Tonne-Kalscheuer Syndrome

A number sign (#) is used with this entry because of evidence that Tonne-Kalscheuer syndrome (TOKAS) is caused by hemizygous mutation in the RLIM gene (300379) on chromosome Xq13.

Description

Tonne-Kalscheuer syndrome (TOKAS) is an X-linked recessive multiple congenital anomaly disorder with 2 main presentations. Most patients exhibit global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait. Affected individuals also have dysmorphic facial features that evolve with age, anomalies of the hands, feet, and nails, and urogenital abnormalities with hypogenitalism. A subset of more severely affected males develop congenital diaphragmatic hernia in utero, which may result in perinatal or premature death. Carrier females may have very mild skeletal or hormonal abnormalities (summary by Frints et al., 2018).

Also see Fryns syndrome (229850), an autosomal recessive disorder with overlapping features.

Clinical Features

Tonne et al. (2015) reported a 3-generation Norwegian family in which 4 males had mental retardation. The patients, who ranged in age from 5.5 to 71 years, had delayed psychomotor development, mild to moderate intellectual disability with poor speech, and autistic features. Mild dysmorphic features included broad forehead, fine hair with receding hairline, hypertelorism, broad nasal bridge, and large nose. Additional features included stiff gait and feeding difficulties. Brain imaging of 2 patients was essentially normal. Female family members were unaffected.

Hu et al. (2016) reported 3 unrelated families (T11, D72, and AU31) with TOKAS. Affected males in 2 families had nonspecific mild to profound intellectual disability. Affected individuals in the third family had intellectual disability, variable behavioral problems, microcephaly, micrognathia, and cryptorchidism. Female family members were unaffected.

Frints et al. (2018) reported 4 unrelated families (families C, E, G, and I) in which several male individuals had a complex multiple congenital anomaly disorder associated with impaired intellectual development and neurologic abnormalities. The authors also reviewed the features of 5 previously reported families, including family B (Tonne et al., 2015) and families D, F, and H (Hu et al., 2016). Frints et al. (2018) also reported a singleton case (family A) with similar features. Overall, there were 40 affected males from 9 families, including 3 fetuses, 8 deceased newborns, 9 boys, and 20 adults. Twelve affected males died at birth due to congenital malformations, most commonly congenital diaphragmatic hernia (CDH) with associated lung hypoplasia. Of the 29 surviving patients, who ranged in age between childhood and late-adult (up to age 75 years), all had global developmental delay apparent in infancy and associated with speech delay, including absent speech in some, and borderline to severe cognitive dysfunction. Almost all had behavioral abnormalities, including shyness and autistic-like features in childhood, and more aggressive features, including temper tantrums or outbursts of anger, anxiety, self-injurious behavior, obsessive-compulsive-like behaviors, and hyperactivity. Three patients had well-controlled seizures. Additional more variable neurologic features included broad-based gait, spasticity with hyperreflexia, tremor, drooling and swallowing difficulties due to velopharyngeal insufficiency, and congenital cardiac defects. Brain imaging, when performed, was typically normal, although some patients had nonspecific white matter abnormalities. At birth, most patients had growth retardation with microcephaly, hypotonia, and dysmorphic facial features including broad forehead, broad and/or high nasal bridge, hypertelorism, straight lateral eyebrows, downslanting palpebral fissures, and small mouth with micrognathia. The facial features evolved, and affected adults showed long narrow face, narrow high nasal bridge, hypotelorism, malar hypoplasia, and downturned corners of the mouth with sad-looking appearance. Some patients had short stature, and most had a lean body build. Most patients also had genital anomalies, including small penis and testes, cryptorchidism, and hypospadias, and well as distal skeletal anomalies, including short broad thumbs, pes planus, and abnormal nails. Carrier females had normal cognition and behavior, but a few had physical features, including short stature, broad thumbs, short distal phalanges, and pes planus. In addition, several carrier females had clinical or biochemical evidence of premature ovarian insufficiency (POI).

Inheritance

The transmission pattern of TOKAS in the family reported by Tonne et al. (2015) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 4 males from a 3-generation Norwegian family with TOKAS, Tonne et al. (2015) identified a hemizygous missense mutation in the RLIM gene (Y356C; 300379.0001). The variant, which was found by whole-exome sequencing, segregated with the disorder in the family.

In affected males from 3 unrelated families with TOKAS, Hu et al. (2016) identified 3 different hemizygous missense mutations in the RLIM gene: P587R (300379.0002), R387C (300379.0003), and R599C (300379.0004). The mutations were found by X-chromosome exome sequencing and segregated with the disorder in the families. Functional studies of the variants were not performed.

In affected members of 4 unrelated families with TOKAS, Frints et al. (2018) identified 4 different hemizygous missense mutations in the RLIM gene: R365C (300379.0005), D598N (300379.0006), R611C (300379.0007), and Y577H. An additional boy with a similar phenotype (family A) carried a hemizygous P77L variant of unknown significance. The mutations were found by whole-genome or whole-exome sequencing, and segregated with the disorder in the families, including in unaffected or mildly affected carrier females. Frints et al. (2018) also reviewed the 4 families, which they referred to as families B, D, F, and H, reported by Tonne et al. (2015) and Hu et al. (2016). All reported mutations occurred in exon 5, except P77L, which was in exon 4. Three mutations, Y356C, R365C, and R387C, were in the putative basic binding domain, and in vitro functional expression studies in HEK293 cells showed slightly increased RLIM ubiquitin ligase activity resulting from these variants compared to wildtype. Similar studies of 4 additional mutations, P587R, D598N, R599C, and R611C, that occurred in the C-terminal catalytic RING-H2 zinc finger domain resulted in decreased ubiquitin ligase activity compared to wildtype. There was no apparent genotype/phenotype correlation. Expression of the missense variants into zebrafish with knockdown of the rlim gene failed to rescue the microcephaly phenotype, suggesting that they all resulted in a loss-of-function effect. Analysis of cells from 14 female carriers showed evidence of highly skewed X inactivation (87-100%) compared to controls, likely silencing the mutant allele.

Animal Model

Frints et al. (2018) found that knockdown of the zebrafish rlim homolog using both morpholino knockdown and CRISPR/Cas9 gene editing resulted in microcephaly.