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An increasing number of genetic syndromes present a challenge to clinical geneticists. A deep learning-based diagnosis assistance system, Face2Gene, utilizes the aggregation of "gestalt," comprising data summarizing features of patients' facial images, to suggest candidate syndromes. Because Face2Gene's results may be affected by ethnicity and age at which training facial images were taken, the system performance for patients in Japan is still unclear. Here, we present an evaluation of Face2Gene using the following two patient groups recruited in Japan: Group 1 consisting of 74 patients with 47 congenital dysmorphic syndromes, and Group 2 consisting of 34 patients with Down syndrome. In Group 1, facial recognition failed for 4 of 74 patients, while 13-21 of 70 patients had a diagnosis for which Face2Gene had not been trained. Omitting these 21 patients, for 85.7% (42/49) of the remainder, the correct syndrome was identified within the top 10 suggested list. In Group 2, for the youngest facial images taken for each of the 34 patients, Down syndrome was successfully identified as the highest-ranking condition using images taken from newborns to those aged 25 years. For the oldest facial images taken at ≥20 years in each of 17 applicable patients, Down syndrome was successfully identified as the highest- and second-highest-ranking condition in 82.2% (14/17) and 100% (17/17) of the patients using images taken from 20 to 40 years. These results suggest that Face2Gene in its current format is already useful in suggesting candidate syndromes to clinical geneticists, using patients with congenital dysmorphic syndromes in Japan.

Takenouchi-Kosaki syndrome (TKS) is a congenital malformation syndrome characterized by severe developmental delay, macrothrombocytopenia, camptodactyly, sensorineural hearing loss, and dysmorphic facial features. Recently, a heterozygous de novo mutation (p.Tyr64Cys) in the CDC42 gene, which encodes a key small GTP-binding protein of the Rho-subfamily, was identified in two unrelated patients with TKS. We herein report a third patient with TKS who had the same heterozygous CDC42 mutation. The phenotype of the patient was very similar to those of the two previously reported patients with TKS; however, she also demonstrated novel clinical manifestations, such as congenital hypothyroidism and immunological disturbance. Thus, despite the heterozygous mutation of CDC42 (p.Tyr64Cys) likely being a hot-spot mutation for TKS, its phenotype may be variable. Further studies and the accumulation of patients with CDC42 mutations are needed to clarify the phenotype in patients with TKS and the pathophysiological roles of the CDC42 mutation.

Silver-Russell syndrome (SRS) is a congenital developmental disorder characterized by intrauterine and postnatal growth failure, craniofacial features (including a triangular shaped face and broad forehead), relative macrocephaly, protruding forehead, body asymmetry and feeding difficulties. Hypomethylation of the H19 differentially methylated region (DMR) on chromosome 11p15.5 is the most common cause of the SRS phenotype. We report the first SRS patient with hypomethylation of the H19-DMR and maternally derived 15q11.2-q13.1 duplication. Although her clinical manifestations overlapped with those of previously reported SRS cases, the patient's intellectual disability and facial dysmorphic features were inconsistent with the SRS phenotype. Methylation analyses, array comparative genomic hybridization, and a FISH analysis revealed the hypomethylation of the H19-DMR and a maternally derived interstitial 5.7 Mb duplication at 15q11.2-q13.1 encompassing the Prader-Willi/Angelman critical region in the patient. On the basis of the genetic and clinical findings in the present and previously reported cases, it is unlikely that the 15q duplication in the patient led to the development of hypomethylation of the H19-DMR and it is reasonable to consider that the characteristic phenotype in the patient was caused by the coexistence of the two (epi)genetic conditions. Further studies are needed to clarify the mechanisms leading to methylation aberrations in SRS.

The Kabuki syndrome (KS, OMIM 147920), also known as the Niikawa-Kuroki syndrome, is a multiple congenital anomaly/mental retardation syndrome characterized by a distinct facial appearance. The cause of KS has been unidentified, even by whole-genome scan with array comparative genomic hybridization (CGH). In recent years, high-resolution oligonucleotide array technologies have enabled us to detect fine copy number alterations. In 17 patients with KS, molecular karyotyping was carried out with GeneChip 250K NspI array (Affymetrix) and Copy Number Analyser for GeneChip (CNAG). It showed seven copy number alterations, three deleted regions and four duplicated regions among the patients, with the exception of registered copy number variants (CNVs). Among the seven loci, only the region of 9q21.11-q21.12 (approximately 1.27 Mb) involved coding genes, namely, transient receptor potential cation channel, subfamily M, member 3 (TRPM3), Kruppel-like factor 9 (KLF9), structural maintenance of chromosomes protein 5 (SMC5) and MAM domain containing 2 (MAMDC2). Mutation screening for the genes detected 10 base substitutions consisting of seven single-nucleotide polymorphisms (SNPs) and three silent mutations in 41 patients with KS. Our study could not show the causative genes for KS, but the locus of 9q21.11-q21.12, in association with a cleft palate, may contribute to the manifestation of KS in the patient. As various platforms on oligonucleotide arrays have been developed, higher resolution platforms will need to be applied to search tiny genomic rearrangements in patients with KS.

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.

We report on a sclerosing bone dysplasia, associated with cutis laxa, enamel dysplasia, and mental retardation. The patient was a 17-year-old Japanese boy of normal height and muscular build. Cutis laxa with prominent veins in the scalp and abdominal wall and delayed eruption of permanent teeth attracted the attention of clinicians in infancy and adolescence, respectively. The clinical manifestations included a progeroid facial appearance with prognathism, wrinkled skin, and interdigital webbing. The intelligence quotient was estimated at 60. Enamel dysplasia was histologically confirmed. Skeletal changes included calvarial hyperostosis, sclerosis of the skull base, an enlarged, sclerotic mandible, broad clavicles and ribs, and diaphyseal undermodeling of the tubular bones. Metaepiphyseal sclerosis or longitudinal striation was found in the long bones. Metaphyseal equivalents of the axial skeleton showed dense osteosclerosis. These clinical and radiological manifestations overlapped with those of Lenz-Majewski syndrome. Unlike the classical phenotype of the disorder, however, he did not show brachymesophalangy with proximal symphalangism or growth failure. The present case may be considered to fall in the mildest end in the phenotypic continuum of Lenz-Majewski syndrome, suggesting that the clinical spectrum of the disorder may be broader than currently thought.

Noonan syndrome (NS) is characterized by short stature, characteristic facial features, and heart defects. Recently, missense mutations of PTPN11, the gene encoding protein tyrosine phosphatase (PTP) SHP-2, were identified in patients with NS. Further, somatic mutations in PTPN11 were detected in childhood leukemia. Recent studies showed that the phosphatase activities of five mutations identified in NS and juvenile myelomonocytic leukemia (JMML) were increased. However, the functional properties of the other mutations remain unidentified. In this study, in order to clarify the differences between the mutations identified in NS and leukemia, we examined the phosphatase activity of 14 mutants of SHP-2. We identified nine mutations, including a novel F71I mutation, in 16 of 41 NS patients and two mutations, including a novel G503V mutation, in three of 29 patients with leukemia. Immune complex phosphatase assays of individual mutants transfected in COS7 cells showed that ten mutants identified in NS and four mutants in leukemia showed 1.4-fold to 12.7-fold increased activation compared with wild-type SHP-2. These results suggest that the pathogenesis of NS and leukemia is associated with enhanced phosphatase activity of mutant SHP-2. A comparison of the phosphatase activity in each mutant and a review of previously reported cases showed that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis.

To clarify the genotype-phenotype correlation of 5p- syndrome, FISH analyses were performed for six patients by using a series of probes spanning 5p13.1-p15.33. Genotypically, break points of deletion were quite different. Three of the six patients were diagnosed as interstitial deletion on chromosome 5p by G-banding method and FISH analysis; however, all of them proved to be entire distal deletions of 5p caused by unbalanced chromosomal translocations. Furthermore, one 5p- syndrome patient was diagnosed only by the FISH analysis using a single probe but not by ordinary chromosomal analyses. Therefore, when ordinary chromosomal analysis cannot detect any deletion in a patient who is phenotypically suspected of 5p- syndrome, multiple FISH analysis or parental chromosomal analysis would be needed for correct diagnosis. Interestingly, one patient with terminal deletion between 5p15.31-pter lacks mental retardation and cat-like crying, indicating that this region might not be responsible for those cardinal features of 5p- syndrome. Further studies on genotype-phenotype correlation will help us better understand 5p- syndrome and also determine functional mapping of the 5p region.

We used magnetic resonance imaging (MRI) to examine the brain of a typical Coffin-Lowry syndrome (CLS) patient. There were many small perivascular focal areas of hypointensity in the white matter on T1-weighted images, similar to those found in mucopolysaccharidosis or perivascular leukomalacia. However, these changes could not seen in another patient we examined. Both patients showed normal urinary mucopolysaccharide patterns with chromatographic analysis. The cause of the MRI result is not known, but it could have a heterogeneous origin, and this result could represent an important indication defining one type of CLS.

We report the case of a Japanese girl with a severe type of Moebius syndrome. Her morphological features were a mask-like face, limitation of horizontal eye movements, severe bulbar palsy, multiple and bilateral arthrogryposis including the elbow, knee, and ankle joints, and clubfeet. After birth, her general condition became worse because of repeated apneic spells and aspiration pneumonias due to dysphagia. She finally required tracheotomy. Computed tomography (CT) of the brain revealed minute calcifications on the fourth ventricle floor; this may have been due to severe damage to the brain stem. It is most likely that the various manifestations in our patient were due to disturbance of the blood supply to arteries perfusing the brain stem and to some other arteries, at a critical stage of fetal development.