Dental and Craniofacial Characteristics in a Patient with Leprechaunism Treated with Insulin-Like Growth Factor-I
Abstract
Leprechaunism is an autosomal recessive disease characterized by elfin-like faces, loss of glucose homeostasis, and severe insulin resistance. This disease is caused by inherited defects of the insulin receptor and is lethal early in life. Perhaps for this reason, the teeth and craniofacial features of patients with leprechaunism have never been reported. In the present case, the patient had been diagnosed with leprechaunism with mutation in the insulin receptor gene and had treatment with recombinant human insulin-like growth factor I (IGF-I) starting at the age of 1 year 7 months. It is of interest that all of his teeth were extremely large and subsequently showed severe crowding in the dental arches. He also showed a large tongue with an anterior open bite. He had a convex facial profile with a remarkably steep mandibular plane angle and large gonial angle. This is the first report of the characteristic phenotypes of the teeth and craniofacial morphology of a patient with leprechaunism treated with IGF-I. In addition, the possible association between these features and long-term IGF-I treatment is discussed.
INTRODUCTION
Leprechaunism is a rare congenital syndrome associated with extreme insulin resistance.1 In addition to insulin resistance, leprechaunism features are characterized by a peculiar elfin-like face (low-set and large ears, depressed nasal bridge with a broad nasal tips, anteverted nares, and thick lips), decreased subcutaneous fat, acanthosis nigricans, retarded intrauterine and postnatal growth, and hirsutism.12
The insulin resistance in leprechaunism has been shown to be caused by mutations in the insulin receptor gene.34 Insulin exerts both metabolic and mitogenic effects on its target cells through the insulin receptor.5 Defects of insulin action result in retarded intrauterine growth and metabolic dysfunction in humans.4–6 In addition, infants with leprechaunism characteristically show hirsutism.2 Like hair, teeth are ectodermal appendage organs; however, the tooth phenotype in patients with leprechaunism is not known because these patients usually do not survive infancy.
Insulin-like growth factor I (IGF-I), a polypeptide with extensive structural homology to insulin (48%), has major insulin-like effects on glucose uptake, glycolysis, and glycogen synthesis in vitro and in vivo.78 Previously, it has been reported that short-term treatment with recombinant human IGF-I (rhIGF-I) improved glucose metabolism in patients with the genetic form of insulin resistance.39 A recent report also showed that long-term treatment with rhIGF-I works effectively to prevent postnatal growth retardation and normalize glucose metabolism in patients with leprechaunism.10 In addition, Di Cola et al8 reported that IGF-I could mimic insulin's effects on glucose metabolism by acting through its own receptor in mice genetically deficient for insulin receptors. However, because IGF-I promotes growth and differentiation in a variety of tissues,11 possible side effects of IGF-I treatment regarding tooth and craniofacial anatomy should be noted.
In the present case study, we found that a patient with leprechaunism showed significantly large-sized teeth and severely crowded malocclusion. He had had long-term treatment with recombinant IGF-I. We discuss below whether the enlargement of tooth size was due to a tooth phenotype caused by the defect of the insulin receptor or due to the side effects of long-term IGF-I treatment. In addition, the patient showed a specific abnormal craniofacial growth pattern, and we also discuss the possible association between it and long-term IGF-I treatment.
CASE REPORT
A patient with leprechaunism, an 11-year 11-month-old boy, presented at the orthodontic clinic of Okayama University Dental Hospital with complaints of crowded teeth and anterior open bite. His height and weight were 133.3 cm (−2.3 SD) and 29.9 kg, respectively (Figure 1). The bone age was 11.5 years, as estimated by hand-wrist radiograph12 (Figure 2). He showed typical features of leprechaunism, including large and low-set ears, depressed nasal bridge with a broad nasal tip, hirsutism, and acanthosis nigricans in the axilla and around the neck (Figure 3). The tongue was large and, when extended, was long enough to reach the mentum (Figure 4). An anterior open bite with an overjet of 3 mm and overbite of −7 mm was observed (Figure 5). Because of enlarged teeth, severe crowding of 23 mm in the maxillary arch and of 19 mm in the mandibular arch was present (Figure 5). Moreover, the upper and lower canines and lower premolars were malformed teeth (Figure 5; Table 1).
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
The panoramic radiograph revealed that all second molar roots were developed and all third molar roots were developing (Figure 6). Cast analysis showed that the size of all teeth was remarkably larger than the Japanese norm13 (Table 1). Cephalometrically, when compared with the normative values for Japanese males of corresponding age,14 the patient had a skeletal Class I jaw base relationship (ANB 1.9°; Figure 7; Table 2). The mandibular length was increased (Ar-Me 111.2 mm), but the mandibular body length and ramus height were within the reference range (Go-Me 72.4 mm, Ar-Go 42.1 mm). The mandibular plane angle was remarkably steep with a significantly large gonial angle (mand. pl.-FH 48.5°, Go.A 153.1°; Figure 7; Table 2). These data indicate that the mandible was protruded but simultaneously rotated in the inferior direction. Both the upper and lower incisors were severely labially inclined (U1/FH 125.7°, L1/FH 45.8°, L1/MP 85.7°; Figure 7; Table 2).
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
These skeletal and dental characteristics were also confirmed in a 3-dimensional computed tomography image, as shown in Figure 8. The condyle was normal in morphology, and the articular disc was positioned properly, as observed in the tomographs and magnetic resonance image, respectively (Figure 9). However, a 6-degree-of-freedom jaw recording system revealed that the condyle moved asymmetrically and that left condylar movement was limited in range during open-and-close jaw movement (Figure 9). The maximum occlusal force and occlusal contact area during maximum clenching showed small values in comparison with the Japanese norm15 (Table 3).
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
Citation: The Angle Orthodontist 78, 4; 10.2319/0003-3219(2008)078[0745:DACCIA]2.0.CO;2
The patient's medical record showed that he was born after 40 weeks of gestation as a normal-for-gestational-age infant with a birth weight and length of 2736 g and 47 cm, respectively. He was diagnosed with leprechaunism at Saitama Children's Medical Center because he showed an extreme degree of insulin resistance (blood glucose, 121 mg/dL; corresponding serum immunoreactive insulin, 3575 μU/mL), hirsutism, large penis, acanthosis nigricans, and delayed mental development.16
Molecular analysis revealed a missense mutation causing substitution of Met for Thr at position 910 of the insulin receptor gene, and this mutation affected insulin binding by impairing receptor processing.16 At the age of 1 year 7 months, he started to receive administration of subcutaneous injection of recombinant human IGF-I (Fujisawa Pharmaceutical Co, Osaka, Japan) twice a day at a dose of 0.1 mg/kg body weight. Thereafter, IGF-I (0.05–0.2 mg/kg body weight) was given daily in the morning and in the evening. At the age of 6 years 8 months, he underwent tonsillectomy. In addition, nephrocalcinosis and cholesteatoma were found by ultrasonic observation.
DISCUSSION
In this patient with leprechaunism treated with rhIGF-I, we observed remarkable enlargement of all his dentition, and all the teeth showed early maturity. Patients with leprechaunism commonly die early in life.1–4 In the present case, the patient has been treated with rhIGf-I from the age of 1 year 7 months. Therefore, the tooth phenotype of leprechaunism cannot be evaluated in this patient independent of the influence of long-term treatment with rhIGF-I. Thus, it is not clear whether the enlargement of the teeth was due to the impaired function of the insulin receptor or due to unfavorable side effects of the long-term IGF-I treatment. “In vitro and in vivo” IGF-I stimulates cell growth in a variety of tissues.11 In tooth development, IGF-I in the continuously erupting rat incisor is expressed in odontoblasts and ameloblasts, and its receptor is also expressed in these cells.17–19 Interestingly, IGF-I increased the mouse tooth germ volume by about twofold compared with 20% fetal calf serum treatment when the tooth germ was cultured in dishes for 6 days.20 In addition, IGF-I stimulates the root elongation of mouse mandibular molars in vitro.21
On the other hand, Laron-type dwarfism is characterized by growth hormone resistance, which leads to an inability to synthesize IGF-I.22 In patients with Laron-type dwarfism who do not receive treatment, a high prevalence of missing third molars (in more than 90% of the patients) and hypodontia (in more than 30% of the patients) compared with the normal population was reported.23 Moreover, permanent teeth in these patients tended to have smaller mesiodistal diameters.23 In addition, although such patients have the clinical feature of prolonged retention of the primary dentition, IGF-I treatment for 1 year induces the loss of deciduous teeth and appearance of permanent dentition.24
Taken together, these findings suggest that IGF-I has strong anabolic effects on tooth development and could affect the size of the teeth and tooth development. However, patients with Rabson-Mendenhall syndrome, which is characterized by extreme insulin resistance caused by mutations in the insulin receptor gene, have early eruption of permanent teeth, dental abnormalities, and irregularly placed and crowded teeth.4 Therefore, it is likely that the enlarged teeth in our patient with leprechaunism were due to some side effect of long-term treatment of IGF-I as well as the tooth phenotype induced by insulin receptor impairment.
The patient showed a skeletal open bite tendency with protruded mandible and increased gonial angle. Anterior open bite is often observed associated with macroglossia and mouth breathing. Our patient actually showed macroglossia. This might have led to protrusion and clockwise rotation of the mandible, presumably to seek wide space in an insufficiently oral cavity. Recently, it has been reported that 4-week administration of IGF-I induced the increases of tongue weight as well as muscle-bundle width and epithelial thickness of the tongue in the 10-week-old rat.25 In addition, the IGF-I receptor was expressed in most of the taste bud cells of adult mice by immunohistochemistry and those of postnatal day 6 mice by in situ hybridization.26 Hence, it is speculated that the tongue might respond to IGF-I more than other craniofacial organs, and the macroglossia observed in patients with leprechaunism might be due to the unfavorable effects of long-term treatment with rhIGF-I. Furthermore, rhIGF-I–induced macroglossia might lead to a characteristic craniofacial growth pattern as a secondary effect. However, this patient needs continuous treatment with IGF-I to survive. In the future treatment of this patient, we have to take special note of the tongue growth and the mandibular growth, taking account of the clockwise rotation. If the skeletal open bite tendency should worsen, glossectomy might be indicated in the future.
It has been reported that most Laron-type dwarfism patients treated with rhIGF-I have an apparent increase in the size of their nasopharyngeal lymphoid tissue.27 Actually, our patient had a history of hypertrophy of tonsil and underwent tonsillectomy at age 6. Hypertrophy of the tonsils has also been reported in leprechaunism and Laron-type dwarfism patients who have been treated with rhIGF-I.1027 Therefore, the hypertrophy of the tonsils in this patient might have been due to IGF-I treatment.
Hypertrophy of the tonsils is the major cause of respiratory obstructions in childhood, and airway obstruction might lead to mouth breathing. The parents of this patient reported that his snoring during sleeping was improved by tonsillectomy, suggesting that hypertrophy of the tonsils might actually have caused airway obstruction in this patient. Respiratory problems possibly cause postural alterations of the mandible and consequently induce clockwise rotation of the mandible with lip incompetence.28
This patient showed very a small maximum occlusal force. In an animal study, insulin receptor substrate–1 deficiency resulted in decreases in various organs weights, such as kidney, brain, intestine, spleen, heart, liver, and gastrocnemius muscle, and transgenically overexpressed IGF-I rescued such weight reduction, except in the gastrocnemius muscle.29 Therefore, a weak occlusal force in this patient might be due to muscle problems that were induced by the insulin receptor mutation in leprechaunism with insufficient rescue by IGF-I. In addition, the present case showed a large gonial angle and steep mandibular plane angle, and it is well known that long-face adults show weak occlusal force.1530 Hence, it is also possible that the weak occlusal force was due to the craniofacial characteristic of a long face.
Our observations suggest that long-term IGF-I treatment could cause unfavorable side effects on tooth size and the craniofacial growth pattern. However, without continuous treatment with rhIGF-I, leprechaunism is a lethal disease. Several groups have reported that this therapy had the benefits of normalizing glucose metabolism and preventing postnatal growth retardation in patients with extreme insulin resistance.3910 The dentition and craniofacial growth of these patients should be carefully monitored by orthodontists to minimize unfavorable side effects as much as possible. Glossectomy and/or tonsilectomy might be indicated if the tongue or the tonsils become large. Tooth extraction treatment might also be indicated if the patients show severely crowded teeth due to their enlarged size.
Previously, these patients could not survive for more than 1 or 2 years. However, recent biotechnology enables treatment of this lethal condition, and consequently, we encountered in this patient a dental and craniofacial phenotype that has not previously been reported. As in this disease, new therapies are constantly being developed for severe and/or fetal diseases. It is therefore likely that orthodontists will have more opportunities in the future to find new types of malocclusion that have not yet been observed.
Photograph of a patient with leprechaunism, aged 11 years 11 months
Hand-wrist radiograph indicates that the bone age was 11.5 years. This was almost coincident with the chronological age
(A) Facial profile shows the low-set ears. (B, C) Close-up of the large ears. (D) Close-up of the depressed nasal bridge with broad nasal tip. (E) Hirsutism of the arm. (F) Acanthosis nigricans around the neck
Photographs of protruded tongue. Note extremely large volume of tongue
Intraoral photographs show that severe crowding in both arches with large size of all the teeth
Panoramic radiograph revealed that all second molar roots were developed and all third molar roots were developing. This indicates that dental age is advanced compared with chronological age
(A) Cephalometric radiograph. (B) Cephalometric tracing. Tracing was superimposed on the mean profilogram. Note that the mandibular length was increased and the mandibular plane angle was remarkably steep with a significantly large gonial angle.
Three-dimensional computed tomography images
(A) Tomographs. (B) Magnetic resonance imaging. Arrows show disc position. Rt indicates right side; Lt, left side; (C), condylar movement and incisal paths during maximum open-and-close jaw movement as detected using a 6-degrees-of-freedom jaw movement recording system
Contributor Notes
Corresponding author: Dr Teruko Takano-Yamamoto, Department of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan (t-yamamo@mail.tains.tohoku.ac.jp)