Numerous Nevoid pigmented papules on sun-exposed and sun-protected skin, starting in adolescence

Case 1

Clinical data
A 60 -year-old gentleman presented with a chief complaint of Numerous Nevoid pigmented papules
on both sun-exposed and sun-protected skin, distributed in a generalized fashion, dating since
adolescence. On general examination, the patient had coarse facies, with broad nasal root,
protruding jaw, and multiple fallen teeth, associated with a protruding swelling in roof of the mouth.
The patient also gave history of excision of several cutaneous lesions.
Case 2

Clinical data
A 15 -year-old female, born to a consanguineous marriage, presented with a chief complaint of
Numerous Nevoid pigmented papules on both sun-exposed and sun-protected skin, distributed in a
generalized fashion, dating since the age of 12. She gives a history of epilepsy. On general
examination, the patient had coarse facies, with frontal bossing, broad nasal root, Mandibular
protrusion, and abnormal dentition.
A suspicious lesion on the lower back
Dermoscopic examination: A blue-white veil – Surface telangiectasia
Preliminary Investigations:

Skin Biopsy:

 Islands of basaloid cells in the upper dermis

 Showing Typical peripheral palisading and dispersed pigment

 A cleft separating the islands from the surrounding stroma

 Case 1
 Case 2
 Based on:

I. Clinical picture
II. Characteristic histopathology

We are confronted with 2 cases of multiple early-onset pigmented basal cell carcinomas (BCCs).

Such a peculiar presentation warranted search for the underlying aetiology.

Differential diagnosis:
Multiple early-onset pigmented Basal cell carcinomas

I. Early exposure to irradiation

• Multiple, early-onset skin malignancies as BCCs

• No history of exposure to irradiation in our case.

• Post-irradiation BCCs occur exclusively at the irradiation field (Unlike this case)

II. Genetic disorders

A. Xeroderma pigmentosum (XP)

• Multiple, early-onset skin malignancies as BCCs.

• No evidence of XP in our patient (Poikiloderma, extensive lentigines and actinic keratoses)

• BCCs predominantly on Sun-exposed skin (Unlike this case)

 B. Bazex Dupre Christol Syndrome (BDCS)

 Multiple, early-onset BCCs

• Congenital Hypotrichosis (Unlike these cases)

• Atrophoderma follicularis (Unlike these cases)

• Multiple Trichoepitheliomas (Unlike these cases)

• Flexural hyperpigmentation (Unlike these cases)

C. Rombo syndrome

• Multiple BCCs

• Typically develop beyond the age of 35 (Unlike these cases)

• Acro-facial erythematous lesions and Telangectasia (Unlike these cases)

• Atrophoderma vermiculatum (Unlike these cases)

• Multiple vellus hair cysts (Unlike these cases)

D. Basal cell nevus syndrome

• Multiple, early onset BCCs

• On sun-exposed and sun-protected skin

• Craniofacial abnormalities

The most likely clinical diagnosis:

Basal cell nevus syndrome (BCNS), AKA Gorlin syndrome.

Further Investigations:
 Guided by the patient’s symptoms and review of literature for extracutaneous manifestations of
BCNS

A. Dental panoramic radiography

 Multiple Odontogenic cysts in the body of the mandible and floor of maxilla in case 1
 A single odontogenic cyst of the body of the mandible in case 2

B. Multislice CT examination of facial bones with 3D reconstruction (case 2)

 A well-defined lytic lesion in the left side of the body of the mandible

 Near-complete opacification of the right maxillary antrum

(Features of multiple odontogenic cysts)

C. Enucleation of the mandibular lesion & Histopathological assessment (case 2)

 Showed typical histopathological features of an odontogenic keratocyst

D. Skull X.ray (case 1)

 Bilamellar calcification of falx cerebri

E. CT Brain

 Bilamellar calcification of falx cerebri

o Case 1
 o Case 2

F. Chest X-ray (Case 1)

G. Bifid ribs

H. CXR of the 2nd case was within normal limits.

Based on the following findings:
III. Clinical picture
IV. Characteristic histopathology
V. Radiographic findings

Final diagnosis

Basal cell nevus syndrome, AKA, Gorlin syndrome

About the diagnosis:

Definition

• An AD genodermatosis

• characterized by:

• A wide range of developmental defects

• Susceptibility to various neoplasms, mainly BCCs

Pathogenesis

Mutation of tumor suppressor PTCH gene

An important inhibitor of Hedgehog Pathway

Downregulation of its expression

Upregulation of Sonic hedgehog pathway

whose downstream proteins lead to cell growth

. BCCs
. Other neoplasms
Incidence

 The world incidence is 1:50000.

Gender:
 Males & females are equally affected

Ethnicity
 influences lifetime risk of developing BCCs.
 White races develop larger number of BCC.

Clinical picture
Cutaneous features

 BCCs

o Range from 0-1000 (average 8).

o Develop in childhood up to 20 years of age.

o Show the classic features of BCC.

o May look like skin tags particularly in children (around the neck).

 Other cutaneous features:

o Palmar / plantar pits

o Milia

o Epidermoid cysts

Extracutaneous features

 Developmental defects:

o Craniofacial abnormalities

o Skeletal defects

o Calcification of falx cerebri

 Odontogenic keratocysts

 Neoplasms other than BCC

o Medulloblastoma

o Rhabdomyosarcoma

o Ovarian and cardiac fibromas

Diagnosis

• Major criteria

o Multiple BCCs (>2) or 1 ≤20 years

o Odontogenic keratocysts of the jaw

o ≥ 3 Palmar/ plantar pits

o Bilamellar calcification of Falx cerebri

o Bifid / fused ribs

o Affected 1st degree relative

• Minor criteria

o Macrocephaly

o Craniofacial abnormalities

(Coarse facies, frontal bossing, Cleft lip or palate)

o Skeletal abnormalities

(syndactyly / scoliosis)

o Non-BCC neoplasms

(Medulloblastoma, ovarian & cardiac fibroma)

• Diagnosis is confirmed by

o 2 major criteria, or 1 major + 2 minor criteria

Our case is a typical case of Basal cell nevus syndrome based on typical clinical,
histopathological, and radiographic features.

Prognosis

• BCCs carry good prognosis, they rarely ulcerate or metastasize.

• Rhabdomyosarcoma and fibrosarcoma carry poor prognosis

Management
• Surveillance

o Periodic total body skin examination (TBSE)

o Periodic radiographs
• Panoramic radiograph of the jaw

• Brain CT \ MRI

• Pelvi-abdominal U\S

• Echocardiography
 • Prophylaxis
o General
• Avoidance of irradiation:

Radiotherapy should not be utilized as a therapeutic modality in BCNS

Risk of invasion or development of new BCCs

o Specific
• Chemoprevention (e.g. Imiquimod)

• Active intervention
o Pharmacological

 Topical

o Imiquimod

o 5-Fluoro-uracil

 Systemic

Sonic Hedgehog pathway inhibitors:

o Vesmodegib

o Sonidegib

o Itraconazole

o NSAIDs

 Procedural

o Photodynamic therapy

o Procedural
 Electrodessication and curettage

o Surgical
 Simple excision

 Mohs micrographic surgery

Management of these cases

 Vesmodigib

 Referral to Maxillofacial surgery department for excision of odontogenic cysts of the mandible

 Genetic counseling
Message
 The occurrence of multiple, or even a single early-onset BCC, should raise suspicion for BCNS

 Upon suspicion; further investigations are warranted:

o Panoramic radiograph of Jaw

o Chest x ray
o Brain CT

 BCNS may present with Non-suspicious skin tag-like and nevoid lesions in childhood.

 Itraconazole is a readily available and affordable therapeutic option for multiple BCCs.