| Abstract|| |
Amelogenesis Imperfecta (AI) is a collective term for a number of developmental conditions characterized by abnormal enamel formation. Only a few cases of AI have been reported to occur in association with syndromes and metabolic conditions. McGibbon Syndrome or AI and Nephrocalcinosis Syndrome are such disorders with defective enamel and renal calcifications. Early diagnosis of this condition is essential to prevent renal failure and death of the patient.
Keywords: Amelogenesis imperfecta, enamel, nephrocalcinosis, McGibbon, renal
|How to cite this article:|
Rajathi J M, Austin RD, Mathew P. McGibbon Syndrome: A report of three siblings. Indian J Dent Res 2013;24:511-4
Enamel is an ectodermal protective covering of the teeth. Fully formed enamel is the most highly mineralized extracellular matrix known, consisting of approximately 96% mineral (hydroxyapetite calcium phosphate crystals) and 4% organic material and water. The high mineral content renders extreme hardness to the enamel. This property enables enamel to withstand the mechanical forces applied during tooth functioning. 
The organic matrix of enamel is made from non-collagenous proteins only and contains several enamel proteins and enzymes. Ninety percent of these proteins are amelogenins. The remaining 10% consists of non-amelogenins such as ameloblastin, enamelin, and tuftelin. The genes responsible for transcribing amelogenin are found on X and Y chromosomes. These enamel proteins are processed extracellularly and degraded by proteinases. Enamelysin (MMP20), Kallikrein 4 are the proteinases responsible for degradation of these enamel proteins in the maturation stage.  Loss of function of these enzymes produces enamel defects or hypomineralized enamel.
| Case Report|| |
A 13-year-old male patient presented with a chief complaint of yellowish discoloration and chipping of the teeth since birth. History revealed that he had suffered from progressive bending of knees from the age of seven. The defect had been surgically intervened at the time of his visit.
The parents of the patient were consanguineously married. They were apparently normal and had normal dentition. The patient was the eldest son. He had an 11-year-old brother and a 9-year-old sister. The dentitions of the other two children were also affected. The youngest sibling, at the age of four had similar progressive and severe bending of the upper and lower limbs, and was diagnosed with renal osteodystrophy secondary to nephrocalcinosis. Family pedigree revealed three affected children born to two unaffected adults. This was suggestive of autosomal recessive pattern of inheritance [Figure 1].
|Figure 1: Family pedigree had three affected children born to two unaffected consanguineous parents suggestive of autosomal recessive pattern of inheritance|
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The three children were examined. Intraoral examination revealed generalized yellow to brown discoloration of teeth, loss of enamel and razor like cusp tips in the premolars and molars [Figure 2]. The second sibling was spared from skeletal deformity. Other factors that cause enamel defects were ruled out and we arrived at a provisional diagnosis of Amelogenesis Imperfecta (AI).
|Figure 2: Intraoral picture revealing generalized yellow to brown discoloration of teeth|
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A skeletal survey was performed. Radiographs of the skull, chest, forearm, and wrist revealed no skeletal deformity, with normal trabecular pattern and bone density in the first two siblings. The skull radiograph of the third sibling revealed beaten metal appearance. Radiographs of the forearm revealed distal bending and deformity [Figure 3] Orthopantamographs revealed normal eruption pattern with enamel defects [Figure 4].
|Figure 3: The skull radiograph revealing beaten metal appearance. Radiograph of the forearm revealing distal bending and deformity|
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Since dental anomalies are significant components of many inherited syndromes, the presence of AI in all the three children was a valuable diagnostic clue for the confirmation of a syndromic diagnosis. Also, since the youngest sibling was already a diagnosed case of nephrocalcinosis, we were suspicious about the presence of the very rare syndrome AI and nephrocalcinosis Syndrome. Other conditions that have tooth hypomineralization as an integral feature like, vitamin D-dependent rickets, hypophosphatemic rickets and skeletal fluorosis were also considered.
Investigations were done for the three children. Hematological investigations were within normal limits. Biochemical investigations for serum calcium, phosphate, uric acid, creatinine, blood urea nitrogen, alkaline phosphatase, urine creatinine, and urine protein revealed normal values. Also, Laboratory investigations for parathyroid hormone and vitamin D were done with no abnormal findings. Renal ultrasound revealed bilateral, multiple scattered echogenic foci in the medulla suggestive of nephrocalcinosis [Figure 5].
|Figure 5: Renal ultrasound showing bilateral, multiple scattered echogenic foci in the medulla suggestive of nephrocalcinosis|
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Considering the presence of AI, bilateral calcifications in the kidney, and normal hematological and biochemical values, a final diagnosis of AI and nephrocalcinosis syndrome was considered in the three siblings. The parents were informed and educated about the presence of the condition. The children were referred to a higher center for the management of the renal disease.
| Discussion|| |
Tooth development involves different molecular processes that are very critical at different stages. Genetic diseases that disrupt key processes during tooth formation result in dental phenotypes characteristic of when and where the defective gene is normally expressed. Such disruptions during crown formation lead to the inherited defects of enamel and dentine. 
Several definitions and classifications for AI have evolved since 1945. Some classifications have been exclusively based on phenotype. Some have used the phenotype as the primary discriminant and the mode of inheritance as the secondary factor in diagnosis. Most recently, it has been proposed by Aldred et al., that the mode of inheritance should be the primary mode of classification, with the phenotype as the secondary discriminant.
In 2003, Aldred et al., defined AI, as a group of developmental conditions, genomic in origin, which affect the structure and clinical appearance of the enamel of all or nearly all the teeth in a more or less equal manner and which may be associated with morphologic or biochemical changes elsewhere in the body. AI may show autosomal dominant, autosomal recessive, sex linked and sporadic inheritance patterns. Genes responsible for AI are AMELX for X-linked AI and ENAM, MMP20, and KLK4 are responsible for autosomal dominant AI. Many other unidentified genes also contribute to the pathogenesis of AI. 
Multiple congenital anomaly syndromes are developmental conditions in which the dental component is pivotal in diagnosis of the condition. Hence, patients with dental anomalies should be carefully and seriously examined for the presence of multiple congenital syndromes. Conditions associated with AI are Tricho-Dento-Osseous Syndrome, Cone-Rod Dystrophy and AI, Kohlschutter Syndrome, McGibbon Syndrome, Vitamin D deficiency rickets, Auto Immune polyendocrinopathy. 
AI with nephrocalcinosis or McGibbon Syndrome is rare and possibly under diagnosed. The first report of this syndrome was in 1972 by McGibbon.  The common characteristics are, the presence of enamel agenesis, intrapulpal calcifications, delayed tooth eruption, and unexplained bilateral nephrocalcinosis. Biochemical investigations reveal normal plasma calcium, 25-OH vitamin D 3 , alkaline phosphatase, and parathyroid functions. Impaired renal function is variable, or delayed to adulthood, despite the presence of typical renal hyperechogenicity in childhood. ,
Nephrocalcinosis was a term coined by Albright in 1934 to describe the deposition of calcium salts in the renal parenchyma in hyperparathyroidism. It should not be considered as a single, distinct disease process. Rather, it should be viewed as a helpful finding for several distinct disease processes, demanding further evaluation. The condition is usually asymptomatic in the early stages. Patients may present with, episodes of urinary tract infections, hematuria, polyuria, and polydipsia. The major long-term complication in patients with medullary nephrocalcinosis is renal failure. Early treatment of reversible causes of renal failure, such as treatment of urinary infections, calculus obstruction, and hypertension, is essential. Once renal failure is established, it must be treated accordingly. 
McGibbon syndrome has been previously reported in consanguineous and non-consanguineous families. , According to Dellow et al., osteopontin and osteoclastin are matrix proteins expressed in kidney. The genes for these proteins are carried on the same chromosome as other genes coding for proteins involved in amelogenesis. Albumin and osteopontin that are expressed in the kidney are also involved in tooth mineralization.  Hence, mutations of genes coding for these proteins is responsible for the phenotype of amelogenesis imperfecta and nephrocalcinosis syndrome. In our case, the parents of the three children were consanguineously married and revealed no such type of teeth discoloration in the past generations. This fact confirms the autosomal recessive pattern of inheritance of this condition.
Diagnosis of AI involves exclusion of extrinsic environmental factors, establishment of likely inheritance pattern, recognition of phenotype, and correlation with dates of tooth formation. Ultrastructural studies and estimation of protein content and amino acid profile are important diagnostic tools in differentiating the type of AI. Patients suffering from AI need supportive clinical care both in terms of clinical and emotional demands. 
| Conclusion|| |
Many sporadic cases of AI associated with nephrocalcinosis have been reported. Therefore, renal ultrasound being a noninvasive and cost-effective procedure can be considered for all patients with AI. This would aid in early identification of the condition as in this case. Moreover, as medicos, adequate awareness and knowledge of the relationship between tooth discoloration and systemic disorders is essential, for it would certainly contribute to early treatment and better prognosis.
| References|| |
|1.||Nanci A, Ten Cate AR. Ten Cate's oral histology : development, structure, and function. 7 th Ed. St. Louis, Mo.: Mosby, Inc.; 2008. p. 141-90. |
|2.||Aldred MJ, Savarirayan R, Crawford PJ. Amelogenesis imperfecta: A classification and catalogue for the 21 st century. Oral Dis 2003;9:19-23. |
|3.||Bailleul-Forestier I, Berdal A, Vinckier F, de Ravel T, Fryns JP, Verloes A. The genetic basis of inherited anomalies of the teeth. Part 2: Syndromes with significant dental involvement. Eur J Med Genet 2008;51:383-408. |
|4.||MacGibbon D. Generalized enamel hypoplasia and renal dysfunction. Aust Dent J 1972;17:61-3. |
|5.||Hall RK, Phakey P, Palamara J, McCredie DA. Amelogenesis imperfecta and nephrocalcinosis syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:583-92. |
|6.||Paula LM, Melo NS, Silva Guerra EN, Mestrinho DH, Acevedo AC. Case report of a rare syndrome associating amelogenesis imperfecta and nephrocalcinosis in a consanguineous family. Arch Oral Biol 2005;50:237-42. |
|7.||Wrong O. Nephrocalcinosis. In: Davison AM, Cameron JS, Grunfeld J, editors. Oxford Textbook of Clinical Nephrology. Vol. 1, 3 rd Ed. Oxford, United Kingdom: Oxford University Press; 2005. p.1375-96. |
|8.||Elizabeth J, Lakshmi Priya E, Umadevi K.M., Ranganathan K. Amelogenesis imperfecta with renal disease - A report of two cases. J Oral Pathol Med 2007;36:625-8. |
|9.||Hunter L, Addy LD, Knox J, Drage N. Is amelogenesis imperfecta an indication for renal examination? Int J Paed Dent 2007;17:62-5. |
|10.||Dellow EL, Harley KE, Unwin RJ, Wrong O, Winter GB, Parkins BJ. Amelogenesis imperfect, nephrocalcinosis, and hypocalciuria syndrome in two siblings from a large family with consanguineous parents. Nephrol Dial Transplant 1998;13:3193-6. |
|11.||Crawford PJM, Aldred M, Bloch-Zupan A. Amelogenesis Imperfecta. Orphanet J Rare Dis 2007;2:17-27. |
J Maria Rajathi
Department of Oral Medicine and Radiology, Rajah Muthiah Dental College and Hospital, Annamalai Nagar, Chidambaram, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]