Dermatological Manifestations of Inherited Cancer Syndromes in Children

Table 1.  Dermatological manifestations of inherited cancer syndromes in children

Condition	Associated features	Associated/observed tumors	Inheritance pattern	Gene(s)	References
Constitutional mismatch repair deficiency	Multiple CALMs Hypopigmented skin macules	Haematological malignancies Brain tumours Gastrointestinal cancers	Biallelic	MLH1 MSH2 MSH6 PMS2	11–14
Xeroderma pigmentosum	Severe sun-sensitivity Marked freckling of sun-exposed areas Premalignant actinic keratoses Xerosis and poikiloderma Ocular involvement: keratitis/corneal opacification and vascularization Increased lid pigmentation; loss of eyelashes Acquired microcephaly Diminshed/absent deep tendon reflexes Progressive sensorineural hearing loss Progressive cognitive impairment	Skin cancers Solid malignancies Ocular neoplasia	AR	XPA ERCC3 XPC DDB2 ERCC4 ERCC5 ERCC1 POLH ERCC2	15–18
Rothmund–Thomson syndrome	Poikiloderma Photosensitivity, leading to a 'butterfly' facial rash Juvenile cataracts Skeletal dysplasia/bone abnormalities	Osteosarcoma Skin cancers Brain tumours Lynch syndrome-associated tumours	AR	RECQL4	19–21
Fanconi anaemia	Pigmentary changes Short stature and skeletal anomalies, especially upper limb Eye malformations and hearing loss CNS malformations and developmental delay Urogenital, cardiac, gastrointestinal and oral abnormalities Up to 25–33% have no congenital anomalies	Haematological malignancy (especially acute myeloid leukaemia) Solid tumours including brain tumors (BRCA2/PALB2), Wilms(BRCA2/PALB2),SCC, hepatic carcinoma	AR	FANCD1 (BRCA2) FANCJ/BRIP1/BACH1 FANCN (PALB2) FANCA FANCC FANCD2 FANCE FANCF FANCG FANCI FANCLFANCM RAD51C (FA-like)	5,22–31
			X-linked	FANCB
Ataxia telangiectasia	Oculocutaneous telangiectasias Pigmentation abnormalities (CALMs) Poikiloderma Seborrhoeic dermatitis Occasionally: atopic anddiscoid eczema, follicularkeratosis, dry skin,hirsutism, vitiligo Progressive cerebellar ataxia Oculomotor apraxia Choreoathetosis Frequent infections/immunodeficiency	Lymphoma, leukaemia Stomach, breast and other solid tumours	AR	ATM	32–41
Bloom syndrome	Sun-sensitive 'butterfly' facial rash Pigmentary abnormalities Low birth weight Short stature/growth deficiency Craniofacial dysmorphisms (narrow cranium; prominent nose and ears) Immunodeficiency	Haematological and solid malignancies	AR	BLM	42,43
Werner syndrome	Lack of pubertal growth spurt Scleroderma-like skin changes, mallelolar skin ulcers, subcutaneous atrophy, premature grey hair Cataracts Diabetes mellitus Myocardial infarction Hoarse voice	Sarcoma Osteosarcoma Melanoma Thyroid carcinoma	AR	WRN (RECQL2)	44–46
Naevoid basal cell (Gorlin–Goltz) syndrome	Palmar/plantar pits, facial milia Meibomian cysts of the eyelids Sebaceous and dermoid cysts Skin tags around the neck Falx calcification Odontogenic jaw keratocysts Macrocephaly; frontal bossing, coarse facies Cleft lip and palate Skeletal anomalies Ocular anomalies	Basal cell carcinoma Medulloblastoma Cardiac fibromas Ovarian fibromas (rarely malignant)	AD	PTCH	7,47–53
Costello syndrome	Deep palmar and plantar creases Curly, or fine sparse hair Loose, soft skin Perinasal and perianal papillomata Failure to thrive; short stature Developmental delay or mental retardation Coarse facial features Diffuse hypotonia; joint laxity; tight Achilles tendons Cardiac involvement	Rhabdomyosarcoma Neuroblastoma Transitional cell carcinoma of the bladder (adolescence)	AD	HRAS	8,54–56
Neurofibromatosis type 1	CALMs, axillary/inguinal freckling, neurofibromas, schwannomas CNS glial tumours	Malignant peripheral nerve sheath tumour	Sporadic, AD	NF1	57,58
Legius syndrome	CALMs, axillary/inguinal freckling, neurofibromas, schwannomas CNS glial tumours	Juvenile myelomonocytic leukaemia	AD	SPRED1	59,60
Neurofibromatosis type 2	Acoustic neuromas, meningiomas of the brain, and schwannomas of the dorsal roots of the spinal cord. Rarely, cutaneous features as for NF1	Possible association with mesothelioma	AD	NF2	4,61,62
Tuberous sclerosis complex	Hamartomas in the skin, brain, heart, kidneys and lungs Cutaneous angiofibromas (often facial), periungual fibromata, shagreen patch, 'ash-leaf' macules, achrocordons, dental pitting and poliosis Epilepsy, learning difficulties, psychological problems and autism	Cardiac rhabdomyomas, renal angiomyolipomas and Wilms tumours	AD	TSC1 TSC2	4,63
Multiple endocrine neoplasia type 1	Parathyroid tumours, gastrointestinal endocrine tumours and adenohypophyseal tumours Lipomas, facial angiofibromas and collagenomas CALMs	Meningioma, Ependymoma	AD	RET	4,64,65
Multiple endocrine neoplasia type 2A	Phaeochromocytoma and primary hyperparathyroidism Cutaneous neuromas, itchy papules and amyloidosis	Medullary thyroid carcinoma	AD	RET	4,66–68
Multiple endocrine neoplasia type 2B	Phaeochromocytoma, a marfanoid habitus and mucosal and digestive ganglioneuromatosis Mucosal neuromas (around the eyes and mouth) and CALMs	Medullary thyroid carcinoma	AD	RET	4,66,70
Carney complex	Cutaneous, cardiac, endocrine and neural myxomas Lentigines, blue naevi and CALMs Multiple endocrine tumours Large-cell calcifying Sertoli cell tumour and psammomatous melanotic schwannomas	Thyroid, colon, pancreatic and ovarian carcinoma and others	AD	PRKAR1A Chromosome 2p16	71,72
Beckwith–Wiedemann syndrome	Exomphalos, macroglossia, hemihypertrophy, macrosomia, linear indentation of the ear lobe, posterior helical ear pit, zosteriform rash, facial naevus flammeus, cutaneous haemangiomas	Hepatoblastoma, Wilms tumour, neuroblastoma or rhabdomyosarcoma	Imprinted	IGF2 CDKN1C (p57) NSD1 LIT1	58,73,74
Wiskott–Aldrich syndrome	Microthrombocytopenia (often causing haemorrhage) Immunodeficiency Eczema Autoimmunity Cancer risk	Leukaemia Myelodysplasia Lymphoma	X-linked	WAS gene	76,77
Chediak–Higashi syndrome	Generalized hypopigmentation (may include partial albinism) Recurrent infections Mild coagulopathy Neurological symptoms	ALL T-cell lymphoma	AR	CHS1/LYST	78–80
X-linked agammaglobulinaemia	Immune deficiency Cellulitis/impetigo Eczema Dermatomyositis-like syndrome	Colorectal Gastric	X-linked	BTK	81–84
X-linked dyskeratosis congenita	Abnormal skin pigmentation Nail dystrophy Mucosal leukoplakia	Haematological malignancy Head and neck SCC Skin and anorectal SCC Gastrointestinal	X-linked (AR and AD forms also exist)	DKC1	85,86
Neuroblastoma	Neuroblastoma, cutaneous metastases, CALMs	Neuroblastoma	AD	Various including: KIF1B PHOX2B ALK	87–89
Nail-patella syndrome	Dysplastic nails with absent or dyspastic patellae. Other features include elbow dysfunction, glaucoma and renal dysfunction	Possible association with colorectal carcinoma	AD	LMX1B	90,91

Cutaneous manifestations are shown in bold face. CALMs, café-au-lait macules; AR, autosomal recessive; AD, autosomal dominant; SCC, squamous cell carcinoma; CNS, central nervous system; NF1, neurofibromatosis type 1; ALL, acute lymphoblastic leukaemia.

AR, autosomal recessive; AD, autosomal dominant; NF1, neurofibromatosis type 1.

Authors and Disclosures

A. Karalis, M. Tischkowitz and G.W.M. Millington*

Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada and Segal Cancer Centre, Jewish General Hospital, Montreal, QC, Canada
*Department of Dermatology, Norfolk and Norwich University Hospital, Norwich NR4 7UZ, U.K.

Correspondence
George Millington. E-mail: george.millington@nhs.uk

Sidebar

What's Already Known About This Topic?

• DNA repair defects, signalling pathway defects and primary immunodeficiency syndromes can be linked to both malignancy and skin disease.

• Clinical testing is available for many of these rare conditions, which permits surveillance and prevention strategies.

What Does This Study Add?

• The review provides a structure for classifying the complex field of paediatric genetic disorders which are linked with both dermatological signs and malignancy.