Takenouchi-Kosaki Syndrome
A number sign (#) is used with this entry because of evidence that Takenouchi-Kosaki syndrome is caused by heterozygous mutation in the CDC42 gene (116952) on chromosome 1p36.
DescriptionTakenouchi-Kosaki syndrome is a highly heterogeneous autosomal dominant complex congenital developmental disorder affecting multiple organ systems. The core phenotype includes delayed psychomotor development with variable intellectual disability, dysmorphic facial features, and cardiac, genitourinary, and hematologic or lymphatic defects, including thrombocytopenia and lymphedema. Additional features may include abnormalities on brain imaging, skeletal anomalies, and recurrent infections. Some patients have a milder disease course reminiscent of Noonan syndrome (see, e.g., NS1, 163950) (summary by Martinelli et al., 2018).
Clinical FeaturesTakenouchi et al. (2015) reported a girl of Japanese and Iranian background, born at term from an uncomplicated gestation with an average birth weight. She had a persistent ductus arteriosus that was repaired at 1 year of age and later underwent a right inguinal hernia repair. She had developmental delay and was unable to walk until age 4. At that time she had developed lymphedema in her right lower leg. At 1 year of age, she was noted to have persistent thrombocytopenia with normal hemoglobin and white cell count. Thrombocytopenia was still present at 9 years of age. At 18 years of age she had platelets as low as 52,000/microL, a white blood count of 3,000/microL, and stable normal hemoglobin. Peripheral blood smear showed enlarged platelets. At 18 years of age her head circumference was -2 SD, height was -1.5 SD, and weight was -1.6 SD. She had distinctive facial features consisting of midface hypoplasia, synophrys, mild ptosis, eversion of the lateral portion of the lower eyelid, exotropia, short philtrum, and thin upper lip. She communicated with simple words. Lymphedema in the right lower leg was still present. Mild contractures in the interphalangeal joins of the 3rd through 5th fingers were present bilaterally.
Takenouchi et al. (2016) described a second girl of Japanese descent with macrothrombocytopenia, lymphedema, and developmental delay. The patient walked at 3 years of age. She had poor visual acuity, congenital nystagmus, and bilateral sensorineural deafness. Ophthalmologic evaluation revealed retinal dysplasia with left congenital falciform retinal detachment. In addition to bilateral lower extremity lymphedema, she had pericardial effusion, hydrothorax, ascites, and hypoalbuminemia. At the age of 14 years, she was diagnosed as having a protein-losing enteropathy secondary to intestinal lymphangiectasia. At 22 years her height was -4.3 SD, weight was -3.0 SD, and head circumference was -5.0 SD. She had severe intellectual disability with no meaningful words, but was able to understand simple commands. Phenotypic anomalies present in both this patient and the patient reported by Takenouchi et al. (2015) included arched eyebrows, mild ptosis, eversion of lateral portion of lower eyelid, exotropia, midface hypoplasia, short philtrum, thin upper lip, malocclusion, camptodactyly, and ventriculomegaly.
Martinelli et al. (2018) reported 15 patients from 13 unrelated families with a clinically heterogeneous but overlapping phenotype associated with heterozygous mutations in the CDC42 gene. The affected individuals were identified through research studies and connected via online web-based genetics matching tools. Core clinical features included poor postnatal growth, sometimes with mild microcephaly, delayed psychomotor development, variable intellectual disability, behavioral disorders or learning disabilities, poor or absent speech, facial dysmorphism, hearing or vision problems, and variable involvement of other systems, including cardiac, immune, hematologic, lymphatic, skeletal, and genitourinary. Dysmorphic features included prominent forehead, bitemporal narrowing, hypertelorism, strabismus, up- or downslanting palpebral fissures, ptosis, synophrys, sparse eyebrows, wide nasal bridge, flared nostrils, bulbous nasal tip, smooth philtrum, long or short philtrum, thin tented upper lip, wide mouth, downturned corners of the mouth, widely spaced teeth, low-set or posteriorly rotated ears, and webbed neck. Additional variable features included hypotonia, skin nevi, lymphedema, thrombocytopenia, hydronephrosis, hypospadias, unilateral renal agenesis, inguinal hernia, immunodeficiency with recurrent infections, optic atrophy, seizures, and cardiac abnormalities such as septal defects, patent ductus arteriosus, and total anomalous pulmonary venous return (TAPVR). Some patients had skeletal anomalies such as contractures and scoliosis as well as distal skeletal anomalies such as clinodactyly, proximally placed thumbs, tapered fingers, camptodactyly, and overlapping toes. Almost all patients showed abnormalities on brain imaging, most commonly enlarged ventricles, periventricular white matter anomalies, and thin corpus callosum. A few patients had more severe abnormalities, including Dandy-Walker malformation, cerebellar atrophy or dysplasia, and cortical atrophy. There was 1 family (family 30153) in which 3 affected individuals had a milder, but similar phenotype, with features of Noonan syndrome, including pectus deformities and pulmonary stenosis.
InheritanceThe transmission pattern of Takenouchi-Kosaki syndrome in 1 family (family 30153) reported by Martinelli et al. (2018) was consistent with autosomal dominant inheritance.
Molecular GeneticsThe patients reported by Takenouchi et al. (2015) and Takenouchi et al. (2016) with macrothrombocytopenia, lymphedema, and developmental delay carried the same heterozygous de novo missense mutation in the CDC42 gene (Y64C; 116952.0001).
In 15 patients from 13 unrelated families with a heterogeneous developmental disorder consistent with TKS, Martinelli et al. (2018) identified 9 different heterozygous missense mutations in the CDC42 gene (see, e.g., 116952.0001-116952.0006). The mutations occurred de novo in 12 unrelated patients; there was 1 family (family 30153) in which 3 affected individuals carried the same mutation. The mutations in most patients were identified by whole-exome sequencing; some mutations were identified by direct sequencing of the CDC42 gene. None of the mutations were found in the ExAC/gnomAD database, and all were predicted to be pathogenic according to ACMG criteria. Based on molecular modeling, predicted functional impact, and in vitro functional studies, the mutations were categorized into 3 main groups, all of which were determined to be pathogenic (see GENOTYPE/PHENOTYPE CORRELATIONS).
Genotype/Phenotype CorrelationsBased on molecular modeling, predicted functional impact, and in vitro functional studies, the mutations identified by Martinelli et al. (2018) were categorized into 3 main groups. Group I mutations (Y64C; R66G, 116952.0002; and R68Q) occurred in the switch II domain, which mediates CDC42 binding to effectors and regulators, and were predicted to interfere with the catalytic activity of the GTPase and/or its capability to transduce signaling. Group I mutations were associated with a syndromic form of thrombocytopenia. Group II mutations (C81F, 116952.0003; S83P, 116952.0004; and A159V) were located within or close to the nucleotide-binding pocket, and were predicted to promote fast GDP/GTP cycling, favoring a hyperactive GTP-bound state. Group II mutations were associated with a variable developmental disorder characterized by striking dysmorphic features resembling a RASopathy. Group III mutations (I21T, 116952.0005; Y23C; and E171K, 116952.0006), located in residues predicted to disrupt interactions with effectors containing a CRIB (Cdc42, Rac interactive binding) motif, were associated with a milder phenotype resembling Noonan syndrome. In vitro studies of selected mutations using recombinant proteins showed variable effects on CDC42 function, including altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors. Group I mutations had defective interaction with tested partner proteins, group II mutations showed variable hyperactive behavior, and group III mutations showed perturbed binding to effectors. In addition, a wound healing assay indicated that the mutations resulted in dysregulated and disturbed cell polarization and proliferation. One specific mutation (E171K), which affects only 1 of the 2 CDC42 isoforms and specifically impaired binding to WASP (300392), resulted in an overall milder clinical phenotype that phenocopied Noonan syndrome. Studies in C. elegans showed that the mutations caused variable disruption of developmental processes, with some mutations acting as a gain of function and others acting as hypomorphs. In general, the group II mutations upregulated multiple signaling pathways. Overall, the findings indicated that CDC42 functions in a large array of developmental processes.
Animal ModelPleines et al. (2010) found that conditional knockout of Cdc42 in mice results in mild thrombocytopenia and increased platelet size (i.e., macrothrombocytopenia).