Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective.

We review advancing and overlapping stages for our understanding of the expressions of six hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903 to 1967), the introduction of robust measurement of serum calcium was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects, and inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased toward severe or striking manifestations. During stage 2 (1959 to 1985), the early formulations of a syndrome were improved. Radioimmunoassays (parathyroid hormone [PTH], gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981 to 2006), the assembly of many cases enabled recognition of further details. For example, hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes ("principal" implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for five syndromes. During stage 5 (1993 to the present), seven syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole-exome sequencing. During stages 4 and 5, the newly identified genes enabled many studies, including robust assignment of the carriers and non-carriers of a mutation. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future. © 2018 American Society for Bone and Mineral Research.

Parathyroid surgery: from inception to the modern day.

Parathyroid surgery has undergone great changes since its inception less than a century ago. It is still the only definitive option available to cure primary or tertiary hyperparathyroidism. This review details the development of parathyroid surgery, our understanding of hyperparathyroidism and the treatment options available. It also discusses the technological advances that have enabled parathyroid localization and prediction of surgical success.

Vignette hyperparathyroidism: glimpse into its history.

The parathyroid gland was first described by Sir Richard Owen. Ivor Sandstrom coined the term glandulae parathyroidiae. Vassale and Generali Francesco observed that tetany occurs following parathyroidectomy. Harald Salvesen firmly established the relationship of the parathyroid gland to calcium metabolism. A patient with skeletal disease and a tumor near the parathyroid gland was described by Max Askanazy in 1904. Schlagenhaufer suggested in 1915 that in an attempt to cure bone disease, solitary parathyroid enlargement, if present, should be excised. The term hyperparathyroidism (HPT) was coined by Henry Dixon and colleagues. The parathyroid surgeries on Albert J. and Charles Martell were the first experience with successful parathyroidectomy. From a grossly symptomatic disease of bones, stones, abdominal groans, and psychic moans, HPT has evolved into asymptomatic HPT. Improvements in knowledge about the pathology of parathyroid diseases, including the genetic basis of HPT, and advances in the surgical techniques have brought about changes in the management of HPT over the decades.

Diagnostic value of micro-CT in comparison with histology in the qualitative assessment of historical human skull bone pathologies.

Cases of pathologically changed bone might constitute a diagnostic pitfall and frequently need histological methods to be etiologically properly evaluated. With micro-computed tomography (microCT), a new epoch of 2D and 3D imaging has been launched. We evaluated the diagnostic investigation of this analytical method versus well established histological investigations of historical human bone. Pathological changes due to various etiologies (infectious, traumatic, endocrinological, neoplasia) observed in autopsy-based macerated human skulls (Galler Collection, Natural History Museum Basel, Switzerland) were investigated by microCT and compared with histological thin ground sections using polarized light. Micro-CT images visualize the architecture of the bone with high spatial resolution without preparation or destruction of the sample in the area to be sectioned. Changes in the bone surfaces as well as alterations of the diploë can be assessed. However, morphological patterns caused by reactive response, such as typical arrangements of collagen fibers, can only be visualized by the microscopic investigation of thin ground sections using polarized light. A great advantage of microCT is the high number of slices obtained so that spatial differences within the areas of the specimen become visible. Micro-CT is a valuable tool for the diagnosis of vestiges of skull bone diseases. Its advantages over histology are the fast, automated image acquisition and the fact that the specimen is not completely destroyed. Only excision of the area to be scanned is necessary, if the specimen is too large to be scanned as a whole. Further, the 3D visualization of the micro-architecture allows an easy orientation within the sample, for example, for the choice of the location of the histological slices. However, the need to differentiate woven from lamellar bone still makes histology an indispensable method.

Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993-2001: an update on the changing epidemiology of the disease.

UNLABELLED: We updated the incidence of primary hyperparathyroidism in Rochester, Minnesota. The lower rates previously noted persisted, whereas parathyroidectomies at our institution remained high. These data suggest an etiologic factor may be responsible for the peak incidence in the 1970s. INTRODUCTION: Automated serum calcium measurements were associated with a dramatic rise in primary hyperparathyroidism in the early 1970s, but a progressive decline in the incidence thereafter was unexpected and suggested a fundamental change in the epidemiology of the disease. Our objective was to evaluate trends in the incidence of primary hyperparathyroidism since 1992. MATERIALS AND METHODS: In this population-based descriptive study, Rochester, MN, residents who met defined diagnostic criteria for primary hyperparathyroidism from January 1993 through December 2001 were identified through the medical record linkage system of the Rochester Epidemiology Project and the Mayo Clinic Laboratory Information System. Changes in incidence were evaluated by Poisson regression. RESULTS: Altogether, 136 Rochester residents (94 women and 42 men) were newly identified with primary hyperparathyroidism in 1993-2001. Their mean age was 56 years, and 93% had definite disease. The overall age- and sex-adjusted (to 2000 U.S. whites) rate during this period was 21.6 per 100,000 person-years, which was less than the annual rate of 29.1 per 100,000 observed in 1983-1992 and 82.5 per 100,000 in July 1974-1982. Although community incidence declined, the number of parathyroidectomies performed at our institution increased during the same period. Serum calcium was deleted from the automated chemistry panel in June 1996, but most subjects remained asymptomatic at diagnosis (95%) with mild hypercalcemia. The majority of subjects were observed without parathyroid surgery (75%), and there was minimal impact on patient management from the 1990 NIH consensus conference on asymptomatic primary hyperparathyroidism. CONCLUSIONS: The lower incidence of primary hyperparathyroidism noted through 1992 has persisted in our community through 2001, whereas parathyroidectomies at our institution remained high. These data suggest that some underlying etiologic factor, in addition to the introduction of automated serum calcium testing, may have been responsible for the peak incidence in the 1970s.

[Friedrich Daniel von Recklinghausen. Biography and significance of his osteopathologic work after more than 100 years]. / Friedrich Daniel von Recklinghausen. Biographie und Bedeutung seiner osteopathologischen Arbeiten nach mehr als 100 Jahren.

Even today the name of F.D. von Recklinghausen is often mentioned in connection with primary and secondary hyperparathyroidism. He was one of the first physicians and scientists to render outstanding services to the classification of structural changes of bones, and in many aspects his work remains valid today. He succeeded through precise and comparative studies in making the disease and symptoms of primary hyperparathyroidism known and thus distinguishing it from other known structural bone diseases. He also described the phenomenon of "bone remodeling" which has become relevant today again. Although his written macroscopic and microscopic observations include meticulously precise differentiations which make it difficult to study them today, they are still of interest in order to follow his basic ideas. This article does not constitute a comprehensive biography, but it contains a description of F.D. von Recklinghausen's important work on bone pathology against the background of the main stages of his life.

[Primary hyperparathyroidism. History]. / L'hyperparathyroïdie primaire. Historique.

The term primary hyperparathyroidism currently refers to the clinical and biological manifestations resulting from the hypersecretion of parathyroid hormone by one or several parathyroid adenomas. This entity is a recent one since it goes back to 1925. The clinical picture resulting from this anomaly, were first described as Recklinghausen's fibrous osteitis, which was not justified since Recklinghausen had not established the relationship between the clinical manifestations and the adenoma discovered by Mandl, then under the name of parathyroid osteosis. This term was justified at a time when the disease presented only bony manifestations with biological evidence. Primary hyperthyroidism is the current appellation, demonstrating that the disease is now a biological disease, often discovered systematically, with therapeutic progress, progress in biological identification and possibility of medical forms without mandatory surgical outcome. Bibliographic references accompany the various stages of this historical reminder.

Possible case of hyperparathyroidism in a Roman period skeleton from the Dakhleh Oasis, Egypt, diagnosed using bone histomorphometry.

A histomorphometric study of thin femoral head sections of a skeletal sample from the Dakhleh Oasis, Egypt, dated from circa 36 B.C. to 400 A.D., identified an adult female (Dk31-A1) in her mid-50s with a high percentage resorption surface with tunneling resorption as is typically found in hyperparathyroidism. Five static histomorphometric bone parameters were measured with the following results for this individual: 1) mean wall thickness, 41.94 micron, 2) trabecular bone volume, 18.54%, 3) surface volume, 4,070 mm2/cm3, 4) mean trabecular diameter, 132 microns, and 5) total resorption surface, 12.31%. The overall histomorphometric features and differential diagnosis support the diagnosis of hyperparathyroidism. We conclude that histomorphometry of dried bone, particularly in this case where preservation is ideal, is a valuable investigative technique for paleopathology.