Kbg Syndrome

A number sign (#) is used with this entry because of evidence that KBG syndrome (KBGS) is caused by heterozygous mutation in the ANKRD11 gene (611192) on chromosome 16q24.

Description

KBG syndrome is characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement that includes global developmental delay, seizures, and intellectual disability (summary by Sirmaci et al., 2011). Sirmaci et al. (2011) noted that it is likely that KBG syndrome is underdiagnosed, since many of the features, including intellectual disability, are mild, and none of the features is a prerequisite for diagnosis.

Clinical Features

Herrmann et al. (1975) described 2 families in which multiple members had short stature, characteristic facies (telecanthus, wide eyebrows, brachycephaly), macrodontia, mental retardation, and skeletal anomalies (abnormal vertebrae, short metacarpals, short femoral necks). Male-to-male transmission occurred in 1 family. (The designation KBG syndrome follows Opitz's practice of using the initials of affected families' surnames.) Fryns and Haspeslagh (1984) described what appeared to be the same disorder in 2 sisters and their mother.

Parloir et al. (1977) reported an extensive family segregating KBG syndrome. Soekarman et al. (1994) provided follow-up information on 3 affected brothers reported by Parloir et al. (1977). They had an affected sister, and 3 other brothers, as well as their mother, were said to have partial expression. The adult height of the affected brothers was far below the 3rd centile, with arm spans exceeding stature by at least 9 cm. Relative shortness of the trunk was apparently secondary to mild vertebral skeletal anomalies observed at a young age, with anterior wedging of vertebrae and irregular upper and lower plates. Karyotype was normal male.

Zollino et al. (1994) diagnosed KBG syndrome in 6 sporadic cases. Two of their patients had hypoplasia of cerebellar vermis, 1 had cystic dysplasia of the kidney, and 1 had megalocornea; see 249310.

Devriendt et al. (1998) described the KBG syndrome in a mother and her daughter. At the age of 8 years and 2 months the daughter showed, on x-ray of the skull, very broad unerupted permanent central frontal incisors. The mother had very broad frontal incisors. The daughter had ventricular septal defect, treated surgically. During childhood, she suffered from chronic constipation and recurrent respiratory tract infections. She was retarded with an intelligence quotient of 58 at the age of 8 years. The mother was mildly mentally retarded and had required special education.

Smithson et al. (2000) reported 2 additional cases of KBG syndrome. They suggested that the diagnostic criteria should include hypertelorism, macrodontia, short stature (less than the 10th percentile), delayed bone maturation, skeletal anomalies, and developmental delay (IQ less than 80).

Tekin et al. (2004) reported a family from central Anatolia in which a father and 2 sons had KBG syndrome. All 3 patients had developmental delay and mild to moderate mental retardation. Physical features included short stature (less than 3rd percentile), a triangular face, low anterior and posterior hairlines, bushy eyebrows, large prominent ears, a long philtrum, anteverted nostrils with hypoplastic alae nasi, and wide upper central incisors. The hands were short with clinodactyly, and 1 of the sons had bilateral accessory cervical ribs, thoracic kyphosis, and irregular vertebral arches. The father also had thoracic kyphosis. All 3 men had undescended testes.

Brancati et al. (2004) reviewed 29 cases of the KBG syndrome in the literature and described 8 new patients. Six of the new patients were sporadic in occurrence, but in 2 families the disorder was transmitted from mildly affected mothers to their affected children. EEG anomalies with or without seizures, mixed hearing loss, palatal anomalies with secondary speech disorder, distinct age-related behavior (hyperactivity, anxiety, and poor concentration), and cryptorchidism are possible additional characteristics of the KBG syndrome. Less common manifestations were posterior fossa malformations, eye defects, and congenital heart defects.

Maegawa et al. (2004) diagnosed KBG syndrome in 3 unrelated boys and the mother of 1 of them. In addition to the characteristic macrodontia and dental anomalies, the patients had atypical facies and skeletal anomalies, including hand anomalies in 3 patients. Mental retardation and developmental delay were also present in 3 patients. In the mother-son case, the mother had a milder phenotype.

Skjei et al. (2007) described male twins with KBG syndrome and reviewed 46 published cases. They recommended that 4 or more of the 8 major criteria be present to make the diagnosis of KBG syndrome: macrodontia of the upper central incisors, characteristic facial appearance, hand anomalies, neurologic involvement, bone age 2 standard deviations below the mean, costovertebral anomalies, postnatal short stature, and presence of a first-degree relative with KBG syndrome. Skjei et al. (2007) stated that macrodontia had been observed in over 95% of reported cases but noted that the high frequency might be due to ascertainment bias.

Inheritance

In the family reported by Tekin et al. (2004) from central Anatolia, a father and 2 sons had KBG syndrome, confirming autosomal dominant inheritance.

Maegawa et al. (2004) reported a mildly affected mother and her severely affected son. Citing previous reports in which males were more severely affected than females (e.g., Parloir et al., 1977), they suggested that inheritance may be X-linked in some cases.

Molecular Genetics

In the Turkish family with KBG syndrome originally reported by Tekin et al. (2004), Sirmaci et al. (2011) performed whole-exome capture followed by next-generation sequencing and identified a heterozygous splice site variant in the ANKRD11 gene (611192.0001) that segregated with disease and was not found in ethnically matched controls. Analysis of ANKRD11 in 9 additional KBG probands, including 3 previously reported by Brancati et al. (2004), revealed heterozygosity for truncating mutations in 4 of them (see, e.g., 611192.0002 and 611192.0003). Sirmaci et al. (2011) noted that although the absence of ANKRD11 mutations in half of the families they studied suggested that KBG syndrome is genetically heterogeneous, variation in the regulatory regions of the gene could not be excluded.

Ansari et al. (2014) identified 2 different de novo heterozygous truncating mutations in the ANKRD11 gene (see, e.g., 611192.0004) in 2 unrelated patients with KBG syndrome. A third unrelated patient had an intragenic deletion in the ANKRD11 gene. The patients were ascertained from a larger cohort of patients with features consistent with Cornelia de Lange syndrome (see, e.g., CDLS1, 122470), thus showing phenotypic overlap between the 2 disorders. All had normal head circumference; detailed clinical features were not provided.