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8 Fundamental Mechanisms ofOrofacial Clefts

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427. Monsoro-Burq AH, Wang E, Harland R.Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction. Dev Cell. 2005;8:167–78.

428. Qi HH, Sarkissian M, Hu GQ, Wang Z, Bhattacharjee A, Gordon DB, Gonzales M, Lan F, Ongusaha PP, Huarte M, Yaghi NK, Lim H, Garcia BA, Brizuela L, Zhao K, Roberts TM, Shi Y. Histone H4K20/ H3K9 demethylase PHF8 regulates zebrash brain and craniofacial development. Nature. 2010;466: 503–7.

429. Liu S, Higashihori N, Yahiro K, Moriyama K.Retinoic acid inhibits histone methyltransferase Whsc1 during palatogenesis. Biochem Biophys Res Commun. 2015;458:525–30.

430. Ding HL, Clouthier DE, Artinger KB. Redundant roles of PRDM family members in zebrash craniofacial development. Dev Dyn. 2013;242(1):67–79.

431. Shull LC, Sen R, Menzel J, Goyama S, Kurokawa M, Artinger KB.The conserved and divergent roles of Prdm3 and Prdm16in zebrash and mouse craniofacial development. Dev Biol. 2020;461(2): 132–44.

432. Gou Y, Li J, Wu J, Gupta R, Cho I, Ho TV, Chai Y, Merrill A, Wang J, Xu J.Prmt1 regulates craniofacial bone formation upstream of Msx1. Mech Dev. 2018;152:13–20.

433. Singh N, Gupta M, Trivedi CM, Singh MK, Li L, Epstein JA. Murine craniofacial development requires Hdac3-mediated repression of Msx gene expression. Dev Biol. 2013;377:333–44.

434. Arnold MA, Kim Y, Czubryt MP, Phan D, McAnally J, Qi X, Shelton JM, Richardson JA, Bassel-Duby R, Olson EN.MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell. 2007;12:377–89.

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436. Ala U. Competing endogenous RNAs, non-coding RNAs and diseases: an intertwined story. Cells. 2020;9:1574.

437. Lee CT, Risom T, Strauss WM. MicroRNAs in mammalian development. Birth Defects Res C. 2006;78:129–39.

438. Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci. 2016;17:1712.

439. Friedman RC, Farh KK, Burge CB, Bartel DP.Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105.

440. Schoen C, Aschra A, Thonissen M, Poelmans G, Von den Hoff JW, Carels CEL.MicroRNAs in palatogenesis and cleft palate. Front Physiol. 2017;8:165.

441. Faller M, Guo F. MicroRNA biogenesis: there’s more than one way to skin a cat. BBA-Mol Cell Biol L. 2008;1779:663–7.

442. Cao H, Wang J, Li X, Florez S, Huang Z, Venugopalan SR, Elangovan S, Skobe Z, Margolis HC, Martin JF, Amendt BA.MicroRNAs play a critical role in tooth development. J Dent Res. 2010;89:779–84.

443. Nie X, Wang Q, Jiao K.Dicer activity in neural crest cells is essential for craniofacial organogenesis and pharyngeal arch artery morphogenesis. Mech Dev. 2011;128:200–7.

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445. Seelan RS, Mukhopadhyay P, Warner DR, Appana SN, Brock GN, Pisano MM, Greene RM.Methylated microRNA genes of the developing murine palate. Microrna. 2014;3:160–73.

446. Eberhart JK, He X, Swartz ME, Yan YL, Song H, Boling TC, Kunerth AK, Walker MB, Kimmel CB, Postlethwait JH. MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis. Nat Genet. 2008;40:290–8.

447. Li A, Jia P, Mallik S, Fei R, Yoshioka H, Suzuki A, Iwata J, Zhao Z. Critical microRNAs and regulatory motifs in cleft palate identied by a conserved miRNA-TF-gene network approach in humans and mice. Brief Bioinform. 2020;21:1465–78.

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Biological Basis

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ofCraniosynostosis

ChristianFreudlsperger andMichaelEngel

9.1 Introduction

The development of the human skull is composed of the ventral viscerocranium, i.e., the facial skull, and the dorsal neurocranium, which encapsulates the developing brain. The neurocranium has dual developmental origin including mesoderm and neural crest cells [1] and consists of the fontal bone, pars petrosa of the parietal bone, temporal bone, and occipital bone. As the occipital and the pars petrosa of the temporal bone are built during chondral osteogenesis, the frontal and parietal bone are formed by dermal osteogenesis. Cranial sutures are formed at the sites of approximation of these bones. The six major skull sutures are the metopic and the sagittal suture, the two coronal sutures, and the two lambdoid sutures. They act as interosseous ligaments and are the primary site of bone growth. The tension on the cranial sutures caused by the expanding brain acts as the adequate stimulus for bone remodeling and therefore coordinates brain growth with bone growth. This process relies on the production of sufcient new bone cells to be released into the bone fronts, while cells within the suture remain undifferentiated. To function as bone growth sites, sutures need to remain patent [2]. Premature obliteration of cranial sutures (i.e., craniosynostosis) by fusion of

C. Freudlsperger (*) · M. Engel Department of Oral and Maxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany e-mail: christian.freudlsperger@med.uni-heidelberg.de

bone fronts suppresses bone growth at this side, enhances growth at patent sutures, and therefore leads to abnormal morphogenesis and craniofacial deformity affecting the growth of viscerocranium, neurocranium, and brain tissue itself [3]. Shaping growth of the human skull mainly takes place from the rst months after conception to the end of the rst year of life. As premature osseous obliteration of cranial sutures mainly takes place intrauterine, craniosynostosis becomes visible shortly after birth. The extent of the craniofacial deformity depends on the affected suture and the moment of intrauterine obliteration: The earlier this obliteration occurs, and the more sutures affected, the greater the deformity. Specic isolated craniosynostosis typically results in pathognomonic deformities, e.g., scaphocephaly due to synostosis of the sagittal suture. However, the biological basis of craniosynostosis is multifactorial and understanding the biological basis starts by recognizing the heterogeneity of their pathogenesis. Craniosynostosis can be divided into primary (with genetic origin) and secondary forms, which are extremely rare. The classication of primary intrauterine craniosynostosis discriminates syndromic and non-syndromic forms, whereas the latter account for approximately 70% of cases [4–6]. Monogenetic mutations are responsible for intrauterine craniosynostosis (85% of cases), and some patients though present chromosomal disorders, i.e., numeric and structural aberrations.

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9.2 Syndromic Forms ofPrimary Craniosynostoses

Over 150 syndromes associated with intrauterine craniosynostoses have been described [7] and are associated with additional congenital anomalies and/or developmental delays, e.g., growth and developmental retardation. However, surgical therapy of craniosynostoses is based on the deformity itself and is not affected by the categorization of a specic syndrome. Nevertheless, these connotations allow precise conclusions concerning inheritance and prognosis.

The rst human craniosynostosis gene was discovered by E. W. Jabs and colleagues in Boston-type craniosynostosis and described a mutation in the human MSX2 gene in an affected family in 1993 [8]. Since then, mutations of the broblast growth factor receptors have been associated with eight syndromic forms of primary craniosynostoses (Crouzon, Apert, Pfeiffer, Jackson-Weiss, Muenke, FGFR2-related isolated coronal synostosis, Crouzon syndrome with acanthosis nigricans, and Beare-Stevenson syndrome). The most common will be discussed in the following section.

9.2.1 Crouzon Syndrome

Crouzon syndrome is a rare disease described by Louis Edouard Octave Crouzon in 1912 and is estimated to occur in 1 case per 60,000 live birth in the United States [9]. It is transmitted in an autosomal dominant manner with variable penetrance and characteristic features including craniosynostosis, maxillary hypoplasia, and exophthalmos. Mandibular prognathism, ocular hypertelorism, and nasal deformity are further malformations associated with Crouzon. It can also cause hearing loss and airway challenges due to deformities in the nasal cavity and nasopharyngeal airway [10] interfering with normal neuropsychological development [11]. Affected sutures are variable leading to brachycephaly, scaphocephaly, trigonocephaly, and cloverleaf skull. Due to abnormal cranial vault formation, patients may present with hydrocephalus result-

ing in elevated intracranial pressures with papilledema, compression of optic nerves, and Chiari malformation [12, 13]. Crouzon syndrome is caused by gain-of-function mutations of the broblast growth factor receptor 2 (FGFR2) (10q25-q26) [14]. The proteins of the broblast growth factor (FGF) family are involved in a wide variety of processes including mitogenesis and morphological effects and are critical during embryogenesis. The FGFR1-3 belongs to the tyrosine kinase superfamily. They are activated by binding to FGF isoforms resulting in dimerization and autophosphorylation, nally affecting multiple downstream targets including canonical Wnt, Src, and STAT signaling as well as protein kinase C, RAS-MAPK, PI3K- AKT, and PLCγ pathways [15, 16]. The abovementioned gain-offunction mutations result in increased afnity of FGFR to FGF, decreased specicity, or enhanced intrinsic receptor activity [17]. Although detailed molecular mechanisms leading to craniosynostosis are not clear, translational research shows that these mutations result in enhanced bone mineralization and FGFR signaling plays an important role in osteoblast differentiation [17].

A distinct type of this disorder is Crouzon syndrome with acanthosis nigricans caused by a specic mutation in the FGFR3 gene (Ala391Glu). Patients present additional characteristic dermatological ndings, choanal atresia, short vertebral bodies, as well as broad, short metacarpals and phalanges [13, 18].

9.2.2 Apert Syndrome

Eugene Charles Apert, a French pediatrician, rst described this autosomal dominant disorder in

1906.

It is an uncommon disease with an estimated prevalence of 1 case per 65,000 live birth and instantly recognizable on the basis of the syndactyly of both the hands and feet [19]. Further characteristic clinical features include brachycephaly, delayed closure of fontanels, dysmorphic features like attened asymmetrical face, downslanting palpebral ssures, hypertelorism, shallow orbits, exorbitism, strabismus, and markedly

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depressed nasal bridge, and cleft palate [13]. In addition, structural brain abnormalities (e.g., ventriculomegaly or malformation of corpus callosum) are associated with Apert syndrome with delayed psychomotor development and mild to moderate intellectual disability [11]. Further ndings are otitis media and conductive hearing loss associated with malformed and/or fused middle ear ossicles, dehiscence of semicircular canals, and cochlear malformations [13]. As well as in Crouzon syndrome, FGFR2 mutations have been identied to be causative in Apert syndrome [20]. Two heterozygous gain-of-function substitutions, Ser252Trp and Pro253Arg, in exon 7 of the FGFR2 gene are responsible for over 98% of Apert syndrome cases [13]. They are transmitted in an autosomal dominant manner and show complete penetrance with variable expressivity. Most mutations occur de novo and are mainly of paternal origin with age effect [13].

9.2.3 Pfeier Syndrome

Rudolf Arthur Pfeiffer, a German pediatrician, rst described this autosomal dominant disorder with complete penetrance and signicant variability in 1964 [21]. It is uncommon and affects one patient per 100,000 newborn. Premature fusion of coronal, lambdoid, and (occasionally) sagittal suture leads to a characteristic wide skull shape with at occiput, high forehead, midfacial hypoplasia, hypertelorism, and proptosis. It is associated with broad thumbs and big toes and variable partial syndactyly on both hands and feet [22]. Delayed psychomotor development, abnormal viscera, ankylosed elbows, exorbitism, and hydrocephaly caused by aqueductal stenosis are rare ndings in patients with Pfeiffer syndrome [22]. Tracheal cartilaginous sleeve, a severe airway anomaly with missing distinct tracheal rings, has been reported in this entity [23]. Pfeiffer syndrome is divided into three major subtypes according to severity (Table9.1). Type II and III phenotypes have an increased risk for early death due to neurological complications [22]. Mutations in FGFR1 (Pro252Arg) and FGFR2 are causative in Type I, whereas Types II and III are caused by

Table 9.1 Major subtypes of Pfeiffer syndrome

•

Pfeiffer type I (classic phenotype)

Pfeiffer type II •

Pfeiffer type III

mutations in FGFR2 [

Brachycephaly, midface hypoplasia,

hand and feet abnormalities

• Normal neurological and intellectual development

• Good outcome

Cloverleaf skull, extreme proptosis,

hand and feet abnormalities, elbow ankylosis or synostosis

Developmental delay and

• neurological complications: limited brain growth due to skull shape, visual impairment due to proptosis

•

Similar to type II, but without

cloverleaf skull

22, 24–26]. About 21% of

patients clinically diagnosed with Pfeiffer syndrome lack FGFR1/2 mutations [13].

9.2.4 Jackson-Weiss Syndrome

Charles Jackson, Lester Weiss, and colleagues rst described this unusual syndrome within a large Amish kindred in 1976 [27]. Jackson-Weiss syndrome is similar to the condition described by Pfeiffer but lacks thumb abnormality. It is of autosomal dominant inheritance with varying phenotypic expression.

Mutations in FGFR2 have been described to

be causative in this rare condition [28, 29].

9.2.5 Muenke Syndrome

Maximilian Muenke and colleagues dened this distinct disorder on a molecular level in 1997 [30]. They identied a common mutation (Pro250Arg) located between the second and third immunoglobulin-like domains of the FGFR3 protein, which is related to the FGFR1 (Pro252Arg) mutation in Pfeiffer and FGFR2 (Pro253Arg) mutation in Apert syndromes. They reported inter- and intrafamilial variability whose main characteristics include bilateral or unilateral coronal synostosis and specic bone anomalies of the hands and feet in some affected individuals. Interestingly, some mutation carriers did not

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show any signs of craniosynostosis, having only macrocephaly or even normal head size. Midface hypoplasia, ptosis, sensorineural hearing loss, and downslanting palpebral ssures are very rare ndings in patients with Muenke syndrome [30].

9.2.6 Saethre-Chotzen Syndrome

First described by Saethre and Chozen in the early 1930s, Saethre-Chotzen syndrome is characterized by unilateral or bilateral synostosis of the coronal suture, limb anomalies, i.e., syndactyly of digits two and three of the hand [31, 32]. Patients present with facial asymmetry in case of unilateral synostosis, characteristic appearance of the ear (small pinna with a prominent superior and/or inferior crus), strabismus, and ptosis [33]. Other dysmorphic features such as parietal foramina, radioulnar synostosis, maxillary hypoplasia, ocular hypertelorism, increased intracranial pressure, short stature, and congenital heart malformations are rare, but have been reported [33]. Cognitive developmental is usually normal. It is important to know that individuals with SCS with no evidence of craniosynostosis have been described. The locus for Saethre-Chotzen syndrome maps to chromosome 7p21-p22, and loss-of-function mutations in TWIST1 have been reported to be causative in Saethre-Chotzen syndrome. TWIST1 encodes an important transcription factor for mesodermal patterning of the calvaria, is expressed in the osteoprogenitor cells of cranial sutures, and is important in osteoblast differentiation. Mutations in TWIST1 result in disruption of the RUNX2 pathway affecting the transcription of FGFR [17, 34, 35].

9.2.7 Craniofrontonasal Syndrome

Craniofrontonasal syndrome, an X-chromosomaldominant disorder with paradoxically greater severity in heterozygous females than in hemizygous males, is caused by mutations in EFNB1, whose gene product ephrin-B1 plays a role in cell

adhesion [36]. It is thought that, in heterozygous females, patchwork loss of ephrin-B1 disturbs tissue boundary formation at the developing coronal suture, whereas in males decient in ephrinB1, an alternative mechanism maintains the normal boundary [36].

Although most of syndromic craniosynostoses show dominant inheritance, approximately half of patients present with de novo mutations. In recent years, causative mutations in over 50 genes have been identied and multiple novel gene/disease associations in syndromic craniosynostosis have been detected by use of nextgeneration sequencing [37, 38].

9.3 Non-syndromic Forms

ofPrimary Craniosynostoses

Non-syndromic craniosynostoses are a group of isolated malformations resulting in premature intrauterine suture fusion: sagittal, coronal, metopic, and lambdoid sutures in decreasing order of frequency. They built a genetically heterogeneous and largely unexplored group, as diagnostic success rates are low in trigonocephaly and scaphocephaly (<1%) and slightly higher in unicoronal (13%), multisuture (15%), or bicoronal (60%) synostosis [17]. Nonsyndromic forms of craniosynostosis are sporadic in more than 95% [39]. As Mendelian patterns of inheritance are uncommon, and the disease likely arises from a combination of polygenic inuences and epigenetic factors, a large cohort of patients is needed to study these complex traits and to identify genetic risk factors. However, recent progress in the genetics of non-syndromic craniosynostosis has been made and reviewed by Timberlake and Persing [38]. By using a trio- based whole-exome sequencing approach including both parents and patients with non- syndromic craniosynostosis, several causal genes and pathways have been identied (see Table9.2). These recent ndings implicate mutations in similar pathways (Wnt, BMP and Ras/ERK) as frequent causes of syndromic and non-syndromic craniosynostoses [38].

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Table 9.2 Genes in which mutations confer high risk of

non-syndromic craniosynostosis recurrence in subsequent offspring, Timberlake and Persing [38]

Gene Mechanism Type SMAD6 SMAD6 is an inhibitor of

BMP signaling. Loss-offunction mutations lead to augmented SMAD signaling

TWIST1 TWIST1 is a basic helix-

loop-helix transcription factor downstream of several developmental signaling pathways. Loss-of-function mutations lead to transcriptional dysregulation

TCF12 TCF12 is a basic helix-loop-

helix transcription factor that heterodimerizes with TWIST1. Loss-of-function mutations phenocopy TWIST1 mutations

ERF ERF shuttles phosphorylated

ERK from the nucleus, thus regulating RAS/MAPK/ERK signaling. Loss-of-function mutations in ERF lead to augmented ERK signaling

MSX2 MSX2 is a transcription

factor downstream of BMP signaling. Mutations at a recurrent codon (p.148) lead to increased DNA-binding afnity and increased transcription at target sites

FGFR3 A recurrent gain-of-function

mutation (p.P250R) in FGFR3 leads to augmented FGF signaling

Sagittal, metopic, combined sagittal and metopic Coronal, sagittal

Coronal, sagittal

Metopic, sagittal, multisuture

Coronal, sagittal

Coronal

9.4 Secondary Craniosynostoses

Secondary craniosynostoses represent an extremely rare form with wide etiologic variety including teratogenic, metabolic, and hematologic disorders as well as developmental disorders, e.g., microcephaly or holoprosencephaly. They uncover at a later point of time of around 12–24months postpartum.

Metabolic disorder-based forms, such as hypophosphatemic rickets, can be associated with loss-of-function PHEX mutations affecting FGF23 expression [40] and prolonged therapy with phosphate-binding antacids and vitamin D

deciency caused by malnutrition [41]. Hyperparathyroidism and lysosomal storage disease are further associated conditions. Teratogenic disorders include congenital infections and radiation exposure to teratogenic chemicals, e.g., alcohol or retinoic acid. Hematologic disorder-based forms can be caused by polycythemia vera, thalassemia, or sickle cell anemia.

9.5 Conclusion

As the biological basis of craniosynostosis is multifactorial and heterogeneous, affected families need to be advised properly in specialized centers with extensive experience in both craniofacial surgery and human genetics. This is particularly true for multisuture and inherited forms of craniosynostoses. However, we advise centerbased treatment even in single-suture craniosynostoses to continue recent research progress.

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26. Schell U, et al. Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Hum Mol Genet. 1995;4:323–8.

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30. Muenke M, etal. A unique point mutation in the broblast growth factor receptor 3 gene (FGFR3) denes a new craniosynostosis syndrome. Am J Hum Genet. 1997;60:555–64.

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org/10.1007/978- 3- 319- 31512- 6_64- 1.

https://doi.

Biological Basis ofBranchial Arch

https://t.me/medicina_free

Diseases

UlrichMeyer

10.1 Introduction

Because tissue and organ structures of the head and neck migrate during fetal development, an understanding of embryologic development helps determine the origin and nature of congenital lesions [1]. Disorders of the frontonasal prominence (FNP) and the rst and second branchial arches (BAs) are generally thought to result from a combination of inadequate migration and formation of facial tissues. Branchial arch disease is the term [2, 3] that describes the pathogenetic basis of a specic subset of craniofacial anomalies, also termed facial dysostoses, which can be subdivided into mandibulofacial dysostosis, which present with craniofacial defects only, and acrofacial dysostosis, which encompasses both craniofacial and limb anomalies. Knowledge of the genetic basis of human disease and its effect on embryologic development has greatly expanded in recent years. These malformations have etiologic and pathogenic similarities, specically their unique deciencies in global processes including ribosome biogenesis, DNA damage repair, and pre-mRNA splicing, all of which affect neural crest cell development and result in similar tissue-specic defects.

U. Meyer (*) Craniofacial Center, Kieferklinik Münster, Münster, Germany

University of Düsseldorf, Westdeutsche Kieferklinik, Moorenstrasse, Düsseldorf, Germany e-mail: info@kieferklinik-muenster.de

https://doi.org/10.1007/978-3-030-46024-2_10

10.2 Pathogenesis ofFacial

Development

Head and face development begins during early embryogenesis with formation of the frontonasal prominence and the pharyngeal arches, which are transient medial and lateral outgrowths of cranial tissue [4–6] (Fig.10.1). These craniofacial structures develop into nerves, muscles, cartilage, bone, and connective tissue, including the body’s primary sense organs and necessary for undisturbed feeding, respiration, and facial expression. The human head and face are anatomically complex structures that form during embryogenesis, from the FNP and the PAs (pharyngeal arches). The FNP gives rise to the forehead and the nose, while the paired PAs give rise to the lower face (the jaw), the neck, and part of the upper thorax (Fig. 10.2). Pharyngeal arch development is dependent upon a multipotent, migratory population of neural crest cells, which generate most of the bone and cartilage of the head and face [7–

10]. Since the discovery of the neural crest, the

special ability of these cells to function as a source of species-specic pattern has been clearly recognized during the last decades. Initially, this observation arose in association with chimeric transplant experiments among differentially pigmented amphibians, where the neural crest origin for melanocytes had been duly noted. Shortly thereafter, the role of cranial neural crest cells in transmitting species-specic information on size

149

150

Superior Ganglion Of

e (XI)

C1 Spinal Ganglion

S1 Spinal Ganglion

Vestibular Pouch

https://t.me/medicina_free

U. Meyer

Cochlear Ganglion (VIII)

Geniculate Ganglion (VII)

Tr igeminal Ganglion (V)

Abducens Nerve (VI)

Tr ochlear Nerve (IV)

Oculomotor Nerve (III)

Ophthalmic Nerve (V1)

Optic Stalk (II)

Maxillary Nerve (V2)

Mandibular Nerve (V3)

Olfactory Nerve (I)

Sacral Plexus

Vestibular Ganglion (VIII)

Glossopharyngeal Nerve (IX)

Superior Ganglion

Of Vagus Nerve (X)

Spinal

Accessory Nerv

Hypoglossal

Nerve (XII)

Cervical Plexus

Phrenic Nerve

Brachial Plexus

T1 Spinal Ganglion

Fig. 10.1 Embryologic body development with corresponding nerve distribution. Source: Reprinted from stihii/

Shutterstock.com with permission

and shape to the pharyngeal arch skeleton as well as in regulating the timing of its differentiation became readily apparent [11–13].

nence and the arches is similar in higher species (Fig.10.3). The head and neck originate from six embryonic structures called the pharyngeal apparati, which resemble the branchial apparatus in sh [14]. Each pharyngeal apparatus comprises a pouch, an arch, a groove, and a membrane. In the fourth week of gestation, neural crest cells migrate from the neural tube to begin the development of the pharyngeal arch ectomesenchyme

Lumbar Plexus

L1 Spinal Ganglion

The basic structure of the frontonasal promi-

Sympathetic Trunk

[12, 13]. Each arch has three layers (endoderm, mesenchyme from ectomesenchyme and mesoderm, and ectoderm), which produce the four primordial components: muscle, artery, nerve, and cartilage. Internally, all these structures are lined with endoderm, forming the pharyngeal pouches (Fig.10.4). Concerning branchial arch diseases, the third layer between the ectoderm and endoderm epithelia is of importance [14–16]. This layer is composed of neural crest cells (NCCs) in the frontonasal prominence, whereas in the pharyngeal arches the mesenchymal core is composed of NCC and mesoderm.

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