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\begin{document}

\title{Two families with Axenfeld-Rieger Syndrome, a case series describing
clinical findings, treatment of the dental anomalies and dentofacial
deformities and a review of the current clinical findings and genetic
knowledge.}



\author[1]{Sanne Andersen}%
\author[1]{Jan Madsen}%
\author[1]{Thomas Kofod}%
\affil[1]{Copenhagen University Hospital Centre of Head and Orthopaedics}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
A descriptive retrospective review of two Danish families with
Axenfeld-Rieger Syndrome. Documenting clinical findings, treatment of
the dental anomalies and dentofacial deformities is described. This
article demonstrates the importance of early diagnosis, referral and
treatment in highly specialized center to receive the best outcome.%
\end{abstract}%



\sloppy


TITLE PAGE

Two families with Axenfeld-Rieger Syndrome, a case series describing
clinical findings, treatment of the dental anomalies and dentofacial
deformities and a review of the current clinical findings and genetic
knowledge.

Authors

Sanne W. M. Andersen\textsuperscript{1}

Jan Hesselberg Madsen\textsuperscript{1}

Thomas Kofod Steengaard\textsuperscript{1}

\textsuperscript{1}Department of Oral and Maxillofacial Surgery,
Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100
Copenhagen, Denmark.

sanne.werner.moeller.andersen@regionh.dk, Blegdamsvej 9, 2100
Copenhagen, telephone 0045 35 45 79 30

Corresponding author:

Sanne Werner Moeller Andersen, sanne.werner.moeller.andersen@regionh.dk,
Drechselsgade 12, 11 th, 2300 Copenhagen, telephone number 00 45 35 45
79 30

Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen
University Hospital, Copenhagen, Denmark.

Data availability statement:

Not applicable.

Funding:

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

Conflict of interest disclosure:

Authors have no conflicts of interest to declare.

Editorial approval statement:

An approval from the data comity was achieved VC-2019-71.

Patient consent statement:

Patients signed an informed consent allowing clinical photos to be
published.

Permission to reproduce material from other sources

Not applicable.

Clinical trial registration

Not applicable.

Acknowledgments

Not applicable.

\emph{ABSTRACT}

A descriptive retrospective review of two Danish families with
Axenfeld-Rieger Syndrome. Documenting clinical findings, treatment of
the dental anomalies and dentofacial deformities is described. This
article demonstrates the importance of early diagnosis, referral and
treatment in highly specialized center to receive the best outcome.

\emph{KEY CLINICAL MESSAGE}

Early diagnose and treatment is important to reduce risk of blindness
and to initiate early treatment of dentofacial abnormalities to improve
functional and aesthetic outcome. A highly specialized multidisciplinary
team is advisable.

\emph{KEYWORDS}

Axenfeld-Rieger syndrome, dental anomalies, maxillofacial anomalies,
craniofacial anomalies.

\emph{INTRODUCTION}

Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder
with complete penetration and variable expressivity (1). The first
description of the inherited syndrome was in 1935 by Rieger (2, 3).
Different estimated incidence has been described 1:200.000 (2), 1:50.000
to 1:100.000 (1). 70\% of the cases are inherited and 30\% are arising
de novo (4). ARS has variable expressivity and it is considered to be a
heterogeneous disorder both morphologically and genetically (2, 3, 5).
There is not reported any racial or sexual predilection (6, 7) and the
syndrome has been described in different ethnic groups, including Asia,
Middle East, South and North America, Africa and Europe (1).

ARS is a combination of anterior chamber cleavage syndrome and nonocular
abnormalities (8). Since 1989 (9) the term ARS has been used
collectively for, Axenfeld's syndrome, Axenfeld's anomaly, Rieger's
anomaly and Rieger's syndrome (10). An overview is giving in table 1
with a description of the different anomalies and syndromes according to
Bender et al. (10). ARS is characterized as a syndrome with malformation
of the anterior segment of the eye in combination with a wide spectrum
of non-ocular abnormalities such as dental, craniofacial and somatic
abnormalities. The wide range of clinical presentation and developmental
disturbances is described by many authors in the literature (2-8, 11,
12) and is listed in table 2. Hypodontia and failure of the
periumbilical skin to involute is most frequently seen (3, 7, 8). A
change in the periumbilical skin can be wrongly diagnosed as umbilical
hernia and lead to unnecessary surgery (1).

Pathogenesis of ARS is assumed to be a genetic failure that results in
development disturbance in the late gestation period. A defect in the
ectodermal tissue due to a change in migration and differentiation of
the neural crest tissue is thought to be the cause (8, 9). The neural
crest cells are responsible for the formation of the craniofacial and
ocular structures including bones, cartilage, dental papillae, pituitary
gland and the umbilical ring (7). ARS is in the literature (1, 13)
divided in to three different types, due to different genetic mutations
and deletions (14, 15) combined with different ocular and systemic
expressions see table 3.

The aim of this study is to present to two families with Axenfeld-Rieger
Syndrome, present their clinical findings, treatment of the dental
anomalies and dentofacial deformities.

\emph{MATERIAL AND METHOD}

\textbf{Editorial policies and ethical considerations}

An approval from the data comity was achieved VC-2019-71 and the
patients signed an informed consent allowing clinical photos to be
published. The study follows the Declaration of Helsinki.

\textbf{Case series}

At the Department of Oral and Maxillofacial Surgery, Copenhagen
University Hospital, Rigshospitalet, we treated and followed four
patients in two Danish families, in the period 1987 to 2019. The
patients were initially referred from private dental practice, dental
school and the public dental healthcare, all with functional and
aesthetic problems, due to malocclusion and reduced chewing function
caused by missing teeth and/or broken prosthetics.

Patient files and radiographs were reviewed concerning dental and
craniofacial anomalies, likewise the treatment performed. Common to all
patients was multiple agenesis and class III malocclusion due to
hypoplastic and retrognathic maxillae. Considering treatment all
patients were treated by a multidisciplinary team of surgeons,
orthodontists and prosthodontists. Three out of four patients had a
corrective Le Fort 1 osteotomy. All had bone augmentation from
mandibular ramus or iliac crest simultaneously with placement of dental
implants. After the healing period fixed oral rehabilitation was
performed. In table 4 a full description of the patient's clinical and
radiographical manifestations and treatment is listed.

All patients were followed in the years after treatment, implant follow
up between 1 and 13 years. Only one implant was lost prior to loading
and the patient received a fixed dental bridge instead, due to the wish
of patient of no further surgeries. All the patients are satisfied with
the treatment both aesthetically and functionally. The patients are all
presented as 4 separate cases with clinical and radiographic findings
and follow up, see figure 1, figure 2, figure 3 and figure 4.

\emph{DISCUSSION}

In patients with ARS it is described (9) that 43\% showed dental
abnormalities and 24 \% had facial anomalies but not all patients show
the same manifestations of abnormalities and anomalies. The different
clinical presentation is probably due to pleiotropic genes affecting the
tissues derived from neural crest cells (16), making it a morphologic
and heterogeneous syndrome. There are many different strategies and
opinions on the timing and planning for correction of the skeletal
anomalies and missing teeth, this force individual planning in each
patient.

In the literature there is, in general an agreement on the importance of
a specialized team for planning and treatment each individual patient,
due to ARS being a syndrome with a wide phenotypic heterogeneity.

Early diagnosis and treatment planning both concerning the dentofacial
appearance and function but also more crucial diagnosing systemic
abnormalities. Missing or delaying diagnosis of abnormalities in the
ocular aspect could increase the risk of a patient to become blind due
to missing prophylaxis and/or postponed initialized treatment. The
diagnosis is made based on the clinical and ophthalmologic examination,
and if ARS is suspected a genetic analyze can be performed.

The treatment plan is depending on a good interdisciplinary team of
ophthalmologist, geneticist, maxillofacial surgeon, orthodontist and
prosthodontist, working as a highly specialized team. Relative to the
dentofacial deformity, early treatment in childhood or early
adolescence, in terms of adaptive growth treatment, eg. Hugo De Clerck
type of treatment could possibly benefit the patients (17).

\textbf{Genetics}Genetic loci have been described to have association
with ARS: FOXC1, Forkhead box protein C1, on chromosome 6p25. PITX2,
Pituitaryn Homeobox 2, on chromosome 4q25. PAX6, on chromosome 11. A
fourth locus had been found on chromosome 13q14 but the gen is not
identified yet (2). FOXC1 mutations are often associated with patients
with ocular abnormalities, hearing and heart defects (10), 50-75\% of
patients with the mutation will develop glaucoma (18). There is 54 known
mutations of FOXC1 gene including missense (n=31), nonsense (n=6) and
deletions, duplications, frameshift, insertions (n=17) (19). The
mutations alter the function of FOXC1 by alteration in the gene
structure, nuclear localization, DNA-binding capacity, transactivation
activity, DNA-binding specify and protein stability. Point mutations are
found to be the most common (20). PITX2 mutations are associated with
ocular and systemic abnormalities (10). PITX2 is an activator for genes
(DIX2) that are essential in teeth and craniofacial development (5, 10).
There is 87 known mutations of PITX2 gene including missense (n=33),
nonsense (n=10), splice-site (n=6) and deletions/insertions/duplications
(n=38) (1). The expression and function of FOXC1 and PITX2 is collected
in Table 5 due to (21), (22)

(2) found that 40 \% of the patients had a mutation in PITX2. A mutation
in PITX2 and FOXC1 is estimated to be responsible for 40\% of the cases
of ARS (10). As stated earlier in table 3 there is a correlation between
the mutations and the type of ARS.

\emph{CONCLUSION}

Only the beginning of the cell biology and molecular genetics is being
understood and 60\% of the genetic basis of ARS in still unknown. Early
diagnose is important due to initiate early treatment hereby reduce the
possible effect of the anterior chamber changes and postpone or
hopefully avoid blindness. Because of the high incidence of glaucoma, it
is crucial to follow the patients frequently and monitor the intraocular
pressure and the appearance of the optic nerve. Likewise, it is
important to initiate early treatment of dental and facial abnormalities
to improve functional and aesthetic outcome. As the care of the patients
is complex it is advisable to have highly specialized multidisciplinary
team to diagnose and treat this patient group.

\emph{ACKNOWLEDGEMENTS}

There is no conflict of interest to declare from any of the authors and
only the listed authors contribute to the article. No financial or
material support was giving.

\emph{REFERENCES}

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2. Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the Eye. In: Gorlin
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ed. Oxford: Oxford University Press; 2001. p. xlv, 1283 p.

3. Jones KL, Smith DW. Rieger Syndrome. In: Jones KL, Smith DW, editors.
Smith's recognizable patterns of human malformation. 6th ed.
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4. O'Dwyer EM, Jones DC. Dental anomalies in Axenfeld-Rieger syndrome.
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5. Dressler S, Meyer-Marcotty P, Weisschuh N, Jablonski-Momeni A, Pieper
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6. Brooks JK, Coccaro PJ, Jr., Zarbin MA. The Rieger anomaly concomitant
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7. Singh J, Pannu K, Lehl G. The Rieger syndrome: orofacial
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8. Waldron JM, McNamara C, Hewson AR, McNamara CM. Axenfeld-Rieger
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13. Amendt BA, Semina EV, Alward WL. Rieger syndrome: a clinical,
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14. Acharya M, Huang L, Fleisch VC, Allison WT, Walter MA. A complex
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development and disease. Human molecular genetics. 2011;20(8):1610-24.

15. Phillips JC. Four novel mutations in the PITX2 gene in patients with
Axenfeld-Rieger syndrome. Ophthalmic research. 2002;34(5):324-6.

16. Shields MB. Axenfeld-Rieger syndrome: a theory of mechanism and
distinctions from the iridocorneal endothelial syndrome. Transactions of
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17. Siddiqui HP, Sennimalai K, Samrit VD, Duggal R, Yadav R. Adjunctive
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18. Berry FB, Mirzayans F, Walter MA. Regulation of FOXC1 stability and
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19. Seifi M, Footz T, Taylor SA, Walter MA. Comparison of Bioinformatics
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2017;38(2):169-79.

20. Yang HJ, Lee YK, Joo CK, Moon JI, Mok JW, Park MH. A Family with
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Korean J Ophthalmol. 2015;29(4):249-55.

21. Strungaru MH, Footz T, Liu Y, Berry FB, Belleau P, Semina EV, et al.
PITX2 is involved in stress response in cultured human trabecular
meshwork cells through regulation of SLC13A3. Invest Ophthalmol Vis Sci.
2011;52(10):7625-33.

22. Saleem RA, Murphy TC, Liebmann JM, Walter MA. Identification and
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\emph{}

\emph{TABLES}

Table 1: Combination of anomalies and syndromes in Axenfeldt Riegers
Syndrome

Table 2: Possible clinical findings in patients with Axenfeldt Riegers
Syndrome

Table 3: Types of Axenfeldt Riegers Syndrome

\emph{}

Table 4: Treatment and clinical findings in the presented four cases

\emph{}

Table 5: Expression and function of genes resulting in Axenfeld Riegers
Syndrome

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