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Lethal Hereditary Vascular Disorders: Osler-Weber-Rendu, Ataxia-Telangiectasia, and Fabry's Disease

Synonyms: OWR—Hereditary hemorrhagic telangiectasia

AT—Louis-Bar syndrome

FD—Anderson-Fabry disease, angiokeratoma corporis diffusum

Etiology: OWR—AD, Chromosome 9 and 12-defect in endoglin or activin receptor-like kinase

AT—AR, 11q22.3 phosphatidylinositol-3-kinase p53 checkpoint regulation FD—XL, Xq22.1, alpha-galactosidase A Associations: OWR—Arteriovenous malformations of the brain, lungs; hepatic fibrovascular tumors

AT—B-cell non-Hodgkin's lymphoma, T-cell CLL, breast cancer, growth retardation

Clinical: OWR—Mucocutaneous telangiectasias, epistaxis, hemoptysis, clubbing, cyanosis

AT—Oculocutaneous telangiectasias, skin photoaging, cerebellar ataxia

FD—Cutaneous nonblanching angiectases, neuropathic pain, cardiomyopathy, renal failure OWR—Mucosal and dermal telangiectasias AT—Dermal elastosis, telangiectasias, pulmonary bronchiectasis, CNS demyelination FD—Mucosal and dermal telangiectasias and angiokeratomas, interstitial lipid deposits N/A

OWR—Good in the absence of pulmonary or CNS malformation or abscess

AT—Invariably fatal, usually early adulthood secondary to infection or lymphoma/leukemia FD—Poor without renal transplantation, better recent outcome with enzyme replacement Complications: OWR—Arteriovenous malformations and abscesses of CNS and lungs

AT—Bronchiectasis, cerebellar ataxia, T-cell leukemia and B-cell lymphoma

FD—Cardiomyopathy, cerebrovascular accident, renal failure Treatment: OWR—Supportive measures

AT—Supportive measures

FD—Alpha-galactosidase A gene therapy shows promise

Pathology:

Staging: Prognosis:

Mucocutaneous vascular ectasia, otherwise referred to as telangiectasia, can be an important harbinger of serious systemic disease. Among a variety of acquired conditions, including hepatic cirrhosis that are responsible for their development, are a heterogeneous group of inherited conditions that entail the development of multiple cutaneous and mucous membrane vascular lesions associated with other life-threatening complications. This chapter deals with the clinical and pathologic features of three such conditions, namely Osler-Weber-Rendu syndrome, ataxia-telangiectasia, and Fabry's disease.

Osler-Weber-Rendu (OWR) syndrome synonymously referred to as hereditary hemorrhagic telangiectasia, was first described by Dr. William Osler in 1907 (1). He described many of the attributes of this distinctive disorder known today, including the characteristic triad of the superficial cutaneous vessels that undergo irreversible dilatation forming telangiectasis, bloody nasal discharge (epistaxis), and its familial tendency (2). The disorder affects all races, although it has been described with a higher incidence in the Dutch Antilles and parts of France. It is known to be an inherited or spontaneously acquired autosomal dominant trait. The overall incidence of the disorder is about 1 in 100,00 persons. The defect involves segments of chromosomes 9 and 12, which encodes for two important endothelial transmembrane receptors, termed endoglin and activin receptor-like kinase 1, respectively. The latter protein is the receptor for transforming growth factor beta, an important modulator of tissue repair and angiogenesis that when defective is thought to lead to defects in endothelial cell junctions and weakness of the supporting perivascular connective tissue resulting in telangiectasis and arteriovenous malformation. The disease typically manifests in early to mid-adulthood with the development of epistaxis. Other common presenting signs include mucosal and cutaneous telangi-ectasis, and other signs of bleeding diathesis including melena and hemoptysis. The telangiectasias consist of discrete red puncta, spider-like branching, and/or linear vascular lesions located in particular on the face, fingers, and oral and nasal mucous membranes (3) (Figure 30.1). Less common findings include headaches stemming from complications associated with cerebral arteriovenous malformation, cyanosis and/or clubbing associated with pulmonary arteriovenous malformation, signs and symptoms of high output cardiac failure produced from pulmonary vascular shunting, fatigue from blood loss and anemia, visual disturbances following intraocular hemorrhage, and fever associated with abscesses following bacterial seeding of the pulmonary or cerebral vascular anomalies (4). Important complications to consider include gastrointestinal and pulmonary bleeding, often necessitating transfusion, cerebrovascular accident, and

Osler Weber Rendu Syndrome
Figure 30.1. Diffuse palmar telangiectasis in Osler-Weber-Rendu syndrome.

infectious complications stemming from the vascular anomalies. The overall mortality is approximately 10% with patients generally succumbing to one of the aforementioned complications. Although estrogen has been reported in the past as producing some measure of therapeutic improvement, current recommendations include supportive measures including prompt recognition and cessation of bleeding (5).

Ataxia-telangiectasia (AT), or Louis-Bar syndrome, was first described by Syllaba and Henner in 1926 and later by the Belgian neuropathologist Dr. Denise Louis Bar in 1941, who detailed the progressive nature of the cerebellar ataxia and distinctive cutaneous telangiectasis of the disorder (6). Its final designation of ataxia-telangiectasia would come in 1957 with the discovery of its association with immunologic defects and the predisposition of afflicted patients to develop recurrent sinopulmonary infections. Today, we know this autosomal recessively inherited disease to involve the 11q22-23 gene that encodes for the ATM protein (7). This protein is an important regulatory phosphoprotein involved with p53-regulated cell cycling and DNA maintenance. Defective ATM function results in increased unregulated DNA synthesis and defective DNA strands predisposed to instability and a hypersensitivity to ionizing radiation. These defects are thus thought to predispose to neoplastic transformation and the increased risk these patients possess for solid organ and lymphoreticular malignancy as well as impact upon T-lymphocyte receptor function leading to immu-nologic dysfunction and a predisposition toward certain types of infection (8,9). The mechanisms that underlie the cerebellar ataxia, growth retardation, and mucocutaneous telangiectasis are not known but have been hypothesized to involve accelerated telomere loss. The disease affects all races and regions of the world and has an estimated incidence of 1 in 100,000 individuals (10). The disease is generally heralded by the development of ataxia in the first years of life. The ataxia commences with abnormal head movements and progresses to involve the gait and abnormal arm movements including tremor and myoclonus, later. Other neurologic findings include choreoathetosis, mask-like facies, and saccadic eye deviation with absent optokinetic nystagmus. The pathogenesis involves spinocerebellar degeneration with demyelination. The mucocutaneous telangiectasias develop by the age of 5 years and in particular involve the conjunctival angles and adjacent periocular skin (Figure 30.2). Accelerated aging (progeric changes) including graying of the hair, facial skin atrophy, seborrheic dermatitis, and mottled pigmentation are also common. Other cutaneous findings include café au lait macules, vitiligo, hypertrichosis, acanthosis nigricans, keratosis pilaris, actinic keratosis, and the presence of nonmelanoma skin cancer. The other major impairment associated with AT is immunologic dysfunction with increased sinopulmonary and ear infections associated with thymic hypoplasia, defective cell-mediated immunity, and reduced serum IgA and IgE immunoglobulin levels. Less prominent features of the disease include mental retardation, atherosclerotic heart disease, diabetes mellitus, and growth impairment. Pathology of the brain shows degeneration of the cerebellar Purkinje and granular cells and spinal column anterior horn and spinal tract degeneration and demyelination. The cutaneous findings include epidermal atrophy with solar elastosis and capillary telangiectasis. Less common findings include the presence of dermal non-caseating granulomas, pigmentary incontinence, and superimposed changes of sebor-

Ear Telangiectasia
Figure 30.2. Conjunctival telangiectasis in ataxia-telangiectasia.

rheic dermatitis or keratosis pilaris. The dermal granulomas consist of epithelioid granulomas that may masquerade as sarcoidosis. Cases of ulcerating or perforating granuloma-tous dermatitis and palisaded granulomatous dermatitis have been described as well (11). Actinic keratosis, basal cell and squamous cell carcinoma may be seen in young patients and as such may suggest the possibility of this disorder. Important complications primarily involve neoplastic and infectious diseases. AT patients have an estimated 100-fold increase in the incidence of malignancy, particularly Hodgkin's and non-Hodgkin's lymphoma, leukemia, and gastric and breast adenocarcinoma (9,10). An important complication of recurrent pulmonary infection is bronchiectasis. AT is invariably fatal with few afflicted individuals living beyond their third decade. The major causes of mortality include pulmonary infection and malignancy. Treatment consists of the aggressive management of infectious disease with antibiotics and prevention with prophylactic administration of immunoglobulins and vaccination. Sunscreens and sun avoidance are important with respect to the cutaneous complications. Increased awareness of oncologic disease with appropriate screening is recommended. Physical, speech, and occupational therapies should be instituted and genetic counseling for the patient and family is encouraged.

Fabry's disease, otherwise referred to as Anderson-Fabry disease or angiokeratoma corporis diffusum, was independently described by Drs. Anderson and Fabry in 1898 (12,13). The disease is inherited as an X-linked trait and involves a defect in glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Over 160 mostly missense-type mutations have been identified within encoding gene segments for alpha-galactosidase (14). Although males are predominantly afflicted, females may rarely present with milder forms of the disease. The disease is worldwide in distribution and although it afflicts all races, whites are overrepresented. The estimated incidence is 1 in 40,000 individuals. The etiology involves the accumulation of glycosphingolipid substrate following lack of enzymatic activity in the tissues of the principal organs involved with the disease (15). As the gene is located on Xq22, males are more severely afflicted, possessing very low to absent galactosidase levels. Carrier females and females with incomplete lyonization of the abnormal X-chromosome allele may develop milder disease stigmata. The disorder has been rarely reported in individuals with normal measured enzyme activity (16). The most important glycosphingolipids that accumulate due to the enzymatic defect are globotriaosylce-ramide and galabiosylceramide. These compounds accumulate primarily within the lysosomes and cytosol of endothelial, pericyte, and smooth muscle cells of the skin, renal, and neurovascular organs. The pathologic alterations stem from endothelial accumulation and disruption with consequent ischemic and degenerative changes. Symptoms are generally ushered in by the development of limb neuropathic pain and cutaneous vascular anomalies in late adolescence or early adulthood. The limb pain is usually exacerbated by exposure to cold and is typically described as burning in quality. The cutaneous changes consist of the development of myriad punctate red-to-blue nonblanching angiectasias particularly situated in the "bathing-suit" area of the lower abdomen and perineum (Figure 30.3) (15). The nonblanching quality of the lesions is an important contrast with tel-angiectasia, which typically blanches with external pressure or diascopy. Similar vascular lesions can be found on the oral mucosa. Other attendant cutaneous findings include lymphedema and hypohidrosis. Important additional systemic signs include various lens opacities that are pathognomonic for the disorder. Distinctive corneal opacities referred to as cornea verticillata are also commonly seen. The cutaneous and ocular findings are overshadowed by the serious systemic complications of visceral organ involvement. The kidneys are severely affected and renal failure is common by the fourth decade. Important signs of renal disease include increasing pro-teinuria and the demonstration of characteristic birefringent lipid globules with a "Maltese cross" pattern in the urinary sediment. The heart is particularly prone to complications stemming from the accumulation of lipids

Causes For Angiokeratomas
Figure 30.3. Diffusely scattered telangiectatic papules on scrotum of patient with angiokeratoma corporis diffusum.

within the vessel walls and myocardium resulting in ischemic complications as well as left ventricular hypertrophy. Congestive heart failure and myocardial infarction are important causes of morbidity and mortality. Additional organs involved include the brain, where cerebrovascular accident is a common complication, and the gastrointestinal tract, where intestinal ischemia may be observed. The pathologic changes involve the progressive dilatation of capillaries and post-capillary venules within the dermis (Figure 30.4). Over time, the abutment adjacent to the epithelium produces epidermal hyperplasia

Telangiectasis
Figure 30.4. Low power photomicrograph depicting superficial dermal capillary telangiectasis in Osler-Weber-Rendu syndrome.

and angiokeratoma formation. Systemic pathologic changes additionally include vascular ectasia, accelerated atherosclerosis, and degenerative changes ascribed to ischemic alteration. The heart shows increased interstitial fibrous and lipid deposits. Glomerular and renal tubular deposits are seen in the kidney. Characteristic lysosomal organelle lamellar inclusions are observed ultrastructur-ally. The diagnosis can be confirmed by direct enzymatic assay of serum, leukocytes, or cultured fibroblasts, or by DNA analysis of the gene. A presumptive diagnosis can be rendered upon careful assessment of the ophthalmo-logic findings, the widespread nature of the angiokerato-mas, and/or the urinary sediment findings. Important entities to consider in the differential diagnosis are other inherited enzyme deficiency syndromes with similar clinical stigmata. These disorders include L-fucosidase and neuraminidase deficiency, among other rarer entities (16-17). Important clues that suggest the latter entities include disseminated angiokeratomas in a female patient and psychomotor and cognitive impairment. The long-term prognosis of patients is determined by renal function status. Renal transplantation has dramatically improved the outcome of patients as transplanted kidneys generally possess normal enzyme activity. Important morbidities, including neuropathic pain and cerebrovas-cular and cardiovascular disease, are treated symptomati-cally with pain and anti-seizure medications, aggressive blood pressure control, and smoking cessation. Recent advances in recombinant gene therapy will likely revolutionize the treatment and long-term outlook of these patients. Recent clinical trials with the recombinant enzyme Fabrazyme (Genzyme Corporation Cambridge, MA) have shown great promise (14).

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