Dermatological Manifestations of Inherited Cancer Syndromes in Children

A. Karalis; M. Tischkowitz; G.W.M. Millington


The British Journal of Dermatology. 2011;164(2):245-256. 

In This Article

Signalling Pathway Defects

Naevoid Basal Cell Carcinoma (Gorlin–Goltz) Syndrome

The naevoid BCC syndrome (NBCC) is characterized by the development of multiple BCCs at an early age.[47] It is caused by germline mutations of the patched (PTCH) gene.[47] Loss of PTCH activity produces constitutive activation of the Sonic Hedgehog (SHH) signalling pathway, where PTCH is the receptor for SHH.[48] SHH is an important regulator of vertebrate organogenesis,[48] controlling cell division in adult stem cells and implicated in the development of some cancers.[46] A family history exists in 70–80% of patients with NBCC, while in 20–30% of cases the mutations are sporadic.[7] NBCC may present in early childhood, but more typically in adolescence or early adulthood.[49] Odontogenic keratocysts of the jaw and palmar or plantar pits are seen in 66–75% and 71–87% of patients, respectively.[49–52] Palmar pits are a particularly useful clinical sign in young children and, together with calcification along the falx cerebri, constitute the major clinical diagnostic criteria.[7] Minor skin manifestations include facial milia, meibomian cysts in eyelids, as well as sebaceous and dermoid cysts.[7] Medulloblastoma occurs in NBCC more than in the general population.[53] An early diagnosis of medulloblastoma should prompt physicians to examine for clinical signs of NBCC.[53] Detailed examination and radiological investigations may also identify asymptomatic parents.[7]

Costello Syndrome

Costello syndrome is a clinically heterogeneous condition caused by sporadic mutations in HRAS,[8] in the Ras–mitogen-activated protein kinase (MAPK) pathway.[54] Cutaneous signs include soft skin, excessive wrinkling and redundant skin over the dorsum of the hands and feet, as well as deep plantar and palmar creases.[8,55] Hair may be curly or fine and sparse; hyperpigmentation may occur and papillomas are very common.[8,55] In over 100 reported cases, 24 have developed malignancy.[8] Specific cancers associated with Costello syndrome in children include rhabdomyosarcoma, neuroblastoma and transitional cell carcinoma of the bladder.[56]

Neurofibromatosis Type 1 and 2 and Legius Syndrome

NF1 (autosomal dominant) results from Ras–GTP pathway dysregulation, which leads to loss of function of neurofibromin.[57,58] This in turn leads to dysregulated cellular proliferation, manifesting as CALMs, neurofibromas, schwannomas and CNS tumours.[57,58] Mutations in SPRED1, another gene involved in the same Ras–MAPK pathway, can produce an NF1-like phenotype (also known as Legius syndrome),[59] which is particularly associated with childhood leukaemia.[60] The NF2 gene product regulates contact-dependent inhibition of proliferation, functioning at the interface between cell–cell adhesion, transmembrane signalling and the actin cytoskeleton.[61] When NF2 is disrupted (neurofibromatosis type 2 is also autosomal dominant), the clinical phenotype is characterized by bilateral acoustic neuromas, meningioma, vestibular schwannomas, as well as mesothelioma,[61] with peripheral skin tumours and CALMs occurring rarely.[4,62]

Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC; autosomal dominant) is characterized by the presence of hamartomas in multiple organ systems, including the skin, brain, heart, kidneys and lungs.[63] Cutaneous manifestations include angiofibromas (often facial), periungual fibromas, the shagreen patch (an irregularly thickened, soft, skin-coloured plaque, usually found in the lumbosacral region), hypopigmented ('ash-leaf') macules, achrocordons, dental pitting and poliosis.[4,63] CNS manifestations include epilepsy, learning difficulties, psychological problems and autism.[63]

Associated tumours include cardiac rhabdomyomas, renal angiomyolipomas and Wilms tumours.[4] Rarer associations include pancreatic carcinoma and parathyroid tumours.[4]

TSC is caused by mutations in either TSC1 or TSC2; the TSC1 gene (chromosome 9) encodes hamartin, a protein that interacts with tuberin (encoded by TSC2; chromosome 16), to form a protein complex that blocks signal transduction of the downstream effectors of the mammalian target of rapamycin.[63] As the protein products of both genes are in the same pathway, this explains why mutations in two different genes can produce similar phenotypes.[63]

Multiple Endocrine Neoplasia

The term multiple endocrine neoplasia (MEN) describes several rare, characteristic, autosomal dominant syndromes of tumours of endocrine glands.[4,64] Both the endocrine and associated nonendocrine tumours may be either benign or malignant.[4,64]

MEN type 1, due to mutations in the MEN1 gene (a putative tumour suppressor), is characterized primarily by parathyroid tumours, gastrointestinal endocrine tumours and pituitary tumours.[64] Other endocrine and nonendocrine neoplasms occur, including lipomas, facial angiofibromas, collagenomas[64] and CALMs.[65]

MEN type 2A (MEN2A), which results from mutations in the RET proto-oncogene,[66] is associated with medullary thyroid carcinoma, phaeochromocytoma and primary hyperparathyroidism.[66] Cutaneous neuromas may also occur[67] and various groups have described symmetrical, itchy lesions over the scapulae in MEN2A families.[4] Some groups have also described an association with cutaneous amyloidosis.[67,68] However, the recent discovery of specific OSMR gene mutations as the cause of familial primary cutaneous amyloidosis suggests that the pathogenesis of cutaneous amyloid is probably independent of RET mutations.[69]

MEN type 2B, which is caused by specific mutations in the RET proto-oncogene,[66] is characterized by medullary thyroid carcinoma, phaeochromocytoma, a marfanoid habitus and mucosal and digestive ganglioneuromatosis.[66] Cutaneous features include mucosal neuromas (around the eyes and mouth)[4] and CALMs.[70]

Carney Complex

Carney complex (CNC) type 1 is caused by an autosomal dominant mutation in the protein kinase A (PKA) regulatory subunit-1α gene (PRKAR1A) on chromosome 17.[71] PRKAR1A is a critical component of type I PKA, the main mediator of cAMP signalling in mammals.[71] A second susceptibility locus has been identified on chromosome 2 (CNC2).[72]

CNC is a multiple neoplasia syndrome involving skin and cardiac myxomas, pigmented skin lesions (lentiginous, with a typical distribution – lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa; also blue naevi and CALMs) and multiple endocrine tumours, including primary pigmented nodular adrenocortical disease, which causes Cushing syndrome.[71] CNC is associated with an increased familial incidence of thyroid, colon, pancreatic and ovarian carcinoma.[71]

Beckwith–Wiedemann Syndrome

Overexpression of the paternal IGF2 growth-factor gene or underexpression of the maternal negative growth-regulator gene CDKN1C (p57) gene,[58] due to epigenetic differential methylation of CpG islands in the gene promoter region,[73] leads to the imprinted disorder Beckwith–Wiedemann syndrome (BWS).[58,73] Other imprinted genes that may cause BWS when differentially methylated include NSD and LIT1.[58]

BWS presents principally with fetal and postnatal overgrowth, usually asymmetrical, and is typified by exomphalos, macroglossia and macrosomia, associated with neonatal hyperinsulinism and hypoglycaemia.[58] The best diagnostic features in BWS are linear indentation of the ear lobe and a posterior helical ear pit.[58] Other cutaneous features include polydactyly, a zosteriform rash present at birth, facial naevus flammeus and both cutaneous and extracutaneous infantile haemangiomas.[58] Children with BWS may develop cancers, including hepatoblastoma, Wilms tumour, neuroblastoma or rhabdomyosarcoma.[74]


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