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Developmental Defects of the Craniofacial Complex and Orthopedic Disorders

J. Timothy Wright DDS, MS

Michael Milano DMD

Luiz Andre Pimenta DDS, MS, PHD

I. Background

Dentists are confronted with diagnostic and treatment challenges for patients with hereditary conditions and unique environmental exposures. Developmental and hereditary disorders vary in their prevalence, morbidity, and need for unique oral health-care management approaches. Providing optimal oral health care is predicated on having a basic understanding of the patient’s underlying systemic and craniofacial condition, their current and future risk for developing oral pathology, and having the skills to manage their oral health needs. Depending on complexity, this can involve a team of oral and medical health-care providers. This chapter reviews some of the more common hereditary conditions affecting the skin, teeth, and bones, and presents dental management approaches.

Description of Disease/Condition

Hereditary Conditions Affecting the Teeth

Thousands of genes are expressed during tooth formation, so it is not surprising that there are many diverse hereditary conditions known to affect teeth. The defects can manifest as changes in the number, shape, size, and/or composition of the teeth. These conditions are genetically and clinically diverse in their presentations and can occur as part of a syndrome or can be isolated to the teeth. Two of the better known hereditary conditions affecting the composition and structure of teeth are amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DGI). These conditions can be challenging to diagnose and manage depending on the specific subtype and its manifestations.

Amelogenesis Imperfecta (AI)

• Most commonly classified into three main categories based on the nature of the enamel defect.¹
• Hypoplastic: thin enamel (see Fig. 17.1).
• Hypomineralized: hypocalcified or hypomaturation.

Figure 17.1 Hypomaturation amelogenesis imperfecta in a young female.

Dentinogenesis Imperfecta (DGI)

DGI and dentin dysplasia type II (DD-II) are the most common hereditary dentin disorders and have an autosomal dominant inheritance. DGI can occur in association with osteogenesis imperfecta (OI) (type DGI-I) or as an isolated defect of teeth (type DGI-II) (see Fig. 17.2).

Figure 17.2 Blue-gray coloration, enamel fracturing, and severe attrition associated with DGI-II.

Hereditary Conditions Affecting the Skin

Many hereditary conditions affect the development of the skin and/or the ectoderm and its appendages. Affected individuals can have increased fragility of the skin or have a lack of development of ectodermally derived appendages and thus can have altered tooth formation.

Ectodermal Dysplasias (EDs)

• Characterized by abnormal development of ectodermally derived tissues, such as skin, hair, nails, sweat glands, and dentition (see Fig. 17.3).
• The current definition of an ED is any condition having two or more affected tissues that are of ectodermal origin.

Figure 17.3 Conical-shaped incisors and hypodontia in an X-linked hypohidrotic ectodermal dysplasia (HED) affected 4-year-old male.

Epidermolysis Bullosa (EB)

• Represents a spectrum of conditions having blistering and mechanical fragility of the skin as their hallmark feature (see Fig. 17.4).
• Given the developmental and structural complexity of the skin, it is not surprising that there is tremendous genetic heterogeneity and marked phenotypic variation in the EB disorders.

Figure 17.4 Blistering of the skin and oral mucosa in a patient with recessive dystrophic epidermolysis bullosa.

Orofacial Clefts (OFCs)

OFCs are congenital malformations characterized by incomplete formation of structures involving the nasal and oral cavities: lip, alveolus, hard and soft palate. OFC may also vary in size, from a defect of the soft palate only to a complete cleft that extends through the bone of the hard palate. Because the lips and the palate develop separately, it is possible for a child to be born with a cleft lip (CL) only, cleft palate (CP) only, or the combination of both cleft lip and palate (CLP) (see Fig. 17.5).

Figure 17.5 Frontal view of a newborn with unilateral complete cleft lip and palate (a); occlusal view of the cleft palate (b).

(courtesy of Dr. Pedro Santiago—Director of Orthodontics and Craniofacial Orthodontist, Duke Cleft/Craniofacial Team)

Defects of the Limbs and Skeleton

Table 17.1. Clinical Features Related to Level of Spinal Cord Injury

C, cervical; T, thoracic; L, lumbar; S, sacral.

Pathogenesis/Etiology

Hereditary Conditions Affecting the Teeth

AI

There are seven genes known to cause AI, with several more likely to be identified in the near future and multiple phenotypes associated with allelic mutations in several of these genes. Collectively, the allelic and nonallelic AI-associated gene mutations result in many different AI types at the clinical and molecular levels. These genes all code for proteins that are important in enamel formation and mineralization.

Hereditary Dentin Disorders

• OI
  • Associated with variable bone fragility that ranges from very mild to lethal at birth.
  • Caused by mutations in the genes that code for type I collagen and other genes involved in bone development.
• DGI in association with OI (type DGI-I)
  • Associated with a marked decrease in dentin mineralization.
• DGI as an isolated defect of teeth (type DGI-II)
  • Caused by mutations in the dentin sialophosphoprotein, a gene that codes for proteins that are critical for normal dentin mineralization.
  • Associated with a marked decreased in dentin mineralization.

Hereditary Conditions Affecting the Skin

EDs

There are many genes (over 50) known to cause ED, and many more will be discovered in the near future. Inheritance patterns include autosomal dominant, autosomal recessive, as well as the most frequently reported type, X-linked. If the mutated gene is critical for early oral epithelium events during tooth formation, such as invagination and proliferation of the oral epithelium, the result is likely to be missing teeth or hypodontia.

EB

The most recent classification of EB identifies four major EB groupings (Table 17.2) and over 30 EB subtypes.³ The four major EB groups include intraepidermal EB (simplex), junctional EB, dermolytic EB (dystrophic), and mixed EB (Kindler syndrome).

Table 17.2. Epidermolysis Bullosa Phenotypes and Treatment

EB is caused by mutations in at least 14 genes.⁴ The causative genes for many of the EB subtypes code for proteins that are important in cell integrity, cell-to-cell adhesion and attaching the dermis and epidermis. Depending on the specific EB type, genetic mutation and thus missing or abnormal protein, there can be significant morbidity involving the soft and hard tissues of the craniofacial complex.

For example, Type VII collagen is critical for maintaining the integrity of the oral mucosa and skin. Consequently, individuals with Type VII collagen mutations (dystrophic EB) often have severely affected oral soft tissues that blister with minimal manipulation and frequently heal with scarring. Type VII collagen is not essential for normal tooth bud development so individuals with dystrophic EB typically have a normally developed dentition.

In contrast, laminin 332 is highly expressed during tooth development so individuals with mutations that affect laminin 332 function (junctional EB) have defects in the enamel of their teeth with generalized enamel hypoplasia. Individuals with recessive dystrophic and junctional EB are at increased risk for developing dental caries due to alterations in the soft tissue that make eating difficult and prolonged and home care difficult. The enamel defects in junctional EB produce additional risk for the development of dental caries.⁵

OFCs

OFC is a defect of formation of the frontonasal process that gives rise to the nose, superior lip, maxilla, and primary palate, or is a defect of the fusion of the frontonasal process with the two maxillary processes. The pathogenesis of CL and CP is complex; the most widely accepted model is multifactorial inheritance, with interaction of genetic and environmental factors.⁶ Craniofacial defects such as CL and CP can occur as an isolated condition, or may be one component of an inherited disease or syndrome.

Defects of the Limbs and Skeleton

Epidemiology

Hereditary Conditions Affecting the Teeth

AI

The AI conditions occur from about 1/700 to 1/15,000 depending on the population. It is believed that the prevalence in the United States is about 1:6000-8000.¹¹

Hereditary Dentin Disorders

The prevalence of DGI-I is not known, although it is thought to occur in 30–50% of people with OI. DGI-III occurs in 1/8000 people in the United States.¹¹ The incidence of DGI-I is 1/100,000.¹²

Hereditary Conditions Affecting the Skin

EDs

The hypohidrotic or ED types associated with diminished sweat gland formation are the most common.

EB

The EB conditions are all rare with the milder forms (simplex) being more common than the severe forms.

OFCs

OFCs are among the most common and treatable birth defects in the United States. Nonsyndromic OFC is the most common congenital malformation affecting on average of about 1/500–750 live newborns annually worldwide.¹³ CL with or without CP is the second most common condition in the United States, with an adjusted prevalence of 10.63/10,000 live births or 1/940 live births.¹⁴ The incidence of CL, with or without CP, varies among different ethnic populations and is presumed to be higher in developing countries. African-Americans have a lower prevalence rate compared with Caucasians.¹⁴ Risk factors that have been identified with CP include maternal behavior (including alcohol and tobacco use); nutrition, and multiple environmental exposures.¹⁵

Defects of the Limbs and Skeleton

Coordination of Care between Dentist and Physician

Treatment of patients with OFC or other craniofacial anomalies is widely regarded as a multi-interdisciplinary enterprise from prenatal and family counseling through adulthood. Patients with other hereditary conditions of skin and bone may require consultation between dentist and physician to safely provide care to allow maintenance of the dentition. Referral to a physician for genetic testing may benefit patients with suspected hereditary conditions of the teeth and skin that may be first recognized in the dental office based on tooth appearance.

Treatment of OFC patients may involve craniofacial or cleft teams and centers, sometimes working in coordination with private practitioners. These centers provide a coordinated, multidisciplinary approach generally including experienced and qualified physicians and health-care professionals from different specialties, such as surgical (plastic and maxillofacial surgeons), ear, nose, and throat specialists; pediatric and general dentists; orthodontists; prosthodontists; speech therapists; psychologists; social workers; and allied health disciplines. Teams have become the standard in assessment and treatment of children with craniofacial anomalies like OFC.¹⁹ The role of dentistry in treating individuals with cleft and craniofacial anomalies is to provide comprehensive preventative and therapeutic oral health care.

II. Medical Management

Identification/Medical History/Physical Examination/Laboratory Testing

Hereditary Conditions Affecting the Teeth

AI

Genetic diagnosis is commercially available for several of the genes known to cause AI, thereby helping to confirm the diagnosis.

Hereditary Dentin Disorders

Several different tests are used to diagnose OI including evaluation of collagen formation by skin fibroblasts and gene sequencing. DGI-II is diagnosed clinically and can now be confirmed by gene sequencing.

Hereditary Conditions Affecting the Skin

EB

Most individuals are diagnosed by their dermatologist using skin biopsies or in consultation with medical geneticists in the natal or neonatal period. Genetic testing can now be used to confirm most EB types.

EDs

Diagnosis is based on initial recognition of the predominant clinical features, which may be first noted in the medical or dental office. Molecular testing is available to confirm the diagnosis of many specific ED types.

OFCs

Prenatal diagnosis can be performed at 13–14 weeks of gestation, when the soft tissues of the fetal face will be clearly visualized sonographically. Ideally, coronal view and axial planes are optimal for visualization of the fetal lip and palate in ultrasound images.²⁰ Three-dimensional ultrasound²¹ and magnetic resonance imaging²² can also provide a clear image of the malformation and may enhance detection of isolated CP. Prenatal diagnosis of CLP is a reality today, and in cases of labial clefts detected during the prenatal period, parent’s psychological aspects can be discussed before the birth of the child. Not only technical preparation regarding the birth, but also a mor/>

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