pheochromocytoma

Multiple Endocrine Neoplasia, Type IIB

Clinical Characteristics
Ocular Features: 

Corneal nerves are medullated and appear prominent.  Neuromas of the lid margins and sometimes the conjunctiva are common features.  Thickening of the entire eyelids may be present.

Systemic Features: 

Some manifestations may be seen in early childhood.  Prominent physical features include full lips, thickened eyelids, high arched palate and a marfanoid habitus.  Medullary carcinoma of the thyroid is almost always present and can be the cause of death in relatively young individuals. Metastases are usually to the regional lymph nodes or to liver, lungs, or bone. Pheochromocytomas and megacolon secondary to gastrointestinal neuromas are commonly seen.  The esophagus sometimes lacks normal motility for the same reason.  Neuromas often lead to thickening of the lips and tongue and can also appear as pedunculated nodules on these structures.  Cafe-au-lait spots and increased pigmentation of the hands, feet, and circumoral areas are frequently present.  Many patients have dysmorphic features suggestive of Marfan syndrome including a typical habitus, pectus excavatum, scoliosis, and pes cavus. Proximal myopathy and peripheral neuropathy are sometimes seen.

Another form of multiple endocrine neoplasia, called MEN2A, differs in the absence of mucosal neuromas and the marfanoid habitus.  MEN2A patients are more likely to have parathyroid hyperplasia.

Genetics

This is an autosomal dominant disorder caused by mutations in the tyrosine kinase domain of the RET gene (10q11.2). This disorder (MEN2B) may be allelic to MEN2A.  Perhaps half of MEN2B cases occur sporadically and in these the mutant RET allele is usually of paternal origin.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment of local lesions is sometimes indicated.  Biochemical testing for pheochromocytoma should be done before any surgery.

References
Article Title: 

Von Hippel-Lindau Syndrome

Clinical Characteristics
Ocular Features: 

Retinal angiomas are a feature of this syndrome, occurring in up to 70% of patients and often diagnosed by about age 25 years.  These hemangioblastomas are often connected to prominent arterioles and venules indicative of their vascular nature.  Capillary hamartomas located on or near the optic nerve may mimic papilledema or papillitis.  However, they may also occur throughout the retina and visual morbidity often results from secondary damage due to hemorrhage, exudates, and traction on the retina. When they are bilateral and multicentric the diagnosis of VHL is highly likely.  Patients with VHL tend to develop such tumors at a younger age and have worse visual outcomes than those in patients without VHL.  The impact on vision is responsible for initial presentation in many patients.

Systemic Features: 

Clinical symptoms typically have their onset during the second decade of life.  These commonly (in 35% of patients) result from the presence of a cerebellar hemangioblastoma while overall more than 60% eventually develop this malignancy.  Up to 40% of patients develop renal cell carcinomas and these are a major cause of death.   However, benign and malignant tumors may appear in many organs including the adrenal glands, pancreas, and spinal cord.  Pheochromocytomas occur in 20-35% of individuals and may be bilateral and multifocal.  These can induce an erythrocythemia. Endolymphatic sac tumors occur in about 10% of patients.  Cystic lesions are often associated with the tumors, especially in the pancreas.

Several subtypes have been proposed based on the pattern of malignancies and the types of mutations found in patients.

Genetics

This is an autosomal dominant cancer susceptibility disorder caused by a mutation in the VHL gene located at 3p26-p25.

There is evidence that the phenotype can be modified by variations in the cyclin D1 gene (CCND1) located at 11q13.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Local excision of isolated lesions can be considered in selected cases.  Photocoagulation and cryotherapy of retinal hamartomas can be considered although outcomes are variable depending on location and size of the lesions.

References
Article Title: 

A genetic register for von Hippel-Lindau disease

Maddock IR, Moran A, Maher ER, Teare MD, Norman A, Payne SJ, Whitehouse R, Dodd C, Lavin M, Hartley N, Super M, Evans DG. A genetic register for von Hippel-Lindau disease. J Med Genet. 1996 Feb;33(2):120-7.

PubMed ID: 
8929948

Genetic analysis of von Hippel-Lindau disease

Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE, Giles RH. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010 May;31(5):521-37.

PubMed ID: 
20151405
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