Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported.

FH tumor predisposition syndrome is characterized by cutaneous leiomyomata, uterine leiomyomata (fibroids), and/or renal tumors. Pheochromocytoma and paraganglioma have also been described in a small number of families. Cutaneous leiomyomata appear as skin-colored to light brown papules or nodules distributed over the trunk and extremities, and occasionally on the face, and appear at a mean age of 30 years, increasing in size and number with age. Uterine leiomyomata tend to be numerous and large; age at diagnosis ranges from 18 to 53 years, with most women experiencing irregular or heavy menstruation and pelvic pain. Renal tumors are usually unilateral, solitary, and aggressive. They are associated with poor survival due to clinical aggressiveness and propensity to metastasize despite small primary tumor size. The median age of detection is approximately age 40 years.

The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts), pulmonary cysts / history of pneumothorax, renal cysts, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life and typically increase in size and number with age. Lung cysts are mainly in the basal lung regions; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Renal tumors can be bilateral and multifocal. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (oncocytic hybrid tumor); clear cell carcinoma and oncocytoma are also common.