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Background: KBG syndrome (KBGS, OMIM: 148050) is a rare genetic disorder characterized by macrodontia, short stature, skeletal abnormalities, and neurological manifestations. The objective of this study is to investigate a case of KBG syndrome caused by a novel frameshift mutation in ANKRD11. Methods and results: We present the case of an 18-year-old Chinese male exhibiting characteristic features including a triangular face, micrognathia, hypertelorism, macrodontia, bushy eyebrows, prominent ears, short stature, low hairline, delayed cognitive development, and scoliosis. Whole exome sequencing identified a novel frameshift variant in the ANKRD11 gene which ultimately led to the diagnosis of KBG syndrome. Conclusion: In this study we have identified a previously unreported frameshift variant (NM_013275.6:c.2589dup) in ANKRD11 that causes KBG syndrome. This finding expands both the molecular and clinical spectrum of this rare genetic disease. [ABSTRACT FROM AUTHOR]

Background: KBG syndrome is a rare autosomal dominant genetic disease characterized by facial dysmorphism, developmental disorders, and short stature. The syndrome is caused by the haploinsufficiency of the ankyrin repeat domain-containing protein 11 (ANKRD11). Recently, there have been concerns that ANKRD11 serves as a tumor suppressor gene. Herein, we report a patient with KBG syndrome, diagnosed with hepatoblastoma at 21 months of age, which required chemotherapy and liver transplantation. Case report: A male infant born by cesarean section at 29+1 weeks of gestation, weighing 1220 g, was diagnosed with pulmonary atresia with ventricular septal defect and large patent ductus arteriosus. Bilateral low-set ears with a preauricular skin tag, left microtia, swelling of left neck, single umbilical artery, bilateral undescended testis, large anterior fontanelle, and bilateral club foot were noted. At a corrected age (CA) of 7 months, exome sequencing was performed, and a heterozygous nonsense pathogenic variant of ANKRD11 was found (c.7195C > T, p.Gln2399∗). Therefore, KBG syndrome was confirmed. At CA of 18 months, the patient presented with lethargy, poor oral intake, and jaundice symptoms and was diagnosed with hepatoblastoma. He received 12 cycles of chemotherapy for 9 months, but multiple hepatic masses remained; therefore, liver transplantation was performed at 28 months of age. Conclusions: KBG syndrome is a rare genetic disorder that has been identified relatively recently, and not all characteristics have yet been identified. The study of our case may provide evidence of cancer risk in patients with KBG syndrome.

Abstract Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.

Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome. [ABSTRACT FROM AUTHOR]

KBG syndrome is a rare genetic disorder caused by heterozygous pathogenic variants in ANKRD11. Affected individuals have developmental delay, short stature, characteristic facial features, and other dysmorphic findings. To date, a spectrum of unspecific neuroradiological defects has been reported in KBG patients, such as cortical defects, white matter abnormalities, corpus callosum, and cerebellar vermis hypoplasia. Deep clinical and neuroradiological phenotyping and genotype of a patient presenting with mild cognitive and behavioral problems were obtained after written informed consent. We herein describe the first KBG patient presenting with cerebellar heterotopia, a heterogeneous malformation characterized by the presence of clusters of neurons within the white matter of cerebellar hemispheres. This novel association broadens the neuroradiological spectrum of KBG syndrome, and further prompts to investigate the potential functions of ANKRD11 in cerebellar development. [ABSTRACT FROM AUTHOR]

BackgroundKBG syndrome (KBGS, OMIM: 148050) is a rare genetic disorder characterized by macrodontia, short stature, skeletal abnormalities, and neurological manifestations. The objective of this study is to investigate a case of KBG syndrome caused by a novel frameshift mutation in ANKRD11.Methods and resultsWe present the case of an 18-year-old Chinese male exhibiting characteristic features including a triangular face, micrognathia, hypertelorism, macrodontia, bushy eyebrows, prominent ears, short stature, low hairline, delayed cognitive development, and scoliosis. Whole exome sequencing identified a novel frameshift variant in the ANKRD11 gene which ultimately led to the diagnosis of KBG syndrome.ConclusionIn this study we have identified a previously unreported frameshift variant (NM_013275.6:c.2589dup) in ANKRD11 that causes KBG syndrome. This finding expands both the molecular and clinical spectrum of this rare genetic disease.

KBG syndrome is an autosomal dominant, polymalformative genetic syndrome that is mainly associated with neurodevelopmental and learning disorders, intellectual disability, behavioral disorders, and epilepsy as well as characteristic dysmorphic features, short stature, and ENT (ear, nose, and throat) abnormalities. However, the diagnostic pathway of these individuals is an element that has not been broadly evaluated. The main aim of this study was therefore to characterize the diagnostic pathway for these individuals, by assessing the different healthcare professionals involved and the main referral elements. This was a multicenter, retrospective, descriptive study. A cohort of 30 individuals with KBG syndrome who were followed up at Poitiers University Hospital and Bordeaux University Hospital we recruited. Pediatricians were the main healthcare professionals who referred individuals for genetic consultation, and the main reason for referral was an assessment of learning delays or intellectual disability, in association with other abnormalities. Pediatricians play a crucial role in the diagnostic guidance of individuals with KBG syndrome, and the main reason for referral remains the assessment of a learning delay or intellectual disability. Healthcare professionals must therefore remain attentive to the child's development and the various anomalies associated with it, in particular characteristic dysmorphic features, behavioral disorders, and statural growth. [ABSTRACT FROM AUTHOR]

KBG syndrome is a rare genetic disorder manifested by craniofacial dysmorphism, skeletal abnormalities, short stature, and developmental delay. The anesthetic management may be challenging due to associated craniofacial and other skeletal abnormalities and possible cardiac defects. We report a case of a 2-year-old child with KBG syndrome presenting with a chylothorax and an abscess on the lower back over the coccygeal region. The child was posted for fistula tract excision and coccygectomy and received sacral erector spinae block as analgesic modality.

KBG syndrome is a genetic disorder characterized by short stature, dysmorphic features, macrodontia, cognitive impairment, and limb anomalies. Epilepsy is an important comorbidity associated with KBG syndrome, although the entire phenotypic spectrum may not be fully appreciated. We identified five new patients with KBG syndrome-related epilepsy and compared their phenotype to previously reported cases in the literature. Five patients with KBG syndrome-related epilepsy were identified. Three patients (60%) were male. Median age of seizure onset was 18 months (interquartile range 5, 32). The epilepsy type was generalized in three patients (60%); in two, the epilepsy type was combined (40%), with focal and generalized seizures. In one patient (20%), the epilepsy syndrome was classifiable and the child was diagnosed with myoclonic-atonic epilepsy. All five patients had pathogenic variants in the ANKRD11 gene. Epilepsy was refractory in two patients (40%). No specific antiseizure medication (ASM) was found to be superior. Literature review yielded 134 cases, median age of seizure onset was 4 years, and seizures were generalized (n = 60, 44%), focal (n = 26, 19%), or combined (n = 13, 10%). An epilepsy syndrome was diagnosed in 12 patients (8.8%). In those with documented response to ASM (n = 49), 22.4% were refractory (n = 11). Our study confirms that few patients with epilepsy and KBG syndrome have an identifiable epilepsy syndrome and generalized seizures are most common. We highlight that epilepsy associated with KBG syndrome may occur before age one year and should be an important diagnostic consideration in this age group. [ABSTRACT FROM AUTHOR]

KBG syndrome is characterised by developmental delay, dental (macrodontia of upper central incisors), craniofacial and skeletal anomalies. Since the identification of variants in the gene (ANKRD11) responsible for KBG syndrome, wider phenotypes are emerging. While there is phenotypic variability within many features of KBG syndrome, epilepsy is not usually markedly severe and movement disorders largely undocumented. Here we describe a novel early onset phenotype of dyskinetic epileptic encephalopathy in a male, who presented during infancy with a florid hyperkinetic movement disorder and developmental regression. Initially he had epileptic spasms and tonic seizures, and EEGs revealed a modified hypsarrhythmia. The epilepsy phenotype evolved to Lennox-Gastaut syndrome with seizures resistant to multiple anti-seizure therapies and the movement disorder evolved to choreoathetosis of limbs and head with oro-lingual dyskinesias. Previous extensive neurometabolic and imaging investigations, including panel-based exome sequencing were unremarkable. Later trio exome sequencing identified a de novo pathogenic heterozygous frameshift deletion of ANKRD11 (c.6792delC; p.Ala2265Profs*72). Review of the literature did not identify any individuals with such a hyperkinetic movement disorder presentation in combination with early-onset epileptic encephalopathy. This report expands the phenotype of ANKRD11-related KBG syndrome to include epileptic dyskinetic encephalopathy.

Ankyrin Repeat Domain 11 (ANKRD11) gene mutations are associated with KBG syndrome, a developmental disability that affects multiple organ systems. The function of ANKRD11 in human growth and development is not clear, but gene knockout or mutation are lethal in mice embryos and/or pups. In addition, it plays a vital role in chromatin regulation and transcription. Individuals with KBG syndrome are often misdiagnosed or remain undiagnosed until later in life. This is largely due to KBG syndrome's varying and nonspecific phenotypes as well as a lack of accessible genetic testing and prenatal screening. This study documents perinatal outcomes for individuals with KBG syndrome. We obtained data from 42 individuals through videoconferences, medical records, and emails. 45.2% of our cohort was born by C‐section, 33.3% had a congenital heart defect, 23.8% were born prematurely, 23.8% were admitted to the NICU, 14.3% were small for gestational age, and 14.3% of the families had a history of miscarriage. These rates were higher in our cohort compared to the overall population, including non‐Hispanic and Hispanic populations. Other reports included feeding difficulties (21.4%), neonatal jaundice (14.3%), decreased fetal movement (7.1%), and pleural effusions in utero (4.7%). Comprehensive perinatal studies about KBG syndrome and updated documentation of its phenotypes are important in ensuring prompt diagnosis and can facilitate correct management. [ABSTRACT FROM AUTHOR]

Tethered cord syndrome (TCS) is characterized by leg pain and weakness, bladder and bowel dysfunction, orthopedic malformations such as scoliosis, and motor deficits caused by the fixation of the spinal cord to surrounding tissues. TCS is surgically treatable and often found in conjunction with other syndromic conditions. KBG syndrome is caused by variants in the ANKRD11 gene and is characterized by short stature, developmental delay, macrodontia, and a triangular face. The current study explores the prevalence of TCS in pediatric KBG patients and their associated signs and symptoms. Patients with KBG were surveyed for signs and symptoms associated with TCS and asked if they had been diagnosed with the syndrome. We found a high proportion of patients diagnosed with (11%) or being investigated for TCS (24%), emphasizing the need to further characterize the comorbid syndromes. No signs or symptoms clearly emerged as indicative of TCS in KBG patients, but some the prevalence of some signs and symptoms varied by sex. Male KBG patients with diagnosed TCS were more likely to have coordination issues and global delay/brain fog than their female counterparts. Understanding the presentation of TCS in KBG patients is critical for timely diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: KBG syndrome is a rare genetic disorder involving macrodontia of the upper central incisors, craniofacial, skeletal, and neurologic symptoms, caused either by a heterozygous variant in ANKRD11 or deletion of 16q24.3, including ANKRD11. Diagnostic criteria were proposed in 2007 based on 50 cases, but KBG syndrome remains underdiagnosed. Methods: Whole exome sequencing (WES) and array comparative genomic hybridization (array CGH) were conducted for genetic analysis and patient phenotypes were characterized based on medical records. Results: Eight patients from seven unrelated families were confirmed with KBG syndrome. All patients (8/8, 100%) had some degree of craniofacial dysmorphism and developmental delay or intellectual disabilities. Triangular face, synophrys, anteverted nostril, prominent ears, long philtrum, and tented upper lip, which are typical facial dysmorphism findings in patients with KBG syndrome, were uniformly identified in the eight patients participating in this study, with co‐occurrence rates of 4/8 (50%), 4/8 (50%), 4/8 (50%), 4/8 (50%), 5/8 (62.5%), and 5/8 (62.5%), respectively. Various clinical manifestations not included in the diagnostic criteria were observed. Six patients had point mutations in ANKRD11, one had an exonic deletion of ANKRD11, and one had a 16q24.3 microdeletion. According to the ACMG guidelines, all mutations were classified as pathogenic. The c.2454dup (p.Asn819fs*1) mutation in Pt 4 was reported previously. The remaining variants (c.397 + 1G>A, c.226 + 1G>A, c.2647del (p.Glu883Argfs*94), and c.4093C>T (p.Arg1365Ter)) were novel. Conclusion: The clinical and molecular features of eight patients from seven unrelated Korean families with KBG syndrome described here will assist physicians in understanding this rare genetic condition. KBG syndrome (OMIM #148050) is a rare genetic disease caused by ANKRD11 gene mutation or deletion of 16q24.3, including ANKRD11, and is characterized by neurodevelopmental disorders, macrodontia, and craniofacial dysmorphism. In addition to its rarity, the spectrum of phenotypes in KBG syndrome is broad, often underdiagnosed, or overlooked. The clinical and molecular features of eight patients from seven unrelated Korean families with KBG syndrome described here will assist in the understanding of this rare genetic condition and contribute to the identification of underdiagnosed patients. [ABSTRACT FROM AUTHOR]

Phenotypic features of KBG syndrome include craniofacial anomalies, short stature, cognitive disability and behavioral findings. The syndrome is caused by heterozygous pathogenic single nucleotide variants and indels in ANKRD11, or a heterozygous deletion of 16q24.3 that includes ANKRD11. We performed genome sequencing on a patient with clinical manifestations of KBG syndrome including distinct craniofacial features as well as a history of mild intellectual disability and attention‐deficit hyperactivity disorder. This led to the identification of a 43 kb intragenic deletion of ANKRD11 affecting the first noncoding exon while leaving the coding regions intact. Review of the literature shows that this is the smallest 5′ deletion affecting only the noncoding exons of ANKRD11. Real‐time polymerase chain reaction demonstrated that the copy number variant was not present in either of the proband's parents, suggesting it occurred de novo. RNA expression analysis demonstrated significantly decreased transcript abundance compared to controls. This provides new evidence for haploinsufficiency as a mechanism of disease in KBG syndrome. [ABSTRACT FROM AUTHOR]

Genomic analysis has revealed that the genes for various chromatin regulators are mutated in many individuals with neurodevelopmental disorders (NDDs), emphasizing the important role of chromatin regulation in nervous system development and function. Chromatin regulation is mediated by writers, readers, and erasers of histone and DNA modifications, with such proteins being defined by specific domains. One of these domains is the SET domain, which is present in enzymes that catalyze histone methylation. Heterozygous loss-of-function mutations of the SETD5 (SET domain containing 5) gene have been identified in individuals with an NDD designated IDD23 (intellectual developmental disorder, autosomal dominant 23). KBG syndrome (named after the initials of the last names of the first three families identified with the condition) is characterized by features that either overlap with or are distinct from those of IDD23 and was initially thought to be caused only by mutations in the ANKRD11 (ankyrin repeat domain containing 11) gene. However, recent studies have identified SETD5 mutations in some KBG syndrome patients without ANKRD11 mutations. Here we summarize the neurobehavioral characterization of Setd5+/-mice performed by four independent research groups, compare IDD23 and KBG phenotypes, and address the utility and future development of mouse models for elucidation of the mechanisms underlying NDD pathogenesis, with a focus on SETD5 and its related proteins. [ABSTRACT FROM AUTHOR]

KBG syndrome (KBGS; OMIM #148050) is a rare disease characterized by short stature, facial dysmorphism, macrodontia of the upper central incisors, skeletal anomalies, and neurodevelopmental disorder/intellectual disability. It is caused by a heterozygous variant or 16q24.3 microdeletions of the ANKRD11 gene (OMIM #611192), which plays a primary role in neuronal development. KBGS traits are variable, and mild expressions of the phenotype may complicate diagnosis. The present work aims at improving the characterization of KBGS in order to facilitate its recognition. A psychopathological evaluation of 17 subjects affected by KBGS found that 10 patients exhibited peculiar behavior related to "paper handling". These children and adolescents performed repetitive activities with paper, reminiscent of the hoarding and ordering behaviors characteristic of obsessive compulsive disorder. Their activities were time consuming and carried out in solitary, and forced interruption could generate intense emotional reactions. Paper handling may thus be understood as a potential distinct KBGS symptom akin to an obsessive compulsive symptom. Further research is needed to verify this claim. [ABSTRACT FROM AUTHOR]

Macrodontia is a dental condition where a tooth or group of teeth are abnormally larger than average. Functional and aesthetic discrepancies may arise in affected individuals resulting in lowering the quality of life. It has been noted that macrodontia is associated with several genetic and endocrine abnormalities. Among which, KBG syndrome is a rare genetic disorder characterized by developmental and dental abnormalities. This case report provides a brief overview of the significance of macrodontia, along with presenting a case of KBG syndrome with atypical features in a South African, 16-year-old female. The dental manifestations are often overshadowed by other more conspicuous and complex syndromic features. Recognition of both the clinical and oral changes that occur in KBG syndrome facilitates accurate diagnosis and appropriate management of this condition. The authors highlight the importance for clinicians to be cognizant of the clinical implications of macrodontia.

KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 (ANKRD11) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11. A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients. [ABSTRACT FROM AUTHOR]

Here we report a case of a 16q24.3 microdeletion KBG syndrome (KBGS) in a fetus. The absence of a well‐defined phenotype poses a challenge for genetic diagnosis. This report demonstrated that the high‐risk chromosome 21 trisomy could be the first manifestation of KBGS, as observed in this case. [ABSTRACT FROM AUTHOR]

KBG syndrome (OMIM #148050) is an autosomal dominant neurodevelopmental disorder characterized by the presence of macrodontia of the permanent central upper incisors, characteristic facial features, delay in development, intellectual disability, short stature, and various skeletal abnormalities. Over 200 affected individuals have been described worldwide, though underdiagnosis is suspected because the characteristic features are variably present and affected individuals can have a mild phenotype. This case series provides a summary of the clinical and molecular characteristics of 10 Chinese KBG syndrome patients recruited from a single center. To our knowledge, this is the first case series for Chinese KBG patients. This case series aimed at exploring potential ethnicity‐related variability in KBG syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background KBG syndrome is a rare autosomal dominant genetic disease mainly caused by pathogenic variants of ankyrin repeat domain-containing protein 11 (ANKRD11) or deletions involving ANKRD11. Herein, we report a novel de novo heterozygous frameshift ANKRD11 variant via whole exome sequencing in a Chinese girl with KBG syndrome. Case presentation A 2-year-2-month-old girl presented with a short stature and developmental delay. Comprehensive physical examinations, endocrine laboratory tests and imaging examination were performed. Whole‐exome sequencing and Sanger sequencing were used to detect and confirm the variant associated with KBG in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools. The patient was diagnosed as KBG syndrome with a short stature and developmental delay, as well as characteristic craniofacial abnormalities, including a triangular face, long philtrum, wide eyebrows, a broad nasal bridge, prominent and protruding ears, macrodontia of the upper central incisors, dental crowding, and binocular refractive error. Her skeletal anomalies included brachydactyly, fifth finger clinodactyly, and left-skewed caudal vertebrae. Electroencephalographic results generally showed normal background activity with sporadic spikes and slow wave complexes, as well as multiple spikes and slow wave complexes in the bilateral parietal, occipital, and posterior temporal regions during non-rapid-eye-movement sleep. Brain MRI showed a distended change in the bilateral ventricles and third ventricle, as well as malformation of the sixth ventricle. Whole exome sequencing revealed a novel heterozygous frameshift variant in the patient, ANKRD11 c.1366_1367dup, which was predicted to be pathogenic through in silico analysis. The patient had received physical therapy since 4 months of age, and improvement of gross motor dysfunction was evident. Conclusions The results of this study expand the spectrum of ANKRD11 variants in KBG patients and provide clinical phenotypic data for KBG syndrome at an early age. Our study also demonstrates that whole exome sequencing is an effective method for the diagnosis of rare genetic disorders.

Abstract Background Growth monitoring is an essential part of primary health care in children and short stature is frequently regarded as a relatively early sign of poor health. The association of short stature and dysmorphic features should always lead to exclude an underlying syndromic disorder. Case presentation We report the case of an Indian school-aged boy with dysmorphic features, intellectual disability and a clinical history characterized by seizures and hearing problems. Although his height was always included in the normal range for age and sex throughout childhood, he presented a short near-adult stature in relation to his mid-parent sex-adjusted target height. This is probably due to a rapidly progressive pubertal development. Conclusions In the presence of characteristic dysmorphic features, intellectual disability, seizures and hearing problems, KBG syndrome should always be considered. This emergent condition presents a wide spectrum of clinical phenotypes and is often associated with adult short stature.

Congenital heart defects (CHDs) are known to occur in 9%–25% of patients with KBG syndrome. In this study we analyzed the prevalence and anatomic types of CHDs in 46 personal patients with KBG syndrome, carrying pathogenetic variants in ANKRD11 or 16q24.3 deletion, and reviewed CHDs in patients with molecular diagnosis of KBG syndrome from the literature. CHD was diagnosed in 15/40 (38%) patients with ANKRD11 variant, and in one patient with 16q24.3 deletion. Left ventricular outflow tract obstructions have been diagnosed in 9/15 (60%), subaortic or muscular ventricular septal defect in 5/15 (33%), dextrocardia in 1/15 (8%). The single patient with 16q24.3 deletion and CHD had complete atrioventricular septal defect (AVSD) with aortic coarctation. Review of KBG patients from the literature and present series showed that septal defects have been diagnosed in 44% (27/61) of the cases, left ventricular tract obstructions in 31% (19/61), AVSD in 18% (11/61). Septal defects have been diagnosed in 78% of total patients with 16q24.3 deletion. Valvar anomalies are frequently diagnosed, prevalently involving the left side of the heart. A distinctive association with AVSD is identifiable and could represent a marker to suggest the diagnosis in younger patients. In conclusion, after precise molecular diagnosis and systematic cardiological screening the prevalence of CHD in KBG syndrome seems to be higher than previously reported in clinical articles. In addition to septal defects, left‐sided anomalies and AVSD should be considered. Clinical management of KBG syndrome should include accurate and detailed echocardiogram at time of diagnosis. [ABSTRACT FROM AUTHOR]

KBG syndrome (KBGS) is a rare autosomal dominant inherited disease that involves multiple systems and is associated with variations in the ankyrin repeat domain 11 (ANKRD11) gene. We report the clinical and genetic data for 13 Chinese KBGS patients diagnosed by genetic testing and retrospectively analyse the genotypes and phenotypes of previously reported KBGS patients. The 13 patients in this study had heterozygous variations in the ANKRD11 gene, including seven frameshift variations, three nonsense variations, and three missense variations. They carried 11 variation sites, of which eight were previously unreported. The clinical phenotype analysis of these 13 patients and 240 previously reported patients showed that the occurrence rates of craniofacial anomalies, dental anomalies, global developmental delays, intellectual disability/learning difficulties, limb anomalies, and behavioural anomalies were >70%. The occurrence rates of short stature, delayed bone age, and spinal vertebral body anomalies were >50%. The frequency of global developmental delays and intellectual disability/learning difficulties in patients with truncated ANKRD11 gene variation was higher than that in patients with missense variation in the ANKRD11 gene (p < 0.05). Collectively, this study reported the genotypic and phenotypic characteristics of the largest sample of KBGS patients from China and discovered eight new ANKRD11 gene variations, which enriched the variation spectrum of the ANKRD11 gene. Variation in the ANKRD11 gene mainly caused craniofacial anomalies, growth and developmental anomalies, skeletal system anomalies, and nervous system anomalies. Truncated variation in the ANKRD11 gene is more likely to lead to global growth retardation and intellectual disability/learning difficulties than missense variation in ANKRD11. [ABSTRACT FROM AUTHOR]

Background: KBG syndrome is a monogenic disorder caused by heterozygous pathogenic variants in ANKRD11 . A recent single-case study suggested that the clinical spectrum of KBG syndrome, classically defined by distinctive craniofacial traits and developmental delay, may include movement disorders., Case Report: We report a 24-year-old patient harboring a pathogenic de novo ANKRD11 frameshift variant. The phenotype was dominated by a progressive tremor-dominant movement disorder, characterized by rest, intention and postural tremor of the hands, voice tremor, head and tongue tremor, increased muscle tone and signs of ataxia. Additionally, the patient had a history of mild developmental delay and epilepsy., Discussion: Adding to the recently described individual, our present patient highlights the relevance of movement disorders as a clinically relevant manifestation of KBG syndrome. ANKRD11 pathogenic variants should be considered in the differential diagnosis of combined tremor syndromes., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

KBG syndrome is characterized by dental, craniofacial and skeletal anomalies, short stature and global developmental delay or intellectual disability. It is caused by microdeletions or truncating mutations of ANKRD11. We report four unrelated probands with this syndrome due to de novo ANKRD11 aberrations that may contribute to a better understanding of the genetics and pathophysiology of this autosomal dominant syndrome. Clinical, cognitive and MRI assessments were performed. Three of the patients showed normal intellectual functioning, whereas the fourth had a borderline level of intellectual functioning. However, all of them showed deficits in various cognitive and socioemotional processes such as attention, executive functions, empathy or pragmatic language. Moreover, all probands displayed marked asymmetry of the uncinate fascicles and an abnormal gyrification pattern in the left frontal lobe. Thus, structural neuroimaging anomalies seem to have been overlooked in this syndrome. Disturbed frontal gyrification and/or lower structural integrity of the uncinate fascisulus might be unrecognized neuroimaging features of KBG syndrome caused by ANKRD11 aberrations. Present results also point out that this syndrome is not necessarily associated with global developmental delay and intellectual disability, but it can be related to other neurodevelopmental disorders or subclinical levels of attention-deficit hyperactivity disorder, autism, communication disorders or specific learning disabilities. [Display omitted] • ANKRD11 aberrations have been associated to KBG syndrome. • Brain structural abnormalities are rarely reported in this syndrome. • We describe two novel mutations in ANKRD11. • Uncinate fascicles asymmetry and frontal sulcation anomalies were found in all cases. • All patients had an IQ > 70, but they showed cognitive and socioemotional deficits. [ABSTRACT FROM AUTHOR]

Mutations or deletions of ANKRD11 gene are responsible for the symptoms of KBG syndrome. The KBG syndrome is a rare genetic disorder which is inherited in an autosomal dominant manner. Affected patients usually have characteristic facial features, macrodontia of the upper central incisors, hand abnormalities, developmental delay and short stature. In the present article we would like to report a clinical and molecular case study of two patients affected by KBG syndrome. The diagnosis of the first patient was confirmed by the identification of the novel pathogenic variant in ANKRD11 gene by next-generation sequencing. The second patient was diagnosed after the detection of a 16q24.2q24.3 deletion encompassing the ANKRD11 gene microarray.

Epigenetic and chromatin regulation of craniofacial development remains poorly understood. Ankyrin Repeat Domain 11 (ANKRD11) is a chromatin regulator that has previously been shown to control neural stem cell fates via modulation of histone acetylation. ANKRD11 gene variants, or microdeletions of the 16q24.3 chromosomal region encompassing the ANKRD11 gene, cause KBG syndrome, a rare autosomal dominant congenital disorder with variable neurodevelopmental and craniofacial involvement. Craniofacial abnormalities include a distinct facial gestalt, delayed bone age, tooth abnormalities, delayed fontanelle closure, and frequently cleft or submucosal palate. Despite this, the dramatic phenotype and precise role of ANKRD11 in embryonic craniofacial development remain unexplored. Quantitative analysis of 3D images of KBG syndromic subjects shows an overall reduction in the size of the middle and lower face. Here, we report that mice with heterozygous deletion of Ankrd11 in neural crest cells (Ankrd11nchet) display a mild midfacial hypoplasia including reduced midfacial width and a persistent open fontanelle, both of which mirror KBG syndrome patient facial phenotypes. Mice with a homozygous Ankrd11 deletion in neural crest cells (Ankrd11ncko) die at birth. They show increased severity of several clinical manifestations described for KBG syndrome, such as cleft palate, retrognathia, midfacial hypoplasia, and reduced calvarial growth. At E14.5, Ankrd11 expression in the craniofacial complex is closely associated with developing bony structures, while expression at birth is markedly decreased. Conditional deletion of Ankrd11 leads to a reduction in ossification of midfacial bones, with several ossification centers failing to expand and/or fuse. Intramembranous bones show features of delayed maturation, with bone remodeling severely curtailed at birth. Palatal shelves remain hypoplastic at all developmental stages, with a local reduction in proliferation at E13.5. Our study identifies Ankrd11 as a critical regulator of intramembranous ossification and palate development and suggests that Ankrd11nchet and Ankrd11ncko mice may serve as pre-clinical models for KBG syndrome in humans.

Background: KBG syndrome is a rare autosomal dominant genetic disease mainly caused by pathogenic variants of ankyrin repeat domain-containing protein 11 (ANKRD11) or deletions involving ANKRD11. Herein, we report a novel de novo heterozygous frameshift ANKRD11 variant via whole exome sequencing in a Chinese girl with KBG syndrome. Case presentation: A 2-year-2-month-old girl presented with a short stature and developmental delay. Comprehensive physical examinations, endocrine laboratory tests and imaging examination were performed. Whole‐exome sequencing and Sanger sequencing were used to detect and confirm the variant associated with KBG in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools. The patient was diagnosed as KBG syndrome with a short stature and developmental delay, as well as characteristic craniofacial abnormalities, including a triangular face, long philtrum, wide eyebrows, a broad nasal bridge, prominent and protruding ears, macrodontia of the upper central incisors, dental crowding, and binocular refractive error. Her skeletal anomalies included brachydactyly, fifth finger clinodactyly, and left-skewed caudal vertebrae. Electroencephalographic results generally showed normal background activity with sporadic spikes and slow wave complexes, as well as multiple spikes and slow wave complexes in the bilateral parietal, occipital, and posterior temporal regions during non-rapid-eye-movement sleep. Brain MRI showed a distended change in the bilateral ventricles and third ventricle, as well as malformation of the sixth ventricle. Whole exome sequencing revealed a novel heterozygous frameshift variant in the patient, ANKRD11 c.1366_1367dup, which was predicted to be pathogenic through in silico analysis. The patient had received physical therapy since 4 months of age, and improvement of gross motor dysfunction was evident. Conclusions: The results of this study expand the spectrum of ANKRD11 variants in KBG patients and provide clinical phenotypic data for KBG syndrome at an early age. Our study also demonstrates that whole exome sequencing is an effective method for the diagnosis of rare genetic disorders. [ABSTRACT FROM AUTHOR]

KBG syndrome is a rare genetic disease characterized mainly by skeletal abnormalities, distinctive facial features, and intellectual disability. Heterozygous mutations in ANKRD11 gene, or deletion of 16q24.3 that includes ANKRD11 gene are the cause of KBG syndrome. We describe two patients presenting with short stature and partial facial features, whereas no intellectual disability or hearing loss was observed in them. Two ANKRD11 variants, c.4039_4041del (p. Lys1347del) and c.6427C > G (p. Leu2143Val), were identified in this study. Both of them were classified as variants of uncertain significance (VOUS) by ACMG/AMP guidelines and were inherited from their mothers. ANKRD11 could enhance the transactivation of p21 gene, which was identified to participate in chondrogenic differentiation. In this study, we demonstrated that the knockdown of ANKRD11 could reduce the p21‐promoter luciferase activities while re‐introduction of wild type ANKRD11, but not ANKRD11 variants (p. Lys1347del or p. Leu2143Val), could restore the p21 levels. Thus, our study report two loss‐of‐function ANKRD11 variants which might provide new insight on pathogenic mechanism that correlates ANKRD11 variants with the short stature phenotype of KBG syndrome. [ABSTRACT FROM AUTHOR]

BackgroundKBG syndrome (OMIM #148050) is a rare, autosomal dominant inherited genetic disorder caused by heterozygous mutations in the ankyrin repeat domain-containing protein 11 (ANKRD11) gene or by microdeletion of chromosome 16q24.3. It is characterized by macrodontia of the upper central incisors, distinctive facial dysmorphism, short stature, vertebral abnormalities, hand anomaly including clinodactyly, and various degrees of developmental delay. KBG syndrome presents with variable clinical feature and severity among individuals. Here, we report two KBG patients who have different novel heterozygous mutations of ANKRD11 gene with wide range of clinical manifestations.Case presentationTwo novel heterozygous mutations of ANKRD11 gene were identified in two unrelated Korean patients with variable clinical presentations. The first patient presented with short stature and early puberty and was treated with growth hormone and gonadotropin-releasing hormone agonist without adverse effects. He had mild intellectual disability. In targeted exome sequencing, a novel de novo frameshift variant was identified in ANKRD11, c.5889del, and p. (Ile1963MetfsX9). The second patient had severe intellectual disability with epilepsy. He had normal height and prepubertal stage at the age of 11 years. He had behavioral problems such as autism-like features, anxiety, and stereotypical movements. Whole exome sequencing (WES) was performed, and the novel heterozygous mutation, c3310dup, p. (Glu110GlyfsTer5) in ANKRD11 was identified.ConclusionKBG syndrome is often underdiagnosed because of its non-specific features and phenotypic variability. Performing a next—generation sequencing panel, including the ANKRD11 gene for cases of developmental delay with/without short stature may be helpful to identify hitherto undiagnosed KBG syndrome patients.

Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to SETD5 gene mutations, falls into this group of disorders. KBG syndrome, caused by ANKRD11 gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A de novo deletion of 116 kb partially involving SETD5 and two de novo frameshift variants in SETD5 were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider SETD5 gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS.

Abstract Background KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. Case presentation Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. Conclusions This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.

Background: Growth monitoring is an essential part of primary health care in children and short stature is frequently regarded as a relatively early sign of poor health. The association of short stature and dysmorphic features should always lead to exclude an underlying syndromic disorder. Case presentation: We report the case of an Indian school-aged boy with dysmorphic features, intellectual disability and a clinical history characterized by seizures and hearing problems. Although his height was always included in the normal range for age and sex throughout childhood, he presented a short near-adult stature in relation to his mid-parent sex-adjusted target height. This is probably due to a rapidly progressive pubertal development. Conclusions: In the presence of characteristic dysmorphic features, intellectual disability, seizures and hearing problems, KBG syndrome should always be considered. This emergent condition presents a wide spectrum of clinical phenotypes and is often associated with adult short stature. [ABSTRACT FROM AUTHOR]

Background: KBG syndrome (OMIM #148050) is a rare, autosomal dominant inherited genetic disorder caused by heterozygous mutations in the ankyrin repeat domain-containing protein 11 (ANKRD11) gene or by microdeletion of chromosome 16q24.3. It is characterized by macrodontia of the upper central incisors, distinctive facial dysmorphism, short stature, vertebral abnormalities, hand anomaly including clinodactyly, and various degrees of developmental delay. KBG syndrome presents with variable clinical feature and severity among individuals. Here, we report two KBG patients who have different novel heterozygous mutations of ANKRD11 gene with wide range of clinical manifestations. Case presentation: Two novel heterozygous mutations of ANKRD11 gene were identified in two unrelated Korean patients with variable clinical presentations. The first patient presented with short stature and early puberty and was treated with growth hormone and gonadotropin-releasing hormone agonist without adverse effects. He had mild intellectual disability. In targeted exome sequencing, a novel de novo frameshift variant was identified in ANKRD11, c.5889del, and p. (Ile1963MetfsX9). The second patient had severe intellectual disability with epilepsy. He had normal height and prepubertal stage at the age of 11 years. He had behavioral problems such as autism-like features, anxiety, and stereotypical movements. Whole exome sequencing (WES) was performed, and the novel heterozygous mutation, c3310dup, p. (Glu110GlyfsTer5) in ANKRD11 was identified. Conclusion: KBG syndrome is often underdiagnosed because of its non-specific features and phenotypic variability. Performing a next—generation sequencing panel, including the ANKRD11 gene for cases of developmental delay with/without short stature may be helpful to identify hitherto undiagnosed KBG syndrome patients. [ABSTRACT FROM AUTHOR]

Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to SETD5 gene mutations, falls into this group of disorders. KBG syndrome, caused by ANKRD11 gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A de novo deletion of 116 kb partially involving SETD5 and two de novo frameshift variants in SETD5 were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider SETD5 gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS. [ABSTRACT FROM AUTHOR]

Cornelia de Lange syndrome (CdLS), Rubinstein–Taybi syndrome (RSTS), and KBG syndrome are three distinct developmental human disorders. Variants in seven genes belonging to the cohesin pathway, NIPBL, SMC1A, SMC3, HDAC8, RAD21, ANKRD11, and BRD4, were identified in about 80% of patients with CdLS, suggesting that additional causative genes remain to be discovered. Two genes, CREBBP and EP300, have been associated with RSTS, whereas KBG results from variants in ANKRD11. By exome sequencing, a genetic cause was elucidated in two patients with clinical diagnosis of CdLS but without variants in known CdLS genes. In particular, genetic variants in EP300 and ANKRD11 were identified in the two patients with CdLS. EP300 and ANKRD11 pathogenic variants caused the reduction of the respective proteins suggesting that their low levels contribute to CdLS‐like phenotype. These findings highlight the clinical overlap between CdLS, RSTS, and KBG and support the notion that these rare disorders are linked to abnormal chromatin remodeling, which in turn affects the transcriptional machinery. [ABSTRACT FROM AUTHOR]

KBG syndrome is an intellectual disability (ID) associated with multiple congenital anomalies in which the macrodontia could be the clue for the diagnosis. It is caused either by heterozygous variant in ANKRD11 gene or 16q24.3 microdeletions that involve the ANKRD11 gene. Here, we report on two unrelated male patients who presented with ID, short stature, webbing of neck, and cryptorchidism. Noonan syndrome was suspected first but the presence of macrodontia in both patients pointed to KBG syndrome which was confirmed thereafter by the identification of a novel pathogenic variant in ANKRD11 gene, c.5488G>T (p.E1830*). Macrodontia was noticed in all the deciduous anterior teeth in Patient 1. This observation was reported previously in few patients, but it seems to be a common feature that could be misdiagnosed as premature eruption of teeth. Therefore, our results confirm that maxillary permanent central incisors may not be the only teeth affected in KBG but also all the deciduous teeth. Interestingly, desquamative gingivitis was additionally noted in Patient 1, which has not been reported previously, however; it could be a coincidental finding. To the best of our knowledge, this is the first report from Egypt. [ABSTRACT FROM AUTHOR]

KBG syndrome (MIM #148050) is an autosomal dominant disorder characterized by developmental delay, intellectual disability, distinct craniofacial anomalies, macrodontia of permanent upper central incisors, skeletal abnormalities, and short stature. This study describes clinical features of 28 patients, confirmed by molecular testing of ANKRD11 gene, and three patients with 16q24 deletion encompassing ANKRD11 gene, diagnosed in a single center. Common clinical features are reported, together with uncommon findings, clinical expression in the first years of age, distinctive associations, and familial recurrences. Unusual manifestations emerging from present series include juvenile idiopathic arthritis, dysfunctional dysphonia, multiple dental agenesis, idiopathic precocious telarche, oral frenula, motor tics, and lipoma of corpus callosum, pilomatrixoma, and endothelial corneal polymorphic dystrophy. Facial clinical markers suggesting KBG syndrome before 6 years of age include ocular and mouth conformation, wide eyebrows, synophrys, long black eyelashes, long philtrum, thin upper lip. General clinical symptoms leading to early genetic evaluation include developmental delay, congenital malformations, hearing anomalies, and feeding difficulties. It is likely that atypical clinical presentation and overlapping features in patients with multiple variants are responsible for underdiagnosis in KBG syndrome. Improved knowledge of common and atypical features of this disorder improves clinical management. [ABSTRACT FROM AUTHOR]

Keishi-Bukuryo-Gan (KBG) syndrome is a rare genetic disorder that can present with dysmorphic facial features as well as skeletal, neurological, and developmental abnormalities. Little is reported or understood about the gynecologic associations with KBG syndrome. Monozygotic twin 14-year-old sisters, both with KBG syndrome, presented independently with abdominal pain, for which they both underwent laparoscopic appendectomies. Intraoperatively, there was no evidence of appendiceal pathology. Both patients were noted to have abnormally appearing elongated ovaries, and 1 was also diagnosed with endometriosis. The aim of this paper was to highlight a possible gynecologic association with KBG syndrome. For providers caring for this unique subset of patients, it could lower the threshold to suspect endometriosis and increase the suspicion for ovarian dysmorphism. [ABSTRACT FROM AUTHOR]

Case studies of a 14-year-old boy, with no significant family history other than his sibling having unilateral epiphyseal dysplasia; and a 25-year-old woman, with no significant family history. Topics include intravenous immunoglobulin therapy was instituted with the diagnosis of common variable immunodeficiency; and Dandy Walker malformation is a brain malformation characterized by posterior fossa enlargement, hypoplasia of the cerebellar vermis, and cystic enlargement of the fourth ventricle.

Abstract Clinical Description KBG syndrome is characterized by macrodontia of upper central incisors, distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys; skeletal findings including short stature, delayed bone age, and costovertebral anomalies; and developmental delay/intellectual disability sometimes associated with seizures and EEG abnormalities. The condition was named KBG syndrome after the initials of the last names of three original families reported in 1975. Epidemiology The prevalence of KBG syndrome is not established. There are over 100 patients reported in the literature. It is likely that KBG syndrome is underreported due to incomplete recognition and very mild presentations of the disorder in some individuals. KBG syndrome is typically milder in females. Etiology Causative variants in ANKRD11 have been identified in affected individuals. The vast majority of identified variants are loss of function, which include nonsense and frameshift variants and larger deletions at 16q24.3. Haploinsufficiency appears to be the mechanism of pathogenicity. Genetic Counseling Familial and de novo cases have been reported. Causative de novo variants occur approximately one third of the time. Transmission follows an autosomal dominant pattern. The syndrome displays inter- and intra-familial variability.

We report the case of a young woman who presented at age 10 years with height on the tenth centile, brachydactyly type E and mild developmental delay. Biochemistry and hormonal profiles were normal. Differential diagnoses considered included Albright hereditary osteodystrophy without hormone resistance (a.k.a pseudopseudohypoparathyroidism), 2q37 microdeletion syndrome and acrodysostosis. She had a normal karyotype and normal FISH of 2q37. Whole genome sequencing (WGS) identified a mutation in the ANKRD11 gene associated with KBG syndrome. We review the clinical features of the genetic syndromes considered, and suggest KBG syndrome be considered in patients presenting with syndromic brachydactyly type E, especially if short stature and developmental delay are also present. [ABSTRACT FROM AUTHOR]

Congenital complete vaginal atresia with cervical aplasia is a rare obstructive reproductive tract malformation. We present a clinical case of a 12 years old girl with a genetic KBG Syndrome, admitted in the Pediatric Unit with acute recurrent abdominal pain, vomiting and dehydratation. Written informed consent was obtained from the patient parents for publication of this case report. The local institutional review board exempted our case from the need for approval. KBG Syndrome is a congenital neurodevelopmental disorder characterized by macrodontia of the incisors, neurological delay, craniofacial anomalies, low stature, among other conditions. The physical examination showed a pubertal development Tanner 4, vulva Pubarca 4, normo-inserted urethral meatus, absent vaginal opening, negative swab test, and primary amenorrhea. An MRI was performed the result of which was: complete vaginal agenesis, septate uterus with cervical aplasia, hematómetra and hematosalpinx. An open Hysterectomy was decided in the context of acute abdominal pain and risk of endometriosis and infection. The patient evolved favorably returning home in few days. According to the bibliographic review, hysterectomy is recommended for cervical agenesis, complete cervical atresia and cervical cord because of the high risk of stenosis. The vaginoplasty is recommended to be performed in late adolescence or young adulthood when the patient is mature enough to agree to the procedure. Considering most of the included studies in this review, it is speculated that uterus preservation may be feasible for patients with cervical external obstruction. Gynecologists tried to preserve uterus and fertility for the patients with complete cervical atresia but the sample size was small. More high quality clinical controlled multicenter trials with longer follow-up are needed for further assessment. [ABSTRACT FROM AUTHOR]

KBG syndrome is a rare neurodevelopmental disorder characterized by intellectual disability, skeletal anomalies, short stature, craniofacial dysmorphism, and macrodontia. ANKRD11 gene mutation and 16q24.3 microdeletion have been reported to cause KBG syndrome. Here, we report two patients with ANKRD11 mutations who initially presented with neurologic symptoms such as developmental delay and seizures. Patient 1 was a 23-month-old boy who presented with a global developmental delay. Language delay was the most dominant feature. He had hypertelorism, hearing impairment, and behavior problems characterized as hyperactivity. A c.1903_1907delAAACA (p.Lys635GInfsTer26) mutation in ANKRD11 was identified with diagnostic exome sequencing. Patient 2 was a 14-monthold boy with developmental delay and seizure. He also had atrial septum defect, and ventricular septal defect. Generalized tonic seizures began at the age of 8 months. Electroencephalography showed generalized sharp and slow wave pattern. Seizures did not respond to antiepileptic drugs. A loss of function mutation c.5350_5351delTC (p.ser1784HisfsTer12) in ANKRD11 was identified with diagnostic exome sequencing. In both cases, characteristic features of KBG syndrome such as short stature or macrodontia, were absent, and they visited the hospital due to neurological symptoms. These findings suggest that more patients with mild phenotypes of KBG syndrome are being recognized with advances in diagnostic exome sequencing genetic technologies. [ABSTRACT FROM AUTHOR]

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat‐containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon–intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx. [ABSTRACT FROM AUTHOR]

KBG syndrome is a rare autosomal dominant disorder caused by constitutive haploinsufficiency of the ankyrin repeat domain‐containing protein 11 (ANKRD11) being the result of either loss‐of‐function gene variants or 16q24.3 microdeletions. The syndrome is characterized by a variable clinical phenotype comprising a distinct facial gestalt and variable neurological involvement. ANKRD11 is frequently affected by loss of heterozygosity in cancer. It influences the ligand‐dependent transcriptional activation of nuclear receptors and tumor suppressive function of tumor protein TP53. ANKRD11 thus serves as a candidate tumor suppressor gene and it has been speculated that its haploinsufficiency may lead to an increased cancer risk in KBG syndrome patients. While no systematic data are available, we report here on the second KBG syndrome patient who developed a malignancy. At 17 years of age, the patient was diagnosed with a left‐sided paratesticular extrarenal malignant rhabdoid tumor. Genetic investigations identified a somatic truncating gene variant in SMARCB1, which was not present in the germline, and a constitutional de novo 16q24.3 microdeletion leading to a loss of the entire ANKRD11 locus. Thus, KBG syndrome was diagnosed, which was in line with the clinical phenotype of the patient. At present, no specific measures for cancer surveillance can be recommended for KBG syndrome patients. However, a systematic follow‐up and inclusion of KBG syndrome patients in registries (e.g., those currently established for cancer prone syndromes) will provide empiric data to support or deny an increased cancer risk in KBG syndrome in the future. [ABSTRACT FROM AUTHOR]