Management of a patient with osteogenesis imperfecta and trisomy 18

Management of a patient with osteogenesis imperfecta and trisomy 18 Léa Bontemps, Christophe Poulain, Marguerite-Marie Landru, Lucy Hoang 1 Interne des Hôpitaux de Paris DES Médecine Bucco-dentaire, Hôpital Albert Chenevier, Créteil, France 2 Docteur en Chirurgie Dentaire, Ancien Interne des Hôpitaux de Paris DES Chirurgie Orale, Créteil, France 3 Docteur en Chirurgie Dentaire, Maitre des Conférences des Universités, Faculté de Chirurgie Dentaire Paris Descartes, Praticien Hospitalier, Assistance Publique Hôpitaux de Paris, Chef de Service de l’Hôpital Albert Chenevier, Créteil, France 4 Docteur en Chirurgie Dentaire, Praticien Hospitalier, Assistance Publique Hôpitaux de Paris, Ancien Assistant Hospitalo-Universitaire, Faculté de Chirurgie Dentaire Paris, Descartes, Hôpital Albert Chenevier,Créteil, France


Introduction
The association of trisomy 18 and osteogenesis imperfecta is rare.Osteogenesis imperfecta (OI) is a type of hereditary congenital osteoporosis, characterized by bone fragility and low bone mass, and is linked to a mutation in the gene encoding type-I collagen [1].Although the prevalence of this disease is not known with certainty, it is estimated that 3000-6000 individuals in France are affected, which is approximately 1 in every 10 000 inhabitants.The condition affects both genders and all ethnic groups [1,2].Functional prognosis depends on the severity of the condition and support: administration of bisphosphonates has modified the functional impact of the disease, especially in growing children.Survival is strongly linked to respiratory impairment.Sillence reported a classification in 1979 [3], in which OI patients are classified into 4 categories: light form (type I), unviable form (type II), the most severe viable form (type III), and an intermediate form between types I and III (type IV).Glorieux has refined this classification [2] by subclassifying type IV into types V, VI, and VII, dividing patients according to well-defined clinical and histological characteristics (Tab.I).The OI-associated oral manifestations most often found are Angle class III, infraocclusion and crossbite.Dental abnormalities in the number and position are also reported in the literature, as well as eruptive delays [4,5] (Tab.II).Amelogenesis imperfecta has never been reported in association with OI.Trisomy 18 or Edward's syndrome, which was first described in 1960 [6], is the second most common trisomy after trisomy 21.Its prevalence is estimated at 1 out of 6000-8000 births, but is actually higher because of the high rate of fetal mortality and abortion following prenatal diagnosis.The risk of occurrence increases with the age of the mother, but the risk of recurrence within the same family is very low (approximately 1%) [7,8] (Tab.III).Amelogenesis imperfecta is not part of the clinical picture of trisomy 18.We report a rare case of a patient with amelogenesis imperfecta associated with trisomy 18.

Observation
A 20-year-old patient living with her parents consulted the dentistry department of Albert Chenevier hospital, in Créteil, along with her younger sister (support person).Anamnesis revealed the presence of type-III OI as well as trisomy 18.The

Pathophysiology
Molecular level [9] Chromosomal anomaly due to the presence of an additional chromosome 18 (trisomy 18).The trisomy 18 phenotype appears to be related to the presence of three copies of the 18q11-q12 bands [7].
Autosomal dominant mutation in one of the genes encoding a-1 (chromosome 17) and a-2 (chromosome 7) type-I collagen chains: -Quantitative abnormality (light and intermediate OI) or -Qualitative abnormality (severe and lethal OI).
Tissue level [1,2] Increased bone remodeling with predominant osteoclast resorption: thinner cortical thickness and fewer and thinner spongy trabeculae.
Other extraskeletal manifestations -Ligament laxity: found at the TMJ level • Joint pain, difficulty in chewing [10] • Developmental anomaly [11] -Bluish discoloration of sclera [1] -Hearing: hearing loss in 58% adults [1] -Cardiovascular system À coagulation abnormalities with uncommon and benign vascular tissue disorders [1] -Renal impairment: hypercalcuria [1] -Neurological impairment: headache, cranial nerve impairment, hyperreflexia [1] Craniofacial manifestations are typical: face emaciated and hypertrophied, microcephaly, dolichocephaly, microretrognathism, hypertelorism, pointed ears The hands show overlapping fingers, small fingernails, and underdeveloped thumbs.At the trunk level, the sternum appears smaller [7,13] Diagnosis Diagnostic criteria: essentially clinical; lack of consensus -Blue sclera -Dentinogenesis imperfecta: mainly found in temporary dentition [9] -Family history of the disease [1,2,9] In case of suspected impairment: mandatory assessment of bone density [2] May be suspected during pregnancy with ultrasound (growth stunting, malformations, multiple choroid plexus cysts, etc.) and confirmed by the fetal karyotype Serum markers (also used to screen for trisomy 21) may be abnormal [7] Prognosis Support Objective: To help the patient acquire optimum motor and functional skills [ patient was currently receiving sodium alginate (Gaviscon ® ), vitamin supplementation, and oral contraceptive agents.The reason for consultation was twofold: dental pain, located on the left maxillary semiarch, and multiple tooth stains.With regard to the periodontal condition, the patient had severe gingival inflammation associated with a significant amount of plaque and tartar on the day of consultation (Fig. 1).The patient was in the phase of establishing young adult dentition with teeth 17 and 27 being partially below the mucous membrane.Tooth 26 was not visible, tooth 23 was absent, and tooth 63 was persistent on the arcade.Crossbite as well as an infraocclusion were observed between sectors 1 and 4; the mandibular interincisal point was offset by 5 mm to the right.An orthopantomogram (OPT) was prescribed (Fig. 2).It confirmed the presence of tooth 23 impacted in the ectopic position between teeth 24 and 25 (Tab.IV).Residual roots were identified at the left maxillary semiarch level in position 26.A cone-beam computed tomography examination was prescribed.It confirmed the presence of left maxillary first molar residual roots associated with periapical X-ray images corresponding to inflammatory lesions of endodontic origin (Fig. 3).The extraction of the roots of tooth 26 was carried out under local anesthesia and conscious sedation by ENEMO at the rate of 12 L/min.With regard to dental coloring, they were brown and chalky white stains.Enamel was porous and with decreased hardness, but normal thickness.The teeth did not present the characteristic opalescence of dentinogenesis imperfecta (DI) classically associated with OI (Figs. 4 and 5).Eventually, amelogenesis imperfecta was diagnosed.No treatment was implemented because the patient was not cooperative.

Discussion
This clinical case is the first report of an amelogenesis imperfecta case associated with OI, in which the latter caused dental abnormalities.The most widely used classification of dental anomalies is that of Shields, dating back to 1973 [16]: it describes the different types of DI and dental dysplasia.DI is classified into three types [16]: type I: associated with OI; type II: the most common, with an autosomal dominant transmission, unassociated with OI transmission; and type III: very rare,
-Pamidronate administered intravenously (IV) [2]: reduction of bone pain, improvement of quality of life, rapid increase of the bone mineral mass Prolonged survival (sometimes up to adulthood) is possible, especially in the case of genetic mosaicism or partial trisomy 21 (by translocation) [7] Decreased risk of fractures [14] -Alendronate in bones: decreased number of fractures [2] NB: The benefit/risk ratio is to be considered for each patient; regular assessment of patient's oral health is essential to track potential infectious foci and prevent a possible osteoradionecrosis of the maxilla [15] Medical management is limited to supportive care, the surgical treatment of malformations does not change the prognosis significantly [7] Fig. 1.Clinical perspective: front occlusion (source: author).reported only in Maryland, in the United States [17].Type-I DI has an autosomal dominant transmission [16].Its degree of impact varies [16] without showing a clear correlation with the nature of the genetic mutation [4,5].It is more visible in the temporary teeth and is clinically characterized by fragile and crumbly enamel.In affected cases, dentin is quickly exposed and shows attrition.Teeth have a color ranging from amber to bluish grey, associated with an opalescent nature [17].Impact is less important in the permanent teeth; crowns can be normal, short, globular, abraded, or a combination of these clinical aspects [17].Nevertheless, frequent enamel fractures and a change in enamel color are observed.Plain radiography shows globular crowns, with marked cervical constriction, short roots, obliteration of the pulp chamber, and a periradicular X-ray image because of early dentin exposure [15][16][17].Enamel thickness and mineralization appear normal [17].In the case of type-III OI, DI is found in 80% cases.However, no clinical or radiographic features characteristic of DI are observed in the patient, whether globular crowns, pulp retraction, periradicular X-ray image, or the opalescent clinical appearance.The present clinical manifestations (brown/chalky stains, decreased enamel hardness) allowed us to raise several diagnoses: anamnesis revealed no fluorine overdose in childhood, eliminating fluorosis; these stains were present on the incisors and first molars as well as on the canines and premolars which enabled us to exclude the MIH diagnosis.Thus, our diagnosis shifted toward amelogenesis imperfecta.Amelogenesis imperfecta (AI) is a hereditary anomaly of the enamel that affects enamel structure and causes clinical abnormalities in all or almost all teeth, either in isolation or associated with a syndrome [18].Four types of AI can be distinguished according to Wiktop [19]: hypoplasia (I), hypomaturation (II), hypomineralization (III), and hypomaturation/hypomineralization with taurodontism (IV).We believed the patient had the hypomature form, as the enamel and the dentin did not show the same radio-opacities [20].There is currently no association between osteogenesis imperfecta and amelogenesis imperfecta in the literature, regardless of the OI or AI type.In the present case, this could be an atypical form of OI,    exceptionally associated with a strictly malformation of the enamel; however, it is more likely that the two pathologies were present concomitantly but without causal connection, such as trisomy 18.To confirm our diagnostic hypothesis, we wanted to conduct a genetic analysis aiming to find the characteristic abnormalities of AI.Unfortunately, despite our explanations, the patient's family refused other medical appointments to make a diagnosis that would not influence the treatment.

Conclusion
Abnormalities in tooth coloring associated with OI are not always related to DI. AI has never been described.The present case highlights the need for a diagnosis offered by an oral cavity specialist to differentiate between these two entities.
* May or may not be detectable in a given patient.

Table II .
[4]tal manifestations in temporary and permanent teeth in patients with OI type III and IV[4].

Table III .
Physiopathology, manifestations, diagnosis and management of OI III and trisomy 18 (source author).

Table IV .
Dental formula.