A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients' dental management.

Abnormal hyperpolarization of the KCNK4 gene, expressed in the nervous system, brain, and periodontal ligament fibroblasts, leads to impaired neurotransmitter sensitivity, cardiac arrhythmias, and endocrine dysfunction, as well as, progressive cell proliferation. De novo gain of function variants in the KCNK4 gene were reported to cause a recognizable syndrome characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG, OMIM# 618381). FHEIG is extremely rare with only three reported cases in the literature. Herein, we describe the first inherited KCNK4 variant (c.730G>C, p.Ala244Pro) in an Egyptian boy and his mother. Variable phenotypic expressivity was noted as the patient presented with the full-blown picture of the syndrome while the mother presented only with hypertrichosis and gingival overgrowth without any neurological manifestations. The c.730G>C (p.Ala244Pro) variant was described before in a single patient and when comparing the phenotype with our patient, a phenotype-genotype correlation seems likely. Atrial fibrillation and joint laxity are new associated findings noted in our patient extending the clinical phenotype of the syndrome. Dental management was offered to the affected boy and a dramatic improvement was noted as the patient regained his smile, restored the mastication function, and resumed his psychological stability.

Individualized digitally designed surgical template for guided soft tissue surgery in cases with severe gingival enlargement: A clinical application in hereditary gingival fibromatosis.

AIM: The purpose of this study was to present the use of computer-assisted periodontal surgery utilizing a novel surgical guide for cases with severe gingival enlargement through a clinical application in a patient with hereditary gingival fibromatosis. MATERIALS AND METHODS: The treatment plan included nonsurgical periodontal therapy, surgical periodontal treatment, and regular periodontal maintenance before the initiation of orthodontic treatment. Due to the increased soft tissue thickness, a surgical guide with a novel design was fabricated to facilitate the periodontal surgery since most of the patient's teeth were malpositioned and underexposed due to fibromatosis. For this purpose, the patient's intraoral scan was merged with a CBCT image in order to plan surgical excisions based on the anatomy of the teeth and the bone contour. RESULTS: The customized surgical guide facilitated the gingivectomy by controlling not only the shape of the initial incisions but also their orientation toward the level of the cementoenamel junction, improving the efficiency of the clinical time compared with freehand surgery and assisting in the verification of the final soft tissue shape, based on the treatment plan. CONCLUSION: Digital technology through the superimposition of multiple data sets can assist in the diagnosis and multidisciplinary management of cases with gingival fibromatosis. The proposed design of the surgical guide can facilitate soft tissue surgery based on the digital treatment plan, leading to more predictable management of the soft tissue, especially in patients with severe gingival enlargement, as in cases with hereditary gingival fibromatosis or drug-induced gingival overgrowth.

Patients with KCNH1-related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome.

De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1-related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic KCNH1 variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of KCNH1-related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain.

Zimmermann-Laband syndrome and infantile systemic hyalinosis: an enigma with two separate terms with overlapping features: a case report.

BACKGROUND: Zimmermann-Laband Syndrome (ZLS) and infantile systemic hyalinosis (ISH) are rare genetic disorders. They are characterized by various spectrum manifestations. In spite of other case reports, this case with features of both syndromes was reported by oral medicine specialists and oral and maxillofacial surgeons. CASE PRESENTATION: In this study, we reported an 18-months old female patient with gingival overgrowth. This phenomenon completely embedded all the erupted teeth. In this case, the presence of multiple papulonodular cutaneous lesions is a newly observed aspect that has rarely been reported in the existing literature. Gingival overgrowth was excised under general anesthesia. At six months of follow-up after surgery, mastication and breathing problems were improved. Aesthetic aspects were ameliorated in terms of gingival appearance. CONCLUSIONS: To date, due to the ambiguous presentations, both syndromes remain an enigma for specialists. A timely diagnosis could be crucial for prognosis and preventing severe further surcharge. Dentists could play an important role in the diagnosis of rare disorders.

Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes.

Deafness and onychodystrophy syndromes are a group of phenotypically overlapping syndromes, which include DDOD syndrome (dominant deafness-onychodystrophy), DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) and Zimmermann-Laband syndrome (gingival hypertrophy, coarse facial features, hypoplasia or aplasia of nails and terminal phalanges, intellectual disability, and hypertrichosis). Pathogenic variants in four genes, ATP6V1B2, TBC1D24, KCNH1 and KCNN3, have been shown to be associated with deafness and onychodystrophy syndromes. ATP6V1B2 encodes a component of the vacuolar H+-ATPase (V-ATPase) and TBC1D24 belongs to GTPase-activating protein, which are all involved in the regulation of membrane trafficking. The overlapping clinical phenotype of TBC1D24- and ATP6V1B2- related diseases and their function with GTPases or ATPases activity indicate that they may have some physiological link. Variants in genes encoding potassium channels KCNH1 or KCNN3, underlying human Zimmermann-Laband syndrome, have only recently been recognized. Although further analysis will be needed, these findings will help to elucidate an understanding of the pathogenesis of these disorders better and will aid in the development of potential therapeutic approaches. In this review, we summarize the latest developments of clinical features and molecular basis that have been reported to be associated with deafness and onychodystrophy disorders and highlight the challenges that may arise in the differential diagnosis.

Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca2+-Activated K+ Channel SK3 Cause Zimmermann-Laband Syndrome.

Zimmermann-Laband syndrome (ZLS) is characterized by coarse facial features with gingival enlargement, intellectual disability (ID), hypertrichosis, and hypoplasia or aplasia of nails and terminal phalanges. De novo missense mutations in KCNH1 and KCNK4, encoding K+ channels, have been identified in subjects with ZLS and ZLS-like phenotype, respectively. We report de novo missense variants in KCNN3 in three individuals with typical clinical features of ZLS. KCNN3 (SK3/KCa2.3) constitutes one of three members of the small-conductance Ca2+-activated K+ (SK) channels that are part of a multiprotein complex consisting of the pore-forming channel subunits, the constitutively bound Ca2+ sensor calmodulin, protein kinase CK2, and protein phosphatase 2A. CK2 modulates Ca2+ sensitivity of the channels by phosphorylating SK-bound calmodulin. Patch-clamp whole-cell recordings of KCNN3 channel-expressing CHO cells demonstrated that disease-associated mutations result in gain of function of the mutant channels, characterized by increased Ca2+ sensitivity leading to faster and more complete activation of KCNN3 mutant channels. Pretreatment of cells with the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole revealed basal inhibition of wild-type and mutant KCNN3 channels by CK2. Analogous experiments with the KCNN3 p.Val450Leu mutant previously identified in a family with portal hypertension indicated basal constitutive channel activity and thus a different gain-of-function mechanism compared to the ZLS-associated mutant channels. With the report on de novo KCNK4 mutations in subjects with facial dysmorphism, hypertrichosis, epilepsy, ID, and gingival overgrowth, we propose to combine the phenotypes caused by mutations in KCNH1, KCNK4, and KCNN3 in a group of neurological potassium channelopathies caused by an increase in K+ conductance.

Zimmermann-Laband syndrome in monozygotic twins with a mild neurobehavioral phenotype lacking gingival overgrowth-A case report of a novel KCNN3 gene variant.

Zimmermann-Laband syndrome is a rare, heterogeneous disorder characterized by gingival hypertrophy or fibromatosis, aplastic/hypoplastic nails, hypoplasia of the distal phalanges, hypertrichosis, various degrees of intellectual disability, and distinctive facial features. Three genes are considered causative for ZLS: KCNH1, KCNN3, and ATP6V1B2. We report on a pair of female concordant monozygotic twins, both carrying a novel pathogenic variant in the KCNN3 gene, identified using exome sequencing. Only six ZLS patients with the KCNN3 pathogenic variant have been reported so far. The twins show facial dysmorphism, hypoplastic distal phalanges, aplasia or hypoplasia of nails, and hypertrichosis. During infancy, they showed mild developmental delays, mainly speech. They successfully completed secondary school education and are socio-economically independent. Gingival overgrowth is absent in both individuals. Our patients exhibited an unusually mild phenotype compared to published cases, which is an important diagnostic finding for proper genetic counseling for Zimmermann-Laband syndrome patients and their families.

Modified gingivoplasty for hereditary gingival fibromatosis: two case reports.

BACKGROUND: Hereditary gingival fibromatosis (HGF) is characterized by sub-epithelial fibromatosis of keratinized gingiva resulting in a fibrotic enlargement of keratinized gingiva. The treatment choice is gingivectomy, which can be performed with an internal or external bevel incision conventionally. However, both techniques can hardly resume the natural status of gingiva, and have a certain recurrence rate, especially in the cases which have limited width of attached gingiva. CASE DESCRIPTION: Two cases of HGF with the chief complaint of difficulty in mastication, pronunciation, and poor esthetics were presented. After the initial periodontal therapy, a novel gingivoplasty modified with a crevicular incision was applied. A full thickness flap above the mucogingival junction and a split flap below the junction were raised. Then, fibrotic connective tissue was completely eliminated and keratinized gingival epithelium was preserved. The fibrotic alveolar bone was shaped by handpiece and bur. Finally, the flap was apically repositioned and sutured. Twelve months after surgery, the gingiva recovered with normal color, contour and consistency. CONCLUSIONS: Compared to traditional gingivectomy, modified gingivoplasty which focuses on eliminating pathological fibrotic connective tissue can completely resume the natural appearance of gingiva and demonstrate no tendency of recurrence.

A 15-year Follow-Up of a Gingivectomy Procedure for Idiopathic Gingival Fibromatosis: A Case Report and Literature Review.

Few long-term reports exist concerning the treatment of idiopathic gingival fibromatosis, which is a rare autosomal dominant genetic disorder associated with non-inflammatory, benign, and chronic fibrous gingival proliferation and which causes serious esthetic problems. The aim of this study was to report a case of idiopathic gingival fibromatosis treated with a gingivectomy using an inverse bevel flap method and comprehensively followed up for 15 years. A female patient visited a pediatric dentist at 7 years of age; however, a gingivectomy was not performed until the age of 20 years because of an uncertain prognosis. Now, more than 15 years after the gingivectomy, there has been no significant recurrence and the disease is well managed. Treatment by gingivectomy with an inverse bevel flap approach may provide long-term prevention of recurrence of gingival fibromatosis into adulthood. The aim of this study was to obtain new findings on the pathogenesis and prognosis of this rare disease and to review the case reports previously published.

Activated KCNQ1 channel promotes fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras.

BACKGROUND AND OBJECTIVE: Activated potassium channels were found to be strongly correlated with gingival overgrowth (GO) phenotype as we reviewed syndromic hereditary gingival fibromatosis (HGF). Nevertheless, the functional roles of potassium channels in gingival fibrosis or gingival overgrowth remained uncovered. The aim of the present study was to explore the pathogenic role of aberrantly activated potassium channel in Hereditary Gingival Fibromatosis (HGF). METHODS: Gingival tissues were collected from 9 HGF patients and 15 normal controls. Expression of KCNQ1 was detected by immunohistochemistry. Gingival fibroblasts were isolated, and outward K+ currents were detected by whole-cell patch-clamp analysis, transmembrane potential was determined by flow cytometry. Normal human gingival fibroblasts (NHGFs) were transfected with KCNQ1 adenovirus or treated with KCNQ1 selective agonist ML277 and antagonist chromanol 293B. Accumulation of Extracellular Matrix (ECM) was measured by Western blotting and Sircol Soluble Collagen Assay. Content of secreted TGF-ß1 was measured by ELISA. Active RAS pull-down assay and cell immunofluorescence were utilized to verify RAS activation. RESULTS: KCNQ1 was upregulated in gingival tissues derived from HGF patients and HGF gingival fibroblasts presented increased outward K+ currents than NHGFs. Overexpression of KCNQ1, or KCNQ1 agonist ML277, promoted fibrotic responses of NHGFs. TGF-ß1 and KCNQ1 channels formed a positive feed-back loop. ML277 generated lateral clustering and activation of Ras on plasma membrane, followed by augmented MAPK/AP-1 signaling pathway output. JNK or ERK1/2 inhibitors suppressed ML277-induced AP-1 and ECM upregulation. CONCLUSION: Activation of KCNQ1 potassium channel promoted fibrogenic responses in NHGFs via Ras/MAPK/AP-1 signaling.

Syndromes with gingival fibromatosis: A systematic review.

OBJECTIVE: The aim of systematic review was to describe the phenotypes and molecular profiles of syndromes with gingival fibromatosis (GF). METHODS: A comprehensive search of PubMed, LILACS, Livivo, Scopus, and Web of Science was conducted using key terms relevant to the research questions and supplemented by a gray literature search. The Methodological Quality and Synthesis of Case Series and Case Reports in association with the Case Series and Prevalence Studies from the Joanna Briggs Institute critical appraisal tools were used for the risk of bias. We followed the PRISMA checklist guidelines. RESULTS: Eighty-four studies reporting GF as an oral manifestation of a syndrome were identified in this review. Enamel renal syndrome was the most frequently reported syndrome with GF, represented by 54 individuals in 19 studies, followed by Zimmermann-Laband syndrome with 24 individuals in 15 studies and Costello syndrome, which was presented in a case series study with 41 individuals. Among reported cases, other clinical manifestations such as hypertrichosis, ectopic gingival calcification, and cherubism were described. CONCLUSIONS: The results emphasize the need of systematic oro-dental-facial phenotyping for future descriptions as well as further molecular analysis in order to better understand the occurrence of syndromic GF.

Hereditary gingival fibromatosis in children: a systematic review of the literature.

OBJECTIVES: Hereditary gingival fibromatosis (HGF) is an uncommon, inherited condition with slow and progressive fibrous hyperplasia of the gingiva. Due to its association with mastication, speech, and occlusion problems, early diagnosis is important. We sought to summarize the available data regarding the epidemiology, clinical characteristics, and outcomes of children with HGF (< 18 years). METHODS: A systematic literature review of the MEDLINE and Cochrane Library databases was conducted with respect to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (end-of-search date: March 1, 2019). RESULTS: A total of 99 articles reporting on 146 patients were included. The mean age was 10.82 ± 3.93 years, and generalized gingival enlargement was seen in 97.16% (95% CI 92.69 to 99.14). Jaw, gingival, and teeth abnormalities; poor oral hygiene; eating; or speech difficulties were typical HGF-induced, while 60.90% had extraoral manifestations (95% CI 52.41 to 68.78). The disease was most commonly inherited in an autosomal dominant manner (88.41%, 95% CI 78.5 to 94.26), and about one-third of the patients had syndromic HGF (33.85%, 95% CI 23.50 to 46.00). Gingivectomy was performed in the majority of cases (91.15%, 95% CI 84.31 to 95.29), and recurrence was seen in 33.85% (95% CI 23.50 to 46.00). CONCLUSION: HGF should be suspected in children with nodularity and gingival fibrosis, teeth abnormalities, or jaw distortion. Family history can help to establish the diagnosis. CLINICAL RELEVANCE: More cases should focus on longer-term follow-up after gingivectomy as disease recurrence is not uncommon.

Seven-year follow-up of a patient with hereditary gingival fibromatosis treated with a multidisciplinary approach: case report.

BACKGROUND: Hereditary gingival fibromatosis (HGF) is rare in clinical practice, and the long-term results of the combined orthodontic-periodontal treatment of HGF are rarely reported. CASE PRESENTATION: This study reports for the first time the results of seven years of follow-up in a seven-year-old girl with HGF. The diagnosis was confirmed by clinical signs, family history and histopathological examination. First, periodontal scaling and oral hygiene reinforcement were performed regularly in the mixed dentition stage. Next, gingivoplasty was performed on the permanent dentition. Two months after the surgery, treatment with fixed orthodontic appliances was conducted. The teeth were polished on a monthly basis, and oral hygiene was reinforced to control gingival enlargement. Gingival hypertrophy recurred slightly, and gingivectomies were performed in the months following the start of orthodontic treatment. Follow-up was performed for 24 months with orthodontic retention, and gingival enlargement remained stable after the combined treatment. CONCLUSIONS: The risk of gingival hyperplasia recurrence during and after orthodontic treatment is high, but satisfying long-term outcomes can be achieved with gingivectomy, malocclusion correction, and regular follow-up maintenance.

Hyaline fibromatosis syndrome: a case presenting with gingival enlargement as the only clinical manifestation and a report of two new mutations in the ANTXR2 gene.

BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare autosomal recessive disorder caused by mutations in the gene for anthrax toxin receptor-2 (ANTXR2). The clinical features of HFS include skin thickening with nodules, papules and plaques, gingival enlargement, joint stiffness and contractures, and systemic manifestations. Notably, in all patients with HFS reported in the literature, gingival enlargement has never occurred alone. CASE PRESENTATION: A case of a child with gingival enlargement as the only clinical manifestation, who was later diagnosed with HFS, is described. In this case, the absence of skin and joint lesions and other characteristic clinical presentations gave rise to a diagnostic problem. This uncommon condition was clinically indistinguishable from other diseases or conditions that presented with diffuse gingival enlargement. A definitive diagnosis of HFS was reached through genetic analysis. Trio whole exome sequencing revealed compound heterozygous mutations of ANTXR2 in this patient and two new mutations were reported. CONCLUSIONS: The findings of this case serve as an important reminder to clinicians. When dental practitioners encounter gingival manifestations of HFS without accompanied skin or joint involvement, there is a need to pay attention to the differential diagnosis and increase awareness of HFS.

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis.

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

A Rare Case of non Syndromic Congenital Idiopathic Gingival Fibromatosis: Electrosurgical Management.

Idiopathic gingival fibromatosis (IGF) is a rare, genetically heterogeneous condition that is usually a part of syndrome or, rarely, an isolated disorder. It is characterized by a slowly progressive, non hemorrhagic, fibrous enlargement of keratinized gingiva which usually begins at the time of eruption of permanent dentition, however very few cases involving the primary teeth have been described in literature. Congenital gingival fibromatosis is very rare condition in which the gingival tissues become thickened and erupting teeth remain submerged beneath hyperplastic tissue masses. This case report discusses the rare case of congenital non syndromic idiopathic gingival fibromatosis in a two year old boy who reported with absence of teeth and incompetent lips. Gingivectomy was done using modified microdissection electrocautery needle to remove the excess gingival tissues. Excised tissue has been examined histologically. The patient was followed up for a period of one year and no recurrence was observed.

Fibroblasts from recurrent fibrotic overgrowths reveal high rate of proliferation in vitro - findings from the study of hereditary and idiopathic gingival fibromatosis.

PURPOSE: Investigate the content of fibrotic fibrils in gingival tissue and the proliferation of fibroblasts collected from recurrent and non-recurrent hereditary gingival fibromatosis (HGF) and idiopathic gingival fibromatosis (IGF). METHODS: Gingival biopsies were collected from HGF (n = 3) and IGF (n = 3) donors with recurrent and non-recurrent gingival overgrowths and from a control group (Ctrl, n = 3). Hematoxylin staining was performed to evaluate the histomorphology of gingival tissue. Heidenhain's AZAN trichrome staining served for visualization of fibrotic fibrils in gingiva. Quantitative analysis of the content of fibrotic fibrils in gingival tissue was performed using a polarized light microscope. Proliferation was evaluated at 24 h, 48 h, and 72 h in fibroblast cultures using a cell proliferation ELISA assay based on 5-bromo-2'-deoxyuridine (BrdU). RESULTS: Numerous blood vessels and fibroblasts were observed in recurrent overgrowths, whereas moderate blood vessels and moderate to scanty fibroblasts were detected in non-recurrent overgrowths. Heidenhain's staining revealed numerous collagen fibers in both recurrent and non-recurrent overgrowths. Quantitative analysis in a polarizing microscope showed significant accumulation of fibrotic fibrils exclusively in the overgrowths with the recurrence. In all time-points, increased proliferation of cells from all recurrent overgrowths was observed, but not from overgrowths which do not reoccur. CONCLUSIONS: The study revealed that recurrent gingival overgrowths consist of highly fibrotic and dense connective tissue with numerous blood vessels and abundant fibroblasts. We also demonstrated that unlike fibroblasts derived from overgrowths, which did not present recurrence, fibroblasts derived from highly fibrotic and recurrent overgrowths maintain high rate of proliferation in vitro.

Exomic and transcriptomic alterations of hereditary gingival fibromatosis.

OBJECTIVE: Hereditary gingival fibromatosis (HGF) is a rare oral disease characterized by either localized or generalized gradual, benign, non-hemorrhagic enlargement of gingivae. Although several genetic causes of HGF are known, the genetic etiology of HGF as a non-syndromic and idiopathic entity remains uncertain. SUBJECTS AND METHODS: We performed exome and RNA-seq of idiopathic HGF patients and controls, and then devised a computational framework that specifies exomic/transcriptomic alterations interconnected by a regulatory network to unravel genetic etiology of HGF. Moreover, given the lack of animal model or large-scale cohort data of HGF, we developed a strategy to cross-check their clinical relevance through in silico gene-phenotype mapping with biomedical literature mining and semantic analysis of disease phenotype similarities. RESULTS: Exomic variants and differentially expressed genes of HGF were connected by members of TGF-ß/SMAD signaling pathway and craniofacial development processes, accounting for the molecular mechanism of fibroblast overgrowth mimicking HGF. Our cross-check supports that genes derived from the regulatory network analysis have pathogenic roles in fibromatosis-related diseases. CONCLUSIONS: The computational approach of connecting exomic and transcriptomic alterations through regulatory networks is applicable in the clinical interpretation of genetic variants in HGF patients.

Homozygous mutation in ELMO2 may cause Ramon syndrome.

We report on a girl, born to first cousin Lebanese parents, with intellectual disability, seizures, repeated gingivorrhagia, enlarged lower and upper jaws, overgrowth of the gums, high arched and narrow palate, crowded teeth, hirsutism of the back, large abdomen and a small umbilical hernia. Cysts of the mandible, fibrous dysplasia of bones, and enlarged adenoids causing around 60% narrowing of the nasopharyngeal airways were noted at radiographic examination. Her brother presented with the same features in addition to a short stature, an ostium secundum, and more pronounced intellectual disability. He died at the age of 8 years from a severe pulmonary infection and repeated bleeding episodes. A clinical diagnosis of Ramon syndrome was made. Whole exome sequencing studies performed on the family revealed the presence of a novel homozygous missense mutation in ELMO2 gene, p.I606S in the affected individuals. Loss of function mutations in ELMO2 have been recently described in another clinically distinct condition: primary intraosseous vascular malformation or intraosseous hemangioma, called VMOS. Review of the literature and differential diagnoses are discussed.

Association of 17q24.2-q24.3 deletions with recognizable phenotype and short telomeres.

Microdeletions of 17q24.2-q24.3 have been described in several patients with developmental and speech delay, growth retardation, and other features. The relatively large size and limited overlap of the deletions complicate the genotype-phenotype correlation. We identified a girl with intellectual disability, growth retardation, dysmorphic features, and a de novo 2.8 Mb long deletion of 17q24.2-q24.3. Her phenotype was strikingly similar to one previously described boy with Dubowitz syndrome (MIM 223370) and a de novo 3.9 Mb long deletion encompassing the deletion of our patient. In addition, both patients had the shortest telomeres among normal age-matched controls. Our review of all 17q24.2-q24.3 deletion patients revealed additional remarkable phenotypic features shared by the patients, some of which have consequences for their management. Proposed novel genotype-phenotype correlations based on new literature information on the region include the role of PSMD12 and BPTF, the genes recently associated with syndromic neurodevelopmental disorders, and a possible role of the complex topologically associated domain structure of the region, which may explain some of the phenotypic discrepancies observed between patients with similar but not identical deletions. Nevertheless, although different diagnoses including the Dubowitz, Nijmegen breakage (MIM 251260), Silver-Russell (MIM 180860), or Myhre (MIM 139210) syndromes were originally considered in the 17q24.2-q24.3 deletion patients, they clearly belong to one diagnostic entity defined by their deletions and characterized especially by developmental delay, specific facial dysmorphism, abnormalities of extremities and other phenotypes, and possibly also short telomere length.