Genetic Tooth Disorders Part I

mutations that occur early in tooth formation

affect the number of teeth formed

mutations that occur late in tooth formation

affect quality of mineralized tissues

hypodontia

missing fewer than 6 teeth (not including third molars)

oligodontia

missing more than 6 teeth (not including third molars)

relatively common to miss

third molars and upper lateral incisors

anodontia

• congenitally missing all primary or permanent teeth

• very rare

• ectodermal dysplasia

homeobox genes contain

180 base pair (nucleotides) region that encodes for the homeodomain

homeodomain

60 amino acid region that binds DNA to regulate transcriptional cascades of downstream genes early in development

Pax 9

• belongs to PAX gene family, which encodes a group of transcription factors

• expressed in ectomesenchyme of tooth bud

• role in early tooth development

mutations of human Pax 9 gene cause

molar hypodontia

MSX genes

• homeobox genes; constitute a large family of transcription factors

• initiate the cascades of co-regulated genes required to produce tissues and

  organs

MSX1 is a

transcriptional repressor

MSX1 haploinsufficiency (only half of the protein level is present)

affects development of all teeth

MSX1 mutations cause

• cleft lip

• cleft palate

• hypodontia

Ser105Stop mutation

• translation stops before the entire protein is made

• complete absence of MSX1 homeodomain

• most severe phenotype: orofacial clefts and tooth agenesis

ectodermal dysplasia

• describes group of inherited disorders characterized by aplasia or dysplasia of tissues of ectodermal origin

• over 150 types

• clinically divided into hidrotic and anhidrotic forms

hypodontia occurs in 80% of cases of

anhidrotic (hypohydrotic) forms of ED

no hypodontia in

hidrotic form

extraoral signs of ED

• sparse fine or coarse curly hair

• abnormally developed nails

• frontal bossing

• prominent lips

• depressed midface and nasal bridge

• soft, thin, and dry eczema-prone skin

anhidrotic ED

• reduced functional sweat glands

• x-linked recessive

• deletions w/in EDA (ectodysplasin A) gene on chromosome X

• hypodontia, hypohidrosis, and hypotrichosis

in rare cases of anhidrotic ED

complete anodontia

EDA associated hypodontia

• teeth are conical, malformed, and widely spaced

• reduced alveolar bone growth and vertical facial height

• lack of development of alveolar ridges —> extremely narrow and concave lingually

supernumerary teeth

• additional to normal complement

• affect primary and permanent dentitions

• in Caucasians, M:F is 2:1

• in Japanese, M:F is 5.5 - 6.5:1

sequelae of supernumerary teeth

• normal eruption of dentition

• failure of eruption

• displacement or rotation

• crowding

• abnormal diastema or premature space closure

• dilaceration, delayed or abnormal root dev. of perm. teeth

• cystic formation

• eruption into nasal cavity

locations of supernumerary teeth

• usually anterior maxilla, followed by mandibular premolar region

• can be single, multiple, unilaterally, bilaterally, in one or both jaws

• more commonly associated with syndromes

• extremely rare in mandibular incisor region

conical

small, peg-shaped conical tooth

tuberculate

• larger than the conical tooth

• more than one cusp

• barrel-shaped

• stunted root formation

• often paired and on palatal aspect of max. central incisors

supplemental

• duplication of teeth at end of tooth series

• most commonly perm. max. lateral incisor

• can be molars as well

odontoma

most common odontogenic benign tumor

compound odontoma

• resembles bag of small teeth

• has cementum, dentin, and enamel

complex odontoma

• not organized

• has cementum, dentin, enamel, and pulp

mesiodens

conical shape located between max. central incisors

paramolar

• supernumerary molar, usually small and rudimentary

• buccal or lingual to max molars OR in interproximal space buccal to second and third molar

distomolar

• distal to 3rd molar, usually small and rudimentary

• rarely delays/impedes eruption of normal tooth

etiology of syndromic supernumerary teeth

genetic mutations of specific genes

• Runx2 (CCD)

• APC (Gardner’s syndrome)

etiology of non-syndromic supernumerary teeth

• unknown but clear hereditary component

• most accepted theory: hyperactivity of dental lamina

supplemental (eumorphic) supernumerary teeth result from

local, independent, conditioned hyperactivity of dental lamina

rudimentary (dysmorphic) supernumerary teeth result from

proliferation of epithelial remnants of dental lamina

cleidocranial dysplasia (CCD) clinical features

• short stature

• late closure of fontanels and sutures

• aplasia of clavicles

• hypertelorism (wide eyes)

• low nasal bridge

• supernumerary teeth

cleidocranial dysplasia (CCD)

• autosomal dominant pattern of inheritance

• heterozygous mutations of Runx2

Runx2

transcription factor essential for bone and tooth development

CCD oral features

• supernumerary teeth

• delayed eruption

• malformed roots

• no cellular cementum

• high palate

• submucousal cleft

familial adenomatous polyposis (FAP)

• causes premalignant colorectal (adenomas) to develop

  • Fulminant FAP: >100 adenomas

  • Attenuated FAP: <100 adenomas

• 100% chance of developing colorectal cancer if untreated, usually by middle age (~39 years)

• extra-intestinal manifestations

  • epidermoid cysts, osteomas, ocular abnormalities

• oral manifestations

  • jaw osteomas, odontomas, supernumerary teeth

• oral signs precede GI symptoms so early diagnosis is life saving

gardner’s syndrome

FAP + extra-intestinal manifestations (epidermoid cysts, osteomas, odontomas, supernumerary teeth, etc.)

genetics of FAP

• autosomal dominant (only one mutated copy of gene is needed)

• 1 in 8300-1400 people; rare

• caused by APC mutation

• 1/3 of cases due to spontaneous mutation

adenomatous polyposis coli (APC)

• tumor suppressor gene located on chromosome 5 (5q21–q22)

• regulates proliferation, migration, adhesion, cytoskeleton stabilization

FAP can be diagnosed by

>100 colorectal adenomas or APC gene mutation

site of APC mutation correlates with

clinical phenotype

mutations in 3’ region of APC gene are associated with

• oral manifestations (supernumerary teeth and odontomas)

• extra-intestinal manifestations

• Gardner’s syndrome (oral manifestations and polyps in intestines)

11-27% of patients have

supernumerary teeth

mutations in central region of APC gene

• cause fulminant APC w/ 1000-5000 polyps

• no oral manifestations

• high risk for colon cancer by age 39

mutations in extreme 5’ region of APC gene

• attenuated form of APC w/ <100 polyps

• no oral manifestations

• still have high risk for colon cancer, but delayed age of onset

mutations in extreme 3’ region of APC gene

• cause attenuated APC w/ high risk of colon cancer

• have oral manifestations that define Gardner’s syndrome (supernumerary teeth, odontomas, osteomas)

dentist is often the first clinician to diagnose

Gardner’s syndrome

appropriate diagnosis is life-saving

medical consult and genetic counseling

management of supernumerary teeth is similar to

CCD patients

PAX9 and MSX1 mutations cause

arrested tooth formation and see clinical hypodontia

Runx2 and APC mutations cause

supernumerary teeth

EDA mutations cause

ectodermal dysplasia whose phenotype includes hypodontia, oligodontia, and in some cases anodontia