Tumour syndromes
Beckwith-Wiedemann Syndrome (BWS)
Key Clinical Features:
Macrosomia
Visceromegaly
Macroglossia
Exomphalos
Genetic Abnormalities:
11p15 abnormalities (requires genetic testing to determine the specific type)
Common Genetic Findings:
KvDMR hypomethylation: 50% of cases, no Wilms tumour risk, unlikely familial risk
CDKN1C mutation: 5% of cases, associated with familial risk
Pathophysiology:
Increased expression of insulin-like growth factor 2 (IGF-2) gene
Somatic overgrowth
Pancreatic islet cell hyperplasia
Great Ormond Street Hospital (GOSH) Guidance:
Blood sugar monitoring for 48 hours; continue if hypoglycaemia is detected
For any BWS other than KvDMR hypomethylation:
Serial abdominal ultrasound every 3-4 months until age 7 for Wilms tumour screening
Screening for other tumours is not recommended
Follow-Up:
Paediatrics for general health and development (especially if hypoglycaemia-related brain injury)
Orthopaedics for hemihypertrophy
GOSH specialised macroglossia service
Prognosis:
Development usually normal by adulthood
BWS facies usually resolve
Tumour Risks (excluding KvDMR hypomethylation):
Wilms tumour (most common)
Hepatoblastoma
Neuroblastoma
Adrenocortical carcinoma
Rhabdomyosarcoma
Renal Complications:
Nephrocalcinosis
Nephrolithiasis
Renal cysts
Recurrent urinary tract infections (UTIs)
Multiple Endocrine Neoplasia (MEN)
MEN 1 (Werner's Syndrome):
Autosomal dominant, chromosome 11q13
PPP:
Pituitary adenomas
Parathyroid hyperplasia
Pancreatic islet cell tumours (e.g., gastrinomas, insulinomas, VIPoma)
Additional Features:
Carcinoid tumours in the gut
Skin lesions
MEN 2A:
Autosomal dominant, RET proto-oncogene
Clinical Features:
Medullary thyroid cancer
Phaeochromocytoma
Primary hyperparathyroidism (all 4 glands)
Lichen amyloidosis (red-brown hyperkeratotic papules, interscapular + extensor surfaces)
Hirschsprung’s disease
MEN 2B:
Clinical Features:
Medullary thyroid cancer
Phaeochromocytoma
Marfanoid habitus
Gangliomatosis (intestines, tongue, lips, eyelids)
Megacolon
Screening:
Always perform blood and urine tests to screen for other tumours when MEN is suspected
Tuberous Sclerosis
Autosomal dominant
Mutations in TSC1 or TSC2
Clinical Features
Dermatological:
Hypopigmented ash leaf spots (oval or leaf-shaped white patches)
Shagreen patch (thickened, rough, skin-coloured lesion, typically on the lower back)
Facial angiofibromas (small, red bumps often found on the cheeks and nose)
Periungual fibromas (fibromas around or under the nails)
Confetti skin lesions (small, hypopigmented spots on the arms and legs)
Neurological:
Cortical tubers (abnormal areas in the brain that can lead to seizures)
Seizures (often presenting as infantile spasms or focal seizures)
Developmental delay and intellectual disability
Autism spectrum disorder
Renal:
Angiomyolipomas (benign kidney tumours, which can cause haematuria and kidney dysfunction)
Renal cysts
Increased risk of renal cell carcinoma
Cardiac:
Rhabdomyomas
Cardiac arrhythmias
Pulmonary:
Lymphangioleiomyomatosis (LAM) (a progressive lung disease, more common in females, leading to respiratory issues)
Ophthalmological:
Retinal hamartomas (benign tumours in the retina)
Retinal achromic patches (hypopigmented areas in the retina)
Other:
Dental enamel pits
Gingival fibromas (fibromas on the gums)
Bone cysts
Polycystic kidney disease (in some cases, due to contiguous gene syndrome with PKD1)
Neurofibromatosis
NF1:
Prevalence: 1:3000
Chromosome 17q11, NF1 mutation
Autosomal dominant
Childhood onset
Diagnostic Criteria (Suggestive Findings: ≥2 Required):
6 café au lait spots
Axillary freckling
Two or more neurofibromas
Optic pathway glioma
Two or more Lisch nodules (identified by slit lamp examination)
Distinctive osseous lesions (e.g., sphenoid dysplasia, tibial pseudarthrosis)
Parent who meets diagnostic criteria for NF1
Germline NF1 pathogenic variant
Other Features:
GI fibromas, leiomyomas, neurofibromas
Scoliosis
Seizures
Congenital arteriovenous fistulas
Malignant peripheral nerve sheath tumours (most common cancer)
NF2:
Adult onset
Chromosome 22
Clinical Features:
Hearing loss
Vertigo
Cataracts
Multiple intracranial pathologies
Von Hippel-Lindau Syndrome
Autosomal dominant
Chromosome 3, VHL tumour suppressor mutation
Clinical Features:
Haemangioblastoma
Phaeochromocytoma
Renal cell carcinoma (RCC)
Pancreatic neuroendocrine tumours
Denys-Drash Syndrome
WT1 mutation, chromosome 11
Autosomal dominant
Clinical Triad:
Disorders of sex development (DSD)
Wilms tumour
Nephrotic syndrome progressing to mesangial renal sclerosis
Li-Fraumeni Syndrome
TP53 mutation
Autosomal dominant
Cancer Risks:
Adrenocortical tumours
Breast cancer
CNS tumours
Osteosarcoma
Soft tissue sarcomas (STS)
WAGR Syndrome
Genetic Basis: 11p13 deletion, involving the PAX6 and WT1 genes
Clinical Features:
Wilms Tumour
Aniridia: Absence of the iris, leading to vision problems such as photophobia, nystagmus, and reduced visual acuity. This condition is congenital and usually present from birth
Genitourinary Anomalies: This may include ambiguous genitalia, hypospadias, or undescended testes in males. Females may have streaked ovaries, which increases the risk of gonadoblastoma
Intellectual Disability: Varying degrees of intellectual disability or developmental delay are common in WAGR syndrome, requiring early intervention and support services
Management: Tumour screening
DICER1 Syndrome
Chromosome 14q32.13
Tumour Risks:
Papillary and follicular thyroid cancer
Pleuropulmonary blastoma (PPB)
Lung and kidney cysts or tumours
Ovarian tumours (children/adults)
Brain tumours
Tumours in the eye or nose and sinuses
Carney Triad
Sporadic
Type of MEN
Clinical Features:
Pulmonary chondroma
Gastrointestinal stromal tumour (GIST)
Extra-adrenal paraganglioma
Carney Complex
Clinical Features:
Myxomatous neoplasms (cardiac, endocrine, cutaneous, neural)
Pigmented lesions of the skin and mucosae, including epithelioid blue nevus (rare)
Carney-Stratakis Syndrome
Familial
Germline mutations in the mitochondrial tumour suppressor gene pathway (SDHD, SDHC, SDHB)
Clinical Features:
GIST
Paraganglioma
References
https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/beckwith-wiedemann-syndrome-bws/ Compiled by:The Clinical Genetics Service with assistance from the Beckwith-Wiedemann Syndrome UK Support Group in collaboration with the Child and Family Information Group at GOSH
Last review date: February 2017
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