International Journal of Paleopathology 26 (2019) 8–13

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International Journal of Paleopathology

journal homepage: www.elsevier.com/locate/ijpp

A probable case of infantile cortical hyperostosis in 2nd–4th centuries AD T

Romania
⁎
Ioana Rusua,b, , Claudia Radua,c, Ovidiu Țentead, Octavian Popescua,b,e, Beatrice Kelemena,b
a
Molecular Biology Center, Interdisciplinary Research Institute on Bio-Nano-Sciences, Babeș-Bolyai University, 400271, Cluj-Napoca, Romania
b
Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babeș-Bolyai University, 400006, Cluj-Napoca, Romania
c
Department of Ancient History and Archaeology, Faculty of History and Philosophy, Babeș-Bolyai University, 400084, Cluj-Napoca, Romania
d
Department of Archaeology, National Museum of Romanian History, 030026, Bucharest, Romania
e
Institute of Biology Bucharest, Romanian Academy, 060031, Bucharest, Romania

A R T I C LE I N FO A B S T R A C T

Keywords: Objective: This study aims to discuss the differential diagnosis for the pathological alterations displayed on an
Roman period infant skeleton from Romania.
Periosteal reaction Materials: One infant skeleton retrieved form the bathhouse of an abandoned Roman fort and dated between the
Stable isotopes 2nd and the 4th centuries AD.
Mitochondrial DNA
Methods: All available skeletal elements were analyzed macroscopically. In addition, the isotopic signatures
(δ13C and δ15N) and the control region of the human mitochondrial genome for this archaeological sample were
analyzed.
Results: Based on dental development and long bone length, the skeleton was aged between birth and 2 months
of age. Pathological lesions were noted on the mandible and diaphyses of long bones, but spared the metaphyses.
Conclusions: The perinatal age of the individual, along with lesion morphology and location, suggests a diagnosis
of infantile cortical hyperostosis.
Limitations: The analysis would benefit from further stable isotope and mitochondrial genome analyses, which
was limited due to the absence of comparative human and faunal remains from the site.
Suggestions for further research: Further multidisciplinary research on human archaeological remains from
Romania would provide a clearer image of past disease and life histories in this geographic area.

1. Introduction the disease even in clinical settings. Moreover, affected individuals

The study of childhood paleopathology is challenging due to specific
attributes of pediatric bone and processes of growth and development
(Lewis, 2007, 2011a). The last decade has witnessed an increased in-
terest in documenting diseases in subadult skeletal assemblages, leading
to a better understanding of their epidemiology within particular
chronological periods (Lewis, 2010, 2011a; Gowland and Western,
2012). One of the most well documented timeframes is the Roman
period. Scurvy, rickets, acquired and genetic anemia, and tuberculosis
are some of the pathological conditions widely documented in Roman
era subadult skeletal material (Lewis and Gowland, 2009; Lewis, 2012,
2010; Lewis, 2011b). However, infantile cortical hyperostosis (ICH), or
Caffey’s disease, is a collagen-related disorder that has rarely been
identified in archaeological specimens, owing to the precarious pre-
servation of subadult skeletal tissue and to the challenges of diagnosing
usually recover from the disease, leaving few remnants of the condition
in the skeletal record (Lewis and Gowland, 2009). Rogers and Waldron
(1988) report two infants from two cemeteries, dated in the Romano-
British and Saxon/Medieval periods. The skeletons, with an age at
death of 10–18 months and 12 months, respectively, displayed gen-
eralized periosteal reactions affecting the cranial and post-cranial
bones, considered by the authors to indicate the presence of ICH.
Bourbou (2010) also describes a probable case of ICH from Byzantine
Crete in a child aged 7.5–8.5 years displaying periosteal lesions on the
skull, axial, and appendicular skeleton. In a more detailed paper, Lewis
and Gowland (2009) document three possible cases of ICH from Roman
Britain, with differential diagnosis presented based on macroscopic,
histologic and radiologic data.
ICH is a benign and self-regressive collagenopathy. The outcome of
the disease is influenced by whether the condition is inherited or

⁎
Corresponding author at: Molecular Biology Center, Interdisciplinary Research Institute on Bio-Nano-Sciences, Babeș-Bolyai University, 400271, Cluj-Napoca,
Romania.
E-mail address: rusu.n.ioana@gmail.com (I. Rusu).

https://doi.org/10.1016/j.ijpp.2019.05.004
Received 28 January 2019; Received in revised form 8 May 2019; Accepted 21 May 2019
Available online 29 May 2019
1879-9817/ © 2019 Elsevier Inc. All rights reserved.
I. Rusu, et al.
sporadic, and the age of onset. The inherited form has a slightly earlier
onset, with 24% of cases displaying the disease at birth, while the
sporadic form is not usually manifested before 9 weeks (Kamoun-
Goldrat and le Merrer, 2008). Prenatal cortical hyperostosis, also
known as Caffey’s Dysplasia, is usually more severe, particularly when
the age of onset is before 35 weeks in utero, in which case the fetus
usually does not survive (Nemec et al., 2012). Clinically, the condition
is manifested as localized lumps on ribs, mandible or long bone dia-
physes (Aufderheide et al., 1998). Affected infants exhibit general ir-
ritability, swelling and decreased motion of the limbs. The condition
most commonly affects the mandible, followed by the long bones, cla-
vicle, scapula, ribs, hands and feet (Aufderheide et al., 1998). As the
mandible is commonly involved, infants often refuse to eat, further
complicating their condition. In cases of severe pain, pseudoparalysis
can also occur (Kamoun-Goldrat et al., 2008).
The aim of this study was to evaluate the skeletal changes observed
on the skeletal remains of an infant from southern Romania dated to the
Roman period. The individual was buried in a bathhouse used by
Roman auxiliary troops (balneum) after the fort was destroyed and
abandoned. Due to the peculiarity of this context, we aimed to com-
plement the information provided by the osteological analysis with data
from available stable isotopes analyses and genetic information.
2. Materials and methods
2.1. Sample background
In the 1st century AD, between 102 and 118 CE, the Roman Empire
extended to the North of the Danube River, attaching this territory to
the Province of Moesia Inferior. A series of Roman forts, among them the
Roman fort from Mălăiești, were in use during the 2nd century AD.
Mălăiești is situated in southern Romania, between the rivers of
Vărbilău and Teleajen (Fig. 1a). At the footsteps of the hill on which the
fort is situated, archaeologists discovered the Roman baths, which were
used by the military personnel; it is not known which auxiliary troops
were stationed there. The fort and its adjacent constructions were in use
for a short period of time (102–118 AD), only in the reign of Trajan. At
the beginning of the reign of Hadrian (117–118 AD), due to the con-
flicts with the Sarmatian and Gaetic populations, the Roman army re-
treated from this area and abandoned all forts, including the one from
Mălăiești, after setting fire to all structures (Țentea and Matei-Popescu,
2015, 2016).
Starting in 2011, a complex archaeological campaign was initiated
at this site, with the aim to exhaustively research the bathhouse. The
construction of the balneum is well preserved, with all of the main
chambers easily identifiable. During the archaeological investigation, in
2014, an infant burial was recovered within the tepid room of the
bathhouse (Fig. 1b). The skeleton was discovered in a supine position,
together with a hand-worked pottery jar and lid, a small number of
beads, and one fragment from an object made of bone (Fig. 2). Strati-
graphically, the burial occurs after the burning of the bathhouse, but at
a time when the walls of the balneum were still standing. The burial was
later covered with construction material originating from the balneum
building. The burial was an isolated occurrence; no other funerary or
non-funerary findings were discovered at the site.
2.2. Osteological and stable isotopes analyses
A detailed osseous and dental inventory was carried out following
the guidelines from Buikstra and Ubelaker (1994). The preservation and
completeness of each osseous fragment were assessed on separate Excel
sheets, by using a 4-scale scoring system adapted from Buikstra and
Ubelaker (1994). In this system, each osseous element was divided by
anatomical parts (70 in total) in order to record possible different levels
of preservation/completeness. The scoring system ranged from 0 to 3,
where 0 was used when the element was missing, 1 – when less than
9
International Journal of Paleopathology 26 (2019) 8–13
50% was available, 2 – when the preservation/completeness was be-
tween 50 and 75%, and 3 - when the preservation/completeness was
above 75%. Age at death was estimated based on dental development
(Ubelaker, 1989) and diaphyseal length measurements (Stloukal and
Hanakova, 1978). Though postmortem damage can be seen on the
skeletal material, the bone surface is well preserved. Dental and osseous
pathological features were assessed and recorded following the guide-
lines from Buikstra and Ubelaker (1994) and Ortner (2003). Stable
isotopes (δ13C and δ15N) analyses and AMS radiocarbon dating were
undertaken at the Beta Analytic Laboratory, Florida, USA on a fragment
from the left humerus (Beta - 394198).
2.3. Molecular analysis
The molecular analysis was performed under sterile conditions,
following strict guidelines and standard precautionary measures in
order to ensure the authenticity of the results (Poinar, 2003; Cooper
and Poinar, 2000; Yang and Watt, 2005). The biological source for DNA
extraction was derived from five dental crowns (one central incisor, one
lateral incisor, two canines and one molar), which were used for two
independent DNA extractions. The experimental steps required aDNA
isolation and amplification of the two HyperVariable Regions (HVR-I
and HVR-II) of the human mitochondrial genome which were per-
formed following the protocol described in detail by Rusu et al. (2018).
3. Results
3.1. Osteological and stable isotopes analyses
The skeleton is represented by fragments from the skull, mandible,
vertebrae, ribs, clavicles, scapulae, humeri, radii, ulnae, femora, and
the right tibia and ilium. The dentition consists of ten deciduous tooth
crowns. The estimated age at death of the analyzed skeleton is between
birth and two months. Macroscopic assessment of the skeleton revealed
the presence of periosteal reaction and proliferation of new bone af-
fecting almost all of the preserved fragments (Table 1). Some fragments
did not allow for clear discrimination between postmortem damage,
pathology, and normal infant’s skeletal tissue. Small foramina were
seen on the left orbital roof, though postmortem destruction hinders a
complete observation. Areas of new bone formation and porosity were
seen on the ectocranial surface of the frontal and parietal bones. Both
pars lateralis of the foramen magnum and temporal bones show a more
extended defect, with granular osteoporosis and an irregular surface
with multiple canals and foramina. No endocranial lesions were ob-
served. The sphenoid, zygomatic bones and maxillary body were not
recovered. The mandibular body shows pitting with areas of new bone
formation (Fig. 3), particularly on the incisive fossae and above the
mylohyoid line. The same lesions were seen on clavicles (Fig. 4) and
scapulae (Fig. 5), especially on the area superior to the spine, and on
the neural arches of the vertebrae. The ribs show pitting and flaring at
the costal end. The right ilium also shows granular osteoporosis and
plaques of new bone formation. All recovered long bones (ulnae, radii,
humeri, femora, right tibia) show extended areas with patches of new
bone formation and porosity on the diaphyses (Fig. 6). In some in-
stances, due to postmortem damage, the profuse layers of new bone can
be clearly distinguished from the original cortex. The proximal femoral
metaphyses have a cribrotic appearance. The preserved right first me-
tatarsal also shows inflammatory pitting.
The ratios for the δ13C and δ15N stable isotopes are -15.6‰ and
+7.9‰, respectively. Radiocarbon dating produced a result of Cal AD
135–335 (2 Sigma calibrated result with 95% probability).
3.2. Molecular analysis
Informative sequences of the mitochondrial control region were
successfully retrieved and replicated. The alignment of clones from
I. Rusu, et al.
Fig. 1. a) Location of the Mălăiești Roman fort (Prahova County) in Romania (map created by I. Rusu using QGIS 2.18.11 (QGIS Development Team, 2016); b)
Location of the recovered individual within the balneum (image provided by O. Țentea).
different PCR products showed, besides the nucleotide mutations con-
firmed in all sequences, the occurrence of misincorporations which are
typical for aDNA molecules (Gilbert et al., 2003). The sample contains
all diagnostic mutations for J2b1a, a descendant maternal lineage of
western Eurasian J macro-haplogroup, as well as a local private poly-
morphism (235 G) on HVS-II (Table 2).
4. Discussion
The pathological alterations documented on the infant skeleton
point to a systemic, chronic condition. A series of diseases are compa-
tible with the lesions displayed in individual under investigation, in-
cluding hemolytic (thalassemia and sickle cell) and megaloblastic an-
emias, scurvy, rickets, and infantile cortical hyperostosis.
Marrow hypertrophy seen in hemolytic and megaloblastic anemias
occurs as a compensatory mechanism to premature hemolysis (Brickley,
2018). The etiology for the disease processes characterized by this pa-
thological feature includes hereditary and acquired factors such as
chronic dietary deficiencies. In megaloblastic anemia, infants are more
prone to developing the condition due to their dependence on the
mother’s own reserves of nutrients, which are transmitted to the baby in
the intra-uterine period and through breastfeeding (Ortner, 2003).
However, in the case of our individual, the frontal and parietal bones do
not display the characteristic areas of pitting and porosity. Moreover,
the perinatal age at death of the infant and the extensive lesions seen on
the skeleton rule out megaloblastic anemia. Thalassemia has been
10
International Journal of Paleopathology 26 (2019) 8–13
described in a series of cases, particularly from the Roman period
(Rohnbogner, 2016; Tomczyk et al., 2016; Lewis, 2012). Its diagnosis is
established based on certain pathognomonic lesions such as hair-on-end
lesions, localized expansions on the ribs with a rib-within-rib radio-
graphic appearance, and facial bones alterations. Though the mandible
exhibits plaques of new bone formation, no other characteristic lesions
are present in the case of this individual. Nonetheless, the young age of
the individual and the possibility of phenotypic variability means tha-
lassemia cannot be ruled out completely.
Scurvy could have been responsible for some of the lesions seen in
the individual. Scorbutic lesions are expected to develop at sites of
musculoskeletal activity due to hemorrhagic bleeding (Brickley and
Ives, 2010). Characteristic pathological foci are identified particularly
on the greater wing of the sphenoid bone, orbital roofs, cranial vault,
and in the metaphyseal and epiphyseal regions of long bones (Klaus,
2014; Stark, 2014; Mays, 2014). In the case of our infant, the cranial
vault and orbital roofs display only limited changes, while, with the
exception of the proximal femur, the metaphyseal and epiphyseal re-
gions are not affected. The general distribution of the lesions argues for
the exclusion of scurvy as a diagnosis.
Vitamin D deficiency (rickets) is manifested through mechanical
deformities, abnormal porosity and flaring of the growth plates
(Brickley and Ives, 2010). This infant displays slight flaring of the
costochondral end of some ribs, but the extended new bone formation is
not consistent with rickets. Additionally, both scurvy and rickets are an
unlikely diagnosis when taking into consideration the age at death of
I. Rusu, et al. International Journal of Paleopathology 26 (2019) 8–13

Fig. 3. New bone formation on the posterior surface of the mandibular body
(overview and detail; images provided by C. Radu).

Fig. 2. The osteological remains of the individual in situ (image provided by

O.Țentea).

Table 1
Degree of preservation and presence of pathological alterations separated by
skeletal element (NBF: new bone formation; Poor: less than 50%; Medium:
between 50–75%; Good: above 75%; for a detailed description of the Scoring
system, please see the Materials and Methods section).
Skeletal element Preservation Pathological changes

Cranium Medium NBF ectocranial surface; foraminae on orbital

roof
Maxilla Not present
Mandible Medium NBF
Vertebrae Poor Pitting, NBF
Ribs Medium Pitting, flaring of the costal end
Clavicle Good NBF
Scapula Good NBF
Fig. 4. New bone formation on the superior surface of the right clavicle
Humerus Good NBF
(overview and detail; images provided by C. Radu).
Radius Medium NBF
Ulna Good NBF
Bones of the hand Not present swelling and inflammation of the periosteum, and new bone formation
Pelvis Good NBF on ilium
Femur Good NBF
on the mandible (Nayak and Samal, 2015). This clinical presentation is
Tibia Poor NBF consistent with the skeletal pathological findings identified in our in-
Fibula Not present dividual. Plaques of pathological new bone are present on almost all of
Bones of the foot Poor Inflammatory pitting the preserved bones, including the mandible and the clavicle, which are
the bones affected most frequently in ICH. Again, as expected in ICH,
the metaphyses are spared. New bone formation displays a layered
the individual analyzed in this study, as an infant’s stores of vitamin C
distribution without becoming homogenous with the underlying cortex,
and D usually do not become depleted before 4 months of age (Ortner,
which suggests an incipient stage of the disease (Kamoun-Goldrat and le
2003).
Merrer, 2008). The perinatal age of the individual also aligns with a
Infantile cortical hyperostosis is a disease characterized by a triad of
diagnosis of ICH, particularly with the inherited form, for which an
systemic symptoms, including irritability and fever, soft tissue swelling,
antenatal onset has been clinically documented (Kamoun-Goldrat and
and underlying cortical bone thickening (Kutty et al., 2010). Typically,
le Merrer, 2008).
a high proportion of the skeleton can be affected, but mandibular in-
With regard to the stable isotopes analysis, a drawback for our at-
volvement is especially characteristic of the condition, reported in more
tempt is represented by the fact that our infant is an isolated burial and
than 70% of clinical cases (Wong and Cheng, 2008). Diagnostic features
no other human or faunal samples were available for analysis.
include age of onset, between birth and 5 months of age, general
Moreover, no other stable isotope studies that we are aware of were

11
I. Rusu, et al.
Fig. 5. New bone formation on the posterior surface of the scapula (overview
and detail; images provided by C. Radu).
Fig. 6. Periosteal new bone formation on the left distal femoral diaphysis
(overview and detail; images provided by C. Radu).
undertaken on samples from this region. However, when comparing the
δ15N stable isotope values of our individual to results achieved on other
subadult population groups dated to the Roman period (Fuller et al.,
2006; Rissech et al., 2016; Keenleyside et al., 2009), we see that our
individual displays low δ15N (7.9‰) stable isotope values.
Nitrogen balance is reflective of the trophic level, which leads to an
increase in δ15N value of 2-3‰ (Tsutaya and Yoneda, 2015) or even
4.1‰ (Beaumont et al., 2018) relative to diet (Schoeninger and DeNiro,
1984; Reitsema, 2013). This allows scholars to infer two phenomena
Table 2
Mitochondrial control region mutations in respect to the rCRS. Unique polymorphisms are highlighted in bold.
HVR-I range HVR-I nucleotide polymorphism HVR-II range
16009–16390 16069T 16126C 57-357
16193T 16278T
International Journal of Paleopathology 26 (2019) 8–13
which lead to tissue enrichment in δ15N, breastfeeding and tissue cat-
abolism in protein-stressed individuals (Craig-Atkins et al., 2018;
Beaumont et al., 2018; Fuller et al., 2005). In thalassemia, sickle cell
anemia, metabolic disease, and fracture trauma, stress-induced nega-
tive nitrogen balance can be seen, with increased δ15N values
(Katzenberg and Lovell, 1999; Olsen et al., 2014). In this individual, the
δ15N value of 7.9‰ is indicative of positive nitrogen balance, which
strongly suggests that the individual was not breastfed and that it was
not experiencing a negative nitrogen balance associated with disease
processes. However, due to the lack of other samples from the same
population group, this result needs to be approached with caution.
In addition to the above-mentioned analyses, genetic investigation
was carried out for this individual as an initial study aiming for the
genetic characterization of the populations inhabiting the territory of
Romania during and after the collapse of the Roman Empire. The in-
dividual analyzed in this study is a member of the J2b1a mitochondrial
haplogroup. The frequency of J2b haplogroup in modern Romanians is
very low, about 1%, according to Turchi et al. (2016). The comparison
between the mtDNA sequence of our individual and previously pub-
lished modern and ancient genetic data reveal that this individual’s
mutation (235 G) is only shared with J2b1a2a samples, which further
implies that this individual possibly belongs to this sub-branch of
J2b1a. To our knowledge, the oldest sequence belonging to J2b lineage
has been found in a Mesolithic sample from Sardinia (Modi et al.,
2017). J2 haplogroup is most prevalent in the Middle East, but the J2b1
maternal lineage is spread across Europe, with highest frequencies
along the Northern Mediterranean coast (Sardinia, Italy) and in Spain
(Pala et al., 2012).
From an archaeological point of view, this burial can be associated
with Sarmatian and Dacian populations who occupied the area after the
Romans left and used some of the remaining buildings (Bârcă, 2013).
Direct radiocarbon dating (AMS) places this burial between 135 and
335 cal AD, therefore after the fort was abandoned, which aligns with
the stratigraphic placement of the burial. An extended study, involving
other mtDNA records, is needed in order to make more robust inter-
pretations regarding the possible association of the J2b1 maternal
lineage to the Sarmatian and Dacian populations.
5. Conclusions
The individual discussed in our analysis was buried in the bathhouse
of a Roman fort after the building had been abandoned and burned by
Roman troops. The burial took place not long after their departure, as
the walls of the building were not yet collapsed. Radiocarbon dating is
in agreement with this finding, placing the life of the individual be-
tween 135 and 335 cal AD. Therefore, the burial can be associated with
a population group that used the Roman buildings after the auxiliary
troops left.
The infant presents a series of skeletal pathological alterations that
can be associated with infantile cortical hyperostosis. Only a handful
cases presenting similar alterations have been identified in archae-
ological contexts dated to the Roman or Byzantine periods. Through
differential diagnosis, which took into consideration other potential
causes of the appearance and distribution of the observed skeletal
changes, a diagnosis of ICH was offered.
HVR-II nucleotide polymorphism Mitochondrial haplogroup Hg quality
73G 150T 152C J2b1a 94.45%
235G 263G 295T
12
I. Rusu, et al.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by the Executive Unit for Financing Higher
Education, Research, Development and Innovation (UEFISCDI),
Romania, grant number PN-II-PT-PCCA-2011-3.1-1153, 229/2013.
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