The most severe case of multiple osteochondromas in paleopathological record is from an Early Medieval burial site in the Venetian Lagoon

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The most severe case of multiple osteochondromas in paleopathological record is from an Early Medieval burial site in the Venetian Lagoon

https://doi.org/10.21203/rs.3.rs-4192117/v1

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In recent years, paleopathological cases from ancient contexts are being increasingly taken into account to reconstruct the clinical history of a number of diseases, in particular congenital ones, at times still featuring in the genes of present-day populations. The skeleton of a male (T97) with an estimated age-at-death of 40–45 years has been found in the Early Medieval phase of an archaeological site in the Venetian Lagoon (north-east Italy). Through the osteoarchaeological study, full skeletal CT, histopathological examination, and comparison with other case studies a diagnosis was made. It is now possible to provide a detailed evaluation of the most severe case of multiple osteochondromas (MO) ever to be documented by paleopathology. T97 currently appears to be the most severe case of MO ever to be attested from archaeological context.

No skeletal remains documented so far, either in Italy or abroad, have revealed such a high number of osteochondromas and chondrosarcomas, i.e. malignant mutations. Moreover, the individual in question appears to have developed all the characteristic features of the pathology, resulting in a unicum in the international landscape. The present case of multiple osteochondroma is useful in understanding the natural clinical dynamics of this disease, providing for the first time a CT scan of a complete skeleton affected, as well as the survival of an individual with severe disabilities in a Medieval context.

Paleopathology

Congenital disease

Chondrosarcoma

Disability

Middle Age

Italy

Examples of multiple osteochondromas from archaeological contexts have been the subject of a recent publication (Murphy and McKenzie 2010) that lists all cases published up to 2010 and lays the grounds for the relative terminology to be used in the field of osteoarcheology. Following World Health Organization guidelines, in fact, the exact definition for the disorder discussed in this paper is multiple osteochondroma (MO; Bovée and Hogendoorn 2002). Another review on the topic of MO, as yet unpublished, is currently under way (Varotto et al. in review).

Multiple osteochondromas, also known as exostoses, is a rare, a genetically-based pathology of the growth cartilage with autosomal dominant transmission, resulting from pathogenic variants of the EXT1 and EXT2 genes (Wuyts and Van Hul 2000; Zak et al. 2002) and characterized by the appearance of bony outgrowths covered in cartilaginous tissue that develop near joints. Its occurrence, as reported in medical literature, is approximately 1:50,000, appearing to be higher in males (1.5:1) (Bovée 2008; Kivioja et al. 2000).

The finding of a single exostosis, or solitary exostosis, is not uncommon in the general population; it is estimated that 1–2% of patients who undergo radiographic investigation present a solitary exostosis (Alabdullrahman and Byerly 2023). Solitary exostosis is approximately six times more frequent than the multiple form and is not a genetically based condition. The presence of two or more exostoses, on the other hand, characterizes MO. Large case series have shown a tendency for the disease to develop in a more severe form in the presence of mutations in the EXT1 gene and in the male sex (Pedrini et al. 2011).

In MO, exostoses generally develop in the first ten years of life, increasing in number and size until the individual reaches skeletal maturity. The first exostoses generally appear in childhood and are rarely present at birth. The clinical expression of the pathology (number, size, location of exostoses) varies from individual to individual, even within the same family.

A study on the natural history of the disease in an Italian case series of 158 paediatric patients suggests that the presence of a greater number of exostoses indicates the evolution of the disease manifested by more severe clinical expressions (Mordenti et al. 2020).

As bony outgrowths covered by a cartilaginous cap, exostoses can be pedunculated or sessile (with a wide implant base) and may vary in size (Bovée 2008). The most frequently affected areas are the long bone extremities, especially the knee, although exostoses can be located in all bones of the skeleton with the exception of the skull.

Exostoses can lead to skeletal deviations or deformities, particularly in the forearm (Madelung-like appearance with shortening of the ulna and bending of the radius; Mordenti et al. 2020) (39–60%), limb length asymmetry (10–50%), valgus or varus knee (8–33%).

Patients with MO generally present a shorter height than general population average; siblings are unaffected. Severe complications can arise from the malignant transformation of an exostosis. The exact incidence of malignant transformation is not well defined (estimated at approximately 0.5-2% of cases; 5–7% in other works) but seems to generally manifest itself in adulthood (Fei et al. 2018). The present paper details the results of the anthropological, paleopathological, radiological and histological analyses carried out on the skeletal remains of an individual (T97) documented in an Early Medieval context. Assessment of the pathognomonic features of T97 with those observed in individuals from other archaeological sites confirmed that the specimen in question constitutes the most severe case of MO ever to be documented in the current global paleopathological record.

Archaeological fieldwork at the site of Jesolo (ancient Equilo; Venice, Italy; GD 45.54544647909237, 12.638599767221457; Fig. 1A) first began in 2011 under the direction of the “Ca’ Foscari” University of Venice (Gelichi et al. 2018). The investigated area is located to the north-east of the modern settlement. Within the ancient settlement of Equilo, and up until the early 20th century, the remains of the cathedral of Santa Maria Assunta, which once formed an imposing structure, were still visible.

Several excavations have been conducted in the past, particularly in the area around the cathedral. These revealed traces of two earlier buildings, one dating back to the 5th century and the other, a three-aisled church with mosaic floors, in all probability to the 6th century.

A series of trenches were excavated not far from the cathedral. From these, a 4th century phase emerged, linked to the presence of a mansio (i.e. a posthouse). Following its destruction, later phases refer to a change in use of the site, repurposed as a burial ground.

In 2018, fieldwork was carried out further north in an area known as San Mauro, where the remains of a three-aisled church had been first documented in 1954. These activities led to the unearthing of the church remains and started to investigate a cemetery area partly referable to the three-aisled structure (Fig. 1B). Traces of an older, single-aisle church with a narthex and side portico were brought to light (8th -9th c. CE) during these excavations. The vast majority of the graves identified so far are associated with this earlier building.

In addition to the archaeological fieldwork conducted in the area, general topographical data was also acquired. Through methods such as geo-resistivity, geoarchaeological analysis and drone surveys, it was possible to reconstruct, with a reasonable degree of accuracy, the ecological landscape in which the ancient settlement of Equilo, situated in an inland lagoon at the mouth of the Old Piave River and spreading across a series of islets intersected by canals, developed over the course the early Middle Ages. During research in the San Mauro area, especial attention was given to the burial area located both inside and around the ecclesiastical buildings. The aim was to conduct a detailed analyses of a significant population sample related to a community between the 8th and 12th century (corresponding to the currently established cemetery time-period). Burial chronology was inferred from radiocarbon dating. In addition to radiocarbon dating, the investigation of the cemetery phases and their correlation with the two structures and adjacent areas made it possible to divide the burial samples into two macro-phases: the Early Medieval and the Late Medieval.

3.1 Case study T97

Currently, 136 burials in the form of plain pits, the majority featuring single inhumations, have been documented at the site of San Mauro.

Several radiocarbon dates were performed on skeletal remains from this context. Based on the absolute chronologies and stratigraphic sequence, it was possible to include all the excavated burials in at least two chronological phases: Early (8th -10th CE) and Late Middle Ages (10th -12th CE) (Battistel et al. accepted). T97 is placed at the end of the Early Middle Ages, as the absolute dating also suggests, and can be associated with the oldest church building (Fig. 1C).

T97 contained an inhumed skeleton in primary deposition, supine and oriented in a north-south direction, the right forearm positioned over the pelvic region, the left arm parallel to the body and the lower limbs extended and converging (Fig. 2). The burial is located below the construction level of a transept wall (SU 148) pertaining to the Late Medieval church and underneath the burial of a sub-adult individual (T102).

The cranium appears in superolateral view, tilted slightly to the left. During the excavation and removal of the skeletal remains, the loss of anatomical connections between the occipital and the atlas and between the atlas and the axis was observed (see figures in supplementary materials L2). On the contrary, a good anatomical connection was noted for both sides of the body at the following joints: scapula-clavicle, right scapula-humerus, elbow, wrist, lumbar vertebrae and sacral bones, sacro-ilium, ankle and tarsal bones. Multiple osteochondromas, associated with some bone length disparities and forearm deformities were already visible at this stage.

3.2 Methods

At present, the skeletal remains of over 170 individuals have been analysed from the site of the San Mauro Monastery.

The skeleton from burial T97 appeared in an excellent state of preservation. Biological sex was established by way of pelvic morphology (Murail et al. 2005; Phenice 1969; Walker 2005). Age-at-death estimated using pubic symphysis (Brooks and Suchey 1990; Todd 1920), auricular surface morphology (Buckberry and Chamberlain 2002), ectocranial suture closure analysis (Meindl and Lovejoy 1985) and the apposition of secondary dentine in the canine (Cameriere et al. 2009). Bone measurements follow the numbering according to Martin and Saller (1959). Height was reconstructed following Raxter et al. (2006). Degree of wear (Molnar 1971), caries, abscesses and teeth calculus (Hillson 1996, 2001) were detected through macroscopic observation. Stress indicators included linear enamel hypoplasia (LEH) (Goodman and Rose 1990), cribra cranii, cribra orbitalia, osteoarthritis (Steckel et al. 2006) and periostitis (Buikstra 2019). The main features of MO frequently observed in modern-day patients, as suggested by Murphy and McKenzie (2010), were all visible in the examined specimen.

Full CT scans of the skeletal remains were performed at the Poliambulatorio Caorlese S.r.l. in Caorle, near Jesolo (Venice) (see figures in supplementary materials L29, 30, 31). 3D CT images of the most affected bones were obtained using RadiAnt, a DICOM visualization software for medical images (Fig. 3) with an intuitive interface featuring a 3D VR (volumetric rendering) tool. This makes it possible to visualize large volumes of data generated by modern CT/RM scanners in three-dimensional spaces, as well as to rotate the volume, change the zoom level and position, adjust the colour and opacity, measure the length, and ultimately reveal hidden structures by removing unwanted volume areas.

A cauliflower-like mass of bone-cartilaginous type adjacent to the left humerus and measuring circa 2.5 cm was chosen for histological analysis. The sample was prepared for decalcification, fixed and immersed for about 6–8 hours in 25 ml of Histo-Decal.

To obtain absolute dating, the sample T97 were analyzed at CEDAD, The Centre for Applied Physics, Dating and Diagnostics, Department of Mathematics and Physics “Ennio de Giorgi”, University of Salento, Lecce, Italy. Dating was done by the radiocarbon method using AMS (Accelerator Mass Spectrometry). The calibration was performed by using the OXCAL software (OxCal v 3.10, Bronk Ramsey (2005); atmospheric data from Reimer et al. (2020).

The skeletal remains from T97 belong to an adult male aged between 40–45 years (canine Rx), with a reconstructed height of 156.4 cm. All teeth were found, except for the right M¹ lost antemortem and left M₃ (agenesis) (figure in supplementary materials L2). Tooth wear is variable (from degree 1 of the left M³ to grade 6 of the left M₁). Caries (stage E) is present on the right M³, dental calculus on all teeth, abscesses on left M¹ and M₂. LEH are recorded on all four canines. Cribra cranii (grade 2) are visible but no cribra orbitalia. Periostitis is present on both femurs and leg bones. Osteoarthritis most commonly appears as marginal lipping in most of the investigated limb joints, but more severe forms were observed (Table S1), such as eburnation of part of the head of the right femur (figure in supplementary materials L13).

Considering that osteochondromas begin to form during childhood development (Buikstra 2019; Siek 2020), it was noted that out of a sample of 98 analysed skeletons (≥ 5 years), only the skeleton from burial T97 was affected by this condition (1.02%).

Multiple bilateral osteochondromas are evident on most of the bones of the appendicular skeleton while the skull, vertebrae and ribs are unaffected. The paleopathological features of the skeletal remains from burial T97 were compared with known archaeological cases of MO (Tables 1–2).

Both sessile and pedunculated osteochondromas are present in T97 (Figs. 4, 5, 7, 8). According to the IOR (Istituto Ortopedico Rizzoli) classification, which identifies three classes of patients based on the presence/absence of deformities and/or limitations, T97 can be included in the IIIB category, i.e. deformities and > 1 site with functional limitation (Mordenti et al. 2021).

Height (about 156.4 cm) falls within the female range and is about 14 cm lower than the male average (Table 3) documented in the burial area of San Mauro. It is also lower than the male average of 166.9 cm and much closer to the female average of 154.5 cm recorded in Medieval Central Italy (Giannecchini and Moggi-Cecchi 2008).

Table 3

Height data from the San Mauro Monastery sample (all measurements are in centimetres).
Sex	n	Min	Max	M	SD	T97
M	15	163.5	176.8	170.5	4.1	156.4
F	17	146.1	163.7	154.8	4.7
M + F	32	146.1	176.8	162.2	9.0

There are length differences between the right and left sides of the clavicles and long bones (Table S2), especially evident in the radius and ulna: the right radius cannot be measured as the proximal end is fragmentary but it is visibly shorter than the left radius (21.9 cm); the right ulna (14.4 cm) is shorter than the left ulna (22.7 cm). Forearm deformities are classified according to the scheme developed by Masada et al. (1989): Type I deformity (formation of primary exostosis in the distal portion of the ulna, which is relatively short compared to the radius) is evident in the right forearm, while Type III deformity (formation of primary exostosis in the metaphysis of the distal radius, resulting in a relative shortening of the radius compared to the ulna) is visible in the left forearm (Fig. 5).

Hand bone defects are evident on the right fifth metacarpal, which is shorter than its left counterpart, and on some phalanges that are larger than others. Osteochondromas are not visible in the hand bones. Only the ends of the left leg were affected by tibiofibular synostosis. Coxa valga on the proximal femurs and valgus deformity of the knee are evident. A valgus deformity of the left ankle is also clear (the subchondral surface of the distal tibial epiphysis tilts outwards in the direction of the fibula), while the right ankle was normal. Asymmetry of the pectoral girdles is present but not of the pelvic girdles (Fig. 6).

In older age groups, a malignant transformation into chondrosarcoma may develop in one or more lesions (Buikstra 2019; Kivioja et al. 2000). Although extremely rare, if the thickness of the chondral cap in vivo is greater than 15 mm, malignant transformation can occur (Klein et al. 2018). Murphy and McKenzie (2010) reported a possible example of malignant transformation of an osteochondroma in the skeletal remains of an individual documented in Stephen Street, Dublin (Coughlan 2007). A possible transformation of large sessile osteochondromas into chondrosarcomas can be observed on the femurs and left fibula of the T97 skeleton (> 15 mm). In particular, the nodular appearance and increased size is evident on the anterior and medial aspect of the right proximal femur, on the posterior and medial aspect of the left proximal femur and on the posterior aspect of the left fibula. The determination of a possible malignant transformation was attempted via histopathological examination of a single irregular cauliflower-like mass of bone-cartilaginous type measuring 2.5 cm in diameter (Fig. 8).

Recent studies have correlated MO with osteoporosis, as it appears that the abnormality of bone mineral density (BMD) also depends on an EXT1 mutation (Lemos et al. 2005), determining that the degree of reduction in bone mass differs according to anatomical location but is not correlated with age (Matsumoto et al. 2020). Osteoporosis is also documented in the present case study, certainly related to the severe stage of MO. In particular, a section of the left humerus observed in restoration (Fig. 9A,B) and the spine in a sagittal CT section show diffuse BMD in the thoracic and lumbar areas (Fig. 9C).

Table 4

Radiocarbon dating of T97.
ID samples	CEDAD code	Material	Radiocarbon Age (BP)(*)	δ¹³C (‰)	Calibrated Age CE (2 sigma)
JES_T97	LTL32267	bone	1024 ± 40	12.5 ± 0.6	897AD ( 4.8%) 921AD 954AD (69.0%) 1052AD 1077AD (21.6%) 1155AD

Several files were added to the supplementary materials: a PDF file with images of the skeleton still in situ (S), a second PDF with images of all skeletal districts arranged in the laboratory (L) and a word document was also included with the tables named in the main text (S1, S2). The complete CT scan of the skeleton is available at the link https://sendanywhe.re/8S7AWX2D.

Osteochondromas in archaeological contexts have been reported regardless of chronology and geographical location. MOs in ancient samples have been reviewed by Murphy and McKenzie (2010) to which work by Kaczmarek and Kozieradzka-Ogunmakin (2013) and Antunes-Ferreira et al. (2014) should be added. Single lesions appear to be the most frequently reported (Arnay-de-la-Rosa et al. 2015; Bennike 1985; Buzon 2005; Čavka et al. 2022; Chamberlain et al. 1992; Gregg and Gregg 1987; Isidro et al. 2017; Ismail et al. 2008; Nicosia et al. 2016; Ortner 2003; Riccomi et al. 2023; Roberts 1985; Rowling 1961; Slaus et al. 2000; Varotto et al. 2021; Vyhnánek et al. 1999; Zapata and Alcaraz 2007).

Evidence of single osteochondromas (Nicosia et al. 2016; Varotto et al. 2021) from Italian archaeological contexts is scarce and no cases of multiple osteochondromas are currently known. Moreover, MO is an incredibly rare example in the entire international palaeopathological record, with just 19 cases known from prehistoric to modern times worldwide.

The case of MO presented in this study is not only the first in Italy, but maybe the one with the most severe paleopathological expression globally, including degeneration into a malignant form (chondrosarcoma) of which a single example can be found in the archaeological record (Coughlan 2007) and comparable only to rare clinical cases today (Chilvers et al. 2021; Ha et al. 2022).

This rareness is simply due to the low prevalence of this genetic disorder as reported in medical literature (1:50,000). Furthermore, in few cases do individuals with MO also develop malignant complications that manifest themselves as chondrosarcoma formations.

The skeleton from T97 was a male of approximately 40 years of age who presented all the characteristic signs of MO, including obvious physical deformities. Consequently, throughout his life he most likely suffered from painful states caused by compression of osteochondromas affecting muscles, tendons and nerves, causing sensory deficits and motor limitations of certain joints, i.e. that of the right forearm, as well as probable walking problems (eburnation of the femoral head). Today, according to the medical literature, a patient suffering from MO is basically unable to practice a sport and in many cases has difficulties to the point of requiring workplace adaptation (Beltrami et al. 2016). In an Early Medieval context such as that of the Venetian Lagoon, the physical activities he would have had to perform went far beyond those of today’s sports practice, heavily impacting his daily life. It is also possible to speculate that the proliferation of the malignant form may have been the cause of death.

According to traditional stereotypes, in the Middle Ages, disabilities, especially congenital ones with physical deformities, were subject to a whole host of superstitious ideas (Metzler 2015), yet individuals with disabilities were a highly visible presence in society. People could be born with a disability, be disabled by diseases such as leprosy or incapacitated by years of backbreaking work. In the present case, it is not possible to know how T97’s impairment was actually perceived, but from a social point of view, if the treatment he received after death is indicative, namely the type of burial and its location in the heart of the burial area, it is reasonable to assume that the man was a fully integrated member of the community to which he belonged. One can therefore imagine that the acceptance and support of this human group ensured his good health and survival well into adulthood (Metzler 2015).

The present case study offers the opportunity to acquire a deeper understanding of this pathology in antiquity, establish the social acceptance of an impairing condition involving a physical deformity and show the extent the pathological expression of MO can reach in the absence of medical-surgical treatment. Furthermore, as the disease recognizes autosomal dominant transmission (i.e. the child of an affected individual will have a 50% chance of contracting the disease in turn) (Wuyts et al. 1993; Wuyts and Van Hul 2000), continued investigation of this burial area could lead to the discovery of other individuals with MO.

Acknowledgments

We would like to thank Alexander Agostini for help with the English translation of the manuscript. We also thank the Poliambulatorio Caorlese S.r.l. (Caorle, Venice) for performing the CT scan of the complete skeleton (www.poliambulatoriocaorlese.it), the Lifebrain Pignatelli Lecce S.r.l. laboratory for the histological analysis (www.cerbahealtcare.it) and the Studio Dentistico Danese-Mazzotta (Lecce) for the CT scan of the mandible.

Author Contributions

Work concept: S.V. and N.L. Excavation and finding data: L.B. and S.V. Archaeological context data: S.G. and S.C. Anthropological and paleopathological analysis: N.L., S.V. and L.B. Supervision: S.G. Manuscript drafting with co-author input: S.V., N.L. and L.B.

Disclosure Statement

No potential conflict of interest has been reported by the authors.

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Table 1 and 2 are available in the Supplementary Files section.

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The most severe case of multiple osteochondromas in paleopathological record is from an Early Medieval burial site in the Venetian Lagoon

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1. Introduction

2. The Archaeological Context

3. Materials and methods

3.1 Case study T97

3.2 Methods

4. Results

5. Discussion and conclusion

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References

Table 1 and 2

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