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To the Editor: Several studies have described the importance of bone and soft tissue paleopathology in detecting and tracing various diseases from the dawn of human civilization.^1-2 Skeletal manifestations of hyperparathyroidism have only rarely been identified in historic material. In the previously oldest example, from a Roman period cemetery from the Dakhleh Oasis in Egypt,³ the diagnosis was suggested by histomorphometric analysis of bone sections. We describe the findings in what we believe represents the oldest published example of hyperparathyroidism, dating to the Early Neolithic period, around 7000 years ago.

Case Description
The skeleton of a 25- to 35-year-old woman comes from an Early Neolithic cemetery from the site of Viesenhäuser Hof (Stuttgart-Mühlhausen, southwest Germany).⁴ The archeological record has shown that the burials belong to the Linear Band Pottery period. This was confirmed by radiocarbon dating that revealed a date for the burial site of 5100 to 4800 BCE. The skeleton showed multiple osseous lesions: deep smooth-walled erosions of 2 lumbar vertebrae (L4 and L5) (Figure 1A) with concomitant fusion of the adjacent L3 and L2 (Figure 1B); compression fracture of L2 with extensive osteophytes at the superior margin; a pathological fracture of T5 with collapse, partial destruction, and angular kyphosis; and 2 deep erosive lesions at the margin of the proximal joint surface of the right humerus.

View larger version (126K): [in this window] [in a new window] Figure 1. Osseous Lesions of the Lumbar Vertebrae and Skull A, Lumbar vertebra showing a deep smooth-walled erosion at the posterior aspect. B, Fused lumbar vertebrae L2 and L3 showing focal diagenetic fossilization and significant general demineralization. Arrowheads indicate level of fusion. C, Osteopenic, granular appearance of the skull vault with loss of distinct trabecular detail. This "salt and pepper skull" represents trabecular resorption within medullary bone.

Methods
To evaluate pathological processes and the state of preservation of the Neolithic skeleton we performed a detailed radiological and histological investigation. The radiological images were prepared using digital radiography (Kodak Direkt View CR 9000; Rochester, NY) and computed tomography (Light Speed Plus; GE Medical Systems, Milwaukee, Wis). For the histological analysis, ground sections were prepared using calcified and decalcified bone slices from the right humerus and a vertebral body following established protocols.^5-6

Results
Despite some focal diagenetic fossilization, plain radiology and computed tomography scans revealed significant general demineralization of the skeleton (Figure 1). Both erosive lesions of L4 and L5 appeared to be well healed without any signs of inner trabecular osteolytic alterations, excluding infectious processes such as spondylitis or a malignant tumor. The images of several phalanges showed scalloped defects with edging appearance, and the vault of the skull showed a "salt and pepper" appearance (Figure 1C). Histological examination showed a significant enlargement of Haversian canals in compact bone and focally broadened endosteal resorption zones. The vertebral specimens revealed areas with cookie-bite defects of the trabecular surface of the cancellous bone (Figure 2). Additionally, several trabeculae provided evidence for tunneling osteoclasia, which typically emerge as a result of intense osteoclastic activity.

View larger version (108K): [in this window] [in a new window] Figure 2. Tunneling Osteoclasia of the Vertebral Trabeculae A, Photomicrograph of a histological section of the vertebral specimen showing the typical "cookie-bite" tunneling osteoclasia of the vertebral trabeculae (asterisks) (unstained, original magnification x400). B, For comparison, a bone tissue section of a recent case of hyperparathyroidism reveals very similar defects at the trabecular surface (asterisks) (hematoxylin-eosin, original magnification x400).

Comment
Examination of the skeleton in this Neolithic individual strongly suggests primary hyperparathyroidism as evidenced by radiological osteopenia, focal tumor-like osseous resorption (osteodystrophia fibrosa cystica), scalloping of phalanges, and salt-and-pepper appearance of the cranial vault. The histological appearance of enhanced endosteal resorption with tunneling osteoclasia is considered virtually pathognomonic for primary hyperparathyroidism.⁵ Parathyroid adenoma causes 90% of primary hyperparathyroidism. The incidence of this disease in current populations is about 30 per 100 000, with untreated mortality of approximately 20%. Assuming an ancient population of only a few million individuals in Central Europe⁷ and a low frequency of investigated skeletons from that period, the lack of identified cases is not surprising. Our observations suggest that this disease was already present in one of the earliest farming populations of Central Europe.

Albert R. Zink, PhD
Division of Palaeopathology
Institute of Pathology
Academic Hospital München-Bogenhausen
Munich, Germany

Stephanie Panzer, MD
Trauma Clinic Murnau
Murnau, Germany

Martinus Fesq-Martin, PhD
Department of Physical Geography
University of Augsburg
Augsburg, Germany

Eva Burger-Heinrich, PhD
Anthro-Service
Munich

Joachim Wahl, PhD
State Office for Historical Monuments of Baden-Wurttemberg
Konstanz, Germany

Andreas G. Nerlich, MD, PhD
andreas.nerlich{at}extern.lrz-muenchen.de
Institute of Pathology
Academic Hospital München-Bogenhausen

1. Aufderheide A. Progress in soft tissue paleopathology. JAMA. 2000;284:2571-2573. FREE FULL TEXT 2. Czarnetzki A, Schwaderer E, Pusch CM. Fossil record of meningioma. Lancet. 2003;362:408. PUBMED 3. Cook M, Molto E, Anderson C. Possible case of hyperparathyroidism in a Roman period skeleton from the Dakhleh Oasis, Egypt, diagnosed using bone histomorphometry. Am J Phys Anthropol. 1988;75:23-30. PUBMED 4. Biel J. Archäologische Ausgrabungen in Baden-Württemberg. Stuttgart, Germany: Theiss; 1982. 5. Milgram JW. Radiologic and Histologic Pathology of Nontumorous Diseases of Bones and Joints. Northbrook, Ill: Northbrook Publishing Co; 1990:735-744. 6. Maat G, Van Den Bos RPM, Aarents MJ. Manual for the preparation of ground sections for the microscopy of bone tissue. Barge's Anthropologica. 2000;7:1-17. 7. Weiss KM. On the number of members of the genus Homo who have ever lived, and some evolutionary implications. Hum Biol. 1984;56:637-649. ISI | PUBMED

Letters Section Editor: Robert M. Golub, MD, Senior Editor.

JAMA. 2005;293:40-42.

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