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European Journal of Medical Genetics 55 (2012) 441e445

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European Journal of Medical Genetics

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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, FrancebMedical Genetics, CHU Bordeaux, Université de Bordeaux, FrancecMedical Genetics, Jeanne-de-Flandre Hospital, CHRU, Lille, FrancedMedical Genetics, Paris Descartes University, Necker Enfants Malades Hospital, Paris, Francee Paediatric Endocrinology, Robert Debré Hospital, Reference Center for Rare Endocrine Growth Diseases, AP-HP, Paris Diderot University, Francef Paediatric Dentistry, CHU Toulouse, Paul Sabatier University, FrancegCentre for Human Genetics, University Hospitals Leuven, Belgium

a r t i c l e i n f o

Article history:Received 20 September 2011Accepted 8 March 2012Available online 30 March 2012

Keywords:KennyeCaffey syndromeSanjad-Sakati syndromeDental anomaliesOligodontiaMicrodontiaEnamel defects

* Corresponding author. 3 Chemin des maraîchers, F31062 Toulouse Cedex 09, France. Tel.: þ33 (0) 562172

E-mail addresses: Isabelle.bailleul-forestier@un(I. Bailleul-Forestier).

1769-7212/$ e see front matter � 2012 Elsevier Massdoi:10.1016/j.ejmg.2012.03.005

a b s t r a c t

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 tubulin-specific 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 article5 new individuals with KCS, are described focusing on oral findings. All cases had short roots and showeddental anomalies as hypo/oligodontia, microdontia. Dental anomalies are a constant feature in KCS,further study is required to better delineate the syndrome.

� 2012 Elsevier Masson SAS. All rights reserved.

1. Introduction

KennyeCaffey syndrome is a rare genetic disorder characterizedby internal cortical thickening and medullary stenosis of thetubular bones, absent diploic space in the skull, growth retardationwith short stature, hypocalcemia mostly due to congenital hypo-parathyroidism, ophthalmologic abnormalities (hyperopia) anddysmorphic features including a prominent forehead, micro-phthalmia, micrognathia and dental anomalies.

The prevalence of KCS is unknown, less than 60 cases have beenpublished to date. Initially, a dominant inherited type of KCS hasbeen described in 5 families [1e4]. The possibility of an autosomalrecessive form has been raised in 1980 [2], and confirmed in 1992[5]. Twenty-four cases of autosomal recessive KCS have been pub-lished, most of them (20/24) associated with parental consan-guinity and originating from Kuwait [2,5e10]. Twenty sporadiccases were also reported. Two different KCS phenotypes are

aculté de Chirurgie Dentaire,929; fax: þ33 (0) 561254719.iv-tlse3.fr, ibailleul@noos.fr

on SAS. All rights reserved.

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 moresevere growth delay, small hands and feet, mental retardation,microcephaly, and immunological deficiency leading to recurrentbacterial infections. The main KCS types 1 and 2 clinical features aresummarized 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 tubulin-specific chaperone E (TBCE). TBCE is required for a- and b-tubulindimerization and microtubules polymerisation [12]. Microtubulesare essential components of the cytoskeleton.Mutations in the samegenewere also reported in the Sanjad-Sakati syndrome (SSS) orHRD(Hypoparathyroidism-Retardation-Dysmorphism) syndrome (MIM241410). Except for the osteosclerosis, clinical features in HRD aresimilar to the ones in KCS type 1.

Oro-dental features associated with KCS reported in the litera-ture include dental caries, enamel defects [10], delayed eruption[13], tooth agenesis [14], and micrognathia [1]. To date, the precisedental phenotype of only one individual with KCS has beendescribed with oligodontia (defined as agenesis of at least sixpermanent teeth), enamel hypoplasia, and abnormalities of crown

Table 1Review of the literature in 55 patients with KennyeCaffey syndrome.

KCS type 1a Recessiveform

KCS type 2b Dominantform

KCS Total

Number of affected patients 24 31 55Sex (male/female) 4/20 15/16 19/36Age�12 years (Mean age: M) 24/24 (M ¼ 3 y) 18/31 (M ¼ 5 y) 42/55 (M ¼ 4 y)>12 years 0/24 13/31 (M ¼ 25 y) 13/55 (M ¼ 25 y)Radiological abnormalitiesCortical thickening and medullary stenosis of long bones 19/22 86% 27/31 87% 46/53 87%Absent diploic space in calvaria 14/19 74% 14/19 74% 28/38 74%Delayed closure of anterior fontanel 4/24 17% 22/24 92% 26/48 54%Growth delayShort stature 23/24 96% 29/31 93% 52/55 94%Intrauterine growth retardation 20/24 83% 8/22 36% 28/46 61%Delayed bone age 13/20 65% 10/20 50% 23/40 57%Growth hormone deficiency 2/13 15%HypocalcemiaHypocalcemia 22/24 92% 25/29 86% 47/53 90%Symptomatic hypocalcemia 21/24 87% 24/29 83% 45/53 85%Congenital hypoparathyroidism 18/20 90% 16/22 73% 34/42 81%Facial featuresProminent forehead 17/19 89% 15/16 94% 32/35 91%Microphthalmia 7/11 64% 16/23 70% 23/34 68%Micrognathia 17/22 77% 10/16 62% 27/38 71%Dental anomalies 11/13 85% 12/15 80% 23/28 82%Relative macrocephaly 2/13 15% 12/13 92% 14/26 54%Microcephaly 13/15 87% 1/13 8% 14/28 50%Ocular findings 18/24 75% 26/30 87% 44/54 81%Hyperopia 7/18 39% 20/26 77% 27/44 61%Strabismus 3/18 17% 6/26 23% 9/44 20%Mental/Psychomotor Retardation 14/17 82% 4/25 16% 18/42 43%Anemia 4/7 57% 7/13 54% 11/20 55%

a [2,5,6,7,8,9,10,18].b [1e4,14,19e29].

Y. Moussaid et al. / European Journal of Medical Genetics 55 (2012) 441e445442

and root morphology of permanent teeth. The aim of the presentstudy is to describe the dental phenotype in 5 unrelated KCS indi-viduals, and to review the clinical data available in the literature [14].

2. Patients and methods

Five individuals, four males and one female, were included inthe study. The average age of the patients is 15 years and rangedfrom 8 to 26. Clinical data of the individuals were obtained from thereferring endocrinologists and geneticists. Molecular analysis of thegene TBCE was required for 3 of the 5 individuals.

From all the individuals a clinical oral examination and anorthopantomogram were available. The orthopantomograms wereanalysed to assess tooth agenesis and root morphology. Extractiondue to decay, orthodontic treatment or periodontal disease, andloss of teeth due to dental trauma were recorded by questioningparents and/or patients.

Fig. 1. Frontal view of a 26 years old patient with KennyeCaffey syndrome type 1 (case2), showing microcephaly, micrognathia, hyperpigmentation of skin around the eyes,and convex nasal ridge.

3. Results

Three males have been diagnosed as KCS type 2 according toclinical, radiological criteria and familial characteristics (no familyhistory, no parental consanguinity). One (case 1) has nomutation inthe TBCE gene. Another male has been diagnosed with KCS type 1according to the clinical, radiological and familial (parentalconsanguinity, a half-brother similarly affected) criteria (case 2);and a TBCE gene mutation (c.155-166del12) was detected in thiscase (Fig. 1).

According to the clinical and radiological criteria (Fig. 2), alsoa girl has been diagnosed with KCS. The array-CGH analysis wasnormal and no mutationwas found in the TBCE gene. The diagnosisis more consistent with KCS type 2 (case 4).

Fig. 2. X-rays of the left foot of a 18 year-old girl with KennyeCaffey syndrome (case4), showing cortical thickening of metacarpals and phalanges, shortness of 1st and 4thmetacarpals and the distal phalanges of the 4th toe.

Table 2Clinical data and oral phenotype in 5 patients with KennyeCaffey syndrome (KCS).

Case, gender, age Case 1: M,12 years

Case 2: M,26 years

Case 3: M,15 years

KCS 1/KCS 2 KCS 2 KCS 1 KCS 2TBCE mutation e þ e

Radiological abnormalitiesMedullary stenosis þ þ þAbsent diploic space in

calvariaþ e þ

Delayed closure ofanterior fontanel

þ e þ

Short stature þ þ þHeight deviation �3DS �12DS ?Intrauterine growth

retardatione e ?

GH/IGF1 deficiency e þ e

HypocalcemiaSymptomatic

hypocalcemiaþ þ ?

Congenitalhypoparathyroidism

þ þ þ

Facial featuresProminent forehead þ þ þMicrophthalmia þ þ þRelative Macrocephaly þ e þMicrocephaly e þ e

Micrognathia þ þ þOcular findingsHyperopia þ þ ?Strabismus þ e þMental retardation e þ ?

Oligodontia þ þ þMissing permanent

teeth15, 12, 25, 35,34, 44, 45

15, 14, 12, 22, 24,25, 27, 37, 35, 34,43, 44, 45

15, 12, 22, 24, 25,35, 34, 32, 44, 45

Enamel hypoplasia þ e þDental morphology abnormalitiesCrown Hypoplasia HypoplasiaMicrodontia 43, 42, 41, 31, 32, 33 13, 23, 33 33, 31, 41, 42, 43Roots e ShortPulp Taurodontism Narrow roots canal

Delayed eruption e þ e

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 clinicalexamination highlights abnormalities of tooth enamel and ofcrown morphology.

4. Discussion

Only 55 cases of KCS were reported in the literature. KCS and theSanjad-Sakati syndrome are allelic disorders despite their clinicalvariability (additional osteosclerosis and susceptibility to bacterialinfection 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 Sanjad-Sakati syndrome) have a recurrent 12 pb deletion in the secondcoding exon of the TBCE gene. HDR syndrome may be geneticallyheterogeneous with one family without TBCE gene mutation andlinked to a new locus at chromosome 4q35 [16]. In this study, therecurrent mutation in the TBCE gene was found in only one subjectfrom North Africa origin. Array-CGH analysis was normal in twoother cases.

Oral manifestations have been reported only once in a malepatient affected with KCS type 2 [14]. This study reports dentalfeatures in 5 KCS individuals; all had congenital missing teeth(hypodontia 1/5, oligodontia 4/5) (Figs. 3 and 4). Teeth agenesisvaries from 4 to 18 teeth. The most frequently absent teeth arethose found in the general population, except for the agenesis of thesecond molars and the mandibular canines. Microdontia affected

Case 4: F,18 years

Case 5:8 years

6. Demir & al.,2007 [14].

Reported cases %(Table 1)

KCS 2 KCS 2 KCS 2? e e

þ þ þ 87%e e e 74%

þ þ þ 17% (KCS1),92% (KCS2)

þ þ þ 94%�6DS ? ?þ e e 83% (KCS1),

36% (KCS2)e e ? 15%

þ þ þ 85%

þ þ þ 81%

þ þ þ 91%þ e þ 68%e e þ 92% (KCS2)þ e e 87% (KCS1)þ e þ 71%

þ ? ? 61%e e e 20%e ? e 82% (KCS1),

16% (KCS2)þ e þ17, 15, 14, 12, 22,24, 25, 27, 37, 35,34, 33, 44, 45, 47

15, 24, 35, 45 18 teeth

þ þ þ

Hypoplasia Bulbous(Macrodontia: 11, 21) 13, 23Short Short Short

s Narrow roots canals ? Narrow roots canals,Calcifications

? e þ

Fig. 3. Orthopantomogram of a 18 year-old girl with KennyeCaffey syndrome andsevere 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 2and 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 permanentcanines and incisors (except for maxillary central incisors).

Y. Moussaid et al. / European Journal of Medical Genetics 55 (2012) 441e445444

especially the lower incisors and canines (Fig. 5). Furthermore, anabnormal morphology of crowns with small cusps and an atypicalform of the frenulum were observed. On the orthopantomogramsabnormal short roots of the permanent teeth were noted. This lastfeature can be found in dentin dysplasia type 1 (rootless teeth, MIM125400) or in Microcephalic Osteodysplastic Primordial Dwarfismtype II syndrome [17]. Moreover, some dysmorphic features inSeckel syndrome could be found in Sanjad-Sakati syndrome.

We report the first French cohort of individuals with KCSincluding clinical and oral data. This review shows that the KCSsyndrome 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.

and root morphology, oligodontia (except for one case). Oralfeatures such as hypo/oligodontia should be included in the diag-nostic features of KCS. Further studies are required to highlight themolecular diagnosis and to better delineate KCS and its allelicdisorders, such as Sanjad-Sakati syndrome.

Acknowledgements

The authors would like to thank the families and the patients fortheir participation in this study.

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