Conservative orthodontic and multidisciplinary approaches for patients with cleidocranial dysplasia in late adolescence or young adulthood.

This case series describes conservative orthodontic and multidisciplinary approaches for treating two patients diagnosed with cleidocranial dysplasia in late adolescence and young adulthood. Most of the impacted permanent teeth erupted spontaneously within 3 to 4 years after surgical extraction of the deciduous and supernumerary teeth. The remaining unerupted permanent teeth were facilitated with traction or extracted followed by implantation or restoration. Repositioning of the maxilla and mandible via orthognathic surgery was also applied to correct skeletal and occlusal discrepancies and lead to satisfying results.

Skeletal and molecular findings in 51 Cleidocranial dysplasia patients from Turkey.

Loss or decrease of function in runt-related transcription factor 2 encoded by RUNX2 is known to cause a rare autosomal-dominant skeletal disorder, cleidocranial dysplasia (CCD). Clinical spectrum and genetic findings in 51 CCD patients from 30 unrelated families are herein presented. In a majority of the patients, facial abnormalities, such as delayed fontanel closure (89%), parietal and frontal bossing (80%), metopic groove (77%), midface hypoplasia (94%), and abnormal mobility of shoulders (90%), were recorded following clinical examination. In approximately one-half of the subjects, wormian bone (51%), short stature (43%), bell-shaped thorax (42%), wide pubic symphysis (50%), hypoplastic iliac wing (59%), and chef's hat sign (44%) presented in available radiological examinations. Scoliosis was identified in 28% of the patients. Investigation of RUNX2 revealed small sequence alterations in 90% and gross deletions in 10% of the patients; collectively, 23 variants including 11 novel changes (c.29_30insT, c.203delAinsCG, c.423 + 2delT, c.443_454delTACCAGATGGGAinsG, c.505C > T, c.594_595delCTinsG, c.636_637insC, c.685 + 5G > A, c.1088G > T, c.1281delC, Exon 6-9 deletion) presented high allelic heterogeneity. Novel c.29_30insT is unique in affecting the P1-driven long isoform of RUNX2, which is expected to disrupt the N-terminal region of RUNX2; this was shown in two unrelated phenotypically discordant patients. The clinical findings highlighted mild intra-familial genotype-phenotype correlation in our CCD cohort.

[The Pierre Marie-Sainton syndrome or cleidocranial dysplasia]. / Cas clinique : Maladie de Marie et Sainton ou dysostose cléido-crânienne.

The Pierre-Marie Sainton syndrome or cleidocranial dysplasia is a rare congenital malformation due to a mutation in the RUNX2 gene, causing disruption in osteoblastic maturation, which results in various skeletal, dental and endocrine abnormalities. These various disorders may also have otorhinolaryngology and psychological consequences. We report the case of a patient with this rare birth defect.

La maladie de Marie et Sainton, ou dysostose cleido-crânienne, est une malformation congénitale héré-ditaire rare liée à une mutation du gène RUNX2, entraînant un déficit de maturation ostéoblastique avec, pour conséquences, différentes anomalies squelettiques, dentaires et endocrinologiques. Ces différents troubles peuvent également avoir des répercussions sur le plan ORL et psychologique. Nous rapportons le cas d'un patient présentant cette malformation congénitale rare.

Audiological evaluation of patients with cleidocranial dysplasia (CCD).

OBJECTIVE: The description of clinical manifestation of hearing problems in cleidocranial dysplasia (CCD) remains limited and incomplete, since CCD constitutes a rare congenital disorder. The study aims to provide a complex panel analysis of the auditory system in patients suffering from the disease. PATIENTS AND METHODS: The study group consisted of 4 children with CCD (aged: 12-15), who underwent orthodontic treatment. A full panel analysis of their auditory systems was performed, including high-frequency audiometry and a new method of middle ear assessment - WBT (Wideband Tympanometry). RESULTS: A slight conductive hearing loss was diagnosed in 3 out of 4 patients. While high frequency audiometry has shown a deterioration of hearing in 3 patients, in one case, the obtained thresholds were within the normal range. A decrease of absorbance in low frequencies has been observed in one or both ears. Only one patient has had a shift of maximum absorbance towards high frequencies in the left ear. CONCLUSIONS: The presented manuscript is the first with a complete evaluation of the auditory system comprising 4 cases of children in a similar age group. All of the examined patients presented an air-bone gap indicating conductive disorders.

Cleidocranial Dysplasia: Management of the Multiple Craniofacial and Skeletal Anomalies.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder caused by mutations in the Runx2 gene. The CCD is characterized by frontal bossing, a patent anterior fontanelle, presence of Wormian bones, midface hypoplasia, multiple dental abnormalities, clavicular hypoplasia or aplasia, skeletal abnormalities, and short stature. The aims of this study are to report the phenotypic manifestations of all patients who presented with CCD and to review the multidisciplinary management of these patients. The longitudinal data of patients with a diagnosis of CCD treated at The Australian Craniofacial Unit from 1980 to 2019 were reviewed. Fourteen patients were identified for inclusion in this study. The age at referral to the unit ranged from 1 week old to 49 years old (mean 11.2 years old). All patients had clinical features of frontal bossing, a patent anterior fontanelle, multiple Wormian bones, midface hypoplasia, abnormal dentition, clavicular hypoplasia/aplasia, and normal intellect. Eleven patients had obstructive sleep apnea. Eight patients had positive family history. Speech issues were found in 6 patients and abnormal hearing was found in 4 patients. Seven patients who underwent skeletal survey were found to have skeletal abnormalities. All patients were evaluated and managed by the multidisciplinary team, which consisted of craniofacial surgeons, pediatric dentists, orthodontists, ENT surgeons, pediatricians, clinical geneticists, radiologists, orthopedic surgeons, and social workers. All patients were treated by dentists/orthodontists requiring multiple surgical interventions and orthodontic treatment. Seven patients who had recurrent ear infection underwent ventilation tube insertion. Seven of 11 patients who had obstructive sleep apnea underwent adenotonsillectomy. Four patients underwent orthognathic surgery to correct midface hypoplasia and malocclusion. Two patients had cranioplasty for correction of metopic depressions. The characteristic findings of patients with CCD involving multiple regions of the body should draw clinicians' attention to the need for multidisciplinary management of these patients.

Cleidocranial dysplasia with growth hormone deficiency: a case report.

BACKGROUND: Cleidocranial dysplasia (CCD) is a rare skeletal disorder with autosomal dominant inheritance that is characterized by hypoplastic clavicles, delayed closure of the cranial sutures, dental abnormalities, and short stature, among other features. The responsible gene for CCD is RUNX2 located on the short arm of chromosome 6p21. In general, there are intrafamilial variations in height among CCD patients. Few studies have reported data on recombinant human growth hormone (rhGH) treatment for patients with CCD; thus, it remains to be elucidated whether rhGH treatment can improve short stature. Here, we report a case of a 6-year-old girl with CCD who has growth hormone deficiency (GHD) and a novel mutation of RUNX2. CASE PRESENTATION: At 5 years of age, this patient was diagnosed with GHD and rhGH treatment was initiated. Thereafter, she was diagnosed with CCD due to the presence of hypoplastic clavicles and an open fontanelle, which was also observed in her mother and brother. She responded well to rhGH treatment; her height improved from - 3.2 SD to - 2.4 SD after 13 months. CONCLUSION: A detailed patient history and physical examination are necessary for the early diagnosis of CCD. Similarly, to ascertain the effect of rhGH treatment, careful evaluation of the patient's final height post-therapy is needed.

Three-dimensional evaluation of morphology and position of impacted supernumerary teeth in cases of cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is a congenital anomaly characterized by the presence of impacted supernumerary teeth and delayed eruption of permanent teeth. However, there has been no detailed investigation on supernumerary teeth in patients with CCD using three-dimensional (3D) imaging techniques. The purpose of this study was to elucidate the morphology and position of supernumerary teeth using 3D images reconstructed from cone-beam computed tomography (CBCT) data in a group of five Japanese subjects (male, 3; female, 2; age, 15.0-25.4 years) with CCD. All five subjects exhibited supernumerary teeth (39 in total; average, 7.8; range, 1-15). All supernumerary teeth were impacted and existed as pairs with adjacent permanent teeth. Comparison of the size (the crown and dental-root lengths, the crown mesiodistal and buccolingual diameters), the number of cusps and dental roots, the position, and direction of supernumerary teeth in relation to the adjacent permanent teeth was analyzed. The results of relationship analyses revealed that, at sites other than the molar region, supernumerary teeth were positioned on the lingual and distal sides and supernumerary teeth resembled the morphology of their adjacent permanent teeth in terms of the number of cusps but were smaller than the adjacent permanent teeth. In the molar region, supernumerary teeth were microdontia, which were apparently small and obscure morphologically. In addition, while all adjacent permanent teeth exhibited normal direction, five supernumerary teeth exhibited inverse direction. The findings of this study will improve our understanding of the characteristics of CCD and provide important information for the pathophysiology and clinical treatment.

[Prenatal diagnosis for two families affected with cleidocranial dysplasia due to novel RUNX2 variants].

OBJECTIVE: To analyze variants of RUNX2 gene in two pedigrees affected with cleidocranial dysplasia and provide prenatal diagnosis for them. METHODS: For the two probands, the coding sequences of the RUNX2 gene were analyzed with PCR and bidirectional Sanger sequencing. To verify the results, peripheral blood samples were collected from their parents and 100 healthy controls. For family 1, umbilical cord blood was also collected for prenatal genetic diagnosis. RESULTS: In family 1, the proband and the fetus both carried a heterozygous c.578G>C (p.Arg193Pro) mutation. For family 2, the proband was found to carry a heterozygous c.909C>A (p.Tyr303X) mutation. The same mutations were not found among their parents and 100 healthy controls. Neither mutation was reported previously. CONCLUSION: Variants of the RUNX2 gene probably underlie the cleidocranial dysplasia in both pedigrees. The results enabled prenatal diagnosis for the affected family.

Combined Orthodontic-Surgical Sequential Treatment of Cleidocranial Dysplasia: A Case Report With 7-Year Follow-up and Review of the Literature.

Cleidocranial dysplasia (CCD) is a rare hereditary disorder characterized by skeletal malformations and dental abnormalities. Mutations of the transcription factor RUNX2 are responsible for the pathogenesis of CCD. We present a case of a 10-year-old boy with CCD, presenting with hypoplastic clavicles, delayed closure of the fontanelles, retarded exfoliation of the deciduous teeth, retarded eruption of the permanent teeth, and multiple impacted supernumerary teeth. Based on the clinical and radiographic examination results showing abnormalities of the bones and teeth, a diagnosis was reached easily, but it was difficult to achieve a complete curative effect. We carried out a highly organized schedule of treatment, including extraction of the deciduous and supernumerary teeth, partial resection of alveolar bone, distraction of impacted teeth, and orthodontic surgery. After 7-year follow-up, the patient has achieved acceptable occlusion and midfacial appearance. The main objectives of this study were to present the diagnosis and treatment of CCD and to emphasize the benefits of combined orthodontic-surgical sequential treatment.

Queratoquiste Odontogénico en un Paciente con Displasia Cleidocraneal: reporte de un Caso / Odontogenic Keratocyst in a Patient with Cleidocranial Dysplasia: case Report

RESUMEN: La displasia cleidocraneal (DCC), es un trastorno autosómico dominante poco común, que involucra principalmente a los huesos que se osifican por vía membranosa; afectando el cierre de fontanelas craneales y el desarrollo de las clavículas, además de anomalías dentales y vertebrales. El objetivo de este manuscrito fue reportar el caso de una paciente con DCC que presentó un queratoquiste odontogénico (QQO) intrasinusal. Presentamos el caso de una paciente de 81 años, diagnosticada en su niñez con DDC, que consultó por un desajuste protésico y molestias en relación a la zona del seno maxilar derecho. Clínicamente se observó desajuste de la prótesis y aumento de volumen de márgenes poco definidos en la zona maxilar derecha, color rosa coral; que se extendía por todo el margen hemimaxilar derecho hasta el fondo de vestíbulo; doloroso a la palpación, con un mes de evolución. Se solicitó CBCT, con el que se pudo verificar la presencia de un desarrollo tumoral de contenido similar a dentículos, ubicado en la totalidad del seno maxilar derecho; extendiéndose hasta el piso de la cavidad nasal y orbitaria. Se estableció la hipótesis diagnóstica de "odontoma compuesto". Se le intervino quirúrgicamente, bajo anestesia general, realizándose una excisión de la lesión; la que era de márgenes definidos, con cambios de coloración en tonos oscuros, con la inclusión de tres piezas dentarias; de aspecto maligno. Se logró enucleación completa, dejando remanente óseo limpio. La pieza fue enviada a estudio histopatológico. En informe histopatológico, describió la presencia de una lesion quistica con pared compatible con queratoquiste.

ABSTRACT: Cleidocranial dysplasia (CCD) is an uncommon autosomal dominant disorder that mainly involves bones that ossify via the membrane, affecting the closure of cranial fontanels and the development of the clavicles, as well as presenting dental and vertebral anomalies. The aim of this manuscritpt was to report a case of a patient with CCD who presented an intrasinusal odontogenic keratocyst.We present an 81-year-old female patient, diagnosed with this syndrome in childhood, who comes to our service for a prosthetic misalignment and discomfort of the right maxillary sinus area. Clinically, there was a mismatch of the prosthesis and an increase in the volume of undefined margins under it, coral pink color, which extended all over the right hemimaxillary margin to the bottom of the vestibule, painful on palpation, with a one month evolution. A CBCT was requested, which revealed the presence of a tumor development with content similar to denticles, located in the entire right maxillary sinus, extending to the floor of the nasal and orbital cavity. The diagnostic hypothesis of "compound odontoma" was established. The patient was operated on in the central ward, under general anesthesia performing the excisional biopsy of the lesion, which showed changes in coloration in dark tones, with defined edges, with the inclusion of three teeth showing malignancy aspects. Complete enucleation was achieved, leaving tumor-free clean bone remnant. In a histopathological report, the presence of a keratocyst wall was described, which is not very compatible given the appearance of the lesion, the presence of the dental pieces included in it, and the behavior of the lesion.

Cleidocranial dysplasia syndrome with epilepsy: a case report.

BACKGROUND: Cleidocranial dysplasia is a rare autosomal dominant disorder resulting in skeletal and dental abnormalities due to the disturbance in ossification of the bones. The prevalence of CCD is one in a million of live births, and epileptic seizures are rarer in this disease. CASE PRESENTATION: Herein, we present a case of a 10-year-old girl, who not only suffered with cleidocranial dysplasia, but experienced frequent seizures. We initiated an anti-epileptic treatment for this patient with dose adjustments to her weight of levetiracetam (10 mg/kg, bid) for 3 months. The epileptic seizures were controlled, but the intelligence level and control of epilepsy need to be followed up for a longer duration. CONCLUSIONS: In clinical practice, if a patient has unusual facies, typical clavicle defect, skull bone enlargement, and unclosed anterior fontanelle, we should consider the possibility of cleidocranial dysplasia, genetic detection are helpful to make a confirmed diagnosis. In such cases, early diagnosis and treatment is important to correct deformities and improve the quality of life of patients.

Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells.

Cleidocranial dysplasia (CCD, #119600), which is characterized by hypoplastic clavicles, open fontanelles, supernumerary teeth and a short stature, is caused by heterozygous mutations in RUNX2. However, it currently remains unclear why suture closure is severely impaired in CCD patients. The closure of posterior frontal (PF) and sagittal (SAG) sutures was completely interrupted in Runx2+/- mice, and the proliferation of suture mesenchymal cells and their condensation were less than those in wild-type mice. To elucidate the underlying molecular mechanisms, differentially expressed genes between wild-type and Runx2+/- PF and SAG sutures were identified by microarray and real-time reverse transcription polymerase chain reaction analyses. The expression of hedgehog, Fgf, Wnt and Pthlh signaling pathway genes, including Gli1, Ptch1, Ihh, Fgfr2, Fgfr3, Tcf7, Wnt10b and Pth1r, which were directly regulated by Runx2, was reduced in the sutures, but not the calvarial bone tissues of Runx2+/- mice. Bone formation and suture closure were enhanced in an organ culture of Runx2+/- calvariae with ligands or agonists of hedgehog, Fgf, Wnt and Pthlh signaling, while they were suppressed and suture mesenchymal cell proliferation was decreased in an organ culture of wild-type calvariae with their antagonists. These results indicate that more than a half dosage of Runx2 is required for the proliferation of suture mesenchymal cells, their condensation and commitment to osteoblast-lineage cells, and the induction of hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in sutures, but not in calvarial bone tissues, and also that the activation of hedgehog, Fgf, Wnt and Pthlh signaling pathways is necessary for suture closure.

Therapeutic Protocol for Orthosurgical Management of Class III Malocclusion in Patients With Cleidocranial Dysostosis.

Cleidocranial dysostosis (CCD) is a congenital skeletal disorder with significant manifestations in facial and dental development. Patients are affected with CCD present maxillary deficiency, late dental eruption, and supernumerary teeth. Early and multidisciplinary approach is necessary to treat CCD patients, especially to manage dental eruption and Class III malocclusion with maxillary deficiency. Several orthodontic and surgical interventions are performed to enable traction and extraction of teeth. Yet the maxillary deficiency may be protracted followed by orthodontic dental compensation. On the other hand, it is important to note that CCD patients' treatment is closely related to the severity of transversal and sagittal deformities, as well as the discrepancies in the lower third of the face. In this context, patients with facial impairment highly affected by CCD may need ortho-surgical decompensation to reach more aesthetic outcomes. The present study reports a case of a 14-year-old young patient affected by CCD. Clinically, the patient presented Class III malocclusion, maxillary deficiency, short lower facial third, posterior crossbite, and anterior open bite leading to facial disharmony. The patient underwent treatment in 2 stages: the interceptive approach aimed to transversally expand the maxilla and promote its protraction; and the corrective phase combined with the orthognathic surgery treated the patients' main complains; the anterior open bite, unerupted teeth, and chin prominence. The treatment approach applied in the clinical report allowed the correction of the malocclusion and facial profile satisfying completely the patient's expectations.

Cleidocranial Dysplasia: A Review of Clinical, Radiological, Genetic Implications and a Guidelines Proposal.

In this review, we aimed to depict the clinical, radiological, and genetic features of cleidocranial dysplasia (CCD) and to suggest management guidelines, based on our experience of 8 cases, with an emphasis given to dental complications.The most common craniofacial features of CCD that stand out are a patency of the anterior fontanelle, an inverted pear-shaped calvaria, a hypertelorism, a general midface retrusion, and a mandible prognathism, associated with an excessive mobility of the shoulders, a short stature, and teeth abnormalities such as supernumerary teeth and failure of eruption, in particular. RUNX2 is the only gene in which mutation is known to cause CCD, but mutations are detected in only 65% of all patients with a clinical diagnosis of CCD. Panoramic radiography is a valuable adjunct in confirming the diagnosis of CCD.Our experience allowed us to conclude that orthodontically aided eruption should always be attempted. However, to stabilize the occlusion and to improve facial esthetics, we recommend associated orthognathic surgery. When orthodontic treatment is partially efficient, prosthetic treatment options bring satisfactory results, in terms of occlusion. Nevertheless, when orthodontic treatment fails, we recommend to preserve as many native teeth as possible, and to combine orthognathic preprosthetic surgery and implant-supported prosthesis.In any case, an individualized treatment protocol, depending on the needs and demand of the patient, the age at diagnosis and social and economic circumstances, should be put forward.

Estudio dínico y molecular en una familia con displasia cleidocraneal / Clinical and molecular study in a family with cleidocranial dysplasia

La displasia cleidocraneal es una displasia ósea infrecuente con patrón de herencia autosómico dominante, que se caracteriza por presentar talla baja, fontanelas amplias, hipoplasia mediofacial, ausencia o hipoplasia de clavículas y alteraciones orodentales. Es producida por mutaciones en el gen RUNX2 localizado en 6p21.1. Se presentan dos adolescentes masculinos (primos hermanos) con displasia cleidocraneal, los cuales mostraron mutación heterocigota, cambio de sentido (c.674G>A, p.R225Q) en el gen RUNX2, caracterizados por presentar fenotipo grave, como ausencia de clavículas, pero con variación en el retardo en el cierre de fontanelas, alteraciones dentales (anomalías en forma y número) y escoliosis, por lo que se demuestra la variación intrafamiliar en estos pacientes con el mismo genotipo.

Cleidocranial dysplasia is an uncommon bone dysplasia with an autosomal dominant inheritance pattern characterized by short stature, large fontanels, midface hypoplasia, absence or hypoplasia of clavicles and orodental alterations. This is produced by mutations in the RUNX2 gene located at 6p21.1. We report two male adolescents (cousins), with cleidocranial dysplasia who presented a heterozygous missense mutation (c.674G> A, p.R225Q) in the RUNX2 gene, characterized by severe phenotype, such as absent clavicles, but with variation in the delayed fontanel closure, dental abnormalities (anomalies in shape and number) and scoliosis, thus demonstrating intrafamilial variation in these patients with the same genotype.

[Clinical and molecular study in a family with cleidocranial dysplasia]. / Estudio clínico y molecular en una familia con displasia cleidocraneal.

Cleidocranial dysplasia is an uncommon bone dysplasia with an autosomal dominant inheritance pattern characterized by short stature, large fontanels, midface hypoplasia, absence or hypoplasia of clavicles and orodental alterations. This is Estudio clínico y molecular en una familia con displasia cleidocraneal Clinical and molecular study in a family with cleidocranial dysplasia produced by mutations in the RUNX2 gene located at 6p21.1. We report two male adolescents (cousins), with cleidocranial dysplasia who presented a heterozygous missense mutation (c.674G> A, p.R225Q) in the RUNX2 gene, characterized by severe phenotype, such as absent clavicles, but with variation in the delayed fontanel closure, dental abnormalities (anomalies in shape and number) and scoliosis, thus demonstrating intrafamilial variation in these patients with the same genotype.

La displasia cleidocraneal es una displasia ósea infrecuente con patrón de herencia autosómico dominante, que se caracteriza por presentar talla baja, fontanelas amplias, hipoplasia mediofacial, ausencia o hipoplasia de clavículas y alteraciones orodentales. Es producida por mutaciones en el gen RUNX2 localizado en 6p21.1. Se presentan dos adolescentes masculinos (primos hermanos) con displasia cleidocraneal, los cuales mostraron mutación heterocigota, cambio de sentido (c.674G>A, p.R225Q) en el gen RUNX2, caracterizados por presentar fenotipo grave, como ausencia de clavículas, pero con variación en el retardo en el cierre de fontanelas, alteraciones dentales (anomalías en forma y número) y escoliosis, por lo que se demuestra la variación intrafamiliar en estos pacientes con el mismo genotipo.

[Cleidocranial dysplasia: a case report]. / Displasia cleidocraneal: reporte de un caso.

INTRODUCTION: Cleidocraneal dysplasia (CCD) is a rare skeletal autosomal dominant syndrome characterized by dental anomalies and bone abnormalities. These clinical manifestations do not require treatment in most cases. The disease is caused by mutation in the gene RUNX2 (CBAF1), located on the short arm of chromosome 6. OBJECTIVE: To report a case of CCD and perform a literature review focused on clinical manifestations and diagnosis. CASE REPORT: A 3 year old patient, who was clinically diagnosed with CCD since birth. The patient showed incomplete development of cranial bones, bell-shaped thorax, adequate dentition and presence of clavicles. Molecular analysis reported that the patient is carrying the pathogenic variant c.674G>A in the RUNX2 gene, confirming the diagnosis. CONCLUSIONS: The CCD is a rare condition, with special clinical features. It is important to establish early diagnosis in these patients in order to offer a better quality of life, and if necessary, appropriate treatment.

Yunis-Varón syndrome caused by biallelic VAC14 mutations.

Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varón syndrome.

A novel, complex RUNX2 gene mutation causes cleidocranial dysplasia.

BACKGROUND: Haploinsufficiency of the runt-related transcription factor 2 (RUNX2) gene is known to cause cleidocranial dysplasia (CCD). Here, we investigated a complex, heterozygous RUNX2 gene mutation in a Chinese family with CCD and the pathogenesis associated with the variations. METHODS: Genomic DNA extracted from peripheral venous blood was taken from the proband, her parents and 3 siblings, and 150 normal controls. Analysis of their respective RUNX2 gene sequences was performed by PCR amplification and Sanger sequencing. Pathogenesis associated with RUNX2 mutations was investigated by performing bioinformatics, real-time PCR, western blot analysis, and subcellular localization studies. RESULTS: We identified 2 complex heterozygous mutations involving a c.398-399 insACAGCAGCAGCAGCA insertion and a c.411-412 insG frameshift mutation in exon 3 of the RUNX2 gene. The frameshift mutation changed the structure of the RUNX2 protein while did not affect its expression at the mRNA level. Transfection of HEK293T cells with a plasmid expressing the RUNX2 variant decreased the molecular weight of the variant RUNX2 protein, compared with that of the wild-type protein. Subcellular localization assays showed both nuclear and cytoplasmic localization for the mutant protein, while the wild-type protein localized to the nucleus. CONCLUSIONS: Our findings demonstrated that the novel c.398-399insACAGCAGCAGCAGCA mutation occurred alongside the c.411-412insG frameshift mutation, which resulted in RUNX2 truncation. RUNX2 haploinsufficiency was associated with CCD pathogenesis. These results extend the known mutational spectrum of the RUNX2 gene and suggest a functional role of the novel mutation in CCD pathogenesis.