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Paleopathological investigations of conditions linked to vitamin D deficiency have increased in the last twenty years, and a suite of skeletal lesions has been established to aid in the diagnosis of vitamin D deficiency disease in subadults and adults. This paper analyzes the occurrence of these lesions in a large skeletal series comprising 3541 Roman period individuals (1st-6th century AD). Sixteen lesions reported in rickets in subadults, and 13 associated with residual rickets and osteomalacia in adults, were analyzed. Among subadults, there were clear associations among post-cranial lesions. Porotic cranial changes were associated with each other, but not with post-cranial lesions. A range of conditions could have produced the cranial lesions. There was a general paucity of correlations between indicators found in adults, and the difficulty in recording bending deformities was clear. Pseudofractures appear to provide a useful means of investigating osteomalacia in adults. In general, a simple algorithmic approach using presence or absence of lesions is unlikely to provide an adequate means of diagnosing vitamin D deficiency in paleopathology. Knowledge and consideration of the underlying physiological mechanisms involved in lesion formation, combined with individual judgement, will be required to differentially diagnose cases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Vitamin D deficiency rickets was considered endemic in the industrialized cities of 19th century England, but was rarely reported in more rural and suburban areas. The commercial excavation of St. John's Church, Redhill, Surrey, UK provided an opportunity to examine to what extent suburban children were affected by rickets and the factors responsible for its development. Seventy-nine non-adults (0-17 years) from St. John's Church were subjected to macroscopic and radiographic analysis to identify skeletal manifestations of vitamin D deficiency. Rachitic lesions were identified in 14/79 individuals (17.7%) aged from six months to six years. Active cases occurred from six months to two years of age with healed cases observed from three to six years. One seven month old infant also displayed healed lesions. The age-specific pattern of active and healed rickets suggests the population was vulnerable to the seasonal restriction of sunlight hours, with the considerably low vitamin D content of the infant diet unable to provide sufficient amounts to maintain metabolic functions. This research demonstrates that rickets was not simply a disease of industrialization but that a variety of factors contributed to its development in groups previously considered to be low risk., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Two rare genetic diseases can cause rickets in children. The critical enzyme to synthesize calcitriol from 25-hydroxyvitamin D, the circulating hormone precursor, is 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase). When this enzyme is defective and calcitriol can no longer be synthesized, the disease 1alpha-hydroxylase deficiency develops. The disease is also known as vitamin D-dependent rickets type 1 or pseudovitamin D deficiency rickets. When the VDR is defective, the disease hereditary vitamin D-resistant rickets, also known as vitamin D-dependent rickets type 2, develops. Both diseases are rare autosomal recessive disorders characterized by hypocalcemia, secondary hyperparathyroidism, and early onset severe rickets. In this article, these 2 genetic childhood diseases, which present similarly with hypocalcemia and rickets in infancy, are discussed and compared., (Copyright 2010 Elsevier Inc. All rights reserved.)

A skeletal disease with features of rickets and simple autosomal recessive inheritance has been discovered in Corriedale sheep in New Zealand. The clinical signs resemble rickets in other species and include decreased growth rate, thoracic lordosis and angular limb deformities. Gross lesions include segmental thickening of physes, growth arrest lines, collapse of subchondral bone of the humeral head, thickened cortices and enthesophytes around distal limb joints. Microscopically, there is persistence of hypertrophic chondrocytes at sites of endochondral ossification, inappropriate and excessive osteoclastic resorption, microfractures and wide, unmineralized osteoid seams lining trabeculae and filling secondary osteons. This study confirms that this skeletal disease of Corriedale sheep is a newly discovered form of inherited rickets and suggests that the genetic defect may be different from inherited forms of rickets described to date in man and animals.

We report the cases of 2 boys and 1 girl suffering from Netherton syndrome. Both boys presented with a non-bullous congenital erythroderma and were diagnosed early as Netherton syndrome with hair biopsies. Both had severe failure to thrive, signs of atopy, several episodes of bacterial infection, and rickets (with a high blood level of vitamin D in the first boy, and vitamin D deficiency in the second). In the third case, the pilar abnormality appeared at the age of 3 years. The girl had ichtyosis linearis circumflexa, failure to thrive and severe constipation. Netherton syndrome is a rare disorder characterized by severe ichtyosis, signs of atopy, immune deficiency and failure to thrive. The disease is severe and comprises many complications in early infancy. It is due to a genetic disorder of recessive autosomal transmission, and the gene, SPINK5, is located in the chromosome 5. Prenatal diagnosis is possible. Two of our patients had rickets, which has never been described in such patients population.

The epiphyseal plates of rachitic chicks fed a vitamin D-deficient and low-calcium diet were examined ultrastructurally at 4, 7, 14, 18 and 21 days old. On and after 14 days, changes were observed. Chondrocytes in resting, proliferating and maturing zones commonly showed a reduction in cell organelles, suggestive of a decrease in synthetic activity of matrix components. In addition, the resting zone cells had numerous intracytoplasmic microfilaments. Mitotic figures were present but not increased in number in the proliferating zone. Autolysosome-like dense bodies in the chondrocytes and clusters of degenerative and necrotic chondrocytes were observed in the proliferating and maturing zones. In the calcifying zone of the rachitic epiphyseal plate, initial calcification was observed characterized by the deposition of apatite crystals in matrix vesicles and the formation of spherical crystal clusters. The crystal clusters were separated from each other by collagen fibrils on which only small amounts of apatite crystals had been deposited. In this zone, hypertrophic chondrocytes responsible for the initial calcification were seen, but not the stellate chondrocytes responsible for the progression of matrix calcification after its initiation. These findings suggest that accumulation of the proliferating and maturing zone cells as a characteristic lesion of the epiphyseal plate in rachitic chicks is caused by a disturbance of cell maturation. Such disturbance in the calcifying zone may explain the progression of the defect in matrix calcification.

We examined the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the growth and differentiation of cultured human hair outer root sheath cells (ORSC) from normal subjects and patients with vitamin D-dependent rickets type II (DDR-II) with alopecia. 1,25(OH)2D3 dose-dependently suppressed the plating efficiency, clonal growth, and DNA synthesis of normal ORSC. It enhanced the cornified envelope formation and caused morphological changes in the cells. All results indicated the existence of specific receptors for 1,25(OH)2D3 in the ORSC, and suggest that 1,25(OH)2D3 is a potent inhibitor of proliferation of ORSC as well as a stimulator of terminal differentiation. However, the cells from DDR-II patients with alopecia did not respond to 1,25(OH)2D3, suggesting a lack of the specific receptors in the cells. The differences in the cellular response to the hormone between the normal ORSC and those from the patients were apparent and easily distinguishable, therefore this experiment may be a rapid and simple diagnostic test for DDR-II patients with alopecia. Large number of hairs were difficult to obtain from patients with alopecia, and we developed a new culture method to accomplish these studies from a few plucked hair follicles. Our system may be useful in the culture of ORSC from limited number of follicles, and could be utilized to analyse the cellular characteristics of ORSC in patients with hair diseases.

Calcifying matrix vesicles (MVs) are released from chondrocytes and osteoblasts in monolayer culture. In the present studies, we tested the ability of rachitic versus normal rat growth plate chondrocytes in micromass or monolayer primary cultures to produce MVs. Unlike earlier reports of in vitro MV biogenesis by chicken chondrocytes in which most MVs were released into the medium, we found that most of the released rat matrix vesicles were entrapped in a newly formed cartilaginous matrix enveloping the cells. These matrix-associated MVs could be isolated by mild collagenase treatment and concentrated by differential centrifugation. Vesicle production slowed in the older 2- to 4-week-old cultures and, unlike vesicle release from cultured chicken chondrocytes, active vesicle production did not show a second burst of activity at 3 to 4 weeks. Alkaline phosphatase (ALP) activity diminished with time in culture in cells and matrix vesicles, suggesting a decrease in differentiative expression. Protein profiles on SDS polyacrylamide gels of native matrix vesicles and culture-derived MVs from rachitic and normal cells were quite similar and showed a typical simplified protein pattern as compared to chondrocyte plasma membrane proteins. There were distinctive proteins migrating at 130, 80 to 95, 66, 43, 20, and 14 kd. Culture-derived MVs showed vigorous in vitro calcifying activity that was ALP related. We conclude that 1) rachitic chondrocytes are essentially normal in their matrix vesicle production; 2) matrix entrapment of MVs is a characteristic of rat chondrocyte cultures; and 3) culture-produced MVs are similar to native MVs in protein profile and calcifiability, and thus can be studied as a model for normal MV composition and calcification.

This study involved comparison of the distribution and integrity of perforating epiphyseal and marrow vessels with the stage of development and integrity of chondrocytes and the distribution of insoluble calcium in the proximal tibial growth plate of 3-week-old vitamin-D3-deficient hypocalcemic chicks and 3-week-old D3-deficient chicks 12, 36, 72, and 120 hours after an oral dose of 10,000 units vitamin D3. The aim was to clarify the mechanisms responsible for chondrocyte hypertrophy and cartilage calcification in the avian growth plate. Within 12 hours after administration of vitamin D3, serum calcium levels rose to normocalcemic levels. The following morphologic changes were first recognizable at the times indicated. Distal portions of previously elongated perforating epiphyseal vessels and adjacent proliferative and maturing chondrocytes underwent necrosis by 12 hours. Chondrocyte necrosis was not preceded by hypertrophy. By 36 hours, vascular and chondrocyte necrosis involved large portions of the thickened proliferating and maturing zone, and perforating epiphyseal vessels were shortened to a normal length. By 72 hours, chondrocyte hypertrophy and calcification resumed around the shortened epiphyseal vessels. By 120 hours, marrow had removed the necrotic cartilage, and morphologically normal growth plate was restored, with perforating epiphyseal and marrow vessels, both ending in a narrow hypertropic cartilage zone. The results indicate that proximity of chondrocytes to perforating epiphyseal vessels is necessary for their viability, but loss of these vessels does not cause hypertrophy. Since hypertrophy and calcification both occur in the proximity of perforating epiphyseal vessels in normocalcemic animals but not in hypocalcemic animals, it is likely that the vessels influence hypertrophy and calcification by delivering calcium to chondrocytes.

Growth plate morphometry and measurements of serum chemistry were correlated to clarify the pathogenesis of hypocalcemic and hypophosphatemic avian rickets. Accumulation of proliferating and maturing cartilage in hypocalcemic chicks is accompanied by increased length and increased variation in length of perforating epiphyseal vessels, decreased number and abnormal arrangement of marrow spaces, an increased proportion of cells to blood vessels in marrow spaces, and a change in the distribution but not the total number of DNA-synthesizing chondrocytes per unit width of growth plate. Accumulation of hypertrophic cartilage in hypophosphatemic rickets is accompanied by no change in length, distribution, or number of perforating epiphyseal vessels, elongation but no change in number or arrangement of marrow spaces, an increase in the relative proportion of blood vessels to cells in the marrow spaces, and no change in distribution but a decrease in total number of DNA-synthesizing chondrocytes per unit width of growth plate. Both types of rickets have decreased amounts of calcified cartilage. These results provide further evidence that hypocalcemia and hypophosphatemia cause morphologically distinct types of rickets in birds. The data indicate that the thickness of the proliferating and maturing region and hence the distance of the hypertrophic zones from the epiphysis are anatomically and temporally related to length of perforating epiphyseal vessels and serum calcium levels. They indicate that in hypocalcemic rickets accumulation of proliferating and maturing cartilage is unlikely to be the result of increased chondrocyte replication and that the relative rates of chondrocyte hypertrophy and resorption of hypertrophic cartilage by marrow are equal. They support the concept that delayed chondrocyte hypertrophy is the major cause of growth plate thickening in hypocalcemic rickets. Data presented in this study, when considered together with data from the literature on hypophosphatemic rickets, support the long-held concept that growth plate thickening in this disease is caused primarily by a decreased rate of resorption of hypertrophic cartilage by marrow relative to the rates of chondrocyte proliferation, maturation, and hypertrophy. The data further support the concepts that growth of cartilage into marrow is a biphasic process including longitudinal growth effected mainly by blood vessels, and resorption of the lateral walls of marrow spaces effected mainly by marrow cells, and that it is the latter phase that is defective in hypophosphatemia.

The processes of growth and remodeling that characterize growing bone are vulnerable to the biochemical effects of uremia. These processes are affected by the alterations in vitamin D metabolism and hyperparathyroidism that commonly occur with chronic renal insufficiency. Uremia interferes with cartilaginous developments as well. These changes, which are similar radiographically to vitamin-D-deficiency rickets, differ in their basic histological and biochemical evolution. They account for growth failure and deformity of long bones, which contribute to the short stature of children with renal insufficiency.