4
Integrated Clinical Genetics/Syndromology for the Orthodontist
James K. Hartsfield, Jr.1–8, Lorri Ann Morford1,8, and Aqib Muhammad Shafi1
1 Department of Oral Health Science, University of Kentucky College of Dentistry, Lexington, KY, USA
2 Department of Microbiology, Immunology and Molecular Biology, University of Kentucky College of Medicine, Lexington, KY, USA
3 Department of Orthodontics and Oral Facial Genetics, Indiana University School of Dentistry, Indianapolis, IN, USA
4 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
5 Department of Orthodontics, University of Illinois at Chicago College of Dentistry, Chicago, IL, USA
6 Division of Oral Development and Behavioural Sciences, University of Western Australia Dental School, Nedlands, WA, Australia
7 Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
8 Hereditary Genomics Laboratory, University of Kentucky College of Dentistry, Lexington, KY, USA
In the field of dentistry, and specifically within orthodontics, patients with notable or unique skeletal and/or craniofacial features are occasionally identified. A study to investigate the knowledge of rare diseases among general and specialist dentists, including orthodontists, showed that most of the practitioners had little or no knowledge about rare diseases, especially among those outside of the university setting compared to those within (Cazzolla et al., 2022). As craniofacial growth and development specialists, orthodontists must be familiar with many of the medical conditions/syndromes their patients may have and understand how these may affect a patient’s treatment. Since approximately 15% of “rare diseases” have orofacial manifestations (Jackowski and Hanisch, 2012), the orthodontist should recognize when a patient has an unusual pattern, two or more signs, that may represent an undiagnosed syndrome (Vig, 1990; Hanisch et al., 2019).
With notable or unique cases, consultation with a clinical geneticist can provide valuable insight into a patient’s condition, particularly when the less common conditions or cases with multiple complexities are encountered in the clinic. The benefits of such a consultation can include: (i) having a previously unrecognized or developing genetic condition diagnosed with appropriate further referral and counseling; and (ii) the clinician orthodontist gaining a better understanding of the patient’s condition and how it may affect their dental and/or orthodontic treatment (Roberts and Hartsfield, 1997). A comparison was done of the orthodontic treatment of 56 patients with a variety of “rare disorders” to a control group of 96 systemically healthy orthodontic patients matched by sex and age range. The rare disorders group required more desensitization sessions, and were treated with mixed appliances (fixed and removable) more often and for longer periods. They also had more frequent complications, such as gingivitis, caries, mucosal ulcers, and recurrent debonding (Arriagada‐Vargas et al., 2022).
Interaction with the clinical geneticist
A referral may be made for evaluation by a clinical geneticist found in the American College of Medical Genetics website after searching for a board‐certified geneticist or genetics clinic (see “Additional resources” 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 the 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, possibility leading to misunderstanding and excess anxiety.
Perhaps the best approach is for the orthodontist’s staff to call the clinical geneticist/genetics clinic to make the referral, giving pertinent information as to 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 like a heart defect, hearing deficit, special classes, growth delay, and so on, along with family history, will be most helpful to the clinical geneticist preparing for the appointment beforehand. Clinical geneticists and genetics clinics may vary in their preappointment needs, and as you interact with your local professionals you will become familiar with their intake protocols. In addition to, or instead of, you or your patient interacting with a clinical geneticist, it is not unusual for a genetic counselor, or a physician assistant or nurse with experience in genetics, to be involved. These individuals, along with laboratory geneticists who perform molecular and biochemical tests, can act together as a genetics team in the care of your patient.
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 for them to call for an appointment, and provide 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, just be sure the patient/family know to expect a call. 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 this is not done beforehand, it is expected that it will be done at the time of the visit to the clinical geneticist/genetics clinic, which will typically take an hour or more for an initial visit (not including waiting time).
The clinical geneticist/genetics clinic may ask for your radiographs, and/or may request medical records from others taking care of the patient. As most physicians and clinical PhDs do not routinely look at panoral, periapical, or cephalometric radiographs, providing a brief description of pertinent findings like those described in this chapter for some of the syndromes, especially pathology or deviations from normal, may be useful to them.
Following your patient’s visit to the clinical geneticist/genetics clinic, you should 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 (e.g. ophthalmology and cardiology examination for a patient suspected of having Marfan syndrome because of the associated developmental eye abnormalities and aortic dissection risk) than for any specific type of orthodontic treatment.
Evolution of the clinical geneticist specialist
The American Board of Medical Genetics (ABMG) originally defined a “clinical geneticist” as an individual who held a clinical degree (MD, DO, DDS, or DMD); had a certificate from a residency program such as but not limited to pediatrics, maternal fetal medicine, oral pathology, or orthodontics; had also completed the required ABMG‐certified clinical genetics residency education and training; and had passed the ABMG Clinical Geneticist examination, consisting of the general genetics exam and a clinically focused exam. Clinical 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, may be referred to as dysmorphologists.
One of the initial members of the ABMG was Dr. Robert J. Gorlin, DDS, MS (1923–2006), a dentist and well‐known author, oral pathologist, and clinical geneticist/dysmorphologist. A few other dentists were also early diplomates of the ABMG, including Dr. David Bixler, DDS, PhD (1929–2005), the first president of the Society of Craniofacial Genetics (now the Society of Craniofacial Genetics and Developmental Biology). 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 (“residency”) programs and could achieve ABMG Diplomate status. These programs were stipulated by the ABMG to be at least two years in length with a wide range of clinical experience in genetics, not just of the craniofacies. There were a handful of dentists who pursued this goal and become 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 legitimize the specialty, as well as to foster improved reimbursement for services provided. Once this goal was achieved and the ABMG become a member of the ABMS in 1991, the stand was taken that the ABMS is involved in medical specialties and therefore in the certification of medical doctors (physicians and osteopaths), not the certification of dentists. Today, to be an active candidate for certification in clinical genetics and genomics by what is now named the American Board of Medical Genetics and Genomics (ABMGG), the individual must hold a US or Canadian MD, DO, or equivalent degree before undertaking the required additional minimum five years of education. Thus, even if a dentist with another specialty wished to go into the now ABMS‐recognized specialty of Clinical Genetics and Genomics, he or she could not become a Diplomate of that specialty. Unfortunately, what was a move forward for the ABMGG proved to be exclusionary for dentists who wished to go into this specialty.
Clinical geneticists, genetic counselors, physician assistants, and nurses who provide clinical genetics services are generally 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 pertinent findings of the oral cavity. Among dentists in general, oral pathologists may have greater knowledge of genetic conditions, but may not have the experience of conditions that manifest to some degree in areas in addition to the oral cavity, and probably do not have the education and experience in making referrals and doing genetic counseling that the clinical geneticist or genetics team member would have.
If the clinical geneticist/genetics team can make or rule out a diagnosis, then the knowledge of the orthodontist, perhaps with some reading in the literature on the condition (see “Additional resources”), can fill in what the clinical geneticist cannot tell you about the effect of the condition on craniofacial growth and other aspects of the orthodontic care. Likewise, referral to a specific oral pathologist, pediatric dentist, or specialist in oral medicine, or another practitioner who has the interest and experience to be of help, may also be supplemented by the orthodontist’s knowledge.
When to refer
How do you recognize when you should seek this referral? All humans vary from one another, without it usually being a concern. One of the difficult tasks faced by any practitioner, whether orthodontist or clinical geneticist, is how to discern normal variation from a 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 that may be considered serious 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 that clinical diagnosis is generally made based on an overall pattern of signs or anomalies. Advancements in genetic testing for those conditions that, because of their etiology, are amenable can certainly help and in some conditions make/confirm the diagnosis. The clinical geneticist will order or recommend such tests to be done when indicated. In addition, with technological advancements, next‐generation sequencing of the DNA exomes that code for proteins (whole‐exome sequencing, WES), or the whole‐genome sequence (WGS), may be done for further detailed investigation, often in cases where the condition/syndrome is not recognized.
In medical genetics, minor anomalies have been useful in three ways. First, some minor anomalies have been external markers of specific “occult” or hidden major anomalies. In addition, most malformation syndromes in medical genetics are recognizable as patterns of minor anomalies. Finally, although 15% of normal newborns have one or more minor anomalies, the finding of 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 evaluation indication (Hoyme, 1993; Jones et al., 2021).
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. Thus the orthodontist can examine/observe the areas (craniofacies and hands) where most minor anomalies occur (Jones et al., 2021). 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 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 able to make a diagnosis or answer all the questions that inevitably follow. One way to approach this is a general discussion of how the orthodontist needs to know about everything that may affect treatment, and that you noticed a few things 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 (not dental) insurance, but may require the orthodontist to call or send a letter to the primary physician explaining your concern, and that you would like a referral for your patient in common to the medical geneticist because of the listed signs, and perhaps also to rule out a specific syndrome.
The primary physician may already have some diagnostic information that will be of use to the orthodontist, but do not be surprised if this person has no more familiarity with medical genetics than you. The reason for your call is that you are trying to do the best for each of your patients, not just the majority who, although they may vary to some degree one from the other, are not markedly affected by a genetic condition.
Artificial intelligence and facial analysis
The use of artificial intelligence (AI) and its integration into modern science by way of multiple medical specialties, including genetics, has helped transform the next generation of clinical practice (Bijarnia‐Mahay and Arora, 2019). AI is increasingly used for clinical diagnosis, including with facial analysis as part of recognizing a variety of developmental/genetic conditions. Many genetic syndromes have characteristic facial features, which may be considered in the differential diagnosis.
Face2Gene (FDNA, Sunrise, FL, USA) is an AI‐based software that uses facial image analysis to help diagnose genetic syndromes. It is a national online tool for the identification of phenotypes based on next‐generation phenotyping (NGP; Liehr et al., 2021). The free Face2Gene app is available to healthcare professionals on the iOS or Android platform, or as software for desktop or laptop computers (https://www.face2gene.com/startclinic). Face2Gene is available to verified US healthcare workers with activation for use by noting your profession, specialty, and if applicable institutional email (Hurst, 2018).
Using a two‐dimensional (2D) facial portrait, each region of the face is scaled to a fixed size and converted to grayscale. The software uses cascaded deep convolutional neural network methodology and facial landmarks that are geometrically analyzed and compared to a database of facial characteristics of various genetic syndromes (Gurovich et al., 2019). These “dysmorphic” features as identified by Face2Gene may be reported to the clinical geneticist/genetics clinic for their use, or with subject permission you can supply the geneticist/genetics clinic with the digital portrait if they use Face2Gene. A list of several of the most likely syndromes is generated.
DeepGestalt is the neural network that drives Face2Gene (Gurovich et al., 2019; Pantel et al., 2020). It utilizes a dataset of over 17,000 images representing over 200 genetic syndromes (Gurovich et al., 2019). In a study of the accuracy of DeepGestalt, using pictures of 323 individuals who had 17 different genetic syndromes and a matched control group also consisting of 323 pictures, there was 91% sensitivity in analysis of the images (Pantel et al., 2020). Like other AI systems, DeepGestalt cannot identify which facial features supported the clinical diagnosis. However, the use of heat map visualization in the app software to identify the fit between areas and suggested syndromes can be used to identify the contributory areas (Gurovich et al., 2019).
It is also important to note that ethnic differences and variations play an important role. Most studies involve the use of Caucasian images for analysis. One study investigated facial morphology in African children with and without intellectual disability (Lumaka et al., 2017). Using Face2Gene resulted in a 37% syndrome diagnosis accuracy rate in Africans. However, with utilization of training techniques, this increased to 94%. Thus, training of the system may be required for increased accuracy in other ethnic groups.
When using Face2Gene to analyze a patient who may or may not have a syndrome, the list of possible syndromes generated should be refined by entering pertinent positive and negative patient history, attributes, or findings. Careful consideration of the characteristics of each listed syndrome compared to the patient must be done before a refined differential diagnosis or final diagnosis is entertained. This may be best left to the geneticist and not shared with the patient or family without review and confirmation by the geneticist.
Selected syndromes and conditions
Table 4.1 is a selective and incomplete survey of conditions/syndromes with brief descriptions (and others on which more information may be gathered from the “Additional resources”), sorted by particular signs, adapted from a number of different references (Babic et al., 1993; Bailleul‐Forestier et al., 2008; Cohen, 1980; Fleming et al., 2010; Hartsfield, 1994; Jones et al., 2021; Schulman et al., 2005; Suri et al., 2004) and other references as cited in the text.
Most of the conditions are rare, and some are only relatively rare, although any of them may be presently recognized or unrecognized in a practice. The tables and online resources noted later – Online Mendelian Inheritance in Man (OMIM), GeneReviews Genetic Testing Registry, Registry of Orofacial Manifestations in People with Rare Diseases, or reference texts (Hennekam et al., 2010; Jones et al., 2021) – may also be of use if a patient comes to you with a particular diagnosis already made. Although not every patient is going to follow what is expected of someone with a particular diagnosis because of inherent variability, the practitioner can better understand a patient’s condition and how it may affect treatment, and also how treatment may affect the patient.
Table 4.1 Selected traits in selected syndromes and conditions.
Source: Adapted from Andreadis et al. (2004); Babic et al. (1993); Bailleul‐Forestier et al. (2008); Cohen (1980); Ernst et al. (2007); Fleming et al. (2010); Hartsfield (1994); Hennekam et al. (2010); Jones et al. (2021); Kikuiri et al. (2018); Papapanou et al. (2018); Schulman et al. (2005); Suri et al. (2004).
| Note: A syndrome or condition listed under a trait may not always, or even often, show the trait in every affected individual. Some syndromes/conditions are listed under more than one trait, which may help in forming a differential diagnosis if the patient has more than one trait and two or more are found in the same condition. Many of these conditions are too severe to be found in patients who are likely to be seen in most orthodontic practices, but may be seen in craniofacial clinics. Some of these conditions are lethal early in life, but are included to illustrate the wide range of conditions that may be associated with the selected traits. This is not intended to be an exhaustive list. Face2Gene, OMIM, and Smith’s Recognizable Patterns of Human Malformation (Jones et al., 2021) are excellent additional resources. |
| Premature tooth exfoliation Occurs often Coffin–Lowry syndrome Early‐onset periodontitis (aggressive periodontitis, stage III grade C, with rapid rate of progression) Hajdu–Cheney syndrome Hypophosphatasia Mandibulofacial dysplasia Pachyonychia congenita Papillon–Lefèvre syndrome Singleton–Merten syndrome Occurs occasionally Chédiak–Higashi syndrome Cherubism Down syndrome Ehlers–Danlos syndrome type VIII (periodontitis type) Hypophosphatemia Oculodentodigital syndrome Yunis Varón syndrome |
| Delayed tooth eruption Aarskog syndrome Acrodysostosis Albright hereditary osteodystrophy Apert syndrome Amelo‐onychohypohydrotic dysplasia Brachmann–de Lange syndrome Carpenter syndrome Cherubism Chondroectodermal dysplasia (Ellis–van Creveld syndrome) Cleidocranial dysplasia (dysostosis) Cockayne syndrome Coffin–Lowry syndrome Coffin–Siris syndrome Congenital hypertrichosis lanuginosa Cross syndrome (has gingival fibromatosis) |
| Dentin dysplasia DeLange syndrome Down syndrome |
| Dyskeratosis congenita Ectodermal dysplasias (some types) Ekman–Westborg–Julin syndrome Enamel agenesis and nephrocalcinosis Epidermolysis bullosa Finlay–Marks syndrome Frontometaphyseal dysplasia GAPO syndrome (growth retardation, alopecia, “pseudoanodontia,” and optic atrophy) Gardner syndrome Gaucher disease Gingival fibromatosis with sensorineural hearing loss Gingival fibromatosis with growth hormone deficiency Goltz syndrome Hallermann–Streiff syndrome Hemifacial microsomia (Goldenhar syndrome, oculoauriculovertebral spectrum) Hurler Scheie syndrome (a type of mucopolysaccharidosis, abbreviated MPS I‐H/S) Hurler syndrome ((MPS I‐H) Hunter syndrome (MPS II) Hyperimmunoglobulinemia E (Buckley syndrome) I‐cell disease (mucolipidosis II) Incontinentia pigmenti (Bloch–Sulzberger syndrome) Killian/Teschler–Nicola syndrome Laband syndrome (has gingival fibromatosis) Levy–Hollister syndrome Maroteaux–Lamy syndrome (MPS IV) McCune–Albright syndrome (polyostotic fibrous dysplasia) Menkes kinky hair syndrome Miller–Dieker syndrome Murray–Puretic–Drescher syndrome (has gingival fibromatosis) Neurofibromatosis Nevoid basal cell carcinoma (Gorlin) syndrome Osteoglophonic dysplasia Osteopathia striata with cranial stenosis Osteopetrosis (marble bone disease) Osteogenesis imperfecta (variable) Otodental dysplasia Parry–Romberg syndrome (progressive hemifacial atrophy) Progeria (Hutchinson–Gilford syndrome) Pyknodysostosis |
| Rutherford syndrome (has gingival fibromatosis) Ramon syndrome (has gingival fibromatosis) Rothmund–Thompson syndrome Sclerosteosis SHORT syndrome |
| Singleton–Merten syndrome Trichodentoosseous syndrome Velocardiofacial syndrome XXXY and XXXXY syndrome (occasionally) |
| Supernumerary teeth Chondroectodermal dysplasia (Ellis–Van Creveld syndrome) Cleidocranial dysplasia Ehlers–Danlos vascular type IV Fabry disease Familial adenomatous polyposis (Gardner syndrome) Incontinentia pigmenti (Bloch–Sulzberger syndrome) Nance–Horan syndrome Oral‐facial‐digital syndrome Saethre–Chotzen syndrome Trichorhinophalangeal syndrome type I (occasionally) |
| Taurodontism Down syndrome (occasionally) Ectodermal dysplasias (some occasionally) Lowe syndrome (occasionally) Oral‐facial‐digital II syndrome (occasionally) Otodental dysplasia Sex chromosome aneuploidies/anomalies with one or more extra X chromosome (e.g. Klinefelter syndrome) Seckel syndrome (occasionally) Trichodentoosseous syndrome Trisomy 18 (occasionally) Williams syndrome X‐linked hypophosphatemic rickets (occasionally) XXXXX syndrome XXX and XXXX syndrome (occasionally) XXXY and XXXXY syndrome (occasionally) |
| Odontoma Encephalocraniocutaneous lipomatosis Gardner syndrome Odontoma‐dysphagia syndrome SATB2‐associated syndrome Schimmelpenning–Feuerstein–Mims (SFM) syndrome (linear sebaceous nevus syndrome) |
| Mandibular deficiency Achondrogenesis types IA and IB Amyoplasia congenita disruptive sequence Aniridia–Wilms tumor association Atelosteogenesis type I Baller–Gerold syndrome Boomerang dysplasia Brachmann–de Lange syndrome Branchio‐oculo‐facial syndrome Campomelic dysplasia Catel–Manzke syndrome Cat‐eye syndrome Cerebro‐costco‐mandibular syndrome Cerebro‐oculo‐facio‐skeletal syndrome Cohen syndrome Cranioectodermal dysplasia Diamond Blackfan anemia (DBA) Escobar syndrome Femoral hypoplasia–unusual facies syndrome Fetal aminopterin/methotrexate syndrome Frontometaphyseal dysplasia Fryns syndrome GAPO syndrome (growth retardation, alopecia, “pseudoanodontia,” and optic atrophy) Hajdu–Cheney syndrome Hallermann–Streiff syndrome Hemifacial microsomia (Goldenhar syndrome, oculoauriculovertebral spectrum) Langer–Giedion syndrome Lethal multiple pterygium syndrome Loeys–Dietz syndrome Mandibuloacral dysplasia Mandibulofacial dysostosis with microcephaly Marden–Walker syndrome Marshall–Smith syndrome Matthew–Wood syndrome Meckel–Gruber syndrome Meier–Gorlin syndrome Melnick–Needles syndrome Microcephalic primordial dwarfing syndrome Microdeletion 2q31.1 syndrome Microdeletion 22q11.2 syndrome Miller syndrome Miller–Dieker syndrome |
| Moebius (Möbius) syndrome Mohr syndrome Mucopolysaccharidosis I H, I H/S Mycophenolate mofetil embryopathy Nablus mask‐like facial syndrome Nager acrofacial dysostosis Neu–Laxova syndrome Opitz G/BBB syndrome Oral‐facial‐digital syndrome Oromandibular‐limb hypogenesis spectrum Oto‐palato‐digital syndrome Type II Pallister–Hall syndrome Pena Shokeir phenotype Peters‐plus syndrome Progeria syndrome Pyknodysostosis Restrictive dermopathy Retinoic acid embryopathy Roberts syndrome Robin sequence (nonsyndromic, or may be syndromic, e.g. Stickler syndrome, velocardiofacial syndrome Russell–Silver syndrome Schwartz–Jampel syndrome SHORT syndrome Shprintzen–Goldberg syndrome Smith–Lemli–Opitz syndrome Stickler syndrome Toriello–Carey syndrome Treacher Collins syndrome Trichorhinophalangeal syndrome type I and type II (Langer–Giedion syndrome) Diploid/triploid mixoploidy syndrome Turner (45X and variants) syndrome Weaver syndrome Wildervanck–Smith syndrome Velocardiofacial syndrome Vici syndrome XXX and XXXX syndrome Yunis Varón syndrome Zellweger syndrome |
| Cleft lip and or cleft palate (Note: there are over 300 “clefting syndromes”) Amnion rupture sequence Apert syndrome Branchio‐oculo‐facial syndrome (pseudocleft) Cleidocranial dysostosis (dysplasia) |
| Deletion 4p syndrome Diastrophic dwarfism Ectrodactyly–ectodermal dysplasia–clefting (EEC) syndrome Fetal alcohol syndrome (cleft palate occasionally) Fetal hydantoin syndrome Fetal valproate syndrome Fryns syndrome Hay–Wells ectodermal dysplasia Hemifacial microsomia (Goldenhar syndrome, oculoauriculovertebral spectrum; occasionally) Larsen syndrome (cleft palate occasionally) Marfan syndrome (cleft palate occasionally) Miller syndrome Mycophenolate mofetil embryopathy Nager acrofacial dysostosis (cleft palate) Nevoid basal cell carcinoma (Gorlin) syndrome Oral‐facial‐digital syndrome I Oral‐facial‐digital syndrome II Otopalatodigital syndrome Popliteal pterygium syndrome (lower lip pits frequent) Rapp–Hodgkin ectodermal dysplasia Roberts syndrome Single median maxillary central incisor (SMMCI) Stickler syndrome (cleft palate) Treacher Collins syndrome (cleft palate) Van der Woude syndrome (variable paramedian lip pits, cleft lip, cleft palate) Velocardiofacial syndrome (cleft palate) Waardenberg syndrome (occasionally) Median Cleft Lip (In the middle of the upper lip, developmentally between the medial nasal prominences, in contrast to the more common cleft lip that is paramedian (lateral) to the mid‐sagittal plane) Frontonasal dysplasia Holoprosencephaly sequence Mohr syndrome Short rib‐polydactyly syndrome, type II (Majewski type) Oral‐facial‐digital syndrome I Oral‐facial‐digital syndrome II Premaxillary agenesis syndrome 18p‐karyotype |
| Midface (malar) deficiency Aarskog syndrome Achondroplasia Atelosteogenesis type I Cleidocranial dysplasia (dysostosis) |
| Coffin–Lowry syndrome Craniosynostoses (including Apert, Crouzon, Pfeiffer, Muenke, and Saethre–Chotzen syndromes) Down syndrome Hajdu–Cheney syndrome Marshall syndrome Maxillonasal dysplasia (Binder syndrome) Miller syndrome Mohr syndrome Singleton–Merten syndrome Stickler syndrome Treacher Collins syndrome Trichorhinophalangeal syndrome I Velocardiofacial syndrome |
| Mandibular prognathism (may be, at least partially, maxillary hypoplasia) Aarskog syndrome Axenfeld–Rieger syndrome (maxillary hypoplasia) Beckwith–Wiedemann syndrome Chondroectodermal dysplasia (Ellis–van Crevald syndrome, occasionally) Cleidocranial dysplasia (dysostosis) Coffin–Lowry syndrome Down syndrome Fabry disease (occasionally) Fragile X syndrome Klinefelter syndrome (and other sex chromosome aneuploidies in males) Marfan syndrome Maxillonasal dysplasia (Binder syndrome) Nevoid basal cell carcinoma (Gorlin) syndrome Osteogenesis imperfecta (types III and IV often) Papillon–Lefèvre and Haim–Munk syndromes Singleton–Merton syndrome (occasionally) Smith–Magenis syndrome Sotos syndrome Tricho‐dento‐osseous syndrome Waardenburg syndrome |
| Long anterior facial height (may be with open bite tendency) Amelogenesis imperfecta Beckwith–Wiedemann syndrome (associated with macroglossia) Fragile X syndrome Klinefelter syndrome (and other sex chromosome aneuploidies in males) Marfan syndrome Velocardiofacial syndrome |
| Facial asymmetry Hemifacial microsomia (Goldenhar syndrome, oculoauriculovertebral spectrum) Hemihypertrophy Neurofibromatosis (occasionally) Parry–Romberg syndrome Saethre–Chotzen syndrome (nasal deviation common) Velocardiofacial syndrome |
| Ocular hypertelorism (increased distance between the eyes, real or apparent) Aarskog syndrome Apert syndrome Cardio‐facio‐cutaneous syndrome Coffin–Lowry syndrome Crouzon syndrome Fetal face syndrome Frontonasal dysplasia Hajdu–Cheney syndrome Hypertelorism–hypospadias syndrome Leopard syndrome Marshall syndrome Nevoid basal cell carcinoma (Gorlin) syndrome Noonan syndrome Oral‐facial‐digital syndrome I Pfeiffer syndrome Saethre–Chotzen syndrome Sotos syndrome Weaver syndrome Waardenberg syndrome |
| Syndromes associated with dental dysplasias (amelogenesis imperfecta, dentinogenesis imperfecta, and dentin dysplasia) Albright hereditary osteodystrophy Amelogenesis imperfecta with nephrocalcinosis (McGibbon syndrome) Autoimmune polyendocrinopathy Cleidocranial dysplasia (dysostosis) Cone–rod dystrophy and amelogenesis imperfecta Ehlers–Danlos syndrome (some types) Familial hypophosphatemic vitamin D–resistant rickets Goldblatt syndrome Hypophosphatasia Hyperphosphatemic familial tumoral calcinosis (HFTC) Kohlschütter–Tönz syndrome Oculodentodigital syndrome |
| Osteogenesis imperfecta (some in type I, mostly in types III and IV) Schimke immunoosseous dysplasia (SIOD) Seckel syndrome Tricho‐dento‐osseous syndrome Tuberous sclerosis Vitamin D–dependent rickets Vitamin D–resistant rickets Williams syndrome |
| Supernumerary teeth (hyperdontia) Cleidocranial dysplasia (dysostosis) Fabry disease (occasionally) Familial adenomatous polyposis (FAP) Gardner syndrome Nance–Horan syndrome |
| Dental agenesis (besides the third molars; avoid the term congenital absence as the teeth are typically absent at birth anyway, at least clinically, and most radiographically as well. Can variably be in families or just one family member. Being associated with some other anomaly, especially in more than one family member is an indication for clinical genetics referral.) Aarskog syndrome Axenfeld–Rieger malformation and Rieger syndrome Cancer (colorectal, epithelial ovarian, rare?) Chondroectodermal dysplasia (Ellis–van Crevald syndrome) Coffin–Lowry syndrome Down syndrome Ectodermal dysplasias Fabry disease (occasionally) Hallermann–Strieff syndrome Hypohidrotic ectodermal dysplasia (HED) Hypohidrotic ectodermal dysplasia and immune deficiency (HED‐ID) Incontinentia pigmenti Johansson–Blizzard syndrome Kallmann syndrome Lacrimo‐auriculo‐dento‐digital syndrome Oculo‐facio‐cardio‐dental syndrome p63 mutation‐related syndromes Single median maxillary central incisor (SMMCI) Tricho‐dento‐osseous syndrome Williams syndrome Wolf–Hirschhorn syndrome |
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. While typically no single malformation or sign is pathognomonic, each can often point us in the direction of what to consider in the referral and differential diagnosis (Babic et al., 1993).
Today, understanding a patient’s medical/genetic condition may help the orthodontist to understand how to help and what to expect from that patient. A more common application of genetics to orthodontic practice in the future may be in how nonsyndromic complex traits – such as external apical root resorption (EARR) associated with orthodontic treatment, Angle Class III malocclusion, or Angle Class II division 2 malocclusion, for example palatally displaced canines – occur and respond to different orthodontic treatment protocols (Hartsfield et al., 2021). Other areas that also require more investigation include the application of genetics for better prediction of individual growth during puberty, and when the orthodontist should send a patient with hypodontia to the medical geneticist for cancer risk evaluation (Bader, 1967; Jaspers and Witkop, 1980; Hartsfield, 2005, 2008, 2009; McLain et al., 1983).
Knowing the diagnosis and characteristics of a genetic condition, or using an evaluation of genetic factors to better anticipate an individual’s risk of disease or developmental abnormality as opposed to the general population, or their growth pattern and/or likely response to a treatment, has been called personalized or precision medicine. Application of this principle to orthodontic practice is known as “personalized or precision orthodontics” (Hartsfield, 2005, 2008, 2009; Hartsfield et al., 2021).
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, which is perhaps due to hypertrophy of the smooth muscles of the esophagus as part of the rare autosomal dominant odontoma–dysphagia syndrome (Bader, 1967).
Taurodontism
Taurodontism is 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 molar teeth than children with nonsyndromic supernumerary teeth (Kan et al., 2010). It can also be found in several conditions and syndromes, including the following.
Tricho‐dento‐osseous syndrome
Tricho‐dento‐osseous (TDO) syndrome is characterized by variably kinky curly hair at birth that 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 whether at least some cases of amelogenesis imperfecta with taurodontism are also caused by mutations in the DLX3 gene, or actually represent milder cases of TDO (Visinoni et al., 2009; Bloch‐Zupan and Goodman, 2006).
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 range from 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).
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 otodental dysplasia include grossly enlarged molar teeth (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, which 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 aneuploidies/anomalies
These are a deviation from the normal XY chromosomes in males and XX chromosomes in females. Studies on tooth crown size and structure in families and in individuals with various sex chromosome anomalies have demonstrated differential direct effects of the human X and Y chromosome genes on growth. The Y chromosome promotes both enamel and dentin growth, whereas the effect of the X chromosome on crown growth seems to be restricted to enamel formation (Alvesalo, 2009; Krusinskiene et al., 2005).
The positive predictive value for Klinefelter syndrome (47,XXY; i.e. a male with an extra X chromosome, which 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, which occurs in 1 out of 2500 females) appear not to have an increased incidence of taurodontism, although they may show increased variation in root morphology, including short roots (Midtbo and Halse, 1994; Varrela et al., 1990). Turner syndrome shows variable short stature, low hairline, low‐set ears, and a broad neck. These patients typically experience gonadal dysfunction (nonworking ovaries), which results in amenorrhea (absence of menstrual cycle; Babic et al., 1993).
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 relative to the anterior cranial base. An extra X chromosome in males affects the jaw relationship in the sagittal plane, typically increasing the length of the mandible, while an extra X chromosome in females results in shorter lengths of the anterior and posterior cranial bases, the calvarium, mandibular ramus, and 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 (Alvesalo, 2009; Babic et al., 1993; Krusinskiene et al., 2005). Face2Gene facial analysis had good to excellent accuracy in discriminating individuals with Turner syndrome from healthy controls and individuals with Noonan syndrome, who share some phenotypic features with Turner syndrome (Kruszka et al., 2020).
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 that 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 toward the incisal edge (screwdriver shaped). Most of the molars deemed to be taurodontic had short total tooth lengths and could thus be defined as having taurodontism without meeting the classic definition (Axelsson, 2005).
Other conditions in which taurodontism is seen more commonly then 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 that further investigation should be made, as several conditions may be of concern to the orthodontist, including a 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
Hypophosphatasia 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 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
Early‐onset periodontitis may occur in the primary dentition (prepubertal periodontitis), develop during puberty (juvenile periodontitis, JP), or 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). An updated classification of periodontitis previously recognized as “chronic” or “aggressive” is now referred to as periodontitis with a staging and grading system. The staging (I–IV) is largely dependent on the severity of disease at its presentation, as well as on the complexity of disease management. Grading provides supplemental information about biological features of the disease. These include a history‐based analysis of the rate of disease progression (A slow, B moderate, C rapid), and the presence of modifiers such as diabetes and smoking. This updated classification now refers to early‐onset periodontitis as aggressive periodontitis, stage III grade C, with a rapid rate of progression (Papapanou et al., 2018).
The early onset of alveolar bone loss may occur by itself (nonsyndromic) or as part of a syndrome. For example, leukocyte adhesion deficiency (LAD) type I and type 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 increased susceptibility to severe infections and early‐onset (prepubertal) periodontitis (Meyle and Gonzales, 2001). LAD type II is also an autosomal recessive disorder in which 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 retardation and intellectual disability (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 aggressive periodontal disease or crowding, to correct antero‐posterior discrepancies, or to reduce bimaxillary protrusion. 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 periodontally 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 as a characteristic sign. 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 successful combined mechanical and antibiotic therapy of periodontitis associated with 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
Singleton–Merten syndrome is 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
Hajdu–Cheney syndrome (HCS) is a heritable, rare disorder of bone metabolism, associated with acroosteolysis, short stature, distinctive craniofacial and skull changes, periodontitis, and premature tooth loss.
A 22‐year‐old female presented with the characteristic clinical features of HCS, 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 positioned posteriorly. The sella turcica was enlarged, elongated, and wide open with slender clinoids (Bazopoulou‐Kyrkanidou et al., 2007; Figure 4.1). 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 have been successfully performed for the mid‐facial retrusion and to eliminate severe snoring during sleep in one case (Satoh et al., 2002).
Conditions in which premature tooth exfoliation may occur occasionally
Ehlers–Danlos syndrome
See under “Connective tissue dysplasia.”
X‐linked hypophosphatemic rickets (X‐linked hypophosphatemia)
In X‐linked hypophosphatemia, 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 dentino‐enamel 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 (Hartsfield, 1994; Smith and Steinhauser, 1971).
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 will be the dental manifestations. In contrast, vitamin D–deficient rickets does not show the dental abnormalities found in X‐linked hypophosphatemic rickets (Hartsfield, 1994). Dental abnormalities in patients with familial hypophosphatemic vitamin D–resistant rickets were prevented or diminished by early treatment with 1‐hydroxyvitamin D (Chaussain‐Miller et al., 2003). Successful treatment has been reported of a relatively mild case with Class II Division 2 malocclusion with severe anterior crowding and lack of mandibular growth with a functional appliance, followed by the extraction of four premolars and the use of edgewise appliances. No unfavorable root resorption or bone defect occurred (Kawakami and Takano‐Yamamoto, 1997).
Figure 4.1 Hajdu–Cheney syndrome. (a) Patient’s left hand demonstrating its small size and the clubbing of the fingertips. (b) Hand–wrist radiographs of the patient demonstrating osteolysis of the distal phalanges and clinodactyly (arrow) of the fifth left finger. (c) Lateral skull radiograph demonstrating bathrocephaly, wormian bones in lambdoid suture, and basilar invagination (arrow). Cephalometric analysis reveals hypoplasia of the midface anteroposteriorly and vertically, with the maxilla and the mandible being set posteriorly. The cranial base is increased (two standard deviations) and the sella turcica is enlarged, elongated, and wide open with slender clinoids.
Source: Bazopoulou‐Kyrkanidou et al. (2007) / with permission from John Wiley & Sons.
Coffin–Lowry syndrome
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