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Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?
YIJOM-4373; No of Pages 6
Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2020.02.002, available online at https://www.sciencedirect.com
Case Report TMJ Disorders
Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth? J. W. Nolte, M. Alders, L. H. E. Karssemakers, A. G. Becking, R. C. M. Hennekam: Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2020 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons.
Abstract. Hemifacial hyperplasia (HFH) is characterized by an increase in volume of all affected tissues of half of the face. It is present at birth, subsequently grows proportionally, and stops growing before adulthood. Unilateral condylar hyperplasia (UCH) consists of progressive asymmetric growth of the mandible and develops typically in early adulthood. Both disorders have an unknown aetiology. The overgrowth limited to one body part suggests somatic mosaicism, as this has been found in other similar localized overgrowth disorders. Often this includes a variant in a gene in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway. Here we report the case of an HFH patient with asymmetry present at birth, in whom a progressive growth pattern similar to UCH subsequently occurred, causing marked mandibular asymmetry. A condylectomy was successfully performed to stop the progressive growth. Somatic mosaicism for a mutation in PIK3CA was detected in the condylar tissue. This finding might indicate that both HFH and UCH can be caused by variants in genes in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway, similar to other disorders that result in asymmetrical bodily overgrowth.
Hemifacial hyperplasia (HFH) is an entity that becomes evident as a marked asymmetry of the face. All affected tissues, including skin, fat, muscles, and bone, are increased in volume. Typically, it is present at birth and shows subsequent proportional growth until the end of puberty, when growth stops1. 0901-5027/000001+06
Unilateral condylar hyperplasia (UCH) is characterized by progressive asymmetry of the mandible, due to increased development of one mandibular condyle. This causes concomitant asymmetry of the whole face, but only bony tissue is affected. Obwegeser and Makek2 recognized two main types: hemimandibular elonga-
J. W. Nolte1, M. Alders2, L. H. E. Karssemakers1, A. G. Becking1,3, R. C. M. Hennekam4 1
Department of Oral and Maxillofacial Surgery, Amsterdam UMC/Emma Children’s Hospital, and Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam, Amsterdam, The Netherlands; 2Laboratory of Genome Diagnostics, Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development, Amsterdam, The Netherlands; 3Department of Oral and Maxillofacial Surgery, Spaarne Gasthuis, Haarlem, The Netherlands; 4Department of Paediatrics and Translational Genetics, Amsterdam UMC/Emma Childrens Hospital, University of Amsterdam, Amsterdam, The Netherlands
Key words: unilateral condylar hyperplasia; hemifacial hyperplasia; genetics; PIK3CA; mandibular asymmetry; hemimandibular hyperplasia; hemimandibular elongation; maxillofacial surgery. Accepted for publication 4 February 2020
tion (HE), characterized by predominantly horizontal asymmetry, and hemimandibular hyperplasia (HH), demonstrating mainly vertical distortion with increased volume. The term hyperplasia in this context is in fact confusing, as histology does not confirm true hyperplasia in all UCH patients3, but for historical reasons we use
ã 2020 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons.
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
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the term here. In UCH, the asymmetry is not present at birth but develops later, typically in early adulthood (mean age 21 years). Progression can be confirmed with bone scintigraphy, and treatment consists of a partial condylectomy to stop the progressive growth4. The aetiology of HFH is poorly understood1,5. Several overgrowth syndromes may show asymmetrical facial overgrowth as part of the general overgrowth, such as Proteus syndrome, neurofibromatosis, and BeckwithWiedemann syndrome68. The genetic background of these syndromes is known, but no genetic cause is known for isolated HFH, although it has been suggested that HFH may be caused by mutations in the (PIK3CA)/PI3K/ (PTEN)/AKT1/mTOR pathway5. The aetiology of UCH is not known either. Inflammation, trauma, endocrine imbalances, hypervascularity, neoplasms, and genetic causes have been suggested, but no evidence is available2,9. Clinically, in both disorders, the overgrowth is localized to the face only, suggesting a somatic mosaicism, which indicates that the mutation is present only in the affected tissue and not in the whole body. Here we report the case of a patient with HFH in whom a condylectomy was performed because of progressive mandibular asymmetry, and in whom investigations of the affected condylar tissue revealed a mutation in PIK3CA.
The size and number of cells of the various tissues were normal. Repeated X-ray examinations (panoramic radiographs) from 8 years of age showed accelerated eruption of the molars on the
right side, with diminished root development. The right side of the mandible including the condyle was enlarged (Fig. 1). In the ensuing years, the facial asymmetry became again more pronounced,
Clinical presentation
The patient was the second-born child of healthy, non-consanguineous parents. His family history was negative for congenital anomalies or asymmetries. The mothers pregnancy had been uneventful; birth was via forceps delivery. Birth weight was 3170 g (10th percentile). The parents noticed a slightly larger cheek on the right side, without any other abnormalities. Subsequent growth in height and skull circumference was normal, as was cognitive development. He was first evaluated because of facial asymmetry at 3 years of age. The right half of his face was more prominent than the left side, especially the cheek, with hyperemic spots. The right side of the tongue was larger than the left side, and permanent incisors were visible on the right side. At the age of 6 years, some excessive soft tissue of the right cheek intraorally, referred to as a hamartoma, was surgically removed. Histology showed fibrous tissue, muscle, and fat, with many nerve fibres.
Fig. 1. Facial clinical and radiological characteristics. (a) Frontal photograph at age 3 years, showing enlargement of the right cheek. (b) Panoramic radiograph at 8 years, showing accelerated eruption of the right side molars. (c) Panoramic radiograph at 14 years, showing enlargement of the right condyle and mandibular half.
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
YIJOM-4373; No of Pages 6
UCH in hemifacial hyperplasia which urged for meatus plasty and bony debulking around the ear canal due to a narrowed ear canal at 16 years of age. The middle ear and inner ear were normal. Subsequent orthodontic treatment allowed an adequate dental occlusion, with median position of the upper and lower midline. At 17 years of age, the asymmetry of the mandible progressed over the course of a few months, with an increase in midline shift and deviation of the mandible. Magnetic resonance imaging (MRI) demonstrated the right-sided mandibular overgrowth and increased fat tissue, including the parot-
id and submandibular glands. Single-photon emission computed tomographycomputed tomography (SPECT-CT) with radioactive labelled technetium showed a significant difference in osteoblastic activity between the left and right condyles (mean 40% and 60%, respectively), confirming the hyperactivity of the right condyle (Fig. 2). The hyperactivity prompted a condylectomy, during which the growth centre was removed. Orthodontic treatment was subsequently provided. No progression of mandibular asymmetry was evident at follow-up after 1 year.
3
Methods
The resected condylar tissue was sent for regular histopathology and for DNA extraction according to the clinical protocol. A panel of eight genes known for overgrowth (AKT1, AKT3, MTOR, PIK3CA, PIK3R2, PTEN, TSC1, and TSC2) and used as standard in individuals with overgrowth, was sequenced by next-generation sequencing (NGS), with minimal ˆ to be able to detect coverage of 500O low grade mosaicism. Enrichment of the target genes was done using a SeqCap EZ
Fig. 2. Facial clinical and radiological characteristics at 17 years of age. (a) Frontal photograph, showing enlargement of the right cheek (proportionally). (b) 3D CBCT, showing enlargement and vertical distortion of the condyle and mandible on the right side. (c) MRI, showing enlarged soft tissues on the right side. (d) SPECT-CT, showing a hyperactive condyle on the right side. (3D CBCT, three-dimensional cone beam computed tomography; MRI, magnetic resonance imaging; SPECT-CT, single-photon emission computed tomography–computed tomography.).
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
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Fig. 3. Resected condylar tissue. (a) Clinical view. (b) Histopathology, showing no abnormalities.
Choice capture kit (Roche NimbleGen, Inc., Madison, WI, USA). The enriched libraries were sequenced on a MiSeq platform (reagent kit v2; Illumina, San Diego, CA, USA) according to the manufacturers recommendations for pairedend 150-bp reads. Alignment of the sequence reads to the human reference genome (hg19) was done using BWA-MEM 0.7.5. (bio-bwa.sourceforge.net/), and variants were called using the GATK 2.8.1 software package (www. broadinstitute.org/gatk/). Filtering of variants was done using Cartagenia Bench Lab NGS (Agilent, Santa Clara, California, USA). All variants within the exon 20 regions were evaluated. Results Histopathology
Histology showed sections through the trabecular bony tissue with normocellular
bone marrow in between, and a normal ratio of hematopoietic series. The progenitor cells of the three series were organoid, without striking hotspots. Superficially, there was fibrous tissue with a thick layer of hyaline cartilage and periosteum underneath (Fig. 3). Targeted exome sequencing
The variant c.3140A > T p.(His1047Leu) in PIK3CA (NM_006218.2) was detected in DNA derived from the mandibular condyle. The variant was present in 38% of the reads, highly suggestive of somatic mosaicism (BioProject ID: PRJNA560479 http://www.ncbi.nlm.nih.gov/bioproject/ 560479). Discussion
The clinical features of HFH comprise unilateral enlargement of all facial tissues, including an enlarged mandibular condy-
le1,10. The HH subtype of UCH is very similar to the skeletal features of an HFH patient. In HFH the asymmetry is present at birth and does not explicitly increase in growth, but continues proportionally until cessation around 18 years of age1. A typical feature of UCH is progression of growth-resembling activity, which usually starts in adolescence4. Therefore, clinically, the present patient showed an overlap of HFH and UCH. A similar combination of HFH and UCH characteristics has not been reported previously in the literature. Shanmugasundaram et al.11 also performed bone scintigraphy in their HFH patient and showed hyperactivity of the overgrown maxilla and mandible, but clinically there was no progressive asymmetric growth, and no quantification of condylar activity was measured. No other studies have been performed to detect a possible genetic background of UCH.
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
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UCH in hemifacial hyperplasia The molecular background of overgrowth disorders is gradually being unravelled and seems to be mainly located in the (PIK3CA)/PI3K/(PTEN)/AKT/mTOR pathway. A PIK3CA-related overgrowth spectrum (PROS) has been described, which comprises syndromes that all show a PIK3CA-activated mutation, but with different overgrowth phenotypes12. Clinically, a wide variation can be seen, from vascular malformations with segmental overgrowth to soft tissue and bone tissue hypertrophy. Asymmetrical facial overgrowth can be present13,14. The detected variant p.(His1047Leu) in the present HFH patient with UCH characteristics, is one of the known PIK3CA-activating variants, as described before in other segmental overgrowth. Lindhurst et al.6 described a mosaicactivating AKT1 mutation as the cause of Proteus syndrome (segmental overgrowth and hyperplasia of multiple tissues and organs). They hypothesized that a milder phenotype could be associated with an occurrence of the somatic mutation later during development, but this was not confirmed in their studies. No association between the proportion of mutant alleles and the overall clinical severity or specific manifestations of the phenotype was found, and their data did not suggest a specific stage during development at which the mutation arose6. The hypothesis that HFH is caused by a somatic mutation early in (embryonic) life and that UCH might be caused by a somatic mutation later in life and, thus, have milder symptoms (affecting only the mandibular/condylar tissue), is therefore less likely. The expression of UCH in the patient described here could be a coincidence. However, the mandibular features of the HH type of UCH are very similar to the features of HFH, and therefore it is very well possible that both HFH and UCH are caused by variants in genes of the molecular overgrowth spectrum that have yet to be identified. Histologically, no consistent histopathological abnormalities are found in UCH. There is a tendency towards an increased number of cartilage islands in the cortical layer of the affected condyles, but this has not been confirmed in all patients3. Also, Yamazaki et al. found no marked true hyperplasia in HFH5, although they reported an increase in vascularity and number and thickness of nerves in the affected soft tissue. In accordance, Yoshimoto et al.15 found no atypical cells or hyperplasia in the cortical bone of the affected side, but did report that osteoblast DNA synthesis and cultured osteoblast
proliferation were markedly increased in the overgrown bone, thereby suggesting that a fibroblast growth factor or its receptor signal transduction pathway may be altered in the affected osteoblasts. In summary, there are similarities between UCH, HFH, and related overgrowth disorders, but with differences between these entities in age of onset, nature and duration of progression, and nature of involved affected tissues. These differences are of clinical significance and allow for the delineation of separate clinical entities. We report the case of a patient with progressive HFH, urging for condylectomy to stop the progressive growth. The growth pattern was similar to UCH, with no histopathological abnormalities present. Genetic proof of overgrowth was confirmed, as a somatic mutation in PIK3CA was detected. Likely, both HFH and UCH can be caused by variants in genes in the (PIK3CA)/PI3K/(PTEN)/ AKT1/mTOR pathway, similar to other disorders that result in asymmetrical bodily overgrowth. Further studies will be set up to search for variants in genes involved in this pathway in both UCH and HFH patients. Funding
None. Competing interests
None. Ethical approval
Ethical approval was sought and considered not required for this case study (Ref. No. W19_101#19.133). Patient consent
Patient written consent was obtained to publish the photographs. Acknowledgements. Department of Orthodontics, ACTA Amsterdam, The Netherlands
References 1. Deshingkar SA, Barpande SR, Bhavthankar JD. Congenital hemifacial hyperplasia. Contemp Clin Dent 2011;2:261–4. 2. Obwegeser HL, Makek M. Hemimandibular hyperplasiahemimandibular elongation. J Maxillofac Surg 1986;14:183–208.
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3. Saridin CP, Raijmakers PGHM, Slootweg PJ, Tuinzing DB, Becking AG, van der Waal I. Unilateral condylar hyperactivity: a histopathologic analysis of 47 patients. J Oral Maxillofac Surg 2010;68:47–53. 4. Nitzan DW, Katsnelson A, Bermanis I, Brin I, Casap N. The clinical characteristics of condylar hyperplasia: experience with 61 patients. J Oral Maxillofac Surg 2008;66:312–8. 5. Yamazaki K, Eng C, Kuznetsov SA, Reinisch J, Yamashita DD, Walker J, Cheung C, Robey PG, Yen SL. Missense mutation in the PTEN promoter of a patient with hemifacial hyperplasia. Bonekey Rep 2015;4:654. http:// dx.doi.org/10.1038/bonekey.2015.21. 6. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann KA, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Maya Kato B, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, OBrien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, WhitewoodNeal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG. Mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011;365:611–9. 7. Lindhurst MJ, Parker VER, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TM, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, ORahilly S, Savage DB, Wakelam MJO, Barroso I, Biesecker LG, Semple RK. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet 2012;44:928–33. 8. Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bove´e JVMG, Rialon KL, Guevara CJ, Alomari AI, Greene AK, Fishman SJ, Kozakewich HPW, Maclellan RA, Mulliken JB, Rahbar R, Spencer SA, Trenor CC, Upton J, Zurakowski D, Perkins JA, Kirsh A, Bennett JT, Dobyns DB, Kurek KC, Warman ML, McCarroll SA, Murillo R, et al. Lymphatic and other vascular malformative/ overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 2015;166 (4). 1048-54.e1-5. 9. Egyedi P. Aetiology of condylar hyperplasia. Aust Dent J 1969:12–7. 10. Austin RD, Srivastava KC, Pranavadhyani G, Shrivastava D. A rare clinical case of true hemifacial hyperplasia. Singap Med J 2013;54:160–3. 11. Shanmugasundaram K, Vaishnavi Vedam VK, Ganapathy S, Sathish S, Satti P. Congenital hemifacial hyperplasia: clinical presentation and literature review. Case Rep Dent 2016;2016. http://dx.doi.org/10.1155/ 2016/5260645. 5260645.
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
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12. Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Herrera-Garcia JD, LuqueValenzuela M, Sanchez-Cano D, LopezGutierrez JC, Ruiz-Villaverde R, TercedorSanchez J. J. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clin Genet 2017;91:14–21. 13. Keppler-Noreuil KM, Parker VER, Darling TN, Martinez-Agosto JA. Somatic overgrowth disorders of the PI3K/AKT/ mTOR pathway and therapeutic strategies. Am J Med Genet C Semin Med Genet 2016;172C:402–21. 14. Mirzaa G, Timms AE, Conti V, Boyle EA, Girisha KM, Martin B, Kircher M, Olds C, Juusola J, Collins S, Park Carter KM, Glass I, Kra¨geloh-Mann I, Chitayat D, Parikh AS, Bradshaw R, Torti E, Braddock S, Burke L,
Ghedia S, Stephan M, Stewart F, Prasad C, Napier M, Saitta S, Straussberg R, Gabbett M, OConnor BC, Keegan CE, Yin LJ, Hwei Meeng Lai A, Martin N, McKinnon M, Addor M-C, Boccuto L, Schwartz CE, Lanoel A, Conway RL, Devriendt K, Tatton-Brown K, Pierpont ME, Painter M, Worgan L, Reggin J, Hennekam R, Tsuchiya K, Pritchard CC, Aracena M, Gripp KW, Cordisco M, van Esch H, Garavelli L, Curry C, Goriely A, Kayserilli. Shendure J, Graham Jr J, Guerrini R, Dobyns WB. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight 2016;1. http://dx.doi.org/10.1172/jci.insight.87623. e87623.
15. Yoshimoto H, Yano H, Kobayashi K, Hirano A, Motomura K, Ohtsuru A, Yamashita S, Fujii T. Increased proliferative activity of osteoblasts in congenital hemifacial hypertrophy. Plast Reconstr Surg 1998;102:1605– 10.
Address: J. W. Nolte Amsterdam UMC Department of Oral and Maxillofacial Surgery Meibergdreef 9 1105 AZ Amsterdam The Netherlands Tel.: +31 20 5663997 E-mail: [email protected]
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2020.02.002, available online at https://www.sciencedirect.com
Case Report TMJ Disorders
Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth? J. W. Nolte, M. Alders, L. H. E. Karssemakers, A. G. Becking, R. C. M. Hennekam: Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2020 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons.
Abstract. Hemifacial hyperplasia (HFH) is characterized by an increase in volume of all affected tissues of half of the face. It is present at birth, subsequently grows proportionally, and stops growing before adulthood. Unilateral condylar hyperplasia (UCH) consists of progressive asymmetric growth of the mandible and develops typically in early adulthood. Both disorders have an unknown aetiology. The overgrowth limited to one body part suggests somatic mosaicism, as this has been found in other similar localized overgrowth disorders. Often this includes a variant in a gene in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway. Here we report the case of an HFH patient with asymmetry present at birth, in whom a progressive growth pattern similar to UCH subsequently occurred, causing marked mandibular asymmetry. A condylectomy was successfully performed to stop the progressive growth. Somatic mosaicism for a mutation in PIK3CA was detected in the condylar tissue. This finding might indicate that both HFH and UCH can be caused by variants in genes in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway, similar to other disorders that result in asymmetrical bodily overgrowth.
Hemifacial hyperplasia (HFH) is an entity that becomes evident as a marked asymmetry of the face. All affected tissues, including skin, fat, muscles, and bone, are increased in volume. Typically, it is present at birth and shows subsequent proportional growth until the end of puberty, when growth stops1. 0901-5027/000001+06
Unilateral condylar hyperplasia (UCH) is characterized by progressive asymmetry of the mandible, due to increased development of one mandibular condyle. This causes concomitant asymmetry of the whole face, but only bony tissue is affected. Obwegeser and Makek2 recognized two main types: hemimandibular elonga-
J. W. Nolte1, M. Alders2, L. H. E. Karssemakers1, A. G. Becking1,3, R. C. M. Hennekam4 1
Department of Oral and Maxillofacial Surgery, Amsterdam UMC/Emma Children’s Hospital, and Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam, Amsterdam, The Netherlands; 2Laboratory of Genome Diagnostics, Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development, Amsterdam, The Netherlands; 3Department of Oral and Maxillofacial Surgery, Spaarne Gasthuis, Haarlem, The Netherlands; 4Department of Paediatrics and Translational Genetics, Amsterdam UMC/Emma Childrens Hospital, University of Amsterdam, Amsterdam, The Netherlands
Key words: unilateral condylar hyperplasia; hemifacial hyperplasia; genetics; PIK3CA; mandibular asymmetry; hemimandibular hyperplasia; hemimandibular elongation; maxillofacial surgery. Accepted for publication 4 February 2020
tion (HE), characterized by predominantly horizontal asymmetry, and hemimandibular hyperplasia (HH), demonstrating mainly vertical distortion with increased volume. The term hyperplasia in this context is in fact confusing, as histology does not confirm true hyperplasia in all UCH patients3, but for historical reasons we use
ã 2020 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons.
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
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the term here. In UCH, the asymmetry is not present at birth but develops later, typically in early adulthood (mean age 21 years). Progression can be confirmed with bone scintigraphy, and treatment consists of a partial condylectomy to stop the progressive growth4. The aetiology of HFH is poorly understood1,5. Several overgrowth syndromes may show asymmetrical facial overgrowth as part of the general overgrowth, such as Proteus syndrome, neurofibromatosis, and BeckwithWiedemann syndrome68. The genetic background of these syndromes is known, but no genetic cause is known for isolated HFH, although it has been suggested that HFH may be caused by mutations in the (PIK3CA)/PI3K/ (PTEN)/AKT1/mTOR pathway5. The aetiology of UCH is not known either. Inflammation, trauma, endocrine imbalances, hypervascularity, neoplasms, and genetic causes have been suggested, but no evidence is available2,9. Clinically, in both disorders, the overgrowth is localized to the face only, suggesting a somatic mosaicism, which indicates that the mutation is present only in the affected tissue and not in the whole body. Here we report the case of a patient with HFH in whom a condylectomy was performed because of progressive mandibular asymmetry, and in whom investigations of the affected condylar tissue revealed a mutation in PIK3CA.
The size and number of cells of the various tissues were normal. Repeated X-ray examinations (panoramic radiographs) from 8 years of age showed accelerated eruption of the molars on the
right side, with diminished root development. The right side of the mandible including the condyle was enlarged (Fig. 1). In the ensuing years, the facial asymmetry became again more pronounced,
Clinical presentation
The patient was the second-born child of healthy, non-consanguineous parents. His family history was negative for congenital anomalies or asymmetries. The mothers pregnancy had been uneventful; birth was via forceps delivery. Birth weight was 3170 g (10th percentile). The parents noticed a slightly larger cheek on the right side, without any other abnormalities. Subsequent growth in height and skull circumference was normal, as was cognitive development. He was first evaluated because of facial asymmetry at 3 years of age. The right half of his face was more prominent than the left side, especially the cheek, with hyperemic spots. The right side of the tongue was larger than the left side, and permanent incisors were visible on the right side. At the age of 6 years, some excessive soft tissue of the right cheek intraorally, referred to as a hamartoma, was surgically removed. Histology showed fibrous tissue, muscle, and fat, with many nerve fibres.
Fig. 1. Facial clinical and radiological characteristics. (a) Frontal photograph at age 3 years, showing enlargement of the right cheek. (b) Panoramic radiograph at 8 years, showing accelerated eruption of the right side molars. (c) Panoramic radiograph at 14 years, showing enlargement of the right condyle and mandibular half.
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
YIJOM-4373; No of Pages 6
UCH in hemifacial hyperplasia which urged for meatus plasty and bony debulking around the ear canal due to a narrowed ear canal at 16 years of age. The middle ear and inner ear were normal. Subsequent orthodontic treatment allowed an adequate dental occlusion, with median position of the upper and lower midline. At 17 years of age, the asymmetry of the mandible progressed over the course of a few months, with an increase in midline shift and deviation of the mandible. Magnetic resonance imaging (MRI) demonstrated the right-sided mandibular overgrowth and increased fat tissue, including the parot-
id and submandibular glands. Single-photon emission computed tomographycomputed tomography (SPECT-CT) with radioactive labelled technetium showed a significant difference in osteoblastic activity between the left and right condyles (mean 40% and 60%, respectively), confirming the hyperactivity of the right condyle (Fig. 2). The hyperactivity prompted a condylectomy, during which the growth centre was removed. Orthodontic treatment was subsequently provided. No progression of mandibular asymmetry was evident at follow-up after 1 year.
3
Methods
The resected condylar tissue was sent for regular histopathology and for DNA extraction according to the clinical protocol. A panel of eight genes known for overgrowth (AKT1, AKT3, MTOR, PIK3CA, PIK3R2, PTEN, TSC1, and TSC2) and used as standard in individuals with overgrowth, was sequenced by next-generation sequencing (NGS), with minimal ˆ to be able to detect coverage of 500O low grade mosaicism. Enrichment of the target genes was done using a SeqCap EZ
Fig. 2. Facial clinical and radiological characteristics at 17 years of age. (a) Frontal photograph, showing enlargement of the right cheek (proportionally). (b) 3D CBCT, showing enlargement and vertical distortion of the condyle and mandible on the right side. (c) MRI, showing enlarged soft tissues on the right side. (d) SPECT-CT, showing a hyperactive condyle on the right side. (3D CBCT, three-dimensional cone beam computed tomography; MRI, magnetic resonance imaging; SPECT-CT, single-photon emission computed tomography–computed tomography.).
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
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Fig. 3. Resected condylar tissue. (a) Clinical view. (b) Histopathology, showing no abnormalities.
Choice capture kit (Roche NimbleGen, Inc., Madison, WI, USA). The enriched libraries were sequenced on a MiSeq platform (reagent kit v2; Illumina, San Diego, CA, USA) according to the manufacturers recommendations for pairedend 150-bp reads. Alignment of the sequence reads to the human reference genome (hg19) was done using BWA-MEM 0.7.5. (bio-bwa.sourceforge.net/), and variants were called using the GATK 2.8.1 software package (www. broadinstitute.org/gatk/). Filtering of variants was done using Cartagenia Bench Lab NGS (Agilent, Santa Clara, California, USA). All variants within the exon 20 regions were evaluated. Results Histopathology
Histology showed sections through the trabecular bony tissue with normocellular
bone marrow in between, and a normal ratio of hematopoietic series. The progenitor cells of the three series were organoid, without striking hotspots. Superficially, there was fibrous tissue with a thick layer of hyaline cartilage and periosteum underneath (Fig. 3). Targeted exome sequencing
The variant c.3140A > T p.(His1047Leu) in PIK3CA (NM_006218.2) was detected in DNA derived from the mandibular condyle. The variant was present in 38% of the reads, highly suggestive of somatic mosaicism (BioProject ID: PRJNA560479 http://www.ncbi.nlm.nih.gov/bioproject/ 560479). Discussion
The clinical features of HFH comprise unilateral enlargement of all facial tissues, including an enlarged mandibular condy-
le1,10. The HH subtype of UCH is very similar to the skeletal features of an HFH patient. In HFH the asymmetry is present at birth and does not explicitly increase in growth, but continues proportionally until cessation around 18 years of age1. A typical feature of UCH is progression of growth-resembling activity, which usually starts in adolescence4. Therefore, clinically, the present patient showed an overlap of HFH and UCH. A similar combination of HFH and UCH characteristics has not been reported previously in the literature. Shanmugasundaram et al.11 also performed bone scintigraphy in their HFH patient and showed hyperactivity of the overgrown maxilla and mandible, but clinically there was no progressive asymmetric growth, and no quantification of condylar activity was measured. No other studies have been performed to detect a possible genetic background of UCH.
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
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UCH in hemifacial hyperplasia The molecular background of overgrowth disorders is gradually being unravelled and seems to be mainly located in the (PIK3CA)/PI3K/(PTEN)/AKT/mTOR pathway. A PIK3CA-related overgrowth spectrum (PROS) has been described, which comprises syndromes that all show a PIK3CA-activated mutation, but with different overgrowth phenotypes12. Clinically, a wide variation can be seen, from vascular malformations with segmental overgrowth to soft tissue and bone tissue hypertrophy. Asymmetrical facial overgrowth can be present13,14. The detected variant p.(His1047Leu) in the present HFH patient with UCH characteristics, is one of the known PIK3CA-activating variants, as described before in other segmental overgrowth. Lindhurst et al.6 described a mosaicactivating AKT1 mutation as the cause of Proteus syndrome (segmental overgrowth and hyperplasia of multiple tissues and organs). They hypothesized that a milder phenotype could be associated with an occurrence of the somatic mutation later during development, but this was not confirmed in their studies. No association between the proportion of mutant alleles and the overall clinical severity or specific manifestations of the phenotype was found, and their data did not suggest a specific stage during development at which the mutation arose6. The hypothesis that HFH is caused by a somatic mutation early in (embryonic) life and that UCH might be caused by a somatic mutation later in life and, thus, have milder symptoms (affecting only the mandibular/condylar tissue), is therefore less likely. The expression of UCH in the patient described here could be a coincidence. However, the mandibular features of the HH type of UCH are very similar to the features of HFH, and therefore it is very well possible that both HFH and UCH are caused by variants in genes of the molecular overgrowth spectrum that have yet to be identified. Histologically, no consistent histopathological abnormalities are found in UCH. There is a tendency towards an increased number of cartilage islands in the cortical layer of the affected condyles, but this has not been confirmed in all patients3. Also, Yamazaki et al. found no marked true hyperplasia in HFH5, although they reported an increase in vascularity and number and thickness of nerves in the affected soft tissue. In accordance, Yoshimoto et al.15 found no atypical cells or hyperplasia in the cortical bone of the affected side, but did report that osteoblast DNA synthesis and cultured osteoblast
proliferation were markedly increased in the overgrown bone, thereby suggesting that a fibroblast growth factor or its receptor signal transduction pathway may be altered in the affected osteoblasts. In summary, there are similarities between UCH, HFH, and related overgrowth disorders, but with differences between these entities in age of onset, nature and duration of progression, and nature of involved affected tissues. These differences are of clinical significance and allow for the delineation of separate clinical entities. We report the case of a patient with progressive HFH, urging for condylectomy to stop the progressive growth. The growth pattern was similar to UCH, with no histopathological abnormalities present. Genetic proof of overgrowth was confirmed, as a somatic mutation in PIK3CA was detected. Likely, both HFH and UCH can be caused by variants in genes in the (PIK3CA)/PI3K/(PTEN)/ AKT1/mTOR pathway, similar to other disorders that result in asymmetrical bodily overgrowth. Further studies will be set up to search for variants in genes involved in this pathway in both UCH and HFH patients. Funding
None. Competing interests
None. Ethical approval
Ethical approval was sought and considered not required for this case study (Ref. No. W19_101#19.133). Patient consent
Patient written consent was obtained to publish the photographs. Acknowledgements. Department of Orthodontics, ACTA Amsterdam, The Netherlands
References 1. Deshingkar SA, Barpande SR, Bhavthankar JD. Congenital hemifacial hyperplasia. Contemp Clin Dent 2011;2:261–4. 2. Obwegeser HL, Makek M. Hemimandibular hyperplasiahemimandibular elongation. J Maxillofac Surg 1986;14:183–208.
5
3. Saridin CP, Raijmakers PGHM, Slootweg PJ, Tuinzing DB, Becking AG, van der Waal I. Unilateral condylar hyperactivity: a histopathologic analysis of 47 patients. J Oral Maxillofac Surg 2010;68:47–53. 4. Nitzan DW, Katsnelson A, Bermanis I, Brin I, Casap N. The clinical characteristics of condylar hyperplasia: experience with 61 patients. J Oral Maxillofac Surg 2008;66:312–8. 5. Yamazaki K, Eng C, Kuznetsov SA, Reinisch J, Yamashita DD, Walker J, Cheung C, Robey PG, Yen SL. Missense mutation in the PTEN promoter of a patient with hemifacial hyperplasia. Bonekey Rep 2015;4:654. http:// dx.doi.org/10.1038/bonekey.2015.21. 6. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann KA, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Maya Kato B, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, OBrien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, WhitewoodNeal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG. Mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011;365:611–9. 7. Lindhurst MJ, Parker VER, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TM, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, ORahilly S, Savage DB, Wakelam MJO, Barroso I, Biesecker LG, Semple RK. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet 2012;44:928–33. 8. Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bove´e JVMG, Rialon KL, Guevara CJ, Alomari AI, Greene AK, Fishman SJ, Kozakewich HPW, Maclellan RA, Mulliken JB, Rahbar R, Spencer SA, Trenor CC, Upton J, Zurakowski D, Perkins JA, Kirsh A, Bennett JT, Dobyns DB, Kurek KC, Warman ML, McCarroll SA, Murillo R, et al. Lymphatic and other vascular malformative/ overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 2015;166 (4). 1048-54.e1-5. 9. Egyedi P. Aetiology of condylar hyperplasia. Aust Dent J 1969:12–7. 10. Austin RD, Srivastava KC, Pranavadhyani G, Shrivastava D. A rare clinical case of true hemifacial hyperplasia. Singap Med J 2013;54:160–3. 11. Shanmugasundaram K, Vaishnavi Vedam VK, Ganapathy S, Sathish S, Satti P. Congenital hemifacial hyperplasia: clinical presentation and literature review. Case Rep Dent 2016;2016. http://dx.doi.org/10.1155/ 2016/5260645. 5260645.
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002
YIJOM-4373; No of Pages 6
6
Nolte et al.
12. Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Herrera-Garcia JD, LuqueValenzuela M, Sanchez-Cano D, LopezGutierrez JC, Ruiz-Villaverde R, TercedorSanchez J. J. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clin Genet 2017;91:14–21. 13. Keppler-Noreuil KM, Parker VER, Darling TN, Martinez-Agosto JA. Somatic overgrowth disorders of the PI3K/AKT/ mTOR pathway and therapeutic strategies. Am J Med Genet C Semin Med Genet 2016;172C:402–21. 14. Mirzaa G, Timms AE, Conti V, Boyle EA, Girisha KM, Martin B, Kircher M, Olds C, Juusola J, Collins S, Park Carter KM, Glass I, Kra¨geloh-Mann I, Chitayat D, Parikh AS, Bradshaw R, Torti E, Braddock S, Burke L,
Ghedia S, Stephan M, Stewart F, Prasad C, Napier M, Saitta S, Straussberg R, Gabbett M, OConnor BC, Keegan CE, Yin LJ, Hwei Meeng Lai A, Martin N, McKinnon M, Addor M-C, Boccuto L, Schwartz CE, Lanoel A, Conway RL, Devriendt K, Tatton-Brown K, Pierpont ME, Painter M, Worgan L, Reggin J, Hennekam R, Tsuchiya K, Pritchard CC, Aracena M, Gripp KW, Cordisco M, van Esch H, Garavelli L, Curry C, Goriely A, Kayserilli. Shendure J, Graham Jr J, Guerrini R, Dobyns WB. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight 2016;1. http://dx.doi.org/10.1172/jci.insight.87623. e87623.
15. Yoshimoto H, Yano H, Kobayashi K, Hirano A, Motomura K, Ohtsuru A, Yamashita S, Fujii T. Increased proliferative activity of osteoblasts in congenital hemifacial hypertrophy. Plast Reconstr Surg 1998;102:1605– 10.
Address: J. W. Nolte Amsterdam UMC Department of Oral and Maxillofacial Surgery Meibergdreef 9 1105 AZ Amsterdam The Netherlands Tel.: +31 20 5663997 E-mail: [email protected]
Please cite this article in press as: Nolte JW, et al. Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?, Int J Oral Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.02.002