Temple-Baraitser Syndrome

A number sign (#) is used with this entry because of evidence that Temple-Baraitser syndrome (TMBTS) is caused by heterozygous mutation in the KCNH1 gene (603305) on chromosome 1q32.

Description

Temple-Baraitser syndrome is a rare developmental disorder characterized by severe mental retardation and anomalies of the first ray of the upper and lower limbs with absence/hypoplasia of the nails. Most patients also have seizures; various dysmorphic facial features have been reported (summary by Jacquinet et al., 2010).

Clinical Features

Temple and Baraitser (1991) reported a 3.5-year-old boy, born of nonconsanguineous Iranian parents, with a severe mental retardation syndrome characterized by hypotonia, seizures, and generalized cerebral atrophy. He had a low frontal hairline with central cowlick, mild hypertelorism, ptosis, and a prominent nose. Skeletal features included small hypoplastic thumb nails and absent great toe nails. Radiographs showed central lucent areas in the distal phalanges of both thumbs resembling pseudoepiphyses. The terminal phalanges of other digits on both hands and feet were hypoplastic.

Gabbett et al. (2008) reported a 4-year-old boy with a similar phenotype to that reported by Temple and Baraitser (1991). He had marked hypotonia, global developmental delay, and seizures. Other features included myopathic facies with flat forehead, broad depressed nasal bridge, epicanthal folds, short columella, long philtrum, broad mouth with downturned corners, and high-arched palate. Both thumbs were terminally broad with hypoplasia of the nail. The halluces were long and broad with nail aplasia bilaterally. Radiographs showed pseudoepiphyses of the thumbs and hypoplasia of all other terminal phalanges. Gabbett et al. (2008) noted that the patient's mother had a seizure disorder and took carbamazepine during pregnancy, which may have accounted for some of the facial dysmorphism. Both Temple and Baraitser (1991) and Gabbett et al. (2008) noted some phenotypic similarities to DOOR syndrome (220500), but neither patient had deafness.

Jacquinet et al. (2010) reported 2 unrelated girls with a phenotype consistent with Temple-Baraitser syndrome. One was born of unrelated Algerian parents and the other of unrelated Chinese parents. The first girl had neonatal hypotonia, mental retardation, and generalized tonic-clonic seizures. Facial dysmorphism included hypertelorism, broad nasal bridge, long philtrum, and a wide mouth with thick vermilion border of the upper lip and downturned corners. Her thumbs were long and proximally set, with hypoplastic thenar eminences and hypoplastic thumb nails. The other distal phalanges were short with normal nails. The halluces were long and tubular, with short distal phalanges and severely hypoplastic nails. Radiographs of the hands and feet showed segmentation in the distal phalanges of the thumbs and the left great toe, giving the appearance of pseudoepiphyses. Proximal epiphyseal ossification centers were missing in the distal phalanges of the first rays. The second child had bilateral anonychia of both halluces, hypoplastic nails of both thumbs, and hypoplastic terminal phalanges with slightly hypoplastic nails on the other fingers. She had hypotonia, poor visual contact, and delayed development. Facial dysmorphic features were mild, with a wide open mouth, thick vermilion border of the upper lip, and downturned corners of the mouth. Array CGH analysis of these 2 patients and the patient reported by Gabbett et al. (2008) did not reveal any abnormalities. Jacquinet et al. (2010) favored sporadic occurrence of the disorder.

Yesil et al. (2014) reported a 3.5-year-old Turkish boy, born of unrelated parents, with clinical and radiologic features consistent with Temple-Baraitser syndrome. The child had severely delayed psychomotor development with poor eye contact and lack of speech. Dysmorphic facial features were mild, and included flat forehead, hypertelorism, epicanthal folds, ears with thick helices, downslanting palpebral fissures, depressed nasal bridge, long philtrum, short columella, thick vermilion border of the lower lip, and a myopathic facies. Other features included short neck, widely spaced nipples, and tapering fingers. The thumbs were proximally placed, with short distal phalanges and small nails. The halluces were elongated and narrow with small nails. Radiographs showed a spindle-shaped distal phalangeal ossification in both thumbs and hypo/aplasia in the halluces. There was increased lucency on the center of bones on distal phalanges of both thumbs and halluces. The patient developed a febrile seizure at age 3. Karyotype revealed 47,XXY, consistent with Klinefelter syndrome.

Simons et al. (2015) reported 2 unrelated girls with TMBTS. The first, born of unrelated white parents of North American descent, presented in infancy with global developmental delay and had onset of seizures at age 4 years. At age 14 years, she had a myopathic face, high anterior hairline, mild malar flattening, depressed nasal bridge with anteverted nares, long philtrum, tented vermilion of the upper lip, and everted thick vermilion of the lower lip. The fingers showed distal hypoplasia, particularly of the thumb. All toes had near to complete absence of the nails. Radiographs showed dysplastic secondary ossification centers of the thumbs and great toes. The patient's mother had a seizure disorder, but no other features. The second girl, born of unrelated Hispanic parents, presented at age 9 months with hypotonia, global developmental delay, and dysmorphic features. She developed seizures at age 8 years. Dysmorphic features included myopathic facies, hypertelorism, wide nasal bridge, thick alae nasi, low hanging columella, full cheeks, everted thick vermilion border of the lips, and long philtrum. The thumbs were bulbous distally with near absence of the nails, and the great toes were long with hypoplastic nails. Hand and foot radiographs showed absence of the proximal secondary ossification centers in the distal phalanges. She had no expressive language at age 9 years.

Molecular Genetics

In 6 unrelated patients with Temple-Baraitser syndrome, Simons et al. (2015) identified 4 different heterozygous missense mutations at highly conserved residues in the KCNH1 gene (603305.0001-603305.0004). Four of the patients had previously been reported (Gabbett et al., 2008, Jacquinet et al., 2010, and Yesil et al., 2014). The mutations, which were found by whole-exome sequencing, occurred de novo in 4 patients. The mothers of 2 patients had epilepsy without other features of the disorder, and each was found to carry a mutation in the mosaic state, suggesting that a low level of mutational load can contribute to epilepsy. In vitro functional expression studies in Xenopus oocytes showed that all mutations caused a decreased threshold of activation and delayed deactivation compared to wildtype, consistent with a gain of function.