Congenital Anomalies最新文献

Germline APC pathogenic variants (PVs) are found in around 5%–10% of patients with hepatoblastoma.¹ Previous studies have shown conflicting opinion about the necessity of the routine genetic testing to identify germline APC PVs.¹ To date, candidates for genetic testing and appropriate analysis method remain unknown. Here, we experienced an infantile case of multiple hepatoblastomas with β-catenin positivity and identified a germline APC PV.

Our patient was the second child of healthy parents. His parents and elder brother, aged 3 years old, had no history of hepatoblastoma or adenomatous polyposis (Figure 1A). At the age of 1 year, he presented with abdominal distention and poor feeding. A huge mass was palpable in his upper right abdomen. The blood test showed high alpha-fetoprotein level (96,129 ng/mL, reference 10–50). Abdominal contrast-enhanced magnetic resonance imaging revealed three liver lesions, which size were almost 1.2 cm in S4 area, 13.0 cm in S5-6 area, and 3.0 cm in S7 area (Figure 1B,C). Multiple hepatoblastomas were diagnosed. No metastasis or vascular infiltrations were seen. After the chemotherapy, a right lobectomy was performed. Pathological examination of the resected main tumor showed a cord-like structure of small atypical cells, which is similar to the fetal liver cells, confirming hepatoblastoma. Immunohistochemistry staining showed positive β-catenin in the nuclei of tumor cells (Figure 1D). After obtaining written consent from the patient's parents for genetic testing, we performed next-generation sequencing in tumor samples and found a previously reported heterozygous nonsense variant, APC (NM_000038.6) c.3340C > T, p.Arg1114*.² This variant was also identified in the peripheral blood by Sanger sequencing. This variant was not identified in either parent (Figure 1A). We shared with his parents the following information: (i) this germline APC variant caused hepatoblastoma in our patient, (ii) due to the potential risk for additional hepatoblastoma, regular checkups were strongly recommended, (iii) our patient may develop a less severe type of adenomatous polyposis from adolescence,² and (iv) this germline APC variant may cause other diseases, including brain tumors and osteoma.

Multiple lesions in identical organs are common in patients with cancer predisposing genetic background. We speculate that multiple hepatoblastomas could be also suggestive of the presence of the germline PVs. We detected positive β-catenin immunostaining in the nuclei of tumor cells in our patient. Previous studies showed (i) in hepatoblastomas with β-catenin positivity, tumor-driving CTNNB1 or APC variants were found in a mutually exclusive nature, (ii) somatic activating CTNNB1 variants are found in 60%–80% of hepatoblastomas, while somatic APC PVs are rarely f

Cranial neural crest cells (NCCs) are critical for craniofacial development. The administration of valproic acid (VPA) to pregnant females causes craniofacial malformations in offspring. However, the in vivo influence of VPA on mammalian cranial NCCs remains unclear. In this study, we aimed to elucidate the developmental stage-specific effect of VPA on cranial NCCs through the administration of a single dose of VPA to pregnant rat females immediately prior to the formation of the cranial neural crest (NC). We performed whole-mount immunohistochemistry or in situ hybridization to examine localization changes of gene transcripts associated with the epithelial–mesenchymal transition of the cranial NC (i.e., cranial NCC formation) and cranial NCC migration. The results showed that Hoxa2 mRNA was abnormally detected and Sox9 mRNA expression was decreased in the midbrain–rhombomere (R) 1/2 NC, which forms cranial NCCs that migrate to the frontonasal mass (FNM) and branchial arch (BA) 1, through VPA administration, thus reducing the formation of SNAI2-positive NCCs. Hoxa2-positive NCCs were detected normally in BA2 and abnormally in FNM and BA1, which are normally Hox-free, implying VPA-induced abnormal cranial NCC migration. In vitro verification experiments using the whole embryo culture system revealed that midbrain–R4 NCC migration was abnormal. These results indicate that VPA reduces the formation/delamination of the midbrain–R1/2 NCCs in a developmental stage-specific manner and subsequently causes the abnormal migration of R4 NCCs, which suggests that the abnormal formation and migration of cranial NCCs contribute to the inhibition of axonal elongation in the trigeminal nerve and a reduction in head size.

Glycogen storage disease type IXa (GSD IXa) results from a defect in the alpha subunit of phosphorylase kinase encoded by PHKA2 with X-linked inheritance. Clinical manifestations include fasting hypoglycemia, hepatomegaly, and growth failure. Various PHKA2 pathogenic variants have been reported, including microdeletions.¹ To date, few breakpoints have been identified, and mechanisms causing microdeletions are not well understood. We report on a pediatric patient with GSD IXa and a novel microdeletion in PHKA2.

The male proband was the first child of healthy, non-consanguineous Japanese parents. His birth length and weight were 48.4 cm (−0.29 SD) and 2.81 kg (−0.42 SD), respectively. Short stature was noted at 15 months of age; at 18 months, he could not stand alone and motor delay was suspected. He was referred to our hospital at 23 months with length and weight of 79.0 cm (−2.2 SD) and 10.5 kg (−0.82 SD), respectively. He could walk with aid and speak meaning words. Physical examination showed a doll-like appearance, abdominal distension, and hepatomegaly. Laboratory examinations showed as follows: white blood cells, 8800/μL (neutrophils 1584/μL); aspartate aminotransferase, 899 U/L; alanine aminotransferase, 554 U/L; creatine kinase 60 U/L; alkaline phosphatase 966 U/L (age matched reference, 395–1339); γ-glutamyl transpeptidase 374 U/L (reference, 6.5–60.0); creatinine, 0.13 mg/dL; uric acid, 7.0 mg/dL. Fasting glucagon loading test showed glucose of 42 mg/dL (before loading) and 64 mg/dL (60 min after loading). Two-hour postprandial glucagon loading test showed glucose of 131 mg/dL (before loading) and 191 mg/dL (30 min after loading). Oral glucose tolerance tests showed basal lactate and pyruvate levels of 7.0 and 0.61 mg/dL, respectively, and peak lactate and pyruvate levels of 32.2 mg/dL (90 min after loading) and 3.03 mg/dL (30 min after loading), respectively. Computed tomography showed hepatomegaly with high density. Phosphorylase kinase enzyme analysis of red blood cells revealed 0.3 nmoL/min/gHb, compared to 9.1 and 10.1 nmoL/min/gHb in two healthy subjects. We thus diagnosed him as having GSD IXa. After obtaining informed consent from his parents, genomic DNA was extracted from peripheral blood samples of the proband and his mother. We tried to amplify all exons and the flanking introns of the exons in PHKA2 (NM_000292.3) in the proband, but we obtained no polymerase chain reaction (PCR) products of exons 20 and 21. We designed several new forward primers located at the intron intervening exons 19 and 20 and the reverse primer located at exon 22. Using these primers, we performed PCR using DNA from the proband or his mother and obtained the products, with the size at 500–650 bp from the proband and 3000 bp and 500–650 bp from his mother (Figure 1A). The PCR products in the proband were subjected to direct sequencing from both directions on the autosequencer. We identified a

The frequency of cleft lip with/without palate (CL/P) in the Mongolian population is approximately 1 in 1314 live births. This research aims to disseminate information about this congenital disability to the public to better understand CL/P, and people's fissures, and review administrative measures, as there is a lack of research in this area. A questionnaire survey was conducted using Google Forms, with 1000 Mongolian participants. Most participants (86.7%) said they had knowledge of the word, whereas 86.2% said they had knowledge of the condition. Most participants' answers were question-related disadvantages of CL/P patients, including statements such as “It's uncomfortable in human relationships” and “It makes an uncomfortable impression on the person you meet the first time.” The results of this study revealed that most Mongolians were aware of CL/P and are concerned about patients. However, the causes of CL/P in the general population remain unknown, and further research is needed in this area.

The pyramidalis muscle (PM) is a paired small triangular muscle of the anterior abdominal wall; however, its physiological significance is unclear. Recent studies have failed to detect this muscle during embryonic period. Hence, the present study aimed to determine the time when PM is emerging and reveal its features using high-resolution magnetic resonance imaging. Fourteen embryos between Carnegie stage (CS)18 and CS23 and 59 fetuses (crown-rump length: 39.5–185.0 mm) were selected for this study. The PM was first detected in one of the three samples at CS20. It was detected in five of the seven samples (71.4%) between CS21 and CS23. Forty-eight samples (81.4%) at early fetal period had PMs on both the right and left sides, and 3 (5.1%) had it only on the right side. Eight samples (13.6%) had no PMs. No side-differences or sexual dimorphisms were detected. The PM length was larger than the width in most samples, although the length/width ratio varied among the samples. The PM/rectus abdominis muscle length and PM/umbilicus-pubic symphysis length ratios were almost constant, irrespective of the crown-rump length. The PM was located ventrally inferior to the rectus abdominis and closer to the medial muscle groups of the lower limb than the rectus abdominis. The present study demonstrated that PM formation occurred in the late embryonic period, and that the frequency, side differences, sex dimorphism, and spatial position of the PM in the early fetal period were similar to those in adults.

Since pregnant women are excluded from clinical trials, it is essential to accumulate post-marketing information to evaluate the effects on the fetus of medication use during pregnancy. The Japan Drug Information Institute in Pregnancy (JDIIP) was established at the National Center for Child Health and Development as a Ministry of Health, Labour, and Welfare project to provide patients with information and conduct follow-up surveys. In this study, we investigated the status of the accumulation of JDIIP consultation cases to identify issues for enhancing clinical information appropriate for use during pregnancy and to examine how information should be collected and provided. In addition, the status of descriptions of Japanese package inserts, which are representative of those used by healthcare professionals as a source of information, was confirmed for medications used by JDIIP consultation cases. The characteristics of the JDIIP consultation cases information were that the contents that needed to be adjusted when evaluating the effects on the fetus of medication use during pregnancy were obtained. In addition, the follow-up rate was 83.1%. However, although the number of consultation facilities has increased, the number of consultations has not, indicating the need to further increase the number. It was found that there is limited information on epidemiological studies of clinical use in Japanese package inserts. To improve clinical information on the appropriate use of medications during pregnancy, it is necessary to accumulate more information in the future, and it is considered necessary to consider new approaches utilizing the JDIIP system.

Congenital tracheal stenosis is a rare life-threatening disorder caused by narrow O-shaped tracheal ring without smooth muscle. Its underlying genetic cause has not been elucidated. We performed whole exome sequencing in a patient with congenital tracheal stenosis and congenital heart defect, and identified a de novo pathogenic TBX5 variant (NM_181486.4:c.680T>C, p.(Ile227Thr)). The Ile227Thr-TBX5 protein was predicted to have a decreased stability by in silico protein structural analyses, and was shown to have a significantly reduced activity for the NPPA promoter by luciferase assay. The results, together with the expression of mouse Tbx5 in the lung and trachea and the development of tracheal cartilage dysplasia in the lung-specific Tbx5 null mice, imply the relevance of TBX5 pathogenic variants to congenital tracheal stenosis.