Albinism

(CHEST 1995; 108:1158-60)

A 30-year-old albino Hispanic man, born in Puerto Rico, presented with a 1-month history of dyspnea, initially occurring on exertion, and gradually progressing to occur at rest. Medical history included a platelet disorder associated with easy bleeding diagnosed about 15 years earlier; this condition had not required treatment. He was not taking medications and had no surgical procedures. He had been advised to avoid aspirin because of his platelet abnormality. He had quit smoking 13 years previously and had no history of intravenous drug abuse or homosexual activity. There was no family history of lung disease.

Physical Examination

A mildly obese, albino man in no apparent distress. Vital signs: normal. Head, eye, ear, nose, throat: bilateral horizontal nystagmus. Chest: bibasilar crackles. Cardiac: a regular tachycardia. Abdomen: soft without hepatosplenomegaly. Extremities: no clubbing, cyanosis, or edema.

Laboratory Findings

Angiotensin-converting enzyme level: normal. Legionella titer: <1:64. Chest radiograph: bilateral patchy densities without pleural effusions (Fig 1). Pulmonary function studies: forced vital capacity, 1.47 L (32% of predicted); [FEV.sub.1], 1.20 L (26% of predicted); total lung capacity, 2.15 L (36% of predicted); diffusing capacity for CO, 29% of predicted; flow-volume loop, consistent with restriction. Ambulatory pulse oximetry (room air): desaturation from a baseline of 95% to 87% saturation. Echocardiogram: normal. High-resolution CT scan: diffuse interstitial lung disease with patchy areas of peripheral fibrosis with honeycombing (Fig 2). Fiberoptic bronchoscopy: normal airways. Transbronchial biopsies: extensive interstitial fibrosis with a lymphocytic infiltration.

What diagnosis is suggested by the clinical presentation?

Diagnosis: Hermansky-Pudlak Syndrome

Hermansky-Pudlak syndrome (HPS) is an autosomal recessively inherited disease manifested by the triad of oculocutaneous albinism, hemorrhagic diathesis, and accumulation of ceroid-like pigment in the reticuloendothelial system. In 1949, Hermansky and Pudlak first described this syndrome in a pair of albinos in Czechoslovakia.

This form of oculocutaneous albinism is described as tyrosine-positive because of the presence of tyrosine in the melanosomes; it is not seen in those with total albinism. Some patients may have pigmentation and not look typically albino-like, since the degree of albinism is variable, especially in deeply pigmented populations. All will have evidence of nystagmus and decreased visual acuity. The bleeding disorder usually is mild, with epistaxis being the most frequent hemorrhagic manifestation. Massive fatal bleeding has occurred following dental extractions and in childbirth.

The hemorrhagic diathesis is due to a platelet storage pool defect with decreased or absent secondary wave of platelet aggregation with adrenaline. Morphologically, the platelets have a reduced number of dense granules that result in a decreased release of platelet adenosine diphosphate and serotonin. Bleeding times may be prolonged or normal at different times in the same patient.

Ceroid is a nonbiodegradable, autofluorescent, yellow-colored, intracellularly stored pigment. Its chemical composition and the defect that causes its accumulation in tissues is unknown. It is theorized to be caused by an abnormality of lysosomal function and may be similar to the storage material in patients with neuronal ceroid-lipofuscinosis.

The syndrome is worldwide in distribution but appears to be most prevalent in southern Holland and in North America among Puerto Ricans from the northwestern part of the island in the towns of Rincon, Aguada, Aguadilla, Hatillo, and Arecibo. In the latter, the prevalence is at least 1 in 946 persons.

Various organs may be affected with reports of cardiomyopathy, granulomatous colitis, and gingivitis. The lung, on biopsy, usually reveals extensive fibrosis which may involve the interstitium, alveolar septum, and peribronchial areas (Fig 3). The alveolar macrophages may demonstrate the yellow-brown staining of ceroid accumulation. This ceroid material may stain weakly positive with Ziehl-Neilsen acid-fast stain. Bronchioles may be dilated and filled with mucus, neutrophils, and desquamated epithelial cells.

Most patients present in the fourth decade with the insidious onset of dyspnea. However, the progression of disease is variable with reports of rapid deterioration within a few months to a slow decline over 16 years. Pulmonary fibrosis is the leading cause of death among HPS patients, with 21 of 36 patients in one study dying between the ages of 35 and 48 years.

Pulmonary function studies generally show restriction with a reduced diffusing capacity. Pulmonary impairment has been noted as early as the second decade of life. Resting hypoxia with worsening on exercise is typical.

Radiographic abnormalities tend to occur later than the pulmonary function changes. The chest radiograph may show a fine reticular pattern or a coarse reticulonodular appearance. In advanced disease, there may be bullous emphysema and bronchiectasis. The diagnosis of tuberculosis in patients with HPS may be problematic due to the presence of granulomas containing ceroid that may stain positive on acid-fast stain.

The diagnosis of HPS usually can be established clinically with the presence of pulmonary fibrosis in an albino from the northwestern part of Puerto Rico. The most reliable method of diagnosing HPS is finding a deficiency of platelet-dense bodies by electron microscopy. Other studies suggestive of the dianosis include a platelet aggregation defect, characteristic pigment in biopsy specimens of the reticuloendothelial system, and positive fluorescent microscopy of urine sediment. Pigment has been noted in alveolar macrophages obtained from bronchoalveolar lavage. Accumulation of pigment is variable and not always seen in the lung, as in the present patient's open-lung biopsy specimen (Fig 3). Ceroid accumulates to the greatest degree in the proximal tubules of the kidney, in the reticuloendothelial system, and in the liver.

Treatment of the lung disease has been supportive. Corticosteroids and other immunosuppressive agents have been tried without success. Lung transplantation currently is the only treatment available for patients with progressive respiratory failure; however, there is a theoretical concern for the recurrence of the disease in the donor lung. As of this date, no patients with HPS have had lung transplants. Ongoing research is being aimed at trying to identify the defective gene. The present patient refused evaluation for lung transplantation. His respiratory failure progressed and he required high-flow supplemental oxygen.

CLINICAL PEARLS

1. The diagnosis of HPS should be considered in an albino, especially a native of Puerto Rico with bleeding tendencies. However, albinism may not be obvious in some Puerto Rican natives because of the variable presentation of the skin pigmentation.

2. Minimal pulmonary function abnormalities may occur prior to seeing evidence on chest radiographs.

3. A deficiency of platelet-dense bodies evidenced by on electron microscopic studies is the most reliable method of diagnosing HPS.

4. Patients with HPS should avoid aspirin and aspirin-containing products. The hemorrhagic diathesis may be ameliorated prior to major surgery with platelet transfusions or cryoprecipitate.

5. Pulmonary fibrosis is the leading cause of death with most patients dying of respiratory failure in the fourth to fifth decades.

SUGGESTED READINGS

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