Autosomal Dominant Diseases

NEUROFIBROMATOSIS (VON RECKLINGHAUSEN'S DISEASE)

Pathogenesis and Pathophysiology. Neurofibromatosis y is no longer considered a single clinical entity and has been divided into at least two distinct forms. y The common form, once known as peripheral neurofibromatosis (NF), is called NF-1, and the rare form, once termed central NF, is NF-2. Both are inherited as autosomal dominant traits, and the gene locus responsible for NF-1 is on chromosome 17 (17q11.2), whereas that for NF-2 is on chromosome 22 (22q11.1 to 22q13.1). These disorders are due to abnormalities in the development of neural crest cells that produce hyperplasia, neoplasia, and dysplasias of the neuroectodermal elements and their supporting structures. Recently, the gene for NF-1 was found to code for a large, ubiquitously expressed protein (neurofibromin). y This protein has structural and functional similarity to a family of proteins that has guanosine triphosphatase-activation properties. This family of proteins is involved in the regulation of the proto-oncogene ras. It has been speculated that the functions of the NF-1 gene product may be related to its ability to regulate ras-mediated cell proliferation.

Epidemiology and Risk Factors. NF-1 occurs in approximately 1 in 4000 to 5000 individuals. About half the cases appear to be sporadic, and the mutation rate has been estimated at 1 in 10,000 gametes per generation, one of the highest mutation rates in humans. Approximately 50 percent of patients have affected relatives, and in nearly all instances the distribution of cases is consistent with an autosomal dominant mode of inheritance. NF-1 is observed in all regions of the world and affects men and women equally. The frequency of NF-2 is not known, and its natural history has been derived from studies of a large Pennsylvania family.

Clinical Features and Associated Disorders. NF-1 is characterized by cutaneous pigmentation, multiple tumors within the central and peripheral nervous systems, and lesions of the vascular and other organ systemsy , y ( ,.T§bIe,„32i2.). Focal hyperpigmented areas and cafe au lait spots, ranging in size from a few millimeters to centimeters, are more commonly found on the trunk than on the limbs, and they are not found on the scalp, soles, or palms ( .Fig 32-1 ). These spots are light brown and result from an aggregation of neural crest-derived pigmented melanoblasts in the basal layer of the epidermis. Cafe au lait spots are present at birth and become more apparent with time. The number of cafe au lait spots probably does not significantly increase after the first several years of life, although the degree of hyperpigmentation usually does. The presence of six or more cafe au lait spots larger than 15 mm in greatest diameter is required for a diagnosis of Nf, a criterion that is most useful when applied to the postpubertal patient. It should be recognized, however, that about 10 percent of the general population have cafe au lait spots without other stigmata of the disease. Less frequent cutaneous changes in NF-1 include diffuse axillary or inguinal freckling and

Figure 32-1 A 9-year-old patient with multiple cafe au lait spots of varying sizes, which are more common on the trunk than on the limbs.

Figure 32-2 Axillary and inguinal region freckling, as observed in this patient, is common in patients with neurofibromatosis.

large areas of faintly increased pigmentation (melanoderma) ( .Fig 32-2.).

Fibroma molluscum, soft or firm papules found in or just below the dermis that vary in size from a few millimeters to one or more centimeters, may also occur ( Fig

32-3 ). They are violaceous in color and vary in configuration from flat or sessile forms to pedunculated or lobulated forms. When compressed, these skin lesions tend to invaginate into the subcutaneous tissue. Hypopigmented spots similar to those observed in patients with tuberous sclerosis, discrete areas of skin hypoplasia, and angiomas may also be present in NF-1. All dermatological abnormalities may appear well before any neurological signs or symptoms occur.

Lisch nodules are iridic melanocytic hamartomas that are age-dependent and are found in 10 percent of patients less than 6 years of age, 50 percent of patients less than 30 years old, and in virtually all affected patients by the age of 50 years ( F.i.g ,„32..-4 ). Optic gliomas, reported in 15 to 20 percent of patients, can present with decreased visual

Figure 32-3 An example of fibroma molluscum, which is a soft or firm papular or polypoid lesion found in or just below the dermis and which ranges in size from a few millimeters to 1 cm or (Courtesy of Dr. Mary Williams, Department of Dermatology, University of California Medical Center, San Francisco.)

Figure 32-4 Lisch's nodules are age-dependent iridic melanocytic hamartomas that are commonly observed in patients with neurofibroma^ Courtesy of Dr. Creig Hoyt, Department of Ophthalmology, University of California Medical Center, San Francisco.)

acuity or visual field defects. y These tumors can involve the optic chiasm and hypothalamus and rarely become manifest as the diencephalic syndrome of infancy. There is some controversy about the nature of the tumor, but optic gliomas of childhood are probably congenital, indolent, and slowly growing hamartomas. Congenital glaucoma may also be a complication of NF-1 and is sometimes associated with neurofibromas of the superior eyelid.

Neural tumors, or neurofibromas, can involve any nerve from the dorsal root ganglia to the terminal twigs of the peripheral nerves, and any organ can be involved ( ...

Fig 32-5 ). Peripheral neurofibromas vary in size and occur more frequently on the trunk than on the limbs. Plexiform neuromas are composed of an overgrowth of neural elements of tumor and connective tissue that infiltrates normal tissue. These larger tumors can be superficial, affecting the skin and subcutaneous tissue, or deep, affecting visceral and adjacent tissues. Intracranial tumors occurring in NF- 1 are primarily meningiomas and gliomas. There is an increased incidence of optic gliomas and neurofibromas in these patients, and schwannomas may also occur and may involve other cranial nerves. Intraspinal tumors can be present and are sometimes accompanied by spinal cord anomalies. While most tumors in this disorder are benign, some neurofibromas may undergo malignant transformation.

The diagnostic criteria for NF-2 require one or more of the following: bilateral eighth nerve masses; a parent, sibling, or child with NF-2; and either a unilateral eighth nerve mass or any two of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity. Bilateral acoustic neuromas become manifest in over 95 percent of affected individuals. Symptoms of acoustic neuromas are usually referable to pressure on the vestibulocochlear and facial nerves, and patients may complain of tinnitus, buzzing, or background noise in the head. Alternatively, the initial symptom may be unilateral loss of hearing, which is noticed when the patient uses the telephone. Typically, symptoms begin in

Figure 32-5 An older teen-age patient with numerous neurofibromefshorf arrow) as well as multiple lesions typical of fibroma molluscuiflong arrow).

the second or third decade, but patients may become symptomatic in the first decade or as late as the ninth. Other features of NF-2 include cafe au lait spots and neurofibromas, although these are less commonly observed than in patients with NF-1. Presenile lens opacities or subcapsular cataracts have been found in nearly 50 percent of patients and may precede the symptoms of acoustic neuromas. Patients with NF-2 may have Schwann cell tumors of other cranial nerves or spinal roots, and meningiomas, astrocytomas, and ependymomas may present in the same patient. Optic gliomas, astrocytomas, and hamartomas are usually not found in this form of NF.

Associated features of NF include mental retardation or seizures, which occur in about 10 percent of NF patients, and about 40 percent have specific learning disabilities and hyperactivity. Occlusive cerebrovascular disease, although rare, can sometimes be demonstrated by angiography, which shows occlusive changes of the supraclinoid segment of the internal carotid artery associated with the telangiectasia characteristic of moyamoya disease.

Macrocephaly and short stature are reported in 10 to 40 percent of NF patients, and a variety of bony changes may also be present (including "ballooning" of the middle fossa, an enlarged or J-shaped sella, and dysplastic changes of the sphenoid). Patients with optic gliomas may have enlarged optic foramina, and bony defects of the orbit and other cranial bones are not uncommon. Scoliosis has been reported in 10 to 40 percent of patients and usually becomes manifest after the age of 6 years. Anterior meningocele, kyphosis, enlarged intervertebral foramina, bowing of the tibia and fibula, and bony overgrowth occur. Precocious puberty may occur in Nf-1 patients with gliomas or hamartomas of the hypothalamus.

NF may be associated with a number of other neoplastic processes with a more than random frequency. These include leukemia, Wilms' tumor, neuroblastoma, multiple endocrine neoplasias, and pheochromocytoma. Of patients with pheochromocytomas, 4 to 23 percent are reported to have neurofibromatosis, whereas fewer than 1 percent of patients with neurofibromatosis have pheochromocytomas. Hypertension may also result from intimal proliferation and fibromuscular changes of the media of the small renal arteries, or from a pheochromocytoma.

Differential Diagnosis. The differential diagnosis of NF-1 is limited to the presence of a family history of the disease and the typical neurological and dermatological findings. NF-2 should be distinguished from sporadic, unilateral acoustic neuroma (SUAN). NF-2 usually presents prior to 40 years of age and is distinguished by the presence of brain and spinal tumors, cafe au lait spots, fibromas, and posterior capsular lens opacities. In contrast, SUAN presents after 40 years and has no associated findings.

Evaluation. The diagnostic tests used in patients with NF should be determined by the findings in the clinical examination because most studies will not be valuable in the asymptomatic NF patient. MRI can be useful in the evaluation of patients with possible intracranial, extracranial, and nerve root neoplasms. This neuroimaging study may also demonstrate incidental "bright areas" in patients with NF-1 that are consistent with "hamartomas" that may represent focal areas of heterotopic or dysplastic tissue. These focal areas of increased signal intensity on T2 images are not associated with vasogenic edema and are primarily seen in the basal ganglia, internal capsule, midbrain, cerebellum, and subcortical white matter. They are not visualized on contrast-enhanced CT. MRI findings suggestive of gliomas include the presence of vasogenic edema, mass effect, cavitation, enhancement with gadolinium, and decreased signal intensity on T1 images. When optic nerve gliomas are suspected, MRI with fat suppression techniques is a useful adjunctive study. The spine of a patient with NF-1 should also be imaged with MRI if there are symptoms or signs of intraspinal or nerve root compression. Isolated neurofibromas may involve the neural foramina and spinal canal, forming the so-called dumbbell tumor. Neoplasms involving the spinal canal and cord are best demonstrated with the use of gadolinium.

Patients who are at high risk for NF-2 should undergo MRI with gadolinium of the head, paying special attention to the cerebellopontine angle and internal acoustic meatus. Careful ophthalmic assessment should be performed to document the presence or absence of posterior capsular lenticular opacities and papilledema. Tests of vestibular and auditory function as well as brain stem auditory evoked potentials should be considered in the evaluation of these patients.

If symptoms suggest the presence of a pheochromocytoma, abdominal and mediastinal imaging should be performed, and neurotransmitter metabolites should be measured. Patients who are having problems with academic achievement should undergo neuropsychological studies to detect the presence and nature of any specific learning disabilities.

Management. Treatment of patients with NF is supportive and symptomatic. Patients with specific learning

disabilities should receive the benefit of special education programs. Patients with seizures should be treated with standard antiepileptic agents. Peripheral neurofibromas are generally indolent and do not require surgical removal unless they are subjected to repeated trauma and abrasion or show rapid growth. Plexiform neuromas may be removed for strictly cosmetic reasons. Intracranial and intraspinal tumors should be treated with neurosurgical intervention, irradiation, or chemotherapy when appropriate. Most investigators suggest managing optic gliomas conservatively, with serial MRI scans and visual field and acuity examinations, rather than by immediate surgery or chemotherapy. y , y The clinical course of patients with NF-2 may be relatively benign, and indications for acoustic neuroma surgery must be made on an individual basis. The presence of an acoustic neuroma does not inevitably lead to deafness and facial disfigurement; moreover, surgery in the region of the cerebellopontine angle is not without risk. Partial removal may be appropriate to preserve useful hearing in some cases. Counseling should address the issues of prognosis, genetics, and psychological and social adjustment.

Prognosis. Neurofibromatosis is a progressive disorder that requires continuous surveillance. The overall prognosis is determined by the location, number, and severity of the tumors that are present. It is important to note that most patients with the disease retain good function.

TUBEROUS SCLEROSIS

Pathogenesis and Pathophysiology. Tuberous sclerosis, or tuberous sclerosis complex (TSC), is an autosomal dominant disorder, and linkage analyses have indicated that the gene is located on the distal long arm of chromosome 9 (9q34). Though not substantiated, other studies have suggested that genetic heterogeneity exists within TSC, the gene in some families being mapped to 11q and in others to 16q. Other cases have been attributed to a gene mutation. Although the genetic basis of the disease has been established, the pathogenesis remains unknown. The lesions involve cells derived from the ectoderm and mesoderm, and the cellular elements demonstrate abnormalities in number and size.

Epidemiology and Risk Factors. Tuberous sclerosis has been identified in all races in all parts of the world. Both sexes are equally affected, and heredity is evident in 50 percent of cases. Prevalence is estimated at 1 in 50,000 to 1 in 300,000 people. This disorder accounts for nearly 1 percent of the institutionalized population in the United States and for 0.3 percent of patients with epilepsy.

Clinical Features and Associated Disorders. Though Bournevilley , y is credited with the first description of the disease, probably von Recklinghausen described it initially. Bourneville believed that the cerebral "scleroses" and renal tumors were associated findings, but he failed to recognize the importance of the typical facial skin lesions. Vogt believed that a triad of clinical findings including seizures, mental retardation, and adenoma sebaceum were characteristic of the disease, U but the criteria for diagnosis have recently been revised (.Tab.le.32i3 ). TSC is characterized by a variety of clinical findings including seizures, varying degrees of mental subnormality, and dysplastic or neoplastic

_TABLE 32-3 -- DIAGNOSTIC CRITERIA FOR TUBEROUS SCLEROSIS COMPLEX (TSC}_

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