Checklists for Pigmented Lesions and Hamartomas

4/2/2019

Congenital Melanocytic Nevi, Cafe au lait Macules and Everything in Between

Barrett Zlotoff, MD Associate Professor University of Virginia

Disclosure of Relationships with Industry

Barrett Zlotoff, MD

Disclosures I have no relevant relationships with industry

1 4/2/2019

Objectives Patterned Pigmentations/Somatic Mosaicisms- Checklist for when to evaluate for associated systemic findings and what to evaluate for – Congenital Melanocytic Nevi – Epidermal and Sebaceous Nevi – Becker’s Nevi – Segmental Pigmentation Disorder – Linear and Whorled Nevoid Hyper/Hypo-melanosis – Broad blaschko-linear patterned pigmentation as a marker for McCune Albright Syndrome – Pigmentation of the genitals – Dermal Melanocytosis and when to worry

Campbell, Ian M., et al. "Somatic mosaicism: implications for disease and transmission genetics." Trends in Genetics 31.7 (2015): 382-392.

Lim, Young H., Zoe Moscato, and Keith A. Choate. "Mosaicism in cutaneous disorders." Annual review of genetics 51 (2017): 123-141. 4

2 4/2/2019

LCMN is a mosaic mutation of NRAS

Initial Visit Checklist

• Does this child have neurocutaneous melanosis? • Is there a melanoma? • What are these weird lumps?

3 4/2/2019

Neurocutaneous melanosis? • 50% who develop symptoms do so prior to 1 year – most by 2 years of age – another small peak at time of puberty – Seizures, hydrocephalus, cranial nerve deficits, mass effects • Number of satellites most predictive – >20 satellites 5 fold increase in risk of NCM – 3 or more small or medium congenital nevi with no “mother ship” • Size – > 20cm increases risk – Infant→ about 6 cm on head and 9 cm on body • Location of LCMN – Posterior midline

Large Multiple small/medium mothership congenital nevus with phenotype multiple satellites

4 4/2/2019

Imaging for NCM • Image if: – LCMN with (10 or more?) satellites – 3 or more small or medium congenital nevi – LCMN with posterior midline (+ spine) • MRI of the brain – Ideally before 6 months of age (3-6 months old) – Try feed and swaddle or sedate to avoid general anesthesia – Non contrast, heavily T1 and T2, volumetric sequences – Spine if possible, particularly if lumbosacral involvement • If positive – Close follow up with Pediatric Neurology – Increases risk for melanoma • Follow up Imaging – only if develop symptoms

5 4/2/2019

Is there a melanoma?

• Risk is around 5% lifetime for LCMN – Half occur before 5 years old and almost all before puberty – Larger size→ higher risk (75% assoc w > 40 cm) – Truncal location and multiple satellites→ increase risk – Risk much higher for melanomas including cutaneous and extra-cutaneous if NCM • Cutaneous MM present as deep, fast growing or ulcerated nodules in the mothership – Palpate – Pictures • CNS melanoma actually may be more common – Especially if there is NCM with a LCMN

6 4/2/2019

What are these weird lumps?

• Proliferative nodules – Don’t increase risk of melanoma – Ulcerate less often and less extensively than melanoma – Atypical histologic feature common on biopsy • Cytologic atypia, architectural disorder, pagetoid spread, high mitotic index • IH, FISH seem to have limited value • Some evidence for reduced methylation in melanomas – Get expert and second opinions

First Follow up Checklist

• Will it fade? • Should we go straight to the surgeon? • Support groups

7 4/2/2019

Will it fade?

Strauss, Roland M., and Julia A. Newton Bishop. "Spontaneous involution of congenital melanocytic nevi of the scalp." Journal of the American Academy of Dermatology 58.3 (2008): 508-511.

8 4/2/2019

Tønseth, Kim A., et al. "Extraordinary large giant Should we go to the surgeon? congenital melanocytic nevus treated with Integra dermal regeneration • Get to know your family template." Plastic and Reconstructive Surgery • Join the support group before discuss Global Open 3.7 (2015). • Complex discussion- experienced surgeon – Has not shown to decrease melanoma risk – Early surgery carries increased anesthesia risk and may not be advantageous – Surgical intervention adverse effects? • Darkening, peripheral lesions, new lesions – Scars vs nevi- function and form – Wait 1 year with photos to assess lightening Kinsler, Veronica, and Neil Bulstrode. "The role of surgery in the management of congenital melanocytic naevi in children: a perspective from Great Ormond Street Hospital." Journal of Plastic, Reconstructive & Aesthetic Surgery 62.5 (2009)

Support Groups- parents immediately, child before school age

Nevus Outreach- www.nevus.org

Nevus Network- www.nevusnetwork.org

9 4/2/2019

Follow up Checklist LCMN • Serial exam with palpation every 3 months first 2 years then q6 months until age 5 then annually – Total body photography to assess for lightening and new lesions • Counsel regarding xerotic skin, pruritus, and hypohidrosis – Ondansetron • Feng, Jing, et al. "Life-threatening blood loss from scratching provoked by pruritus in the bulky perineal nevocytoma variant of giant congenital melanocytic nevus in a child." Journal of the American Academy of Dermatology 53.2 (2005): S139-S142. • Counsel not to limit activity due to fear

• Low threshold for neurodevelopmental assessment

• The hope: – RAF and MEK inhibitors for tx of LCMN and NCM

Small and Medium CMN

10 4/2/2019

MM in small/intermediate CMN

• Most were superficial • Age range 18 to 79 years.

Illig L, et al. Congenital nevi less than or equal to 10 cm as precursors to melanoma. 52 cases a review, and a new conception. Arch Dermatol. 1985;121:1274-81.

Checklist Small and Medium CMN • Risk of Melanoma low – <1% over a lifetime – Occur after puberty • Periodic evaluation after puberty with photos • Discussion of removal – Functional concerns – Psychosocial/Cosmetic concerns – Usually wait till after 3 yo

11 4/2/2019

The exception to the rule

• 8 year-old Report of MM arising in CMN • Change over months • No regular medical monitoring done prior to visit for nodule • PET scan and sentinel node neg • NED 12 months later Lalor L et al. Busam K, Shah K. Prepubertal Melanoma Arising within a Medium-Sized Congenital Melanocytic Nevus. Pediatr Dermatol. 2016;33(6):e372-e374.

Favorite References

• Price, Harper N. "Congenital melanocytic nevi: update in genetics and management." Current opinion in pediatrics 28.4 (2016)

• Kinsler, V. A., et al. "Melanoma in congenital melanocytic naevi." British Journal of Dermatology (2017).

• Kinsler, V. A., et al. "The role of surgery in the management of congenital melanocytic naevi in children: a perspective from Great Ormond Street Hospital." Journal of Plastic, Reconstructive & Aesthetic Surgery 62.5 (2009)

• Kinsler, V.A., et al. “Complications of congenital naevi in children: analysis of 16 years’ experience and clinical practice.” British Journal of Dermatology (2008)

12 4/2/2019

Nevus Sebaceous is mosaic HRAS or KRAS Mutation

Epidermal (Keratinocyte) Nevus is mosaic of HRAS, KRAS,NRAS, PIK3CA, FGFR3, FGFR2, Keratin 1/10 mutations

13 4/2/2019

Larsabal, M., et al. "Mosaic mutations in FGFR3 and FGFR2 are associated with naevoid acanthosis nigricans or RAVEN (round and velvety epidermal naevus)." British Journal of Dermatology (2018).

Tsubota, Akiko, et al. "Keratin 1 gene mutation detected in epidermal nevus with epidermolytic hyperkeratosis." Journal of Investigative Dermatology 127.6 (2007): 1371- 1374.

Checklist for EN and NS

• Detailed Physical Exam to determine – Extent – Multifocality (mouth, genitals, scalp) – musculoskeletal abnormalities

• Detailed History to ask about – Developmental milestones – Seizures – Issues with vision

14 4/2/2019

Localized NS Checklist • Tumor growth – Benign: • trichoblastomas, syringocystadenoma papilliferum – Malignant: • Basal cell cancer most common • < 1% in 651 excised NS in children (Rosen et al 2009)

• Excise? When? – Psychosocial, risk of general anesthesia, family ethic/culture – There is no rush→ after 3 yo due to anesthesia issues – Check in around puberty when thickening

15 4/2/2019

Localized EN Checklist

• Less risk of tumors • No medical reason to excise, based on disfigurement • Rule out associated overgrowth syndromes like CLOVES, SOLAMEN, Proteus

16 4/2/2019

Extensive/Multifocal NS Checklist • Neurology Consult – 7% in recent cohort of 196 patients w neurologic issues – More common with centrofacial involvement – Intellectual disability and seizures most common – Screening imaging not helpful unless symptoms • 75% will have normal imaging • Ophthalmology Consult – 2% in recent cohort of 196 patients – More common with neurologic abnormalities – Choristomas, colobomas, strabismus most common • Skeletal exam and look for scoliosis – Scoliosis, gait, limb length, shoe wear patterns – Check calcium and phosphate hypophosphatemic vitamin D-resistant rickets • Bone pain, impaired mobility, bony deformities ( birth to puberty)

17 4/2/2019

Extensive/Multifocal EN Checklist • Neurology Consult • Ophthalmology Consult • Skeletal Exam • Consider hypophosphatemic vitamin D-resistant rickets – Bone scans, calcium, phosphorous

• Is it epidermolytic keratinocytic nevus?

Ross, Rustin, et al. Journal of the American Academy of Dermatology 59.1 (2008) 36

18 4/2/2019

Epidermolytic keratinocyte EN

• Consider biopsy at some point • Important for genetic counseling – Keratin 1, 10 mutations – Risk of offspring with epidermolytic ichthyosis – Especially if nevus is over gonads or extensive • Gonadal mosaicism highly variable

Groesser, Leopold, et al. Journal of Investigative Dermatology 133.8 (2013): 1998-2003. 38

19 4/2/2019

Phakomatosis Pigmentokeratotica

• Linear epidermal nevus + speckled lentiginous nevus

• HRAS or KRAS somatic mosaicism in a multipotent progenitor cell

• More likely to have systemic involvement than either alone – neurologic, ocular, musculoskeletal, urologic, renal or vascular

• Increase in non-dermatologic malignancy – Urologic and nephrologic tumors – Rhabdomyosarcomas

Prieto‐Barrios, M., et al. "Phacomatosis pigmentokeratotica: a case of HRAS mosaicism causing rhabdomyosarcoma." British Journal of Dermatology 179.5 (2018): 1163-1167.

❖ Same HRAS mutation found in both the PPK and the rhabdomyosarcoma

20 4/2/2019

Favorite References

• Moody, Megan N., Jennifer M. Landau, and Leonard H. Goldberg. "Nevus sebaceous revisited." Pediatric dermatology 29.1 (2012): 15-23.

• Asch, Sarah, and Jeffrey L. Sugarman. "Epidermal nevus syndromes: New insights into whorls and swirls." Pediatric dermatology (2017).

• Ovejero, D., et al. "Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment." Osteoporosis International 27.12 (2016): 3615-3626.

• Om, Amit, et al. "Phacomatosis Pigmentokeratotica: A Mosaic RAS opathy with Malignant Potential." Pediatric dermatology 34.3 (2017): 352-355.

Becker’s Nevus (post zygotic beta-actin mutation)

21 4/2/2019

Becker’s Nevus Checklist

• Is it in a female over the breast? – Watch breast development – Consider spironolactone 50-100 qd during thelarche • If extensive rare skeletal or muscular abnormalities (like epidermal nevus syndrome) – Scoliosis most common • Increased sebum production – Tinea versicolor, acne, pityrosporum folliculitis • Selenium sulfide wash

22 4/2/2019

A funny café au lait spot: Could this be NF1?

Checklist for patterned pigmentation • What is the pattern here? – Checkerboard, blaschkonian, round – Jagged coast or smooth – Café au lait or just café – Midline cutoff? • Detailed physical exam – Are there other birth marks, CALM, skin findings, macrocephaly, or stigmata of NF1 or other diseases – JXG and nevus anemicus- NF1 • Detailed History – Developmental milestones – Issues with vision, musculoskeletal – Endocrine or precocious puberty

23 4/2/2019

Lavoine, N., et al. "Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort." Journal of medical genetics (2015):

• Double hit of Lynch Syndrome genes- Can have multiple CALM, axillary freckling and hyperpigmented “mini macules” and other features of NF1 • CMMRD - more hematologic (NHL), colorectal cancer, hi grade gliomas, medulloblastomas

• Any patient with diagnosis of “sporadic NF1” who develops a malignancy other than malignant peripheral nerve sheath tumor, JMML or optic glioma at an early age should be evaluated for CMMRD

Treat, James. "Patterned pigmentation in children." Pediatric Clinics 57.5 (2010): 1121-1129.

24 4/2/2019

Segmental Pigmentation Disorder

• Blocky, segmental, hyper/hypo-pigmented, patches with midline cutoffs • Smooth borders • Café au lait, not just café

• Generally good prognosis (Hogeling M, Frieden IJ. Br J Dermatolog 2010) – Ask about developmental milestones – Talk about CNS and eyes but no routine referrals – Sun protection, self tanners

If the pigmentary mosaicism is more blaschkonian

25 4/2/2019

“Linear and Whorled” Nevoid Hyper/Hypo-melanosis • Useful term for pigmentary change in more swirly whorly, blaschkonian pattern • Perhaps more systemic findings then segmental pigmentation disorder (30% in this study)- >if hypo+hyper – Nehal et al. Arch Dermatol, 1996 • 54 patients with nevoid hyper and hypo pigmentation • 15/54 had neurologic abnormalities, usually developmental delay and seizures • 3/54 hemihypertrophy • 2/54 cardiac: PDA, VSD • 1 with conical teeth, 1 with scoliosis • Detailed exam and history

González-Enseñat, M. Antonia, et al. Archives of dermatology 145.5 (2009): 576-578.

26 4/2/2019

Mosaic partial trisomy 13 • Phyllion= leaf “phylloid hypopigmentation” • Hypogpigmented round or oval asymmetric patches, reminiscent of the leaves of a begonia • CNS defects, neurodevelopmental issues, absence corpus callosum, conductive hearing loss, choroidal and retinal coloboma, craniofacial defects, digital and other skeletal anomalies

Happle, R. "Phylloid hypomelanosis and mosaic trisomy 13: a new etiologically defined neurocutaneous syndrome." Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 52.1 (2001): 3-5. 53

Is this McCune Albright?

• CALM is most common presenting sign – Usually present at birth – Unilateral with sharp midline cutoff – “Broad blaschko-linear pattern” – Usually darker- just café, with no milk – Jagged “coast of Maine” border

• Look for oral pigmentation – Vermillion and mucosal pigmenation

27 4/2/2019

Pichard, Dominique C., et al. "Oral pigmentation in McCune- Albright syndrome." JAMA dermatology 150.7 (2014): 760- 763.

28 4/2/2019

If worry for McCune Albright:

• Bone survey for polyostotic fibrous dysplasia (not always near pigment) – Craniofacial 90% by 3.5 yrs old • Painless lump – Extremities 90% by 14 yrs old • Limp, pain, pathologic fracture • Endocrine abnormalities (hyperfunctioning) – Hyperparathyroid, pituitary adenomas (GH), adrenal adenomas (Cushing, aldosteronism), thyroid cysts, testicular Leydig/Sertoli cell hyperplasia • Precocious puberty – Menstrual spotting – Scrotal thickening and enlargement • Gene requires affected tissue- mosaic

29 4/2/2019

CALM looking macule of the genitals

PTEN Hamartoma Syndrome (Bannayan Riley Ruvalcaba)

30 4/2/2019

If lentigines of penis or vulva: • Look for – Macrocephaly – Lipomas – Vascular malformations – Oral papillomas, acral keratoses, acanthosis nigricans – Joint hyperextensibility, scoliosis

• Ask about – Hypotonia, developmental delay, autism – Hamartomatous intestinal polyps (PHx, FHx)

Favorite References

• Treat, James. "Patterned pigmentation in children." Pediatric Clinics 57.5 (2010): 1121-1129. • Shah, Kara N. "The diagnostic and clinical significance of café-au-lait macules." Pediatric Clinics 57.5 (2010): 1131-1153. • Rieger, E., et al. "Melanotic macules following Blaschko's lines in McCune‐Albright syndrome." British Journal of Dermatology 130.2 (1994): 215-220. • Varga, Elizabeth A., et al. "The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly." Genetics in Medicine 11.2 (2009): 111.

31 4/2/2019

Checklist Dermal Melanocytosis

• Location – Periocular location is more concerning for associated malignancy or glaucoma

• Associated birthmarks – Capillary malformations might think of phakomatoses – Café au laits, might think about constitutional mismatch repair deficiency

• Progressive rather than regressive – More appear and after birth, get darker, get more extensive, more defined borders or ragged borders – Might think about metabolic disorder

32 4/2/2019

• Whether you see conjunctival involvement or not- Eye exam if periocular • Glaucoma • Uveal melanoma – Reported with Nevus of Ota (1/400) • Shields, Carol L., et al. "Association of ocular and oculodermal melanocytosis with the rate of uveal melanoma metastasis: analysis of 7872 consecutive eyes." JAMA ophthalmology 131.8 (2013): 993- 1003. – Reported with phakomatosis pigmentovascularis • Shields, Carol L., et al. "Phacomatosis pigmentovascularis of cesioflammea type in 7 patients: combination of ocular pigmentation (melanocytosis or melanosis) and nevus flammeus with risk for melanoma." Archives of Ophthalmology 129.6 (2011): 746-750. – Usually associated with other mutations in concert with GNAQ- like BAP1 • Yearly ocular exam before puberty, bi-annual after puberty 65

Nevus of Ito and other locations

• Risk of melanoma in this and other (non-periocular) locations vanishingly low

• No real worrisome associations unless extensive all over the body

33 4/2/2019

Dermal Melanocytosis with Capillary Malformation

Brittain, Paul, Erica J. Walsh, and Aimee C. Smidt. "Blotchy baby: a case of phakomatosis pigmentovascularis." The Journal of pediatrics 162.6 (2013): 1293-1293.

34 4/2/2019

Phakomatosis Pigmentovascularis

Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis • Used to think PPV was due to non-allelic twin spotting • Post-zygotic mosaic activating mutations in GNA11 and GNAQ – Same genes as Sturge Weber – G-protein alpha subunit gene mosaic condition, like McCune Albright • Identical mutation in both capillary malformation areas and dermal melanocytosis areas to pluripotent progenitor cell • Other factors such as location and background ethnic skin color factors control expression

35 4/2/2019

Sturge Weber? • If High risk – Argument MRI is not 100% sensitive • Requires contrast • Requires GA • Perhaps just refer to Pediatric Neuro to be educated – Evidence for ASA preventing Sz is not clear

Zallmann, Michaela, et al. Pediatric dermatology (2017).

Phakomatosis Pigmentovascularis (and extensive dermal melanocytosis) • About 50% have extracutaneous involvement in some series – Neurologic conditions include • psychomotor retardation, seizures, and cerebral atrophy; • symptoms typically present within the first months of life – Ophthalmologic associations include • conjunctival melanocytosis, episcleral vascular malformations, and glaucoma • Melanoma choroid and conjunctiva – Overgrowth of soft tissues or limbs

• Referral to ophthalmology, neurology, and close neurodevelopmental monitoring recommended.

36 4/2/2019

Ashrafi, Mahmoud Reza, et al. "Diffuse dermal Armstrong-Javors, Amy, melanocytosis in two patients with Sandhoff and Catherine J. Chu. disease and mucopolysaccharidosis VI." "Child neurology: International journal of dermatology 53.6 Exaggerated dermal (2014): 736-738. melanocytosis in a hypotonic infant: a harbinger of GM1 gangliosidosis." Neurology 83.17 (2014): e166-e168.

Franceschini, Darin, and James G. Dinulos. "Dermal melanocytosis and associated disorders." Current opinion in pediatrics 27.4 (2015): 480-485. 73

Dermal melanocytosis as a clue to constitutional mismatch repair deficiency repair syndrome

Polubothu, S., et al. "Atypical dermal melanocytosis: a diagnostic clue in constitutional mismatch repair deficiency syndrome." The British journal of dermatology 177.5 (2017): e185.

37 4/2/2019

Favorite References

• Franceschini, Darin, and James G. Dinulos. "Dermal melanocytosis and associated disorders." Current opinion in pediatrics 27.4 (2015): 480-485. • Zallmann, Michaela, et al. "Screening for Sturge‐Weber syndrome: A state‐of‐the‐art review." Pediatric dermatology (2017). • Thomas, Anna C., Kinsler, Veronica, et al. "Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis." Journal of Investigative Dermatology 136.4 (2016): 770-778.

• Large congenital melanocytic nevi are different from small and medium • Extensive epidermal and sebaceous nevi more worrisome then localized – Phakomatosis pigmentokeratotica higher risk for badness • Becker’s and breast hypoplasia • Constitutional mismatch repair deficiency can look like NF1 • Some patterned pigmentations to not worry about – Segmental pigmentary disorder not so much • Some patterned pigmentary pigmentations to worry about – Swirly whorly nevoid hyper or hypopigmentation if extensive – Phylloid→ Trisomy 13 mosaicism – broad blaschko-linear→McCune Albright can take till puberty to fully manifest • Macrocephaly and genital melanotic macule→ think PTEN • Dermal melanocytosis- annual eye exams for periocular. Should we evaluate forehead involvement like you would a PWS? • Phakomatosis pigmentovascularis- check eyes and neurodevelopmental