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Oral manifestations of patients with Kenny–Caffey Syndrome
European Journal of Medical Genetics 55 (2012) 441e445
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Review
Oral manifestations of patients with KennyeCaffey Syndrome Youssra Moussaid a, Didier Griffiths b, Béatrice Richard b, Anne Dieux c, Martine Lemerrer d, Juliane Léger e, Didier Lacombe b, Isabelle Bailleul-Forestier f, g, * a
Paediatric Dentistry, Garancière Paris Diderot University, France Medical Genetics, CHU Bordeaux, Université de Bordeaux, France c Medical Genetics, Jeanne-de-Flandre Hospital, CHRU, Lille, France d Medical Genetics, Paris Descartes University, Necker Enfants Malades Hospital, Paris, France e Paediatric Endocrinology, Robert Debré Hospital, Reference Center for Rare Endocrine Growth Diseases, AP-HP, Paris Diderot University, France f Paediatric Dentistry, CHU Toulouse, Paul Sabatier University, France g Centre for Human Genetics, University Hospitals Leuven, Belgium b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 September 2011 Accepted 8 March 2012 Available online 30 March 2012
KennyeCaffey syndrome (KCS) is a rare osteosclerotic bone dysplasia characterized by hypocalcemia, short stature, ophthalmological features, and teeth anomalies. The TBCE gene coding for a tubulinspecific chaperone E, is located at chromosome 1q42-q43, and is responsible for the recessive form. After reviewing the literature, we found around 60 cases, however with limited dental data. In this article 5 new individuals with KCS, are described focusing on oral findings. All cases had short roots and showed dental anomalies as hypo/oligodontia, microdontia. Dental anomalies are a constant feature in KCS, further study is required to better delineate the syndrome. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: KennyeCaffey syndrome Sanjad-Sakati syndrome Dental anomalies Oligodontia Microdontia Enamel defects
1. Introduction KennyeCaffey syndrome is a rare genetic disorder characterized by internal cortical thickening and medullary stenosis of the tubular bones, absent diploic space in the skull, growth retardation with short stature, hypocalcemia mostly due to congenital hypoparathyroidism, ophthalmologic abnormalities (hyperopia) and dysmorphic features including a prominent forehead, microphthalmia, micrognathia and dental anomalies. The prevalence of KCS is unknown, less than 60 cases have been published to date. Initially, a dominant inherited type of KCS has been described in 5 families [1e4]. The possibility of an autosomal recessive form has been raised in 1980 [2], and confirmed in 1992 [5]. Twenty-four cases of autosomal recessive KCS have been published, most of them (20/24) associated with parental consanguinity and originating from Kuwait [2,5e10]. Twenty sporadic cases were also reported. Two different KCS phenotypes are * Corresponding author. 3 Chemin des maraîchers, Faculté de Chirurgie Dentaire, 31062 Toulouse Cedex 09, France. Tel.: þ33 (0) 562172929; fax: þ33 (0) 561254719. E-mail addresses: [email protected], [email protected] (I. Bailleul-Forestier). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2012.03.005
currently recognized: the autosomal recessive form or KCS type 1 (MIM 244460) and the dominant form or KCS type 2 (MIM 127000). The autosomal recessive form differs from the type 2 by a more severe growth delay, small hands and feet, mental retardation, microcephaly, and immunological deficiency leading to recurrent bacterial infections. The main KCS types 1 and 2 clinical features are summarized in Table 1. The recessive KCS type is located at chromosome 1q42-q43 [11] and is due to mutations in the TBCE gene coding for the tubulinspecific chaperone E (TBCE). TBCE is required for a- and b-tubulin dimerization and microtubules polymerisation [12]. Microtubules are essential components of the cytoskeleton. Mutations in the same gene were also reported in the Sanjad-Sakati syndrome (SSS) or HRD (Hypoparathyroidism-Retardation-Dysmorphism) syndrome (MIM 241410). Except for the osteosclerosis, clinical features in HRD are similar to the ones in KCS type 1. Oro-dental features associated with KCS reported in the literature include dental caries, enamel defects [10], delayed eruption [13], tooth agenesis [14], and micrognathia [1]. To date, the precise dental phenotype of only one individual with KCS has been described with oligodontia (defined as agenesis of at least six permanent teeth), enamel hypoplasia, and abnormalities of crown
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Y. Moussaid et al. / European Journal of Medical Genetics 55 (2012) 441e445
Table 1 Review of the literature in 55 patients with KennyeCaffey syndrome.
Number of affected patients Sex (male/female) Age 12 years (Mean age: M) >12 years Radiological abnormalities Cortical thickening and medullary stenosis of long bones Absent diploic space in calvaria Delayed closure of anterior fontanel Growth delay Short stature Intrauterine growth retardation Delayed bone age Growth hormone deficiency Hypocalcemia Hypocalcemia Symptomatic hypocalcemia Congenital hypoparathyroidism Facial features Prominent forehead Microphthalmia Micrognathia Dental anomalies Relative macrocephaly Microcephaly Ocular findings Hyperopia Strabismus Mental/Psychomotor Retardation Anemia a b
KCS type 1a Recessive form
KCS type 2b Dominant form
KCS Total
24 4/20
31 15/16
55 19/36
24/24 (M ¼ 3 y) 0/24
18/31 (M ¼ 5 y) 13/31 (M ¼ 25 y)
42/55 (M ¼ 4 y) 13/55 (M ¼ 25 y)
19/22 14/19 4/24
86% 74% 17%
27/31 14/19 22/24
87% 74% 92%
46/53 28/38 26/48
87% 74% 54%
23/24 20/24 13/20
96% 83% 65%
29/31 8/22 10/20
93% 36% 50%
52/55 28/46 23/40 2/13
94% 61% 57% 15%
22/24 21/24 18/20
92% 87% 90%
25/29 24/29 16/22
86% 83% 73%
47/53 45/53 34/42
90% 85% 81%
17/19 7/11 17/22 11/13 2/13 13/15 18/24 7/18 3/18 14/17 4/7
89% 64% 77% 85% 15% 87% 75% 39% 17% 82% 57%
15/16 16/23 10/16 12/15 12/13 1/13 26/30 20/26 6/26 4/25 7/13
94% 70% 62% 80% 92% 8% 87% 77% 23% 16% 54%
32/35 23/34 27/38 23/28 14/26 14/28 44/54 27/44 9/44 18/42 11/20
91% 68% 71% 82% 54% 50% 81% 61% 20% 43% 55%
[2,5,6,7,8,9,10,18]. [1e4,14,19e29].
and root morphology of permanent teeth. The aim of the present study is to describe the dental phenotype in 5 unrelated KCS individuals, and to review the clinical data available in the literature [14]. 2. Patients and methods Five individuals, four males and one female, were included in the study. The average age of the patients is 15 years and ranged from 8 to 26. Clinical data of the individuals were obtained from the referring endocrinologists and geneticists. Molecular analysis of the gene TBCE was required for 3 of the 5 individuals. From all the individuals a clinical oral examination and an orthopantomogram were available. The orthopantomograms were analysed to assess tooth agenesis and root morphology. Extraction due to decay, orthodontic treatment or periodontal disease, and loss of teeth due to dental trauma were recorded by questioning parents and/or patients. 3. Results Three males have been diagnosed as KCS type 2 according to clinical, radiological criteria and familial characteristics (no family history, no parental consanguinity). One (case 1) has no mutation in the TBCE gene. Another male has been diagnosed with KCS type 1 according to the clinical, radiological and familial (parental consanguinity, a half-brother similarly affected) criteria (case 2); and a TBCE gene mutation (c.155-166del12) was detected in this case (Fig. 1). According to the clinical and radiological criteria (Fig. 2), also a girl has been diagnosed with KCS. The array-CGH analysis was normal and no mutation was found in the TBCE gene. The diagnosis is more consistent with KCS type 2 (case 4).
Fig. 1. Frontal view of a 26 years old patient with KennyeCaffey syndrome type 1 (case 2), showing microcephaly, micrognathia, hyperpigmentation of skin around the eyes, and convex nasal ridge.
Y. Moussaid et al. / European Journal of Medical Genetics 55 (2012) 441e445
443
A summary of the clinical data is provided in Table 2. The clinical examination highlights abnormalities of tooth enamel and of crown morphology. 4. Discussion
Fig. 2. X-rays of the left foot of a 18 year-old girl with KennyeCaffey syndrome (case 4), showing cortical thickening of metacarpals and phalanges, shortness of 1st and 4th metacarpals and the distal phalanges of the 4th toe.
Only 55 cases of KCS were reported in the literature. KCS and the Sanjad-Sakati syndrome are allelic disorders despite their clinical variability (additional osteosclerosis and susceptibility to bacterial infection for KCS type 1) [12,15]. They share an ancestral haplotype, suggesting a common founder effect. The Middle Eastern cases (more than 30 pedigrees; 8 with KCS type 1 and 26 with SanjadSakati syndrome) have a recurrent 12 pb deletion in the second coding exon of the TBCE gene. HDR syndrome may be genetically heterogeneous with one family without TBCE gene mutation and linked to a new locus at chromosome 4q35 [16]. In this study, the recurrent mutation in the TBCE gene was found in only one subject from North Africa origin. Array-CGH analysis was normal in two other cases. Oral manifestations have been reported only once in a male patient affected with KCS type 2 [14]. This study reports dental features in 5 KCS individuals; all had congenital missing teeth (hypodontia 1/5, oligodontia 4/5) (Figs. 3 and 4). Teeth agenesis varies from 4 to 18 teeth. The most frequently absent teeth are those found in the general population, except for the agenesis of the second molars and the mandibular canines. Microdontia affected
Table 2 Clinical data and oral phenotype in 5 patients with KennyeCaffey syndrome (KCS). Case, gender, age
Case 1: M, 12 years
KCS 1/KCS 2 KCS 2 TBCE mutation e Radiological abnormalities Medullary stenosis þ Absent diploic space in þ calvaria Delayed closure of þ anterior fontanel Short stature þ Height deviation 3DS Intrauterine growth e retardation GH/IGF1 deficiency e Hypocalcemia Symptomatic þ hypocalcemia Congenital þ hypoparathyroidism Facial features Prominent forehead þ Microphthalmia þ Relative Macrocephaly þ Microcephaly e Micrognathia þ Ocular findings Hyperopia þ Strabismus þ Mental retardation e Oligodontia Missing permanent teeth
þ 15, 12, 25, 35, 34, 44, 45
Case 2: M, 26 years
Case 3: M, 15 years
Case 4: F, 18 years
Case 5: 8 years
6. Demir & al., 2007 [14].
KCS 1 þ
KCS 2 e
KCS 2 ?
KCS 2 e
KCS 2 e
þ e
þ þ
þ e
þ e
þ e
87% 74%
e
þ
þ
þ
þ
þ 12DS e
þ ? ?
þ 6DS þ
þ ? e
þ ? e
17% (KCS1), 92% (KCS2) 94%
þ
e
e
e
?
83% (KCS1), 36% (KCS2) 15%
þ
?
þ
þ
þ
85%
þ
þ
þ
þ
þ
81%
þ þ e þ þ
þ þ þ e þ
þ þ e þ þ
þ e e e e
þ þ þ e þ
91% 68% 92% (KCS2) 87% (KCS1) 71%
þ e þ
? þ ?
þ e e
? e ?
? e e
61% 20% 82% (KCS1), 16% (KCS2)
þ 17, 15, 14, 12, 22, 24, 25, 27, 37, 35, 34, 33, 44, 45, 47 þ
e þ 15, 24, 35, 45 18 teeth
þ þ 15, 14, 12, 22, 24, 15, 12, 22, 24, 25, 25, 27, 37, 35, 34, 35, 34, 32, 44, 45 43, 44, 45 e þ
Enamel hypoplasia þ Dental morphology abnormalities Crown Hypoplasia Hypoplasia Microdontia 43, 42, 41, 31, 32, 33 13, 23, 33 Roots e Pulp Taurodontism Delayed eruption
e
þ
þ
Hypoplasia Bulbous 33, 31, 41, 42, 43 (Macrodontia: 11, 21) Short Short Short Narrow roots canals Narrow roots canals ? e
?
e
þ
13, 23 Short Narrow roots canals, Calcifications þ
Reported cases % (Table 1)
444
Y. Moussaid et al. / European Journal of Medical Genetics 55 (2012) 441e445
and root morphology, oligodontia (except for one case). Oral features such as hypo/oligodontia should be included in the diagnostic features of KCS. Further studies are required to highlight the molecular diagnosis and to better delineate KCS and its allelic disorders, such as Sanjad-Sakati syndrome. Acknowledgements The authors would like to thank the families and the patients for their participation in this study. References
Fig. 3. Orthopantomogram of a 18 year-old girl with KennyeCaffey syndrome and severe oligodontia (case 4). 15 permanent teeth are missing (17, 15, 14, 12, 22, 24, 25, 27, 37, 35, 34, 33, 44, 45, 47), and teeth have severely short, tapered and obliteraited roots.
Fig. 4. Orthopantomogram of a 10 year-old boy with KennyeCaffey syndrome type 2 and oligodontia (case 3), showing absence of 10 permanent teeth (15, 12, 22, 24, 25, 35, 34, 32, 44, 45), short roots, molars with divergent roots, and microdontia of permanent canines and incisors (except for maxillary central incisors).
especially the lower incisors and canines (Fig. 5). Furthermore, an abnormal morphology of crowns with small cusps and an atypical form of the frenulum were observed. On the orthopantomograms abnormal short roots of the permanent teeth were noted. This last feature can be found in dentin dysplasia type 1 (rootless teeth, MIM 125400) or in Microcephalic Osteodysplastic Primordial Dwarfism type II syndrome [17]. Moreover, some dysmorphic features in Seckel syndrome could be found in Sanjad-Sakati syndrome. We report the first French cohort of individuals with KCS including clinical and oral data. This review shows that the KCS syndrome was always related to dental anomalies, including crown
Fig. 5. Buccal view of a 15 year-old boy with KennyeCaffey syndrome type 2 (case 3), showing anterior cross-bite, and microdontia of permanent canines.
[1] F.M. Kenny, L. Linarelli, Dwarfism and cortical thickening of tubular bones. Transient hypocalcemia in a mother and son, Am. J. Dis. Child. 111 (1966) 201e207. [2] F. Sarría, J. Toledo, M.L. Toledo, S. Vega, M. López, Bueno, Diaphysary tubular stenosis (KennyeCaffey’s syndrome): presentation of four observations, An. Esp. Pediatr 13 (1980) 373e380. [3] F. Majewski, W. Rosendahl, M. Ranke, K. Nolte, The Kenny syndrome, a rare type of growth deficiency with tubular stenosis, transient hypoparathyroidism and anomalies of refraction,, Eur. J. Pediatr. 136 (1981) 21e30. [4] E.J. Enriquez, F. Toledo, M. Bustamante-Cruz, G.M. Cruz, Congenital medullary tubular stenosis. A case of Caffey-Kenny syndrome, Acta. Orthop. Scand 59 (1988) 326e327. [5] P. Franceschini, A. Testa, G. Bogetti, E. Girardo, A. Guala, G. Lopez-Bell, et al., KennyeCaffey syndrome in two sibs born to consanguineous parents: evidence for an autosomal recessive variant, Am. J. Med. Genet. 42 (1992) 112e116. [6] Y.K. Abdel-Al, L.T. Auger, F. el-Gharbawy, KennyeCaffey syndrome. Case report and literature review, Clin. Pediatr. (Phila) 28 (1989) 175e179. [7] I. Bergada, A. Schiffrin, H. Abu Srair, P. Kaplan, J. Dornan, D. Goltzman, et al., Kenny syndrome: description of additional abnormalities and molecular studies, Hum. Genet. 80 (1988) 39e42. [8] M.A. Sabry, T.I. Farag, A.A. Shaltout, M. Zaki, Z. Al-Mazidi, S.J. Abulhassan, et al., KennyeCaffey syndrome: an Arab variant? Clin. Genet. 55 (1999) 44e49. [9] M.A. Sabry, M. Zaki, S.J. Abul Hassan, D.G. Ramadan, M.A. Abdel Rasool, S.A. al Awadi, et al., KennyeCaffey syndrome is part of the CATCH 22 haploinsufficiency cluster, J. Med. Genet. 35 (1998) 31e36. [10] K. Tahseen, S. Khan, R. Uma, R. Usha, M.M. Al Ghanem, S.A. Al Awadi, et al., KennyeCaffey syndrome in six Bedouin sibships: autosomal recessive inheritance is confirmed, Am. J. Med. Genet. 69 (1997) 126e132. [11] G.A. Diaz, K.T. Khan, B.D. Gelb, The autosomal recessive KennyeCaffey syndrome locus maps to chromosome 1q42-q43,, Genomics 54 (1998) 13e18. [12] R. Parvari, E. Hershkovitz, N. Grossman, R. Gorodischer, B. Loeys, A. Zecic, et al., Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive KennyeCaffey syndrome, Nat. Genet. 32 (2002) 448e452. [13] J. Caffey, Congenital stenosis of medullary spaces in tubular bones and calvaria in two proportionate dwarfsemother and son; coupled with transitory hypocalcemic tetany, Am. J. Roentgenol. Radium. Ther. Nucl. Med. 100 (1967) 1e11. [14] T. Demir, D. Kecik, Z.C. Cehreli, KennyeCaffey Syndrome: oral findings and 4year follow-up of overlay denture therapy, J. Dent. Child. (Chic) 74 (2007) 236e240. [15] G.A. Diaz, B.D. Gelb, F. Ali, N. Sakati, S. Sanjad, B.F. Meyer, et al., Sanjad-Sakati and autosomal recessive KennyeCaffey syndromes are allelic: evidence for an ancestral founder mutation and locus refinement, Am. J. Med. Genet. 85 (1999) 48e52. [16] W. Courtens, W. Wuyts, M. Poot, K. Szuhai, J. Wauters, E. Reyniers, et al., Hypoparathyroidism-retardation-dysmorphism syndrome in a girl: a new variant not caused by a TBCE mutationeclinical report and review,, Am. J. Med. Genet. A 140 (2006) 611e617. [17] H. Lin, G. Sue, C. Berkowitz, J. Brasel, R. Lachman, Microdontia with severe microcephaly and short stature in two brothers: osteodysplastic primordial dwarfism with dental findings, Am. J. Med. Genet. 58 (1995) 136e142. [18] I. Agarwal, S. Danda, J.X. Scott, T.S. Kumar, T. Mammen, KennyeCaffey syndrome, Indian J. Hum. Genet. 12 (2006) 96e98. [19] S. Churesigaew, KennyeCaffey syndrome, J. Med. Assoc. Thai 77 (1994) 554e559. [20] R.S. Frech, W.H. Mc Alister, Medullar stenosis of tubular bones associated with hypocalcemic convulsions and short stature, Radiology 91 (1968) 457e461. [21] W.H. Hoffman, K. Kovacs, S. Li, A.S. Kulharya, B.L. Johnson, M.S. Eidson, et al., KennyeCaffey syndrome and microorchidism, Am. J. Med. Genet. 80 (1998) 107e111. [22] K. Kozlowski, J. Weisenbach, G. Kosztolanyi, KennyeCaffey syndrome. Case report, Radiol. Med. (Torino) 95 (1998) 669e671. [23] J.L. Larsen, J. Kivlin, W.D. Odell, Unusual cause of short stature, Am. J. Med. 78 (1985) 1025e1032.
Y. Moussaid et al. / European Journal of Medical Genetics 55 (2012) 441e445 [24] W.K. Lee, A. Vargas, J. Barnes, A.W. Root, The KennyeCaffey syndrome: growth retardation and hypocalcemia in a young boy,, Am. J. Med. Genet. 14 (1983) 773e782. [25] G. Rebolleda Fernández, F.J. Muñoz Negrete, B. Garcia Martín, C. Lozano, Bilateral optic atrophy in Kenny’s syndrome, Acta Ophthalmol. (Copenh) 70 (1992) 135e138. [26] T. Yorifuji, J. Muroi, A. Uematsu, KennyeCaffey syndrome without the CATCH 22 deletion, J. Med. Genet. 35 (1998) 1054.
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[27] C.E. Tsai, P.C. Chiu, M.L. Lee, Kenny syndrome: case report and literature review, J. Formos. Med. Assoc. 95 (1996) 793e797. [28] M.G. Wilson, R.F. Maronde, V.G. Mikity, N.W. Shinno, Dwarfism and congenital medullary stenosis (Kenny syndrome), Birth. Defects. Orig. Artic. Ser. 10 (1974) 128e132. [29] P. Timoney, F. Darcy, K. McCreery, W. Reardon, D. Brosnahan, Characterization of optical coherence topography findings in KennyeCaffey syndrome, J. AAPOS 11 (2007) 291e293.
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Review
Oral manifestations of patients with KennyeCaffey Syndrome Youssra Moussaid a, Didier Griffiths b, Béatrice Richard b, Anne Dieux c, Martine Lemerrer d, Juliane Léger e, Didier Lacombe b, Isabelle Bailleul-Forestier f, g, * a
Paediatric Dentistry, Garancière Paris Diderot University, France Medical Genetics, CHU Bordeaux, Université de Bordeaux, France c Medical Genetics, Jeanne-de-Flandre Hospital, CHRU, Lille, France d Medical Genetics, Paris Descartes University, Necker Enfants Malades Hospital, Paris, France e Paediatric Endocrinology, Robert Debré Hospital, Reference Center for Rare Endocrine Growth Diseases, AP-HP, Paris Diderot University, France f Paediatric Dentistry, CHU Toulouse, Paul Sabatier University, France g Centre for Human Genetics, University Hospitals Leuven, Belgium b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 September 2011 Accepted 8 March 2012 Available online 30 March 2012
KennyeCaffey syndrome (KCS) is a rare osteosclerotic bone dysplasia characterized by hypocalcemia, short stature, ophthalmological features, and teeth anomalies. The TBCE gene coding for a tubulinspecific chaperone E, is located at chromosome 1q42-q43, and is responsible for the recessive form. After reviewing the literature, we found around 60 cases, however with limited dental data. In this article 5 new individuals with KCS, are described focusing on oral findings. All cases had short roots and showed dental anomalies as hypo/oligodontia, microdontia. Dental anomalies are a constant feature in KCS, further study is required to better delineate the syndrome. Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords: KennyeCaffey syndrome Sanjad-Sakati syndrome Dental anomalies Oligodontia Microdontia Enamel defects
1. Introduction KennyeCaffey syndrome is a rare genetic disorder characterized by internal cortical thickening and medullary stenosis of the tubular bones, absent diploic space in the skull, growth retardation with short stature, hypocalcemia mostly due to congenital hypoparathyroidism, ophthalmologic abnormalities (hyperopia) and dysmorphic features including a prominent forehead, microphthalmia, micrognathia and dental anomalies. The prevalence of KCS is unknown, less than 60 cases have been published to date. Initially, a dominant inherited type of KCS has been described in 5 families [1e4]. The possibility of an autosomal recessive form has been raised in 1980 [2], and confirmed in 1992 [5]. Twenty-four cases of autosomal recessive KCS have been published, most of them (20/24) associated with parental consanguinity and originating from Kuwait [2,5e10]. Twenty sporadic cases were also reported. Two different KCS phenotypes are * Corresponding author. 3 Chemin des maraîchers, Faculté de Chirurgie Dentaire, 31062 Toulouse Cedex 09, France. Tel.: þ33 (0) 562172929; fax: þ33 (0) 561254719. E-mail addresses: [email protected], [email protected] (I. Bailleul-Forestier). 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2012.03.005
currently recognized: the autosomal recessive form or KCS type 1 (MIM 244460) and the dominant form or KCS type 2 (MIM 127000). The autosomal recessive form differs from the type 2 by a more severe growth delay, small hands and feet, mental retardation, microcephaly, and immunological deficiency leading to recurrent bacterial infections. The main KCS types 1 and 2 clinical features are summarized in Table 1. The recessive KCS type is located at chromosome 1q42-q43 [11] and is due to mutations in the TBCE gene coding for the tubulinspecific chaperone E (TBCE). TBCE is required for a- and b-tubulin dimerization and microtubules polymerisation [12]. Microtubules are essential components of the cytoskeleton. Mutations in the same gene were also reported in the Sanjad-Sakati syndrome (SSS) or HRD (Hypoparathyroidism-Retardation-Dysmorphism) syndrome (MIM 241410). Except for the osteosclerosis, clinical features in HRD are similar to the ones in KCS type 1. Oro-dental features associated with KCS reported in the literature include dental caries, enamel defects [10], delayed eruption [13], tooth agenesis [14], and micrognathia [1]. To date, the precise dental phenotype of only one individual with KCS has been described with oligodontia (defined as agenesis of at least six permanent teeth), enamel hypoplasia, and abnormalities of crown
442
Y. Moussaid et al. / European Journal of Medical Genetics 55 (2012) 441e445
Table 1 Review of the literature in 55 patients with KennyeCaffey syndrome.
Number of affected patients Sex (male/female) Age 12 years (Mean age: M) >12 years Radiological abnormalities Cortical thickening and medullary stenosis of long bones Absent diploic space in calvaria Delayed closure of anterior fontanel Growth delay Short stature Intrauterine growth retardation Delayed bone age Growth hormone deficiency Hypocalcemia Hypocalcemia Symptomatic hypocalcemia Congenital hypoparathyroidism Facial features Prominent forehead Microphthalmia Micrognathia Dental anomalies Relative macrocephaly Microcephaly Ocular findings Hyperopia Strabismus Mental/Psychomotor Retardation Anemia a b
KCS type 1a Recessive form
KCS type 2b Dominant form
KCS Total
24 4/20
31 15/16
55 19/36
24/24 (M ¼ 3 y) 0/24
18/31 (M ¼ 5 y) 13/31 (M ¼ 25 y)
42/55 (M ¼ 4 y) 13/55 (M ¼ 25 y)
19/22 14/19 4/24
86% 74% 17%
27/31 14/19 22/24
87% 74% 92%
46/53 28/38 26/48
87% 74% 54%
23/24 20/24 13/20
96% 83% 65%
29/31 8/22 10/20
93% 36% 50%
52/55 28/46 23/40 2/13
94% 61% 57% 15%
22/24 21/24 18/20
92% 87% 90%
25/29 24/29 16/22
86% 83% 73%
47/53 45/53 34/42
90% 85% 81%
17/19 7/11 17/22 11/13 2/13 13/15 18/24 7/18 3/18 14/17 4/7
89% 64% 77% 85% 15% 87% 75% 39% 17% 82% 57%
15/16 16/23 10/16 12/15 12/13 1/13 26/30 20/26 6/26 4/25 7/13
94% 70% 62% 80% 92% 8% 87% 77% 23% 16% 54%
32/35 23/34 27/38 23/28 14/26 14/28 44/54 27/44 9/44 18/42 11/20
91% 68% 71% 82% 54% 50% 81% 61% 20% 43% 55%
[2,5,6,7,8,9,10,18]. [1e4,14,19e29].
and root morphology of permanent teeth. The aim of the present study is to describe the dental phenotype in 5 unrelated KCS individuals, and to review the clinical data available in the literature [14]. 2. Patients and methods Five individuals, four males and one female, were included in the study. The average age of the patients is 15 years and ranged from 8 to 26. Clinical data of the individuals were obtained from the referring endocrinologists and geneticists. Molecular analysis of the gene TBCE was required for 3 of the 5 individuals. From all the individuals a clinical oral examination and an orthopantomogram were available. The orthopantomograms were analysed to assess tooth agenesis and root morphology. Extraction due to decay, orthodontic treatment or periodontal disease, and loss of teeth due to dental trauma were recorded by questioning parents and/or patients. 3. Results Three males have been diagnosed as KCS type 2 according to clinical, radiological criteria and familial characteristics (no family history, no parental consanguinity). One (case 1) has no mutation in the TBCE gene. Another male has been diagnosed with KCS type 1 according to the clinical, radiological and familial (parental consanguinity, a half-brother similarly affected) criteria (case 2); and a TBCE gene mutation (c.155-166del12) was detected in this case (Fig. 1). According to the clinical and radiological criteria (Fig. 2), also a girl has been diagnosed with KCS. The array-CGH analysis was normal and no mutation was found in the TBCE gene. The diagnosis is more consistent with KCS type 2 (case 4).
Fig. 1. Frontal view of a 26 years old patient with KennyeCaffey syndrome type 1 (case 2), showing microcephaly, micrognathia, hyperpigmentation of skin around the eyes, and convex nasal ridge.
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443
A summary of the clinical data is provided in Table 2. The clinical examination highlights abnormalities of tooth enamel and of crown morphology. 4. Discussion
Fig. 2. X-rays of the left foot of a 18 year-old girl with KennyeCaffey syndrome (case 4), showing cortical thickening of metacarpals and phalanges, shortness of 1st and 4th metacarpals and the distal phalanges of the 4th toe.
Only 55 cases of KCS were reported in the literature. KCS and the Sanjad-Sakati syndrome are allelic disorders despite their clinical variability (additional osteosclerosis and susceptibility to bacterial infection for KCS type 1) [12,15]. They share an ancestral haplotype, suggesting a common founder effect. The Middle Eastern cases (more than 30 pedigrees; 8 with KCS type 1 and 26 with SanjadSakati syndrome) have a recurrent 12 pb deletion in the second coding exon of the TBCE gene. HDR syndrome may be genetically heterogeneous with one family without TBCE gene mutation and linked to a new locus at chromosome 4q35 [16]. In this study, the recurrent mutation in the TBCE gene was found in only one subject from North Africa origin. Array-CGH analysis was normal in two other cases. Oral manifestations have been reported only once in a male patient affected with KCS type 2 [14]. This study reports dental features in 5 KCS individuals; all had congenital missing teeth (hypodontia 1/5, oligodontia 4/5) (Figs. 3 and 4). Teeth agenesis varies from 4 to 18 teeth. The most frequently absent teeth are those found in the general population, except for the agenesis of the second molars and the mandibular canines. Microdontia affected
Table 2 Clinical data and oral phenotype in 5 patients with KennyeCaffey syndrome (KCS). Case, gender, age
Case 1: M, 12 years
KCS 1/KCS 2 KCS 2 TBCE mutation e Radiological abnormalities Medullary stenosis þ Absent diploic space in þ calvaria Delayed closure of þ anterior fontanel Short stature þ Height deviation 3DS Intrauterine growth e retardation GH/IGF1 deficiency e Hypocalcemia Symptomatic þ hypocalcemia Congenital þ hypoparathyroidism Facial features Prominent forehead þ Microphthalmia þ Relative Macrocephaly þ Microcephaly e Micrognathia þ Ocular findings Hyperopia þ Strabismus þ Mental retardation e Oligodontia Missing permanent teeth
þ 15, 12, 25, 35, 34, 44, 45
Case 2: M, 26 years
Case 3: M, 15 years
Case 4: F, 18 years
Case 5: 8 years
6. Demir & al., 2007 [14].
KCS 1 þ
KCS 2 e
KCS 2 ?
KCS 2 e
KCS 2 e
þ e
þ þ
þ e
þ e
þ e
87% 74%
e
þ
þ
þ
þ
þ 12DS e
þ ? ?
þ 6DS þ
þ ? e
þ ? e
17% (KCS1), 92% (KCS2) 94%
þ
e
e
e
?
83% (KCS1), 36% (KCS2) 15%
þ
?
þ
þ
þ
85%
þ
þ
þ
þ
þ
81%
þ þ e þ þ
þ þ þ e þ
þ þ e þ þ
þ e e e e
þ þ þ e þ
91% 68% 92% (KCS2) 87% (KCS1) 71%
þ e þ
? þ ?
þ e e
? e ?
? e e
61% 20% 82% (KCS1), 16% (KCS2)
þ 17, 15, 14, 12, 22, 24, 25, 27, 37, 35, 34, 33, 44, 45, 47 þ
e þ 15, 24, 35, 45 18 teeth
þ þ 15, 14, 12, 22, 24, 15, 12, 22, 24, 25, 25, 27, 37, 35, 34, 35, 34, 32, 44, 45 43, 44, 45 e þ
Enamel hypoplasia þ Dental morphology abnormalities Crown Hypoplasia Hypoplasia Microdontia 43, 42, 41, 31, 32, 33 13, 23, 33 Roots e Pulp Taurodontism Delayed eruption
e
þ
þ
Hypoplasia Bulbous 33, 31, 41, 42, 43 (Macrodontia: 11, 21) Short Short Short Narrow roots canals Narrow roots canals ? e
?
e
þ
13, 23 Short Narrow roots canals, Calcifications þ
Reported cases % (Table 1)
444
Y. Moussaid et al. / European Journal of Medical Genetics 55 (2012) 441e445
and root morphology, oligodontia (except for one case). Oral features such as hypo/oligodontia should be included in the diagnostic features of KCS. Further studies are required to highlight the molecular diagnosis and to better delineate KCS and its allelic disorders, such as Sanjad-Sakati syndrome. Acknowledgements The authors would like to thank the families and the patients for their participation in this study. References
Fig. 3. Orthopantomogram of a 18 year-old girl with KennyeCaffey syndrome and severe oligodontia (case 4). 15 permanent teeth are missing (17, 15, 14, 12, 22, 24, 25, 27, 37, 35, 34, 33, 44, 45, 47), and teeth have severely short, tapered and obliteraited roots.
Fig. 4. Orthopantomogram of a 10 year-old boy with KennyeCaffey syndrome type 2 and oligodontia (case 3), showing absence of 10 permanent teeth (15, 12, 22, 24, 25, 35, 34, 32, 44, 45), short roots, molars with divergent roots, and microdontia of permanent canines and incisors (except for maxillary central incisors).
especially the lower incisors and canines (Fig. 5). Furthermore, an abnormal morphology of crowns with small cusps and an atypical form of the frenulum were observed. On the orthopantomograms abnormal short roots of the permanent teeth were noted. This last feature can be found in dentin dysplasia type 1 (rootless teeth, MIM 125400) or in Microcephalic Osteodysplastic Primordial Dwarfism type II syndrome [17]. Moreover, some dysmorphic features in Seckel syndrome could be found in Sanjad-Sakati syndrome. We report the first French cohort of individuals with KCS including clinical and oral data. This review shows that the KCS syndrome was always related to dental anomalies, including crown
Fig. 5. Buccal view of a 15 year-old boy with KennyeCaffey syndrome type 2 (case 3), showing anterior cross-bite, and microdontia of permanent canines.
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