Archives of Oral Biology 83 (2017) 272–281

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Archives of Oral Biology

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

Review

Structural, mechanical and chemical evaluation of molar-incisor MARK

hypomineralization-affected enamel: A systematic review
⁎
Karim Elhennawya, , David John Mantonc, Felicity Crombiec, Paul Zaslanskyb, Ralf J. Radlanskid,
Paul-Georg Jost-Brinkmanna, Falk Schwendickeb
a
Department of Orthodontics, Dentofacial Orthopedics and Pedodontics, Charité − Universitätsmedizin Berlin, Germany, Aßmannshauser Str. 4-6, 14197 Berlin,
Germany
b
Department of Operative and Preventive Dentistry, Charité − Universitätsmedizin Berlin, Aßmannshauser Str. 4-6, 14197 Berlin, Germany
c
Oral Health Cooperative Research Centre, Melbourne Dental School, University of Melbourne, Melbourne, Victoria, Australia
d
Department of Oral Structural Biology, Charité − Universitätsmedizin Berlin, Aßmannshauser Str. 4-6, 14197 Berlin, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Objectives: To systematically assess and contrast reported differences in microstructure, mineral density, me-
Enamel chanical and chemical properties between molar-incisor-hypomineralization-affected (MIH) enamel and un-
Developmental defects affected enamel.
Hypoplasia Methods: Studies on extracted human teeth, clinically diagnosed with MIH, reporting on the microstructure,
MIH
mechanical properties or the chemical composition and comparing them to unaffected enamel were reviewed.
Microstructure
Electronic databases (PubMed, Embase and Google Scholar) were screened; hand searches and cross-referencing
Chemical composition
were also performed.
Results: Twenty-two studies were included. Fifteen studies on a total of 201 teeth investigated the structural
properties, including ten (141 teeth) on microstructure and seven (60 teeth) on mineral density; six (29 teeth)
investigated the mechanical properties and eleven (87 teeth) investigated the chemical properties of MIH-af-
fected enamel and compared them to unaffected enamel. Studies unambiguously found a reduction in mineral
quantity and quality (reduced Ca and P content), reduction of hardness and modulus of elasticity (also in the
clinically sound-appearing enamel bordering the MIH-lesion), an increase in porosity, carbon/carbonate con-
centrations and protein content compared to unaffected enamel.
Findings: were ambiguous with regard to the extent of the lesion through the enamel to the enamel-dentin
junction, the Ca/P ratio and the association between clinical appearance and defect severity.
Conclusions: There is an understanding of the changes related to MIH-affected enamel. The association of these
changes with the clinical appearance and resulting implications for clinical management are unclear.
Clinical significance: MIH-affected enamel is greatly different from unaffected enamel. This has implications for
management strategies. The possibility of correlating the clinical appearance of MIH-affected enamel with the
severity of enamel changes and deducing clinical concepts (risk stratification etc.) is limited.

1. Introduction the enamel matrix, so that human dental enamel eventually consists of
95 wt.% mineral in the form of hydroxyapatite (Carlstrom,
Dental enamel is the hardest and most mineralized structure in the Glas, & Angmar, 1963; Gustafson & Gustafson, 1968; Robinson et al.,
human body. Amelogenesis commences with the bell stage of tooth 1979; Robinson et al., 1987; Suckling & Thurley, 1984).
development. Ameloblasts are located in the inner enamel epithelium When one of the relevant processes, i.e. matrix production, matrix
and undergo a sequence of maturation stages, which eventually enable secretion, matrix arrangement, crystal formation or matrix resorption is
them to produce a protein-rich enamel matrix. Once secreted by the altered or disturbed, a compromised enamel structure may result.
ameloblast, matrix granules aggregate as nanospheres, which form a Macroscopic quantitative defects, which are mainly caused by a dis-
complex 3-dimensional framework for the arrangement of the enamel turbance to amelogenesis during the matrix secretion phase, are defined
crystals. At the same time, a series of enzymes control the resorption of as enamel hypoplasia (Clarkson, 1989; Mahoney, Ismail,

⁎
Corresponding author at: Charité Centre for Dental Medicine Department of Orthodontics, Dentofacial Orthopedics and Pedodontics Aßmannshauser Str. 4-6, 14197 Berlin, Germany.
E-mail address: karim.elhennawy@charite.de (K. Elhennawy).

http://dx.doi.org/10.1016/j.archoralbio.2017.08.008
Received 10 June 2017; Received in revised form 15 July 2017; Accepted 14 August 2017
0003-9969/ Crown Copyright © 2017 Published by Elsevier Ltd. All rights reserved.
K. Elhennawy et al. Archives of Oral Biology 83 (2017) 272–281

Kilpatrick, & Swain, 2004; Commission on Oral Health, and used scales/indices were not specified initially, as a large range of
Research & Epidemiology. Report of an FDI Working Group, 1992; measures and scales/indices were expected to be applied, with some
Suckling and Thurley, 1984; Suckling, 1989, 1998), however, qualita- outcome data also being qualitative (e.g. description of microscopic
tive defects, caused by disturbances in either the calcification or ma- images).
turation phase are defined as enamel hypomineralization (Suckling,
Elliott, & Thurley, 1983; Suckling & Thurley, 1984; Suga, 1983; Suga, 2.3. Information sources
1989).
The term Molar Incisor Hypomineralization (MIH) was first defined Medline via PubMed, Embase via Ovid and Google Scholar were
in 2001 by Weerheijm and colleagues as demarcated, qualitative de- searched. In addition, reference lists of identified full-texts were
velopmental defects of enamel affecting a minimum of one permanent screened and cross-referenced. The search period was from January 1,
molar with or without involvement of the incisors (Weerheijm, 2000 to February 28, 2017 and limited to studies published from 2000
Jälevik, & Alaluusua, 2001). Similar defects also occur in second pri- and onwards, as it was not assumed that a large number of studies on
mary molars – hypomineralized second primary molar (HSPM) (Elfrink, this issue would be published before that; and earlier studies were likely
Schuller, Weerheijm, & Veerkamp, 2008; Elfrink et al., 2012; Elfrink to have poorly or incorrectly indexed the condition. Study authors were
et al., 2013; Mittal & Sharma, 2015). MIH defects have different grades contacted if required to obtain full-texts. Neither authors nor journals
of severity (mild to severe); moreover, the clinical appearance varies were blinded to reviewers. No language restriction was set; studies in
from creamy/white through yellow to brown color with or without languages other than English or German were translated by native
post-eruptive breakdown (PEB). A relatively high MIH prevalence of 3 speakers.
to 22% and of 2 to 40% has been reported in Europe and in the world,
respectively, although indices used have varied (Garcia-Margarit, 2.4. Search strategy
Catala-Pizarro, Montiel-Company, & Almerich-Silla, 2014; Jälevik,
2010; Kukleva et al., 2008). The following search, combining two search blocks and employing
Despite intensive efforts to understand the etiology of MIH, it has Boolean operators, was adapted for each database:
not been fully elucidated. A multifactorial pathogenesis with a possible (Mottled enamel) OR non endemic mottling of enamel) OR internal
genetic component has been hypothesized (Alaluusua, 2010; Crombie enamel hypoplasia) OR cheese molars) OR non-fluoride enamel opa-
et al., 2009; Elhennawy & Schwendicke, 2016; Silva, Scurrah, Craig, cities) OR idiopathic enamel opacities) OR enamel hypomineralization)
Manton, & Kilpatrick, 2016). The management of MIH is considered OR enamel hypomineralization) OR hypomineralized molars) OR
challenging for the patients, the caregivers and the dentist. Different molar-incisor hypomineralization) OR molar-incisor-hypomineraliza-
treatment modalities are available, ranging from prevention of PEB and tion) OR molar-incisor-hypomineralization) OR molar incisor hypomi-
dental caries, management of hypersensitivity and pain, through re- neralization) OR molar incisor hypomineralization) OR molar-incisor
storative treatment or extraction with or without subsequent ortho- hypomineralization) OR mih))
dontic alignment of adjacent teeth (Elhennawy & Schwendicke, 2016; AND
Lygidakis, 2010; Weerheijm, 2003). (Mechanical properties) OR histology) OR histologic) OR mor-
To understand the pathogenesis of MIH, but also to derive appro- phology) OR morphologic) OR Mineral density) OR X-ray micro-
priate management strategies, knowledge of the alterations of MIH-af- tomography) OR Transmission electron microscopy) OR Protein con-
fected compared with unaffected enamel is needed. A number of au- tent) OR SEM) OR HME) OR FT-Raman) OR XRD) OR 3D x-ray
thors have reported on structural, mechanical and chemical properties microscopy) OR scanning electron microscopy) OR enamel hardness)
of MIH-affected enamel, however, these studies have, at first glance, OR XRMA) OR ToF-SIMS Analysis) OR Ultrastructure) OR fracture) OR
reported ambiguous findings and applied a vast range of different mineral) OR proteins) OR microscopy) OR microscopic) OR hardness)
analytical methods. By appraising the available evidence systematically OR elastic)).
and comparing study methods and findings, common and conflicting
aspects might be highlighted, and possible reasons for the heterogeneity 2.5. Data management
between studies might be better understood. This, eventually, should
contribute to (a) a better understanding of the changes in MIH, with the A piloted spreadsheet was used for data extraction and manage-
discussed relevance for both basic and applied dental sciences, and (b) ment.
lead to recommendations of what studies and how future investigations
in the field should be conducted, i.e. identify knowledge gaps or derive 2.6. Selection process
a set of methods which seem valid and reproducible for application
here. The aim was to systematically collect, evaluate and contrast Two authors (FS, KE) screened titles independently and compared
available studies on the structural, physical and chemical alterations of their findings. In case of disagreement, titles were included to obtain
MIH-affected compared with unaffected enamel. full-texts. Full-texts were assessed independently after de-duplication.
In cases of disagreement, studies were included after consensus was
2. Methods reached through discussion.

2.1. Eligibility criteria 2.7. Data collection and analysis

This systematic review was limited to studies Data extraction was performed by one reviewer (KE) and double-
checked by two other reviewers (FS, PZ). Disagreements were resolved
• of extracted human teeth, diagnosed with MIH clinically,. through discussion.
• reporting on the microstructure, mechanical properties or the che- The following items were collected: author names, year of pub-
mical composition of MIH-affected versus unaffected enamel. lication, sample size, lesion severity, lesion color, storage medium,
analytical methods used and the results.
2.2. Outcomes Results were compared between studies and common and con-
flicting findings identified. Reporting was separated into structural,
The primary outcomes were the morphological, mechanical and mineral density, chemical and mechanical properties, while studies
chemical properties of MIH-affected enamel. The outcome measures were additionally ordered along the used analytical instrument.

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K. Elhennawy et al. Archives of Oral Biology 83 (2017) 272–281

Fig. 1. Flowchart of the study.

Risk of bias assessment was not performed, as no validated instru- teeth had been studied (Tables 1 and 2).
ment was available to evaluate the included in vitro studies, but also as Ten studies (141 teeth) reported on the microstructure of MIH-af-
the reporting in nearly all studies would have been insufficient for as- fected enamel. Different methods such as light microscopy (LM), po-
sessment when applying clinically-used risk of bias instruments (e.g. larized light microscopy (PLM), scanning electron microscopy (SEM)
with regards of examiner blinding etc.). and transmission electron microscopy (TEM) were used.
Four studies (Crombie, Manton, Palamara, Zalizniak,
3. Results Cochrane, & Reynolds, 2013; Fagrell, Salmon, Melin, & Norén, 2013;
Jälevik & Norén, 2000; Taube et al., 2015) used LM and PLM, with MIH-
3.1. Search and included studies affected teeth showing increased porosity ranging from 5 to 25% in
comparison to normal enamel (Crombie, Manton, et al., 2013; Fagrell
From 3624 identified studies, the full-texts of 33 were evaluated, et al., 2013; Jälevik & Norén, 2000); creamy/white colored lesions and
and 23 studies included (Fig. 1). The 23 included studies (243 teeth), those without PEB being the least porous lesions (Crombie, Manton,
reported on the structural, mechanical and the chemical properties of et al., 2013; Jälevik & Norén, 2000). The degree of porosity correlated
MIH enamel (Tables 1 and 2). to the degree of clinical opacity of the lesion (Crombie, Manton, et al.,
2013; Gambetta-Tessini, Marino, Ghanim, Adams, & Manton, 2017;
Jälevik & Norén, 2000). One study reported that creamy/white lesions
3.2. Structural properties
were situated in the inner parts of enamel while yellow/brown lesions
extended through the whole enamel layer (Jälevik & Norén, 2000).
A total of 15 studies evaluated the structural properties (micro-
However, the majority of studies reported that MIH lesions extended
structure and mineral density) of MIH-affected enamel. In total, 201

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Table 1
Included studies’ characteristics (studies ordered chronologically).

Authors/year MIH teeth Control teeth Storage medium Severity Color Methods

Jälevik and Norén, (2000) 73 1 Neutral-buffered 4% formaldehyde na Creamy/white, yellow/brown PLM

Jälevik et al. (2001) 17 Sound enamel of MIH Neutral-buffered 4% formaldehyde na Creamy/yellow SIMS, XRMA
tooth
Fearne et al. (2004) 2 2 Tap water na Yellow/brown XMT, 3D XM
Mahoney, Rohanizadeh, et al. (2004) 8 2 Deionized water, containing thymol Severe na SEM, XRD, BSE, EDS, microindentation
crystals
Mahoney, Ismail, et al. (2004) 8 2 Deionized water, containing thymol Severe na SEM, microindentation
crystals
Jälevik et al. (2005) 73 Sound enamel of MIH Neutral-buffered 4% formaldehyde na na SEM, microradiography
tooth
Xie et al. (2008) 3 4 Hank’s solution with thymol crystals na na TEM, SEM, nanoindentation
Farah et al. (2008) 5 Sound enamel of MIH Distilled water with thymol crystals na na Nanoindentation, LF
tooth
Chan et al. (2010) 2 Sound enamel of MIH Hank’s solution na na Nanoindentation, SEM, FIB
tooth
Fagrell et al. (2010) 4 Sound enamel of MIH 70% ethanol na na SEM, vickers micro-hardness tester, XRMA
tooth
Farah, Drummond, et al. (2010) 10 10 Distilled water with thymol crystals Diff. severities Normal, white chalky, yellow, XMT, LF
brown
Farah, Monk, et al. (2010) 10 6 Distilled water with thymol crystals Diff. severities Opaque-white, yellow, brown SDS-PAGE, mass spectrometry

275
Farah, Swain, et al. (2010) 10 10 Distilled water with thymol crystals Diff. severities Opaque-white, yellow, brown XMT
Mangum et al. (2010) 5 Sound enamel of MIH Blotted dry and stored frozen na na SDS-PAGE, mass spectrometry, mineral-binding assays
tooth
Crombie, Manton, et al. (2013) 25 Sound enamel of MIH Neutral-buffered 4% formaldehyde Severe Creamy/white, yellow/brown PLM, SEM, TMR, microindentation
tooth
Fagrell et al. (2013) 13 Sound enamel of MIH 70% ethanol Severe na LM, PLM, XMCT
tooth
Bozal et al. (2015) 1 1 na Mild and moderate Creamy/white, yellow/brown EDS, SEM
Fraser et al. (2015) 3 Sound enamel of MIH na Diff. severities White, yellow and brown SEM-EDS, Raman spectrometry
tooth
Martinović et al. (2015) 10 10 na Severe na SEM with EDS, BSE
Taube et al. (2015) 5 Sound enamel of MIH 70% ethanol na na LM, PLM, XRD, SEM, FT-infrared spectroscopy, FT-Raman
tooth spectroscopy
Melin et al. (2015) 7 Sound enamel of MIH 70% ethanol Severe na ToF-SIMS analysis, XRMA analysis, SEM
tooth
Garot et al. (2016) 8 Sound enamel of MIH na na na XMCT
tooth
Gambetta-Tessini et al. (2017) 22 2 na na Creamy/white, yellow/brown Micro-CT, QLF-D

Abbreviations: PLM, polarized light microscopy; SIMS, secondary ion mass spectroscopy; XRMA, x-ray microanalysis; XMT, x-ray microtomography; 3D XM, 3D x-ray microscopy; LF, laser fluorescence; FIB, focused ion beam; TCA, trichloracetic
acid; XRD, x-ray diffraction; BSE, back scattered electron; EDS, energy dispersive x-ray spectrometer; XMCT, x-ray micro-computed tomography; micro-CT, micro-computed tomography; LM, light microscopy − stereo microscopy; SDS-PAGE,
sulphate-polyacrylamide gel electrophoresis; na, not available; Nr., number; TMR, transverse microradiography; ToF-SIMS, time of flight secondary ion mass spectroscopy; Diff., different; Ss, sample size; iMH, idiopathic molar hypomineralization;
QLF-D, quantitative light-induced fluorescence-digital
Archives of Oral Biology 83 (2017) 272–281
 Table 2
Main results of the included studies (studies ordered along outcome category and chronologically).

Authors/year Outcome Ss Methods Results

K. Elhennawy et al.

Structural properties (microstructure and mineral density)

Jälevik and Norén, (2000) MS 74 PLM MIH enamel showed areas of porosities of varying degrees
Yellow/brown defects were more porous than the white/cream defects
Yellow/brown defects extended the whole enamel layer
Creamy/white defects extended only in the inner parts of enamel
Fearne et al. (2004) MD 4 XMT, 3D XM Significant decrease in the mineral content of up to 20% of MIH enamel compared with the control enamel
The mineralization gradient of MIH enamel from enamel-dentin junction (EDJ) to surface is reversed compared to
that of normal enamel
Mahoney, Rohanizadeh, et al. (2004) MS 10 SEM MIH enamel showed:
Disorganized enamel rods, variable rod width and loss of distinct boundaries between rods
Jälevik et al. (2005) MS 73 SEM with and without acid etching, The packing of hydroxylapatite crystals seemed looser and less well organized in MIH enamel
Microradiography
The border between normal and MIH enamel was distinct and followed the direction of the rods
Etching of MIH enamel could not create a normal etch relief
Xie et al. (2008) MS 7 TEM, SEM MIH enamel showed:
A less dense prism structure, loosely packed apatite crystals and a wider sheath region
Chan et al. (2010) MS 2 TEM, SEM Prism sheaths in the transition as well as the affected lesion are less able to hold the prisms together
Fagrell et al. (2010) MS 4 SEM with and without acid etching In MIH enamel, porous zones extended from cuspal parts to the buccal and/or the lingual areas
The cervical parts of the enamel appeared normal
MIH enamel had less distinct prism borders and crystals and more marked inter-prismatic space
Farah, Drummond, et al. (2010) MD 20 XMT, LF The degree of staining of MIH enamel, as assessed visually or by LF, may be used clinically to reflect the severity of
the defect
Farah, Swain, et al. (2010) MD 20 XMT MIH enamel showed normal thickness and MD was highest near the EDJ and then decreased towards the outer
enamel.
MD of MIH enamel was on average about 19% lower than in sound enamel

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Crombie, Manton, et al. (2013) MS 10 PLM, SEM The MIH lesion affected the full enamel depth
The porosity of the bulk of the lesions as measured using PLM was ≤ 5% but areas with > 25% porosity were
present
Fagrell et al. (2013) MS, MD 13 LM, PLM, XMCT Normal enamel had a well-organized and distinct prism and crystal structure in contrast to the hypomineralized
enamel, which had less distinct prism borders and crystals and more marked inter-prismatic space.
The hypomineralized enamel appeared more porous than normal enamel.
The enamel prisms in the hypomineralized enamel appeared to be covered by a structureless layer, in some
locations appearing as less etched
Bozal et al. (2015) MS 2 SEM with and without acid etching After acid etching, the tooth with MIH diagnosis did not show the typical patterns of demineralization (type I and
type II) found in normal enamel
Taube et al. (2015) MS 5 LM, PLM The hypomineralized enamel extended from the EDJ towards the enamel surface and the border between normal
and hypomineralized enamel followed the enamel prisms
The hypo mineralized enamel appeared to be covered with a structure less layer, without the typical prismatic
structure, possibly representing organic material
Less organized prism structure was found in MIH enamel
Garot et al. (2016) MD 8 XMCT MIH enamel showed a mineral density reduction of 19% compared to control enamel
Gambetta-Tessini et al. (2017) MD 24 micro-CT, QLF-D Cervical enamel in hypomineralized enamel is mostly not affected.
MD gradients in demarcated hypomineralized lesions were abnormal in both enamel and dentine.
The porosity was 21% greater in hypomineralized lesions compared to control enamel.
Mechanical properties (microhardness, modulus of elasticity)
Mahoney, Rohanizadeh, et al. (2004) Hard, ME 10 Microindentation MIH affected enamel showed lower hardness and modulus of elasticity
Unaffected enamel in test group compared to enamel of control group:
Similar hardness and modulus of elasticity
Mahoney, Ismail, et al. (2004) Hard, ME 10 Microindentation The mechanical properties of the enamel closest to the CEJ are similar to those seen in the control teeth.
However, as the indentations are placed more coronally towards the cuspal region, both the hardness and modulus
of elasticity decrease significantly
The mechanical properties are ≈ 20% that of unaffected enamel (80% decrease)
Farah et al. (2008) Hard, ME 5 Nanoindentation Reduction of hardness and modulus of elasticity in the affected parts of the tooth
Chan et al. (2010) Hard, ME 2 Nanoindentation Transition region has lower mechanical properties compared to the unaffected region
(continued on next page)
Archives of Oral Biology 83 (2017) 272–281
 Table 2 (continued)

Authors/year Outcome Ss Methods Results

Affected region has lower mechanical properties than both regions

K. Elhennawy et al.

Fagrell et al. (2010) Hard 4 Vickers micro-hardness tester Significant reduction in the hardness of MIH enamel compared with the control enamel
Crombie, Manton, et al. (2013) Hard 10 Microindentation Significant reduction in the hardness of MIH enamel compared with the control enamel
Chemical properties
Jälevik et al. (2001) Min comp, C conc 17 SIMS, XRMA Hypomineralized enamel had a higher content of carbon (C)
Calcium (Ca) as well as the phosphorus (P) concentration was lower than in normal enamel
The mean Ca/P ratio in hypomineralized areas was significantly lower than in the adjacent normal enamel
Mg and K concentrations were slightly higher in hypomineralized areas, especially towards the surface.
Mahoney, Rohanizadeh, et al. (2004) Min comp 10 XRD, BSE, EDS Ca/P ratio not significantly different of control group
Increase in the magnesium percentage in the MIH group
No change in the content of Na and K was found
Fagrell et al. (2010) Min comp 4 XRMA No significant difference was found regarding the Ca/P ratio between test and control enamel
A relation between micro hardness and the Ca/C ratio in hypomineralized and normal enamel was found
Farah et al. (2008) Organic cont 5 LF LF cannot quantify the amount of the organic content or report on the severity of MIH
Farah, Monk, et al. (2010) Pro cont 16 SDS-PAGE, mass spectrometry MIH enamel showed 8–21-fold higher protein content than sound enamel
Brown enamel had the highest protein content
Yellow/brown enamel showed the greatest abundance of serum albumin and alpha-1-antitrypsin as well as the
presence of antithrombin III
The intrinsic enamel protein ameloblastin was also identified, in the brown enamel sample only
Mangum et al. (2010) Pro cont 5 SDS-PAGE, mass spectrometry Affected enamel has higher protein content than normal, but a near-normal level of residual amelogenins
Affected enamel was found to have accumulated various proteins from oral fluid and blood
Crombie, Manton, et al. (2013) Min comp, Carbonate 15 TMR Significant decrease in the mineral content of MIH enamel compared with the control enamel
conc
Significant increase in the Carbonate content of MIH enamel compared with the control enamel
Bozal et al. (2015) Min comp 2 EDS The mineral composition of the affected surfaces had lower Ca and P content and higher O and C
Fraser et al. (2015) Min comp, Pro cont 3 SEM-EDS, Raman spectroscopy Slight depletion of the calcium and phosphorus within the hypomineralised lesions

277
Decreased levels of hydroxyapatite and/or elevated levels of protein than in normal enamel
Martinović et al. (2015) Min comp, C conc 20 SEM-EDS, BSE Reduction of the Ca/P ratio by 5–20%
Increased C content compared to normal enamel
Taube et al. (2015) Min comp, C conc, Pro 5 SEM, FT-infrared spectroscopy, FT-Raman Significant decrease in the mineral content of MIH enamel compared with the control enamel
cont spectroscopy
Significant increase in the C content of MIH enamel compared with the control enamel
Significant increase in the protein content of MIH enamel compared with the control enamel
Melin et al. (2015) Min comp 7 ToF-SIMS Analysis, XRMA Analysis, SEM Ca/P ratio not significantly different of control group
Increase in the magnesium percentage in the MIH group
Higher Mg, lower Na and K concentrations and different CL profiles were found in MIH enamel

Abbreviations: Ss, sample size; MS, microstructure; MD, mineral density; ME, modulus of elasticity; Min comp, mineral composition; C conc, carbon concentration; Pro cont, protein content; Organic cont, organic content; C, carbon; Ca, calcium;
P, phosphorus; O, oxygen, Mg, magnesium; Na, sodium; K, potassium; CL, chlorine; EDJ, enamel-dentin junction; CEJ, cemento-enamel junction; PLM, polarized light microscopy; SIMS, secondary ion mass spectroscopy; XRMA, x-ray
microanalysis; XMT, x-ray microtomography; 3D XM, 3D x-ray microscopy; LF, laser fluorescence; FIB, focused ion beam; XRD, x-ray diffraction; BSE, back scattered electron; EDS, energy dispersive x-ray spectrometer; XMCT, x-ray micro-
computed tomography; LM, light microscopy − stereo microscopy; SDS-PAGE, sulphate-polyacrylamide gel electrophoresis; nc, not clear; TMR, transverse microradiography; ToF-SIMS, time of flight secondary ion mass spectroscopy; iMH,
idiopathic molar hypomineralization.
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through the full thickness of enamel, starting at the enamel-dentin (mineral composition, protein concentration and carbon/carbonate
junction (EDJ) and ending at the enamel surface (Crombie, Manton, concentration) of MIH-affected enamel (Bozal et al., 2015; Crombie,
et al., 2013; Fagrell et al., 2013; Gambetta-Tessini et al., 2017). Manton, et al., 2013; Fagrell et al., 2010; Farah et al., 2008; Farah,
TEM and SEM had been used in seven studies (Bozal, Kaplan, Monk, Swain, & Drummond, 2010b; Jälevik, Odelius, Dietz, & Norén,
Ortolani, Cortese, & Biondi, 2015; Chan, Ngan, & King, 2010; Crombie, 2001; Mahoney, Rohanizadeh, et al., 2004; Mangum, Crombie,
Manton, et al., 2013; Fagrell, Dietz, Jälevik, & Norén, 2010; Jälevik, Kilpatrick, Manton, & Hubbard, 2010; Martinović, Ivanović,
Dietz, & Norén, 2005; Mahoney, Ismail, et al., 2004; Xie, Kilpatrick, Milojković, & Mladenović, 2015; Fraser et al., 2015; Melin et al., 2015;
Swain, Munroe, & Hoffman, 2008) to determine the ultrastructure of Taube et al., 2015). Nine studies (70 teeth) reported on the mineral
MIH-affected enamel. MIH-affected enamel showed less dense prism concentration of MIH-affected enamel. Different methodologies such as
structure, partial loss of prismatic pattern, loosely packed crystals, less x-ray microanalysis (XRMA) (Fagrell et al., 2010; Jälevik et al., 2001;
distinct prism borders, more marked inter-prismatic space and wider Melin et al., 2015), x-ray diffraction (XRD) (Mahoney, Rohanizadeh,
sheath regions (Bozal et al., 2015; Chan et al., 2010; Crombie, Manton, et al., 2004), secondary ion mass spectroscopy (SIMS) (Jälevik et al.,
et al., 2013; Fagrell et al., 2010; Jälevik et al., 2005; Xie et al., 2008). 2001) and energy dispersive x-ray spectrometry (EDS) (Bozal et al.,
Three studies (Bozal et al., 2015; Fagrell et al., 2013; Jälevik et al., 2015; Fraser et al., 2015; Mahoney, Rohanizadeh, et al., 2004), were
2005) used SEM to assess acid-etched MIH enamel, and found an ab- used in the analysis of the mineral composition of MIH-affected enamel.
normal etching pattern compared to normal enamel. The number of All authors concluded that MIH-affected teeth showed a significant
cracks and deep pores was increased in MIH-affected enamel due to decrease in the mineral content compared to normal enamel. Six studies
acid-etching (Bozal et al., 2015). concluded that there was no significant difference regarding the Ca/P
Three studies (Bozal et al., 2015; Chan et al., 2010; Farah, Swain, ratio in both MIH-affected and normal enamel (Bozal et al., 2015;
Drummond, Cook, & Atieh, 2010; Mahoney, Rohanizadeh, Ismail, Crombie, Manton, et al., 2013; Fagrell et al., 2010; Mahoney,
Kilpatrick, & Swain, 2004) used TEM, SEM, x-ray microtomography Rohanizadeh, et al., 2004; Melin et al., 2015; Taube et al., 2015), whilst
(XMT) and nanohardness testing to investigate the microstructure, two studies reported a significant reduction in the Ca/P ratio (Jälevik
mineral density and mechanical properties of the transitional area, et al., 2001; Martinović et al., 2015).
which was defined as the clinically sound/healthy area adjacent to the The protein content of MIH-affected teeth was evaluated by four
demarcated MIH-lesion and found that this transitional region had less studies (23 MIH-affected teeth) using different methods such as SDS-
mineralized prism sheaths than unaffected-enamel despite its clinically polyacrylamide gel electrophoresis (SDS-PAGE), Raman spectrometry
normal appearance. and mass spectrometry (Farah, Monk, et al., 2010; Fraser et al., 2015;
Mangum et al., 2010; Taube et al., 2015). Agreement existed on a
3.3. Mineral density (MD) significantly higher protein content found in MIH-affected enamel in
comparison to sound enamel.
Seven studies (60 MIH teeth) reported on the mineral density (MD) Three studies investigated the protein content and concentration of
of MIH-affected enamel. Six studies (46 MIH teeth) using XMT, also differently colored MIH enamel and found that yellow and brown le-
termed x-ray micro-computed tomography (XMCT) reported a sig- sions had the highest protein content, however, ameloblastin was only
nificant decrease in the mineral density (mean 19% to 20%) in MIH- found in the brown lesion (it is to be noted that one tooth contained
affected teeth compared to that of normal enamel. Another study brown lesions in this study). Ameloblastin was not found in yellow or
(Crombie, Manton, et al., 2013) used transverse microradiography white MIH lesions. Higher concentrations of serum albumin, alpha-1-
(TMR) to determine the degree of hypomineralization, and found an antitrypsin and antithrombin III were present in yellow and brown le-
average mineral content of 59 vol% mineral compared with 86 vol% sions than in white lesions (Farah, Monk, et al., 2010; Fraser et al.,
mineral in normal enamel (Carlstrom et al., 1963; Fagrell et al., 2013; 2015; Mangum et al., 2010).
Farah, Drummond, Swain, & Williams, 2010; Farah, Swain, et al., 2010; Three studies using EDS, XRD, XRMA and SIMS (32 MIH-affected
Fearne, Anderson, & Davis, 2004; Gambetta-Tessini et al., 2017; Garot teeth) addressed the carbon content in MIH-affected teeth (Crombie,
et al., 2016). Manton, et al., 2013; Jälevik et al., 2001; Martinović et al., 2015; Taube
Mineral density decreased from the cemento-enamel junction (CEJ) et al., 2015) and all of them agreed that a significant increase in the
to the occlusal surface but increased again in the cusp tip region; the carbon concentration existed in MIH-affected enamel compared to
mineral density was highest near the enamel-dentin junction (EDJ), normal enamel. One study (15 MIH teeth) evaluated carbonate content
moreover, a decrease in the mineral density in the transitional area and also concluded a higher carbonate content in comparison to normal
adjacent to the borders of the MIH lesions was reported (Farah, Swain, enamel (Crombie, Manton, et al., 2013).
et al., 2010).

3.4. Mechanical properties 4. Discussion

Six studies evaluated the mechanical properties (hardness and Hypersensitivity, PEB and their effect on quality of life, coupled
modulus of elasticity) of MIH-affected teeth (29 teeth) (Table 1 and 2). with the poor restorative and therapeutic outcomes, dental fear, in-
In general, the hardness and the modulus of elasticity of the MIH-af- adequate effect of local anesthetics and time-consuming and costly re-
fected enamel showed significantly lower values compared to normal interventions, make MIH a challenging condition for patients, care-
enamel (Chan et al., 2010; Crombie, Manton, et al., 2013; Fagrell et al., givers and dentists. Understanding the nature of these demarcated
2010; Farah et al., 2008; Mahoney, Ismail, et al., 2004; Mahoney, qualitative developmental defects is therefore of scientific and clinical
Rohanizadeh, et al., 2004). significance in order to prevent and/or manage the condition appro-
Four studies found a significant decrease in the mineral density, priately. Twenty-two studies reported on different (structural, me-
structural and mechanical properties of the transitional region com- chanical and chemical) properties of MIH-affected enamel; many of
pared to the unaffected healthy enamel (Bozal et al., 2015; Chan et al., them confirming each other. However, when contrasting the study
2010; Farah, Swain, et al., 2010; Mahoney, Rohanizadeh, et al., 2004). findings it also became apparent that both heterogeneity in assessment
methods and in the experimental details, as well as a rather un-
3.5. Chemical properties standardized presentation and interpretation of findings led to a
number of conflicting results.
Twelve studies (90 teeth) reported on the chemical properties

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4.1. Agreements in the current research mineral composition of the Ca/P ratio was reported to be either similar
to normal enamel (Crombie, Manton, et al., 2013; Fagrell et al., 2010;
A number of agreed findings were reported in the included studies. Mahoney, Rohanizadeh, et al., 2004), or reduced by 5–20% (;
Generally, MIH-affected enamel is characterized by a reduction in the Martinović et al., 2015). Similarly, MIH lesions were found to extend
mineral quantity and quality (reduced Ca and P content), a reduced from the surface of the enamel to the EDJ by most studies, while one
hardness and modulus of elasticity (also in the clinically sound-ap- study found creamy/white defects to be restricted to the inner layer of
pearing enamel bordering the MIH lesion), increased porosity, in- enamel. Sample preparation and sectioning angulation/direction along
creased carbon and carbonate concentrations and higher protein con- the long axis of the enamel prisms might play an important role here,
tent compared to normal enamel (Crombie, Manton, et al., 2013; leading to possible artefact and misleading results. Studies employing
Elhennawy & Schwendicke, 2016; Farah, Monk, et al., 2010; Farah, three-dimensional assessment methods might circumvent this problem
Swain, et al., 2010; Gambetta-Tessini et al., 2017; Jälevik & Norén, and are helpful to explore this issue, or avoid such artefacts.
2000). Enamel crystals appear to be less densely packed in MIH than The MD was associated with the clinical appearance (color) of the
sound enamel, with thicker prism sheaths and inter/intra-prismatic lesion, with lower MD in darker (brown) lesions compared with
organic content (Jälevik et al., 2005; Mahoney, Ismail, et al., 2004; creamy/white lesions, when measured by micro-CT (Farah, Swain,
Mahoney, Rohanizadeh, et al., 2004; Xie et al., 2008). Acid etched MIH et al., 2010; Gambetta-Tessini et al., 2017; Jälevik et al., 2001). Using
enamel has more cracks and deep pores combined with poor/abnormal TMR, a slight difference of MD was found between differently colored
etching patterns (Bozal et al., 2015; Fagrell et al., 2013; Jälevik et al., lesions. It should be noted, however, that this association was not un-
2005). ambiguously confirmed and did not reach statistical significance
Protein content of MIH-affected enamel was significantly higher (Crombie, Manton, et al., 2013). It is possible that the different as-
than that of normal enamel (between 3 and 21 times). Serum albumin, sessment methods (2- versus 3-dimensional) and different tooth storage
alpha-1-antitrypsin, antithrombin III, and Type I collagen were identi- media, machine settings and image resolutions as well as sample size
fied in MIH-affected enamel (Farah, Monk, et al., 2010; Mangum et al., may play a role here (Garot et al., 2016). In any case, such findings call
2010). These proteins seem to play a role in hypomineralization, as for a critical assessment of the methods used to determine MD.
enamel mineralization can be directly inhibited through albumin The clinical appearance (color and PEB) of the affected-enamel was
binding to mineral, a serum protein not usually found in mature en- found to be associated with MD by a number of studies (Crombie,
amel, or inhibition by kallikrein 4, by alpha-1-antitrypsin, and antith- Manton, et al., 2013; Fagrell et al., 2013; Fearne et al., 2004; Gambetta-
rombin. Kallikrein is a glycosylated serine protease responsible for Tessini et al., 2017), whilst others did not confirm the association
cleaving enamel matrix proteins before their export from the hardening (Crombie, Cochrane, Manton, Palamara, & Reynolds, 2013; Farah,
enamel (Bartlett & Simmer, 2014). Associated with the higher protein Swain, et al., 2010; Gambetta-Tessini et al., 2017). It is of great re-
content was also the unambiguously reported higher carbon and car- levance to re-assess this association, as the clinical severity grading
bonate content (up to 10% compared with 3% in normal enamel). It along the lesion color is currently used for deriving a treatment deci-
was claimed that high protein and low mineral content may be con- sion. Future research in this area may suggest the need to consider
sidered as a risk factor for PEB (Crombie, Manton, et al., 2013; Jälevik multiple factors in determining the severity of MIH. In general, it
et al., 2001; Martinović et al., 2015), with this risk being higher in should be highlighted that only one third of studies took the clinical
yellow/brown than creamy/white MIH enamel. appearance (color) of the affected-enamel into consideration while in-
Clinically, these findings are relevant: MIH enamel is not as struc- vestigating structural properties (Bozal et al., 2015; Crombie, Manton,
turally supportive as sound enamel, which could mean that coverage of et al., 2013; Farah, Monk, et al., 2010; Fearne et al., 2004; Gambetta-
any residual MIH enamel adjacent to cavities should be performed Tessini et al., 2017; Jälevik, 2001; Jälevik & Norén, 2000), and only
using fracture-resistant (flexural strong) restorative materials (such as four studies (Crombie, Manton, et al., 2013; Fagrell et al., 2013; Fearne
resin composite (possibly fiber-reinforced), or indirect restorations, and et al., 2004; Gambetta-Tessini et al., 2017) included lesions with PEB,
not glass ionomer cements or amalgam). Conditioning MIH enamel for while the latter is especially relevant from a patient’s and clinician’s
adhesive restorations might need different protocols, as acid-etching perspective. Future studies on the structure of MIH-affected enamel
might result in different bond strengths and etch patterns compared to should describe the clinical appearance in detail, best linked with
unaffected enamel; a couple of studies reported on bond strength be- clinical symptomatology of the tooth (if available).
tween restorations and MIH-affected enamel, showing the relevance of
a possible pretreatment for removing proteins from the enamel should 4.3. Recommendations towards future studies
be explored further, as such treatment could result in improved resin
penetration into the enamel, thus improving both the enamel hardness A number of recommendations can be deduced from the present
and the bond strength (Chay, Manton, & Palamara, 2014; William, review. Firstly, the findings call for a consensus as to which parameters
Burrow, Palamara, & Messer, 2006). need further investigation and which not. There seems to be ample
Infiltrating MIH enamel using low viscosity resins has been at- evidence as to certain aspects like MIH enamel being more porous, with
tempted, but was largely unsuccessful (Kumar, Palamara, decreased mineral density and content and inferior mechanical prop-
Burrow, & Manton, 2012; Natarajan, Fraser, Swain, erties, whilst other aspects require further research, such as the asso-
Drummond, & Gordon, 2015). As resin infiltration of MIH enamel might ciation between clinical appearance and histological findings, the
(a) reduce the enamel permeability, thus reducing the risk of hy- properties of the transitional enamel (between affected and unaffected
persensitivity, and (b) increase the inherent hardness and flexural enamel), and the role and characteristics of the dentine underlying the
strength of the enamel as well as bond strength to it, thus improving the MIH-affected enamel. Secondly, given the high risk of artefacts and the
longevity of adhesive restorations (Chay et al., 2014; William et al., difficulties in comparing and validating findings across studies, future
2006), further research into adapting the infiltration protocol might be studies should not employ one, but several analytical methods to ‘tri-
clinically useful. Again, the removal of proteins from the porous enamel angulate’ findings, increasing their robustness and validity. Thirdly, an
seems of relevance here, as infiltration is unlikely to occur into protein- agreed set of methodologies should be used to explore specific para-
rich enamel. meters in a standardized way, for example concerning storage medium,
sample preparation protocol, 2- or 3-dimensional assessments etc. This
4.2. Heterogeneity and ambiguity in current research will also to help address the second aspect (comparability across stu-
dies). An internal control of sound enamel, preferably from the same
A range of heterogeneous findings was reported. For example, the tooth, should always be assessed, again reducing the risk of bias. By

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doing so, the transitional region between sound and affected enamel dx.doi.org/10.1016/j.jdent.2009.11.003.
Chay, P. L., Manton, D. J., & Palamara, J. E. (2014). The effect of resin infiltration and
should be studied as well. This area is relevant, as it might need re- oxidative pre-treatment on microshear bond strength of resin composite to hypomi-
moval (i.e. tissue removal might need to extend beyond the clinically neralised enamel. International Journal of Paediatric Dentistry, 24(4), 252–267. http://
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Clarkson, J. (1989). Review of terminology, classifications, and indices of developmental
mechanical properties. defects of enamel. Advances in Dental Research, 3(2), 104–109. http://dx.doi.org/10.
Some attention may be missing regarding the structures supporting 1177/08959374890030020601.
the enamel in MIH-affected teeth. Heijs et al. investigated dentin be- Commission on Oral Health, Research & Epidemiology. Report of an FDI Working Group
(1992). A review of the developmental defects of enamel index (DDE Index).
neath MIH-affected enamel and reported a significant increase of the International Dental Journal, 42(6), 411–426.
inter-globular dentin using SEM; however, they did not identify any Crombie, F., Manton, D., & Kilpatrick, N. (2009). Aetiology of molar-incisor hypomi-
structural differences compared with normal dentin (Heijs, Dietz, neralization: A critical review. International Journal of Paediatric Dentistry/the British
Paedodontic Society [and] the International Association of Dentistry for Children, 19(2),
Norén, Blanksma, & Jälevik, 2007). Future studies should include an
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assessment of the underlying dentin that could be associated with PEB, Crombie, F. A., Cochrane, N. J., Manton, D. J., Palamara, J. E., & Reynolds, E. C. (2013).
as well as developing an understanding of the proteins remaining in Mineralisation of developmentally hypomineralised human enamel in vitro. Caries
MIH enamel and how these might be altered or changed to improve Research, 47(3), 259–263. http://dx.doi.org/10.1159/000346134.
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Hypomineralized second primary molars: Prevalence data in Dutch 5-year-olds.
Defects with PEB should be included in analytical studies, as these have Caries Research, 42(4), 282–285. http://dx.doi.org/10.1159/000135674.
the greatest subjective impact on patients and pose the biggest chal- Elfrink, M. E., ten Cate, J. M., Jaddoe, V. W., Hofman, A., Moll, H. A., & Veerkamp, J. S.
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Dentistry, 41(11), 974–978. http://dx.doi.org/10.1016/j.jdent.2013.08.024.
Elhennawy, K., & Schwendicke, F. (2016). Managing molar-incisor hypomineralization: A
Understanding the structural, mechanical and chemical properties systematic review. Journal of Dentistry, 55, 16–24. http://dx.doi.org/10.1016/j.jdent.
of MIH-affected teeth is important for both the researcher and the 2016.09.012.
Fagrell, T. G., Dietz, W., Jälevik, B., & Norén, J. G. (2010). Chemical, mechanical and
clinician. Based on the studies included in this review, a basic under-
morphological properties of hypomineralized enamel of permanent first molars. Acta
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amel was found. Certain aspects, however, are reported ambiguously, 00016351003752395.
which raises questions towards the methodologies used, and calls for a Fagrell, T. G., Salmon, P., Melin, L., & Norén, J. G. (2013). Onset of molar incisor hy-
pomineralization (MIH). Swedish Dental Journal, 37(2), 61–70.
standard set of protocols and outcome measures in studies investigating Farah, R. A., Drummond, B. K., Swain, M. V., & Williams, S. (2008). Relationship between
the properties of MIH enamel. Linking basic-research knowledge, for laser fluorescence and enamel hypomineralisation. Journal of Dentistry, 36(11),
example, with regards to lesion extension, the transitional region be- 915–921. http://dx.doi.org/10.1016/j.jdent.2008.07.012.
Farah, R., Drummond, B., Swain, M., & Williams, S. (2010). Linking the clinical pre-
tween sound-appearing and clinically affected enamel, or the structural sentation of molar-incisor hypomineralisation to its mineral density. International
changes when conditioning affected enamel using acids or self-etch Journal of Paediatric Dentistrythe British Paedodontic Society [and] the International
adhesives etc., with clinical protocols (e.g. regarding risk stratification, Association of Dentistry for Children, 20(5), 353–360. http://dx.doi.org/10.1111/j.
1365-263X.2010.01061.x.
or restorative procedures) should be a focus of future studies. Farah, R. A., Monk, B. C., Swain, M. V., & Drummond, B. K. (2010). Protein content of
molar-incisor hypomineralisation enamel. Journal of Dentistry, 38(7), 591–596.
Conflict of interest http://dx.doi.org/10.1016/j.jdent.2010.04.012.
Farah, R. A., Swain, M. V., Drummond, B. K., Cook, R., & Atieh, M. (2010). Mineral
density of hypomineralised enamel. Journal of Dentistry, 38(1), 50–58. http://dx.doi.
The authors declare that they have no conflict of interests and all org/10.1016/j.jdent.2009.09.002.
authors have read and approved the final draft. Fearne, J., Anderson, P., & Davis, G. R. (2004). 3D X-ray microscopic study of the extent
of variations in enamel density in first permanent molars with idiopathic enamel
hypomineralisation. British Dental Journal, 196(10), 634–638. http://dx.doi.org/10.
Funding 1038/sj.bdj.4811282 [discussion 625].
Fraser, S. J., et al. (2015). A Raman spectroscopic study of teeth affected with molar-
This research did not receive any specific grant from funding incisor hypomineralisation. Journal of Raman Spectroscopy, 46(2), 202–210.
Gambetta-Tessini, K., Marino, R., Ghanim, A., Adams, G. G., & Manton, D. J. (2017).
agencies in the public, commercial, or not-for-profit sectors. Validation of quantitative light-induced fluorescence-digital in the quantification of
demarcated hypomineralized lesions of enamel. Journal of Investigative and Clinical
Ethical approval Dentistry. http://dx.doi.org/10.1111/jicd.12259.
Garcia-Margarit, M., Catala-Pizarro, M., Montiel-Company, J. M., & Almerich-Silla, J. M.
(2014). Epidemiologic study of molar-incisor hypomineralization in 8-year-old
Not applicable. Spanish children. International Journal of Paediatric Dentistry/the British Paedodontic
Society [and] The International Association of Dentistry for Children, 24(1), 14–22.
http://dx.doi.org/10.1111/ipd.12020.
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