Dura mater involvement in ochronosis (alkaptonuria)

Archives of Pathology & Laboratory Medicine, Jul 2001 by Liu, Wendy, Prayson, Richard A

* Clinical manifestations of alkaptonuria have been well described and are most commonly characterized by ochronosis or pigmentation of connective tissue. Sites most commonly involved in ochronosis include joints, heart, skin, and kidney. We describe a 66-year-old woman with a history of alkaptonuria who had widespread ochronosis. The dura mater showed extensive pigment deposition, which was evident both grossly and microscopically at autopsy. To our knowledge, description of dura mater involvement by ochronosis has not been previously reported in the literature.

(Arch Pathol Lab Med. 2001;125:961-963)

Ochronosis (alkaptonuria) is an autosomal recessive disorder characterized by increased urinary excretion of homogentisic acid. The gene responsible for the disorder has been localized to chromosome 3q.1 The disorder is caused by an enzyme deficiency that results in an inability to catabolize homogentisic acid, an intermediary component in the metabolism of tyrosine and phenylalanine. Accumulation of the homogentisic acid manifests itself both grossly and microscopically as black pigmentation, most commonly found in 4 locations: joints, cardiovascular system, kidney, and skin. We report a case of prominent pigment deposition in the dura mater of the brain. To our knowledge, this is the first such case reported.

REPORT OF CASE

The patient is a 66-year-old, white woman with a known history of alkaptonuria. Her medical history includes hereditary hemorrhagic telangiectasia, diabetes, asthma, chronic obstructive pulmonary disease, transient ischemic attacks, pulmonary hypertension, hypothyroidism, and tobacco use. Seven years previously, she had undergone an aortic valve replacement for aortic stenosis. She most recently presented with a progressive dysrhythmia and was found to have prosthetic aortic stenosis and mitral stenosis with extensive calcification. She underwent aortic and mitral valve replacements. Black pigmentation was noted at the time of surgery in the intima of the entire heart, especially at the site of prior surgery. Prominent calcification was also noted at the aortic arch and area around the aortic valve annulus. She underwent reconstruction of the aortic root with enlargement of the aortic root and pericardial patch placement. Her postoperative course was complicated by pulmonary hypertension. She also subsequently developed acute renal failure, sepsis with fevers, methemoglobinemia, and gastrointestinal bleeding. The patient became obtunded, the family elected to withdraw support, and the patient died. A complete autopsy was performed.

Urine obtained at the time of autopsy was sent to Specialty Laboratories Inc (Santa Monica, Calif) for chemical analysis. The diagnosis of alkaptonuria was confirmed by the presence of markedly elevated homogentisic acid levels (1568 pg/mg of creatinine, 780 times the normal level). A pyroglutamic acid (5-oxoproline) level was also markedly elevated (1843 (mu)g/mg of creatinine, 18 times the normal level). Elevated levels of pyroglutamic acid are not typically described in patients with alkaptonuria but may occur in hawkinsinuria.

HISTOPATHOLOGIC FINDINGS

Salient autopsy findings noted the deposition of black pigment in skin and multiple organs, including heart, aorta, skin, kidney, trachea/bronchi, and joints including intervertebral disks. A pigmented calculus was found in the pelvis of the right kidney, measuring 1.5 x 0.9 cnn. Other significant findings at autopsy included bilateral acute bronchopneumonia, upper gastrointestinal hemorrhage, acute tubular necrosis, and hepatic centrilobular necrosis.

The dura appeared dusky in color and demonstrated multiple regions, which appeared mottled by black pigment (Figure 1). Several prominent blackened blood vessels were also noted in the dura. The dural covering of the spinal cord also showed pigmentation adjacent to intervertebral disk. Pia-arachnoid and brain and spinal cord parenchyma did not appear grossly pigmented.

Microscopically, the dark brown pigment was prominently noted in the connective tissue of the dura (Figure 2). Granular pigment was noted lying free in the collagen bundles and rarely within macrophages. Pigmentation was also observed within the intima and media of arterial walls, particularly in vessels situated within the dura (Figure 3). Blood vessel endothelial cells also appeared to contain granules of pigmented material. No pigmentation was observed in the pia-arachnoid or brain or spinal cord parenchyma. The pigment granules did not stain with Prussian blue for iron. Staining with a Fontana-Masson for neuromelanin was noted but did not bleach with hydrogen peroxide, which is more characteristic of melanin pigment. Other abnormalities were not noted in the brain and spinal cord.

COMMENT

Dura. mater is the outer covering of the brain and is composed of 2 mesoderm-derived connective tissue lar ers. Pigments that can be rarely found in dura include bile and melanin. Bile pigment may be encountered in patients with marked hyperbilirubinemia and affords the dura a green-yellow coloration. Melanin pigment, associated with melanocytes, is more typically leptomeningeal based, particularly in the ventral medulla and cervical spinal cord regions. Its presence is more prominently observed in darkly pigmented individuals and in certain pathologic conditions, including meningeal melanocytosis and certain tumors (melanocytoma and melanoma).2