pigmentation of the sclera and conjunctiva.

Lentigines, a prominent feature of this syn- drome, are scattered throughout the body but appear mostly on the face, specifically the eye- lids, conjunctiva, nasal bridge, ears, vermillion lip border, and oral mucosa. Carney syndrome can be distinguished from LEOPARD syndrome (multiple lentigines, electrocardiographic con- duction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retarda- tion of growth, and sensorineural deafness) by the involvement of the oral mucosa and the ab- sence of dysmorphic features.

Cardiac and cutaneous myxomas are another clinically significant feature of this syndrome.

Myxomas of the skin manifest as non-tender dermal nodules in the second decade of life. Atri- al myxomas, complicated by congestive heart failure, pulmonary edema and emboli, account for up to 20% of deaths in affected patients [33].

III.17.6.2 Diagnosis

Diagnostic criteria for Carney syndrome require two or more of the following findings:

1. Spotty skin pigmentation (lentigines, blue nevi)

2. Cutaneous or mucosal myxomas 3. Cardiac myxomas

4. Primary pigmented nodular adrenocorti- cal disease

5. Pituitary adenomas 6. Sertoli cell tumors 7. Thyroid carcinoma

8. Psammomatous melanotic schwannoma

170 C.G. Aber, E.A. Connelly, L.A. Schachner

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III.17.6.3 Management

Dermatological examination with appropriate referral to cardiology, endocrinology, gynecol- ogy, and urology.

III.17.7 Occult Spinal Dysraphism/

Tethered Cord

Spinal dysraphism describes a spectrum of con- genital anomalies characterized by incomplete fusion of the midline vertebral column. Skin- covered lesions without exposed neural tissue fall under the heading of spina bifida occulta.

Often, congenital midline cutaneous lesions represent the only clues of the diagnosis. Some reports describe midline lumbar–sacral pig- mented lesions, including melanocytic nevi,

which are associated with occult spinal dysra- phism [25, 40]. Studies demonstrate that a com- bination of two or more congenital midline le- sions is a strong marker of spina bifida occulta.

III.17.7.1 Management

Magnetic resonance imaging (MRI) of the lum- bar sacral spinal area is a non-invasive optimal choice to detect spinal dysraphism or other in- traspinal lesions (lipomas, hemangiomas) [8, 18]; however, MRI requires sedation of a young patient. Although less sensitive, high-resolution spinal ultrasound allows effective, non-invasive screening of spinal dysraphism [18] in a new- born before ages 3–5 months (before the poste- rior spine ossifies).

References

1. Carney JA (1995) The Carney complex (myxomas, spotty pigmentation, endocrine overactivity and schwannomas). Dermatol Clin 13:19–25

2. Bett BJ (2006) Large or multiple congenital mela- nocytic nevi: occurrence of neurocutaneous me- lanocytosis in 1008 persons. J Am Acad Dermatol 54:767–777

3. Bale SJ, Digiovanna JJ (2001) Cancer-associated genodermatosis and familial cancer syndromes with cutaneous manifestations. Clin Dermatol 19:284–289

4. Ball NJ, Kho GT (2005) Melanocytic nevi are as- sociated with neurofibromas in neurofibromatosis, type I, but not sporadic neurofibromas. A study of 226 cases. J Cutan Pathol 32:523–532

5. Brasfield RD, Das Gupta TK (1972) Von Reckling- hausen’s disease: a clinicopathological study. Ann Surg 175:86–104

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C

Core Messages

■ Melanocytic lesions are associated with a number of syndromes: neurocutane- ous melanosis; xeroderma pigmento- sum; NF-1; familial atypical multiple mole melanoma syndrome; Carney syndrome; and spina bifida occulta.

■ Skin findings, such as large congenital melanocytic nevi or café-au-lait macules, can provide the outward clue of a systemic disorder.

■ Recognizing associated findings is essential to ascertaining a diagnosis.

■ Certain syndromes (neurocutaneous

melanosis, NF-1, Carney syndrome)

require further diagnostic studies to

evaluate and monitor serious associated

anomalies.

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