Unveiling Charles II, the last King of the Habsburg Spanish Empire, in a portrait by Juan Carreño de Miranda (1685).

PURPOSE: Charles II (1661-1700) was the last King of the Habsburg dynasty. He was physically and mentally disabled and died at just 39 years old. Here, the authors attempt to investigate the correlations between his signs and symptoms and the physical appearance on the painting. METHODS: Charles II has been portraited by Juan Carreño de Miranda in a painting that may provide precious information about his premature death. RESULTS: It has been suggested that inbreeding beside other endocrinological disorders were of the major causes responsible for illness and ultimately his death. CONCLUSION: Possible endocrinological diseases have been hypothesized.

Child development, physiological stress and survival expectancy in prehistoric fisher-hunter-gatherers from the Jabuticabeira II shell mound, South Coast of Brazil.

In this study, we shed light on the interdependency of child growth, morbidity and life expectancy in the fisher-hunter-gatherers of the Jabuticabeira II shell mound (1214-830 cal B.C.E. - 118-413 cal C.E.) located at the South Coast of Brazil. We test the underlying causes of heterogeneity in frailty and selective mortality in a population that inhabits a plentiful environment in sedentary settlements. We reconstruct osteobiographies of 41 individuals (23 adults and 18 subadults) using 8 variables, including age-at-death, stature, non-specific stress markers (cribra orbitalia, porotic hyperostosis, periosteal reactions, periapical lesions and linear enamel hypoplasia), as well as weaning patterns based on stable isotope data to examine how stress factors module growth and survival. Our results show that shorter adult statures were linked to higher morbidity around weaning age and higher chances of dying earlier (before 35 years) than taller adult statures. In addition, short juvenile stature was related to physiological stressors and mortality. The adult "survivors" experienced recurrent periods of morbidity during childhood and adulthood, possibly associated with the high parasite load of the ecosystem and dense settlement rather than to malnourishment. An association between early-stress exposure and premature death was not demonstrated in our sample. To explain our data, we propose a new model called "intermittent stress of low lethality". According to this model, individuals are exposed to recurrent stress during the juvenile and adult stages of life, and, nevertheless survive until reproductive age or later with relative success.

From dwarves to giants: South American's contribution to the history of growth hormone and related disorders.

The aim of this article is to present a historical review on giants and dwarves living in South America and the contribution of South America's researchers to scientific advances on growth hormone (GH) and human disorders related to GH excess and GH deficiency (GHD). We went back in time to investigate facts and myths stemming from countless reports of giants who lived in the Patagonia region, focusing on what is currently known about gigantism in South America. Additionally, we have reviewed the exceptional work carried out in two of the world's largest cohorts of dwarfism related to GH-IGF axis: one living in Itabaianinha, Brazil, suffering from severe GHD due to a mutation in the GHRH receptor (GHRHR) gene, and the other living in El Oro and Loja provinces of Ecuador, who are carriers of GH receptor gene mutation that causes total GH insensitivity (Laron syndrome). Importantly, we present an overview of the outstanding medical contribution of Jose Dantas de Souza Leite, a Brazilian physician that described the first cases of acromegaly, and Bernardo Alberto Houssay, an Argentine researcher graced with the Nobel Prize, who was one the first scientists to establish a link between GH and glucose metabolism.

Two cases of skeletal dysplasia from New Kingdom (c. 1400-1050 BCE) Tombos, Sudan.

OBJECTIVE: This project investigates two cases of skeletal dysplasia from archaeological excavations of the New Kingdom Period (c. 1400-1050 BCE) portion of the Tombos cemetery in Sudan. MATERIALS: Fair to well-preserved skeletal remains of two individuals, one adult and one juvenile, are examined here. METHODS: All available skeletal elements were analyzed macroscopically. A differential diagnosis was conducted for each individual. RESULTS: The adult individual, U36.Sh2.B10, displays bilateral mesomelic dysplasia and Madelung's deformity. The juvenile individual, U36.Sh2.B5, also displays bilateral mesomelic dysplasia and characteristics associated with Madelung's deformity. CONCLUSIONS: A differential diagnosis of Léri-Weill dyschondrosteosis (LWD) is suggested for the adult female individual (U36.Sh2.B10). The second case (U36.Sh2.B5) is an approximately three to five-year-old individual and is difficult to diagnose given the young age; however, LWD remains the most likely diagnosis. SIGNIFICANCE: There are few cases of LWD in the paleopathological literature, and fewer still of juveniles. The cases described are useful examples in expanding research demonstrating the variability in the expression of skeletal dysplasias in juveniles and adults. LIMITATIONS: Taphonomic alterations and fragmentation of the crania and portions of the postcrania limited the observation of the full suite of characteristics associated with skeletal dysplasias. U36.Sh2.B5 is difficult to diagnose given the individual's young age and the possibility that this individual had not yet developed the more observable characteristics associated with these conditions. SUGGESTIONS FOR FURTHER RESEARCH: Researchers are encouraged to continue examining the range of expression of skeletal dysplasias in juveniles and adults.

Weight and height growth of malnourished school-age children during re-feeding. Three historic studies published shortly after World War I.

BACKGROUND: In view of the ongoing debate on "chronic malnutrition" and the concept of "stunting" as "a better measure than underweight of the cumulative effects of undernutrition and infection (WHO)", we translate, briefly comment and re-publish three seminal historic papers on catch-up growth following re-feeding after severe food restriction of German children during and after World War I. The observations were published in 1920 and 1922, and appear to be of particular interest to the modern nutritionist. RESULTS: The papers of Abderhalden (1920) and Bloch (1920) describe German children of all social strata who were born shortly before World War I, and raised in apparently "normal" families. After severe long-standing undernutrition, they participated in an international charity program. They experienced exceptional catch-up growth in height of 3-5 cm within 6-8 weeks. Goldstein (1922) observed 512 orphans and children from underprivileged families. Goldstein described very different growth patterns. These children were much shorter (mean height between -2.0 and -2.8 SDS, modern WHO reference). They mostly failed to catch-up in height, but tended to excessively increase in weight particularly during adolescence. CONCLUSION: Whereas Abderhalden and Bloch illustrate rapid height catch-up in children from intact social background, Goldstein's observations in orphans and children from poor social background parallel the growth patterns observed in children of modern middle and low-income countries. The historic observations question the current concept of stunting as prima facie evidence of malnutrition and chronic infection, and support the view that "the child's longitudinal growth is largely independent of the extent and nature of the diet".

Endochondral growth disruption during vitamin D deficiency rickets in a mid-19th century series from Bethnal Green, London, UK.

OBJECTIVES: Vitamin D affects many aspects of cartilage and skeletal development. Inconsistent findings currently exist regarding the impact of vitamin D deficiency on childhood growth. This study aims to evaluate the impact of vitamin D deficiency on childhood skeletal development by exploring long bone growth in children with healed and active rickets. MATERIALS AND METHODS: Forty-four known-age children (2 months to 12 years) with rickets and 99 without rickets were compared with modern reference data from North America. Diaphyseal lengths of children with active rickets (34.1%, 15/44), healed rickets (65.9%, 29/44), and without rickets (99/143, 69.2%) were expressed as a percentage of expected length and an average percentage value was calculated across all available long bones. RESULTS: Combined data for all six long bones revealed that children with active rickets had achieved only 75.3% of their expected size whereas, on average, children with healed rickets had achieved 81.6% of their expected size. On average, children without skeletal evidence of rickets had achieved 83.7% of their expected size. Children with severe skeletal manifestations of active rickets had a lower average percentage of expected size (70.4%) than the remainder of children affected by the condition. DISCUSSION: Pronounced growth faltering existed in children with active rickets and affected the upper and lower limb, indicating systemic growth failures during the deficiency. Poor maternal health, early weaning and inadequate infant feeding, and lack of sunlight exposure likely contributed to the development of rickets. Complex interactions between pathological conditions, nutritional deficiencies and vitamin D deficiency may have exacerbated growth impacts.

Stunting, starvation and refeeding: a review of forgotten 19th and early 20th century literature.

AIM: To scrutinize to what extent modern ideas about nutrition effects on growth are supported by historic observations in European populations. METHOD: We reviewed 19th and early 20th century paediatric journals in the Staatsbibliothek zu Berlin, the third largest European library with an almost complete collection of the German medical literature. During a three-day visit, we inspected 15 bookshelf meters of literature not available in electronic format. RESULTS: Late 19th and early 20th century breastfed European infants and children, independent of social strata, grew far below World Health Organisation (WHO) standards and 15-30% of adequately-fed children would be classified as stunted by the WHO standards. Historic sources indicate that growth in height is largely independent of the extent and nature of the diet. Height catch-up after starvation was greater than catch-up reported in modern nutrition intervention studies, and allowed for unimpaired adult height. CONCLUSION: Historical studies are indispensable to understand why stunting does not equate with undernutrition and why modern diet interventions frequently fail to prevent stunting. Appropriateness and effect size of modern nutrition interventions on growth need revision.

Overlapping genetic pathways in the skeletal dysplasias of a middle woodland individual: A case study.

Studies of interacting/overlapping genetic skeletal disorders are rare for populations today, but even more so for archaeological contexts. The skeletal remains of an adult female (EZ 3-7-1) were excavated in the 1980s from the Middle Woodland (50BC-AD400) context of the Elizabeth site (11PK512) in the lower Illinois Valley (LIV), USA. Reported here are the standard score (z-score) comparisons of the measured skeletal differences of EZ 3-7-1 with a reference sample and a re-analysis of the individual's pathological changes, with special consideration placed on refining the disease diagnosis. The impressive preservation and meticulous recovery of these skeletal remains have provided the opportunity to identify the first and earliest archaeological example of an individual (EZ 3-7-1) with a combined genetic skeletal dysplasia, Leri-Weill dyschondrosteosis and achondroplasia.

The History of Growth Hormone Treatment for GHD in Japan.

In Japan, treatment of growth hormone deficiency with pituitary-extracted human growth hormone (phGH) was covered by health insurance for the first time in 1975. However, because of the shortage of phGH, the Foundation for Growth Science (FGS) was founded in 1977 to control the use of the product by its registration system and to collect pituitary glands in Japan. In 1986, recombinant human growth hormone was first approved. Since then, the FGS has been involved in the harmonization of growth hormone measurement, assessment for treatment eligibility according to the diagnostic criteria by the research group of the Ministry of Health and Welfare, and database generation and its utilization.

Artistic representations of short stature, a tentative diagnosis.

Throughout human history, disease-related short stature has represented a source of fascination. Following the recent advances in genetics and molecular biology, several hundreds of possible causes are now to be considered. We present herein a few examples of the diagnosis approach of such cases from art sources (sculptures, paintings or photographs for the most recent periods), associated or not with biographical data, allowing semiological and anthropological analyses. The explored period spans from antic great civilizations to 19th Century Western societies. The palaeopathological diagnosis method is based upon medical approach. It includes a search for possible associated abnormalities and the distinction between proportioned, mainly related to hormonal disorders (particularly growth hormone deficiency), and non-proportioned cases especially associated with genetic skeletal dysplasias. Among this latter category, achondroplasia is the most represented cause of short stature. Other more exceptional etiologies are also reported.

History of zinc in agriculture.

Zinc was established as essential for green plants in 1926 and for mammals in 1934. However, >20 y would pass before the first descriptions of zinc deficiencies in farm animals appeared. In 1955, it was reported that zinc supplementation would cure parakeratosis in swine. In 1958, it was reported that zinc deficiency induced poor growth, leg abnormalities, poor feathering, and parakeratosis in chicks. In the 1960s, zinc supplementation was found to alleviate parakeratosis in grazing cattle and sheep. Within 35 y, it was established that nearly one half of the soils in the world may be zinc deficient, causing decreased plant zinc content and production that can be prevented by zinc fertilization. In many of these areas, zinc deficiency is prevented in grazing livestock by zinc fertilization of pastures or by providing salt licks. For livestock under more defined conditions, such as poultry, swine, and dairy and finishing cattle, feeds are easily supplemented with zinc salts to prevent deficiency. Today, the causes and consequences of zinc deficiency and methods and effects of overcoming the deficiency are well established for agriculture. The history of zinc in agriculture is an outstanding demonstration of the translation of research into practical application.

Growth hormone treatment in Japan: past, present, and future.

Growth hormone (GH) treatment was approved for growth hormone deficiency (GHD) in Japan in 1975. Since then, GH treatment has been approved for treating five other diseases with short stature. However, available data on adult height after long-term GH treatment is limited to patients with GHD and Turner syndrome. Although adult height of patients with GHD has improved with early diagnosis and early initiation of treatment, the adult height after long-term GH treatment is still not so satisfactory because the therapeutic dose used in Japan is smaller than that used in US and Europe. With early diagnosis, early high-dose treatment, and low-dose estrogen replacement therapy, both adult height and quality of life (QOL) of the patients with Turner syndrome have been improved.

History of growth hormone therapy.

The first human to receive GH therapy was in 1956; it was of bovine origin and was given for 3 wk for metabolic balance studies revealing no effects. By 1958, three separate laboratories utilizing different extraction methods retrieved hGH from human pituitaries, purified it and used for clinical investigation. By 1959 presumed GHD patients were being given native hGH collected and extracted by various methods. Since 1 mg of hGH was needed to treat one patient per day, >360 human pituitaries were needed per patient per year. Thus, the availability of hGH was limited and was awarded on the basis of clinical research protocols approved by the National Pituitary Agency (NPA) established in 1961. hGH was dispensed and injected on a milligram weight basis with varied concentrations between batches from 0.5 units/mg to 2.0 units/mg of hGH. By 1977 a centralized laboratory was established to extract all human pituitaries in the US, this markedly improved the yield of hGH obtained and most remarkably, hGH of this laboratory was never associated with Creutzfeld-Jacob disease (CJD) resulting from the injection of apparently prior- contaminated hGH produced years earlier. However, widespread rhGH use was not possible even if a pituitary from each autopsy performed in the US was collected, this would only permit therapy for about 4,000 patients. Thus, the mass production of rhGH required the identification of the gene structure of the hormone, methodology that began in 1976 to make insulin by recombinant technology. Serendipity was manifest in 1985 when patients who had received hGH years previously were reported to have died of CJD. This led to the discontinuation of the distribution and use of hGH, at a time when a synthetic rhGH became available for clinical use. The creation of a synthetic rhGH was accompanied by unlimited supplies of hGH for investigation and therapy. However, the appropriate use and the potential abuse of this hormone are to be dealt with. The illegitimate use of rhGH, unequivocally the abuse by athletes is, and should be, of primary concern to society and should be halted. The abuse of prescribing rhGH in an attempt to retard the aging process also should receive attention.

Physical growth and development of the malnourished child: contributions from 50 years of research at INCAP.

This paper reviews the main findings and policy implications of 50 years (1949-1999) of research conducted by INCAP on growth and development. Topical areas reviewed include a) maternal size and birthweight and the causes of intrauterine growth retardation (IUGR), b) patterns and causes of postnatal growth retardation, c) the relative importance of genetics and the environment in explaining differences in growth among populations, d) the implications of being small, for both children and adults, e) bone growth and maturation and dental development, f) menarche, and g) methodological contributions such as anthropometric reference data, quality control of data collection, development of risk indicators and use of anthropometry in nutrition surveillance systems. Key contributions to knowledge by INCAP include a) characterization of growth failure and maturational delays as mainly occurring during the intrauterine period and the first 3 years of life b) clarification of the role of small maternal size and of inadequate dietary intakes during pregnancy as major causes of intrauterine growth failure, c) evidence that diarrheal diseases and poor dietary intakes are the principal causes of growth failure in early childhood, d) demonstration that environmental factors related to poverty, and not genetic or racial ancestry, account for most of the differences in growth between populations, e) evidence that growth failure predicts functional impairment in the child as well as in the adult andf) demonstration that nutrition interventions are effective in preventing growth failure and its consequences, if targeted to needy women and young children. INCAP's work has contributed knowledge that has informed and improved policies and programs aimed at overcoming maternal and child undernutrition and promoting optimal growth and development.

Growth hormone: the expansion of available products and indications.

Growth hormone is a widely used hormone. This article describes its historical use, current indications and studies for possible future uses.

Vitamin a deficiency and clinical disease: an historical overview.

Vitamin A deficiency has a plethora of clinical manifestations, ranging from xerophthalmia (practically pathognomonic) to disturbances in growth and susceptibility to severe infection (far more protean). Like other classical vitamin deficiency states (scurvy, rickets), some of the signs and symptoms of xerophthalmia were recognized long ago. Reports related to vitamin A and/or manifestations of deficiency might conveniently be divided into "ancient" accounts; eighteenth to nineteenth century clinical descriptions (and their purported etiologic associations); early twentieth century laboratory animal experiments and clinical and epidemiologic observations that identified the existence of this unique nutrient and manifestations of its deficiency; and, most recently, a flowering of carefully conducted clinical studies and field-based randomized trials that documented the full extent and impact of deficiency among the poor of low- and middle-income countries, which in turn changed global health policy.