KBG syndrome (KBGS)

Was ist KBG syndrome (KBGS)?

KBG syndrome is a very rare genetic disorder. It is named from the initials of the first families diagnosed with the syndrome.

As a congenital malformation syndrome, distinctive facial features, facial dysmorphism, skeletal abnormalities, and intellectual disability are common symptoms of this rare disease.

Very often individuals with the syndrome are also diagnosed with autism spectrum disorder, hyperactivity and/or anxiety.

Syndrome Synonyms:
Dento-maxillo-facial syndrome Macrodontia, Mental Retardation, Characteristic Facies, Short Stature, And Skeletal Anomalies

Was Genveränderungen verursachen KBG syndrome (KBGS)?

Das KBG-Syndromes tritt aufgrund einer Mutation im ANKRDII-Gen auf. Es wird in einem autosomal dominanten Muster vererbt.

Im Fall einer autosomal dominanten Vererbung ist nur ein Elternteil der Träger der Genmutation, und sie haben eine 50% ige Chance, sie an jedes ihrer Kinder weiterzugeben. Syndrome, die in einer autosomal dominanten Vererbung vererbt werden, werden durch nur eine Kopie der Genmutation verursacht.

Aufgrund der Dokumentation schwererer männlicher Fälle wurde jedoch auch eine X-chromosomale Vererbung vorgeschlagen.

Syndrome, die in einem X-chromosomal-rezessiven Muster vererbt wurden, betreffen im Allgemeinen nur Männer. Männer haben nur ein X-Chromosom, und daher verursacht eine Kopie einer Genmutation das Syndrom. Frauen mit zwei X-Chromosomen, von denen nur eines mutiert ist, sind wahrscheinlich nicht betroffen.

Bei Syndromen, die in einem X-verknüpften dominanten Muster vererbt werden, verursacht eine Mutation in nur einer der Kopien des Gens das Syndrom. Dies kann in einem der weiblichen X-Chromosomen sein, und in dem einen X-Chromosom haben Männer. Männer neigen dazu, schwerwiegendere Symptome zu haben als Frauen.

Was sind die wichtigsten symptome von KBG syndrome (KBGS)?

The main symptoms of KBG syndrome may vary between individuals and may also vary in the extent of their severity.

The syndrome's typical facial characteristics include a triangular face, upturned nose, widely spaced eyes, bushy eyebrows, a thin upper lip, and a large nasal bridge. Large teeth and particularly large upper front teeth are characteristic of the syndrome, as are dental abnormalities.

Other potential symptoms include skeletal and bone abnormalities, congenital heart defects, hearing loss, and seizures.

Intellectual disability and developmental delay are also common amongst individuals diagnosed with the syndrome.

Possible clinical traits/features:
Long philtrum, Long palpebral fissure, Macrodontia, Low anterior hairline, Low posterior hairline, Low-set, posteriorly rotated ears, Narrow mouth, Anteverted nares, Macrotia, Intellectual disability, Abnormal form of the vertebral bodies, Abnormality of dental enamel, Aplasia/Hypoplasia of the eyebrow, Cervical ribs, Abnormality of the ribs, Abnormality of femur morphology, Abnormality of calvarial morphology, Widely-spaced maxillary central incisors, Radial deviation of finger, Reduced number of teeth, Vertebral arch anomaly, Clinodactyly, Telecanthus, Thick eyebrow, Microcephaly, Triangular face, Strabismus, Round face, Thoracic kyphosis, Vertebral fusion, Autosomal dominant inheritance, Oligodontia, Rib fusion, Single transverse palmar crease, Syndactyly, Short neck, Pointed chin, Postaxial hand polydactyly, Delayed skeletal maturation, Brachydactyly, Facial asymmetry, Finger syndactyly, Cryptorchidism, EEG abnormality, Cleft palate, Underdeveloped nasal alae, Global developmental delay, Cognitive impairm

Wie wird jemand getestet? KBG syndrome (KBGS)?

Die ersten Tests für das KBG-Syndrom können mit einem Screening der Gesichtsanalyse über die FDNA Telehealth Telegenetics-Plattform beginnen, mit der die Schlüsselmarker des Syndroms identifiziert und die Notwendigkeit weiterer Tests umrissen werden können. Eine Konsultation mit einem genetischen Berater und dann einem Genetiker wird folgen. 

Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.

Medical information on KBG syndrome

This is a short stature syndrome that includes intellectual disability, facial dysmorphism and broad teeth. Macrodontia of the upper central incisors is a distinctive feature in some patients. KBG syndrome is caused by mutations in the ANKRD11 gene and microdeletions in 16q24.3.
Intellectual disability is variable. Some achieve an IQ of approximately 60. The head shape is brachycephalic with biparietal prominence, and the face is round with a prominent telecanthus and prominent eyebrows. The teeth are broad, the incisors may be fused, and there may be dental crowding. The lips are thin, and the upper lip is shaped like a hunter's bow. There might be block vertebrae, short femoral necks and short tubular bones in the hands. Cervical ribs are common, and the bone age is delayed.
KBG are the initials of the first patient described. The cases reported subsequently (Novembri et al., 1983; Tollaro et al., 1984; Zollino et al., 1994) seem to represent a heterogeneous group, and many do not have the characteristic extremely broad and fused incisors reported in the original cases.
Rivera-Vega et al., (1996) reported a possible case with conductive bilateral hypoacusia and stenosis of the left pulmonary artery.
Devriendt et al., (1998) reported a possibly affected mother and daughter.
Smithson et al., (2000) report two further male cases and provide a good review.
Ten families, including Tekin et al., (2004) and Brancati et al., (2004) were studied by Sirmaci et al., (2011). Mutations in ANKRD11 were found in half, including the Tekin et al., (2004) family. Eight Italian patients were reported by Brancati et al., (2004). Deafness (mild) occurred in five, and three had submucous clefts with secondary speech problems. All the patients were hyperkinetic and anxious during childhood, but this was not seen (one patient) in adulthood. Brachydactyly was common, as were EEG abnormalities. Tekin et al., (2004) reported a family with dominant inheritance. A father and his two sons were affected. All were mildly intellectually disabled and had the wide central incisors. All had some degree of synophris. The two boys had a longish featureless philtrum but were without the characteristic hunter's bow shape to the upper lip.
The condition is thoroughly reviewed by Skjei et al., (2007) who suggest diagnostic criteria (quite complicated).
Non-specific brain anomalies were noted in 52% of the patients, including five anomalies of the posterior fossa and one periventricular nodular heterotopia. Periventricular nodular heterotopia has been reported (Oegema et al., 2010). Thirty-one percent of the patients presented with epilepsy successfully treated with monotherapy. Developmental delay was reported in 91% and learning difficulties in 94%. Results of IQ testing were available for 15 patients and were in the normal (borderline) range in five, mild intellectual disability in eight, and moderate range in two. Abnormal behavior was noted in 51% of the patients, including temper tantrums, hyperactivity, attention deficit, anxiety, lack of self-confidence, frustration intolerance, aggressiveness, and depression. Sleep disorders occurred in 39% of the patients. Autism was less frequent in KBG than had been reported previously. According to the study, KBG syndrome is compatible with autonomous life in adulthood. New clinical findings with a potential impact on the follow-up of patients were described, such as precocious puberty and a case of malignancy.
Another case with a microdeletion of 16q24.3 was reported by Miyatake et al., (2013). The patient reported by Khalifa et al., (2013) had a partial deletion of ANKRD11 and features suggestive of KBG. His mother was a mosaic (38% of cells) and had a milder phenotype.
Twenty patients from 13 families (all had mutations) were described by Ockeloen et al., (2015). These authors found that some of the other teeth may be large; there are talon cusps and an unusual nose, which is upturned with a bulbous tip. Cardiac assessment is recommended. A third of their patients had conductive hearing loss.
Goldenberg et al., (2016) reported a clinical and molecular study of 39 patients affected by KBG syndrome, including 20 patients with ANKRD11 mutations and 19 with 16q24.3 deletions involving ANKRD11. Mutations in ANKRD11 were all loss-of-function mutations: 10 were frameshift mutations and seven nonsense mutations. Most deletions removed the 5'end or the entire coding region of ANKRD11. All patients presented with dysmorphic facial features. Facial gestalt was characteristic in all cases and allowed the diagnosis in young children as well as in adults. The most specific facial features included the shape of the nose and mouth: a prominent nose with a high nasal bridge, a wide nasal base, and a bulbous tip with thick alae nasi and anteverted nares. The philtrum was long, flat, and was protuberant in young children. The upper lip was thin with a marked cupid's bow and thin vermillion border. Brachycephaly with a triangular face and prominent cheekbones was typical. Synophrys and hypertelorism were frequent, and some patients had epicanthic folds or ptosis. The authors suggested that macrodontia should no longer be considered a mandatory feature. Macrodontia was found in 18/26 (69%) patients with permanent teeth, and two young patients had macrodontia of decidual teeth. Typical hand anomalies were present in 70% of patients including brachydactyly and fifth finger clinodactyly. Stature was below -1 SD in 67% of cases; 41% of patients had short stature below -2 SD. Advanced puberty was reported in 16% of patients: four girls and a boy.
Four patients had mild scoliosis without any structural anomaly, and three females had a caudal appendage. Velopharyngeal insufficiency or submucous cleft palate leading to severe speech disorder was reported in 21%, heart defects in 26% (atrioventricular septal defect, ventricular septal defect, aortic or mitral insufficiency, mitral ballooning or pulmonary stenosis). Bilateral hearing loss was present in 31% of cases (sensorineural, conductive or mixed).
Low et al., (2016) described 32 KBG patients from 27 families. Speech delay and learning difficulties were almost universal and variable behavioural problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included conductive hearing loss, recurrent middle ear infection, palatal abnormalities and feeding difficulties. A new feature of a wide anterior fontanelle was recognized with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half of the patients.
Novara et al., (2017) described 12 patients with 16q24.2-q24.3 deletions, ranging from 343 kb to 2.3 Mb; 11 of them encompassed the ANKRD11 gene. Eleven were de novo. Clinical characteristics included mild-to-moderate developmental delay, mild-to-moderate intellectual disability, prominent upper central incisors, characteristic facial anomalies, significantly delayed bone age, postnatal short stature, ocular problems (mainly refraction defects), and congenital heart disease (ventricular septum defect as the most frequent). Dysmorphic features were prominent forehead, round face, and broad nose. Bianchi et al., (2017) described a seven years old female patient with KBG syndrome and bilateral conductive hearing loss due to a de novo mutation of ANKRD11 gene.
A female with a heterozygous frameshift mutation in the ANKRD11 gene was reported by De Bernardi (2018). Novel characteristics were a prominent and elongated coccyx with caudal appendage and a large calcaneous.

* This information is courtesy of the L M D
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