Introduction

In the field of dentistry, and specifically within the discipline of orthodontics, patients with notable or unique skeletal and/or craniofacial features are occasionally identified. As craniofacial growth and development specialists, orthodontists must be familiar with many of the relatively common medical conditions/syndromes their patients may have, and understand how these may affect a patient’s treatment. In addition, the orthodontist should recognize when a patient has an unusual pattern, two or more signs, which may represent an undiagnosed syndrome (Vig, 1990).

In the notable or unique cases, consultation with a clinical geneticist can provide valuable insight into a patient’s condition, particularly when the less common cases or cases with multiple complexities are encountered in the clinic. The benefits of such a consultation can include: (1) having a previously unrecognized or developing genetic condition diagnosed with appropriate further referral and counseling, and (2) the clinician orthodontist gaining a better understanding of the patient’s condition and how it may affect dental and/or orthodontic treatment (Roberts and Hartsfield, 1997).

Interaction with the Clinical Geneticist

A referral may be made for evaluation by a clinical geneticist by calling the number given on the American College of Medical Genetics or GeneTests websites after searching for a board certified geneticist or genetics clinic (see the additional resources section at the end of the chapter). Although the orthodontist’s staff may schedule the appointment, unless the patient or parent is present at the time of scheduling, availability of the family for appointments may not be known. Alternatively, the phone number of the clinical geneticist or genetics clinic may be given to the family. Family members, however, may not be able to fully convey what the patient is being referred for, and with internet accessibility prevalent, any condition mentioned (even as a clinical possibility to rule out) may be read about in detail without anxiety-relieving clarification.

Perhaps the best approach is for the orthodontist’s staff to call the clinical geneticist/genetics clinic to make the referral, giving pertinent information including your name and address, the patient’s name and address, and the reason for the referral. This does not necessarily have to be to rule out a named syndrome. A list of your concerns or findings, including reported medical history such as a heart defect, hearing deficit, or diabetes mellitus, etc., will be most helpful for the clinical geneticist’s pre-appointment preparation.

It is suggested for convenience and confidentiality that you or your office tell the clinical geneticist/genetics clinic that you will give their number to the patient/family to call for an appointment, and give any additional information such as family history, primary or other physicians and dentists involved in their care, and insurance coverage. Some clinical geneticists/genetics clinics will call the patient/family for an appointment themselves. The clinical geneticist/genetics clinic may send out a family questionnaire form to the patient and/or family to ask about medical history, and to construct a family tree called a ‘pedigree’. If not done beforehand, it is expected that this will be done at the time of the visit to the clinical geneticist, which will typically take an hour or more for an initial visit.

The clinical geneticist/genetics clinic may ask for radiographs, and/or may request medical records from other involved health professionals. As most physicians and PhDs do not routinely look at pan-oral, periapical or lateral cephalometric radiographs, providing a brief description of pertinent findings for some of the syndromes, especially pathology or deviations from normal, may be useful.

Following the visit of your patient to the clinical geneticist, expect a letter summarizing the family history, medical history, examination, discussion, diagnosis or differential diagnosis, genetic counseling if given, and recommendations. The latter are more likely to be for any genetic testing or further medical referral than for any specific type of orthodontic treatment.

Evolution of the Clinical (Medical) Geneticist Specialist

The American Board of Medical Genetics (ABMG), which was founded in 1980, historically recognized several genetic disciplines pertaining to direct patient care and laboratory services. These disciples included medical, clinical, and laboratory genetics as well as genetic counseling. Initially a ‘medical geneticist’ was defined by the ABMG as an individual holding a PhD, who had completed the required ABMG-certified medical genetics education, training and experience (including some clinical genetics activity), and had passed the ABMG medical geneticist examination (consisting of the general genetics examination for all ABMG diplomats, and a specialized examination for medical geneticists). Since the ABMG-certified medical genetics education and training required the genetic assessment of at least 50 clinical cases, it was not unusual for a ‘medical geneticist’ with a PhD to see and counsel patients regularly after achieving ABMG diplomate status. Over time, relatively few individuals pursued the designation of ‘medical geneticist’ and, hence, education and training programs for this discipline were subsequently dropped by the ABMG.

In contrast, the ABMG originally defined a ‘clinical geneticist’ as an individual who held a clinical degree (MD, DO, DDS, or DMD), had also completed the required ABMG-certified clinical genetics education and training, and had passed the ABMG clinical geneticist examination consisting of the general genetics examination for all ABMG diplomates and the specific examination for the designation ‘clinical geneticist’. Clinical or medical geneticists, who see patients and examine them for unusual physical features, particularly those that may occur with a congenital abnormality or in a pattern recognized as some syndrome, are often referred to as dysmorphologists.

One of the first members of the ABMG was Dr Robert J Gorlin, DDS, MS (1923–2006), an oral pathologist and well-known author and clinical geneticist/dysmorphologist. Another early diplomate of the ABMG was Dr David Bixler, DDS, PhD (1929–2005), the first president of the Society of Craniofacial Genetics and the founder of the Oral Facial (Craniofacial) Genetics Training Program at Indiana University, Indianapolis, USA. Thus, at the inception of the ABMG, dentists along with physicians played key roles in defining and establishing the functions of a geneticist in patient care. At that time, both dental and medical professionals could be accepted into ABMG-approved clinical genetics fellowship programs and could achieve ABMG diplomate status. These programs were stipulated by the ABMG to be at least 2 years in length with a wide range of clinical experience in genetics, not just of the craniofacies. A handful of dentists also pursued this goal and became diplomates of the ABMG as clinical geneticists.

Early on, one goal of the ABMG was to become recognized as a member of the American Board of Medical Specialties (ABMS), thus helping to recognize and legitimatize the specialty, as well as to foster improved reimbursement for services provided. In 1991, this goal was achieved and the ABMG became a member of the ABMS. The stand was taken that the ABMS is involved in medical specialties and therefore would certify only medical doctors (physicians and osteopaths) and not dentists. Today, to be an active candidate for ABMG certification as a clinical geneticist, the individual must hold a US- or Canadian-earned or the equivalent of an earned MD or DO degree, have had 2 years in an Accreditation Council for Graduate Medical Education (ACGME)-accredited clinical residency program in another medical specialty, had 2 years in an ACGME-accredited residency in clinical genetics (or 4 years in an accredited clinical genetics residency program), have a valid medical license, and have demonstrated competence to provide comprehensive genetic diagnostic, management, therapeutic, and counseling services. Thus even if a dentist with another specialty went into what was now a recognized specialty (medical genetics) in medicine, they could not become a diplomate of that specialty. Unfortunately what was a move forward for the ABMG proved to be exclusionary for dentists who wished to go into this specialty.

Clinical geneticists (including those who had been certified as medical geneticists) are typically located at major medical centers, especially children’s hospitals. While they will typically have a wide range of experience in genetic conditions, including craniofacial anomalies, they may not be as familiar with those that are predominantly of the oral cavity. Since ABMG-certified dentists are rare, and none will be certified in the future unless they also have a medical degree, where does the orthodontist send a patient for a referral? The recommendation is to refer to a clinical geneticist if possible.

Clicking on ‘Find A Certified Geneticist’ on the homepage (www.abmg.org) of the ABMG will take you to a webpage where you may search by name or locale. An additional source of genetics clinics and geneticists may be found by clicking on ‘Clinic Directory’ at the GeneTests website (www.ncbi.nlm.nih.gov/sites/GeneTests). If the medical geneticist can make or rule out a diagnosis, then the knowledge of the orthodontist, perhaps with a bit of reading in the literature (see the additional resources section at the end of chapter) on the particular condition, can fill in what the clinical geneticist cannot tell you about the effect of the condition on craniofacial growth and other aspects of orthodontic care. Likewise referral to a specific oral pathologist, pediatric dentist, or specialist in oral medicine, or other practitioner who has the interest and experience to be of help, may also supplement the orthodontist’s knowledge.

When to Refer?

How do you recognize when to seek this referral? We all vary from one another, without it usually being a concern. One of the difficult tasks faced by any practitioner, orthodontist, or medical geneticist, is how to discern normal variation from minor anomaly (Vig, 1990). A minor anomaly is a structural feature seen in less than 4% of the general population, which is of no cosmetic or functional significance to the affected individual. Minor anomalies may or may not have diagnostic significance.

Even major anomalies or signs (those that require medical/surgical intervention) vary among individuals with the same etiological syndrome, meaning clinical diagnosis is generally made on the basis of total pattern of signs or anomalies. Advancements in genetic testing for those conditions that, because of their etiology, are amenable can make/confirm the diagnosis in some conditions. The clinical geneticist will order or recommend such tests when indicated. However, there is often no single genetic test that can be relied on to make a diagnosis independent of clinical correlation.

In medical genetics, minor anomalies (unusual morphological features that are of no serious medical or cosmetic consequence to the patient) have been useful in three ways. First, some minor anomalies have been external markers of specific ‘occult’ or hidden major anomalies. In addition, the vast majority of malformation syndromes in clinical genetics are recognizable as patterns of minor anomalies. Finally, although 15% of normal newborns have one or more minor anomalies, finding three or more minor anomalies is unusual, occurring in 0.5% of newborns. The risk of having a major ‘hidden’ abnormality increases proportionately with the number of minor anomalies present, with three or more signaling a 90% risk of one or more major structural defect, which is an indication for evaluation (Hoyme, 1993; Jones and Smith, 2006).

Minor anomalies may occur in any part of the body. While it would not be expected for the orthodontist to physically examine all body areas, he or she is expected to examine the craniofacies as well as intraorally, and may readily observe the hands as well, where most minor anomalies occur (Jones and Smith, 2006). A familial pattern may be superficially ascertained promptly by asking if anyone else in the family has a similar feature of interest, or by asking who in the family the patient most resembles, and in what way (stature, similar eyes, jaw profile, etc.). In addition, subjective evaluation of the patient’s ability to function, as well as a general medical surgery history and questions about the patient being or having been in ‘special’ classes, may indicate that a medical genetics referral is warranted. This may require some explanation to the patient and/or family members as the orthodontist is typically not in a position to make a diagnosis, or answer all the questions that inevitably follow. One way to approach this is a general discussion of the orthodontist’s need to know anything that may affect treatment, noting the potential factors that could be ruled out by consultation with a specialist in medical genetics.

Depending on the patient’s insurance, this will often be covered at least partially by medical insurance, but may require the orthodontist to call or send a letter to the primary physician explaining concerns, and that you would like a referral for your patient in common to the medical geneticist because of the listed signs, and to perhaps also rule out a specific syndrome, or of course follow up on whatever referrals the medical geneticist recommends for diagnosis or treatment besides orthodontics. The primary physician may already have some diagnostic information useful to the orthodontist.

As an educator I have often been asked by students: ‘What do we need to know?’ My response has been, ‘Tell me about all the patients you will ever see, and then we can start from there.’ No one knows every condition or syndrome that any of our patients may present to us, but we can be aware of when something seems out of the usual range of variation, particularly if more than one unusual feature is present. The following is a selective and incomplete survey of conditions/syndromes with brief descriptions regarding each one of them. The list is incomplete and there are many more conditions, which can be referenced with the help of the additional resources provided at the end of this chapter. While typically no single malformation or sign is pathognomonic, it may direct us to consider the referral and differential diagnosis (Cohen, 1980; Babic et al., 1993; Hartsfield, 1994, L Suri et al., 2004; Schulman et al., 2005; Jones and Smith, 2006; Bailleul-Forestier et al., 2008; Fleming et al., 2010). Some of the conditions are rare, and some are only relatively rare, although any of them may be presently recognized or unrecognized in your practice. Box 7.1 and resources noted later may also be useful if a patient comes to you with a particular diagnosis already made. Although not every patient will manifest what is expected of someone with a particular diagnosis, these resources can help the practitioner better understand a patient’s condition and how it may affect treatment and how treatment may affect the patient.

Radiographic Signs

Odontoma

The presence of an odontoma should alert the practitioner to inquire about the concurrent presence of dysphagia (difficulty in swallowing) or a family history of dysphagia that is perhaps due to hypertrophy of the smooth muscles of the esophagus as a part of the rare autosomal dominant odontoma–dysphagia syndrome (Bader, 1967).

Odontogenic Keratocyst

See nevoid basal cell carcinoma (Gorlin) syndrome in maxillary hypoplasia section.

Taurodontism

Found in about 2.5% of Caucasian adults as an isolated (nonsyndromic) trait (Jaspers and Witkop, 1980). Individuals with nonsyndromic hypodontia are more likely to show taurodontism of the permanent first molars, whereas children with nonsyndromic supernumerary teeth are not (Kan et al., 2010). It can also be found in several conditions and syndromes, including the following syndromes.

Trichodentoosseous Syndrome (TDO)

The features of TDO include variably kinky curly hair at birth, which straightens about half of the time after infancy; thin, pitted enamel, taurodontism; and, in approximately 80% of affected individuals, thickening of cortical bone (including of the skull). The natural straightening of the hair during infancy complicates the diagnosis of TDO and makes differentiating between TDO and amelogenesis imperfecta with taurodontism difficult in many cases. While TDO is caused by mutations in the DLX3 gene, it is not clear if at least some cases of amelogenesis imperfecta with taurodontism are also caused by mutations in DLX3, or actually represent milder cases of TDO (Bloch-Zupan and Goodman, 2006; Visinoni et al., 2009).

The teeth are typically small, and often have a slight yellow-brown coloration, although there can be considerable variability in the clinical appearance of the teeth in affected individuals even within the same family. The teeth maybe mildly affected with normal color and a slight size reduction, to severe enamel hypoplasia and markedly reduced size. The incidence of dental abscesses is increased, and hypodontia may be present (Wright et al., 1997). The eruption of teeth may also be delayed (Suri et al., 2004). A detailed cephalometric analysis of the craniofacial structures in individuals with TDO did not establish a distinct craniofacial phenotype, although the cranial base length, cranial base angle, and length of the body of the mandible were all increased compared with unaffected relatives (Lichtenstein et al., 1972).

Otodental Dysplasia

Features of this syndrome include grossly enlarged molars (globodontia), taurodontism, high-frequency sensorineural hearing deficit, and eye coloboma (part of the eye does not form due to failure of fusion of the intraocular fissure, and may be apparent externally as a ‘notch’ in the iris). Tooth eruption may also be delayed (Suri et al., 2004). Dental management has been described as interdisciplinary and complex, including regular follow-up, extraction of teeth as indicated and orthodontic treatment (Bloch-Zupan and Goodman, 2006).

Sex Chromosome Aneuplodies/Anomalies

Sex chromosome aneuplodies/anomalies involve deviation from the normal XY chromosomes in males and XX chromosomes in females. The positive predictive value for Klinefelter syndrome (47, XXY, i.e. a male with an extra X chromosome that affects approximately 1.2 in 1000 males), given a male patient with taurodontism and a learning disability, is 84% (Schulman et al., 2005). In addition to tall stature for the family, a tendency toward mandibular prognathism and decreased facial height may also be present.

In contrast to the increase in taurodontism with an extra X chromosome, females lacking an X chromosome (Turner syndrome, 45, X and variations, occurs in 1 in 2500 females) appear not to have an increased incidence of taurodontism, although they may show increased variation in root morphology, including short roots (Varrela et al., 1990; Midtbo and Halse, 1994). Patients with Turner syndrome show variable short stature, low hairline, low-set ears, and broad necks. These patients typically experience gonadal dysfunction (nonworking ovaries), which results in amenorrhea (absence of menstrual cycle) (Bader, 1967).

Depending on the sex, lack of an X chromosome or the presence of an extra X chromosome produces opposite effects on cranial base flexion, jaw displacement, and maxillary and mandibular inclination to the anterior cranial base. An extra X chromosome in males affected the jaw relationship in the sagittal plane, typically increasing the length of the mandible, while an extra X chromosome in females resulted in shorter lengths of the anterior and posterior cranial bases, the calvarium, mandibular ramus, and the posterior and upper anterior face.

The lack of an X chromosome in females (Turner syndrome) results predominantly in cranial base changes, so that the mandible is short in the sagittal plane, whereas the maxilla is of normal length. The extra Y chromosome in 47, XYY males results in larger craniofacial dimensions than in normal males, without substantial effects on dimensional ratios and plane angles. In general, there is a skeletal height and craniofacial growth-promoting effect from an extra Y chromosome, and a delaying effect from an extra X chromosome (Babic et al., 1993; Krusinskiene et al., 2005; Alvesalo, 2009).

Williams Syndrome

Physical features of this condition include characteristic facial features with full prominent cheeks, wide mouth, long philtrum, small nose with depressed nasal bridge, heavy orbital ridges, medial eyebrow flare, dental abnormalities, hoarse voice, growth retardation, and cardiovascular abnormalities (most commonly supravalvular aortic stenosis and/or peripheral pulmonary artery stenosis). The cognitive profile is distinctive, consisting of strengths in auditory memory, language, and face-processing, but extreme weakness in visual-spatial, numerical, and problem-solving abilities.

Cephalometric analysis shows the anterior and posterior cranial bases are shorter in individuals with Williams syndrome, although the cranial base angle is normal. The frontal and occipital bones are thicker, and the shape of the sella turcica may be unusual. Marked deficiency of the bony chin in combination with a large mandibular plane angle can give the impression of a retrusive mandible. Hypodontia is frequent, and the teeth tend to be small. Maxillary and mandibular incisors in both jaws are often tapered towards the incisal edge (screwdriver-shaped). Most of the molars deemed as being taurodontic have short total tooth lengths and can thus be defined as having taurodontism without meeting the classical definition (Axelsson, 2005).

Other conditions in which taurodontism is seen more commonly than in the general population include trisomy 18, some types of ectodermal dysplasia, Down syndrome, Mohr (oral-facial-digital, type II) syndrome, Seckel syndrome, Lowe syndrome, and X-linked hypophosphatemic rickets (X-linked hypophosphatemia; see under conditions in which premature tooth exfoliation may occur occasionally) (Cichon and Pack, 1985; Kan et al., 2010).

History of Premature Tooth Exfoliation

A history of primary teeth exfoliation prior to the age of 5 years in the absence of trauma is an indication to investigate further, as a number of conditions that concern orthodontists include the risk of additional tooth loss. The early exfoliation of primary teeth resulting from periodontitis has been observed occasionally in children. Along with hypophosphatasia, early-onset periodontitis appears to be the most common cause of premature exfoliation of the primary teeth, especially in girls (Hartsfield, 1994).

Hypophosphatasia

The disease is characterized by improper mineralization of bone caused by deficient tissue nonspecific alkaline phosphatase activity in serum, liver, bone, and kidney. Increased levels of urinary phosphoethanolamine are also seen. Diagnostic tests should include the determination of serum alkaline phosphatase levels for parents and siblings (Hu et al., 1996).

The typical dental finding diagnostic of hypophosphatasia in children is premature exfoliation of the anterior primary teeth associated with deficient cementum. The loss of teeth in the young child may be spontaneous or may result from a slight trauma. Early exfoliation of the primary teeth is usually associated with the juvenile type of hypophosphatasia, although such a history may also be present in the adult type. Severe gingival inflammation will be absent. The loss of alveolar bone may be limited to the anterior region. Treatment of patients with hypophosphatasia may be problematic because of the risk of permanent tooth loosening during orthodontic procedures (Macfarlane and Swart, 1989).

Early-Onset Periodontitis

This may occur in the primary dentition (prepubertal periodontitis), develop during puberty (juvenile periodontitis, JP), or may be characterized by exceedingly rapid loss of alveolar bone (rapidly progressive periodontitis). Because several forms of early-onset periodontitis (e.g. localized prepubertal periodontitis, localized JP, and generalized JP) can be found in the same family, the expression of the underlying genetic etiology appears to have the potential to be influenced by other genetic and environmental factors (Schenkein, 1998).

Early-onset periodontitis may occur by itself (nonsyndromic), or as a part of a syndrome. For example, leukocyte adhesion deficiency (LAD) types I and II are autosomal recessive disorders of the leukocyte adhesion cascade. LAD type I has abnormalities in the integrin receptors of leukocytes, leading to impaired adhesion and chemotaxis, which results in an increased susceptibility for severe infections and early-onset (prepubertal) periodontitis (Meyle and Gonzales, 2001). In LAD type II, the severity of the general infectious episodes is much milder than those observed in LAD type I, although there is chronic severe periodontitis. Furthermore, patients with LAD type II, present other abnormal features, such as growth and mental retardation, which are related to the primary defect in fucose metabolism or specific transporter of GDP-fucose into the Golgi apparatus causing no fucolysation and no surface expression (Etzioni and Tonetti, 2000).

Orthodontic movement of teeth into previously affected areas has been reported to be successful after a short healing period following extractions secondary to periodontal disease, crowding, to correct anteroposterior discrepancies, or reduce bimaxillary protrusion (McLain et al., 1983). Teeth that have lost periodontal support may be indicated in particular for extraction. For example, it has been claimed that after orthodontic space closure, bony contours and attachment levels on repositioned second and third molars will be superior to those possible if the affected first molars were retained and treated.

As for any patient, each case is unique, and the treatment plan depends on close collaboration with the periodontist, the stability of the remaining teeth, and possible substitutions that would result in a functional occlusion. Periodontal evaluations should be scheduled as often as orthodontic appointments to monitor the condition during tooth movement (McLain et al., 1983).

Papillon–Lefèvre and Haim–Munk Syndromes

Two of the many different types of palmoplantar keratoderma (thickened skin over the palms and soles of the feet that may appear to be darkened or ‘dirty’) differ from the others by the occurrence of severe early-onset periodontitis with premature loss of the primary and permanent dentition. Lateral cephalometric analysis of eight patients with Papillon-Lefèvre syndrome revealed a tendency toward a Class III skeletal relationship with maxillary retrognathia, decreased lower facial height, retroclined mandibular incisors, and upper lip retrusion (Bindayel et al., 2008).

It has been reported that following a successful combined mechanical and antibiotic therapy of periodontitis associated with the Papillon–Lefèvre syndrome, moderate orthodontic tooth movements may be possible within a complex interdisciplinary treatment regimen (Lux et al., 2005). Haim–Munk syndrome is characterized in addition to features seen in Papillon-Lefèvre syndrome by arachnodactyly (long and thin fingers and toes), acroosteolysis (destruction of the digit tips, including the bone,), and onychogryphosis (hypertrophy and curving of the nails, giving them a claw-like appearance) (Hart et al., 1997).

Singleton–Merten Syndrome

A rare condition with dentin dysplasia and poor dental root development, progressive calcification of the thoracic aorta, calcific aortic stenosis, osteoporosis, and expansion of the marrow cavities in hand bones like that observed in anemia. Generalized muscle weakness and atrophy may also be present. Maxillary hypoplasia has also been noted (Singleton and Merten, 1973; Feigenbaum et al., 1988).

Hajdu–Cheney Syndrome

A heritable, rare disorder of bone metabolism, associated with acroosteolysis, short stature, distinctive craniofacial and skull changes, periodontitis, and premature tooth loss. Bazopoulou-Kyrkanidou et al. (2007) reported the case of a 22-year-old affected woman, who presented characteristic clinical features including short stature, small face, prominent epicanthal folds, thin lips, small mouth, and short hands. Biochemical, hematological, and hormonal parameters were normal. Tests for bone mineral density were indicative of osteoporosis. Cephalometric analysis revealed hypoplasia of the mid-face and increased cranial base angle; the maxilla and the mandible were set posterior. The sella turcica was enlarged, elongated, and wide open with slender clinoids.

The mandible may be underdeveloped as well as the maxilla and mid-face. Le Fort III maxillary distraction osteogenesis and advancement genioplasty followed by orthodontia were successfully performed for a mid-facial retrusion and to eliminate severe snoring during sleep in a reported case (Satoh et al., 2002).

Conditions in Which Premature Tooth Exfoliation May Occur Occasionally

Ehlers–Danlos Syndrome

See ‘Connective tissue dysplasia’ section later in the chapter.

X-Linked Hypophosphatemic Rickets (X-Linked Hypophosphatemia)

In addition to short stature and bowing of the lower extremities, there are often dental manifestations, including apical radiolucencies, abscesses (that may result in premature exfoliation of teeth), and fistulas associated with pulp exposures in the primary and permanent teeth. The pulp exposures relate to the pulp horns extending to the dentinoenamel junction or even to the external surface of the tooth. The thin, hypomineralized enamel may abrade easily, exposing the pulp. Dental radiographs show rickety bone trabeculations and absent or abnormal lamina dura (Smith and Steinhauser, 1971; Hartsfield, 1994).

There are other types of hypophosphatemia with overlapping clinical features and different modes of inheritance and genes involved. Generally, the more severe and earlier the onset, the more severe dental manifestations will be. In contrast, vitamin D-deficient rickets does not show the dental abnormalities found in X-linked/>