Zellweger syndrome

Adrenoleukodystrophy (ALD) is a rare genetic metabolic disorder. It is characterized by progressive dysfunction of the adrenal gland and demyelination of nerve cells in the brain due to impaired peroxisomal function. Peroxisomes are intracellular organelles that contain enzymes necessary for lipid metabolism.1

Adrenoleukodystrophy encompasses 2 rare and distinct genetic disorders, X-linked ALD (an X-linked recessive disorder) and neonatal ALD (an autosomal recessive disorder). In both forms of ALD, high levels of very long chain fatty acids accumulate in various organs due to the absence of peroxisomes. This accumulation is most severe in the brain and adrenal glands, and results in a variety of neurologic problems and endocrine dysfunction.

Impairment of more than one peroxisomal function can lead to a subgroup of even rarer diseases including Zellweger syndrome. This syndrome is an autosomal recessive disorder characterized by facial dysmorphism, neonatal hypotonia, psychomotor retardation, and hepatomegaly, and it is usually fatal in infancy.1 In genetic terms, Zellweger syndrome overlaps neonatal ALD: both disorders are caused by abnormalities of the same genes.

In patients with ALD, the adrenal glands are of normal shape, but small. Each gland usually weighs less than 2 g,2,3 but its architecture is preserved. The diminutive size of the adrenal gland in ALD has been attributed to an (as yet incompletely explained) "adrenalytic" process,2 referring to the dystrophy implied in the term ALD.

Histologically, the adrenal cortex shows changes mainly in the zona fasciculata and zona reticularis. These changes consist of variably enlarged cortical cells, with abundant striations and macrovacuoles in the cytoplasm. The "balboning" of cells, considered pathognomonic for ALD, is a result of accumulation of smooth endoplasmic reticulum and lipid material. The ballooned cells may form nodules. The nucleus may be either vesicular or hyperchromatic. The zona glomerulosa and adrenal medulla are minimally affected in ALD.

The accompanying images are of an adrenal gland affected by ALD, from the autopsy of a male infant diagnosed with Zellweger syndrome. The infant was the only child of a homeless mother. He had failed to thrive since birth and had developed seizure disorder, hypotonia, jaundice, and hepatosplenomegaly. The diagnosis was made based on this constellation of clinical manifestations. The infant died of sepsis and respiratory failure 10 weeks after birth.

Autopsy showed the presence of abnormal adrenal glands and multiple congenital abnormalities. Both left and right adrenal glands were small, with normal shape, and weighed 0.3 and 0.2 g, respectively (Figure A; bar, 1 nun). Histologic examination of the adrenal gland showed nodules composed of variably enlarged cortical ballooned cells with abundant waxy cytoplasm that were arranged in a pseudotubular pattern in the inner portion of the cortex (Figures B, C, and D show progressively higher-power magnifications of the affected adrenal glands, hematoxylin-eosin stain). Normal zonation of the gland was not evident. The adrenal medulla was not affected (Figure B).

The other abnormalities found at autopsy included simian creases, low-set ears, and frontal bossing. We also noted thymic hypoplasia, bilateral undescended testis, hepatosplenomegaly, intrahepatic paucity of bile ducts, and extrahepatic biliary atresia with marked cholestasis. We rendered a postmortem diagnosis of ALD, in the setting of Zellweger syndrome.

References

1. Moser HW, Moser AB, Chen WW, Watkins PA. Adrenoleukodystrophy and Zellweger syndrome. Prog Clin Biol Res. 1990;321:511-535.

2. Powers JM, Schaumburg HH. The adrenal cortex in adrenoleukodystrophy. Arch Pathol. 1973;96:305-310.

3. Lloyd RV, Douglas BR, Young WF. Endocrine Diseases. Washington DC: Armed Forces Institute of Pathology; 2002:203-205. Atlas of Non-tumor Pathology.

Xia Chen, MD; Ronald A. DeLellis, MD; Syed A. Hoda, MD

Accepted for publication July 22, 2002.

From the Departments of Pathology, New York Presbyterian Hospital & Weill Medical College of Cornell University, New York, NY (Drs Chen and Hoda) and Rhode Island Hospital, Brown University School of Medicine, Providence, RI (Dr DeLellis).

Reprints: Xia Chen, MD, New York-Presbyterian Hospital & Weill Medical College of Cornell University, Starr 1028, Box 93, 525 E 68th St, New York, NY 10021 (e-mail: xiachen@nyp.org).

Copyright College of American Pathologists Jan 2003
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