Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.
Wolf-Hirschhorn syndrome is a genetic syndrome that includes growth failure, mental retardation, congenital heart disease, typical facial features and epilepsy. This syndrome is associated with a microdeletion of the short arm of chromosome 4. Familial Mediterranean fever is a hereditary autoinflammatory disorder characterized by fever and serosal inflammation that affects abdomen, chest and joints. This disorder is associated with mutations in MEFV located on chromosome 16p. We report a case of a child with Wolf-Hirschhorn syndrome presenting with recurrent fever, vomiting and diarrhea and diagnosed with familial Mediterranean fever. MEFV sequence showed complex allele mutations. Colchicine shortens the duration and ameliorates the severity of symptoms, which avoid hospitalization. We discuss the difficulty in diagnosing these two relatively rare comorbities and review literatures.
To treat six patients with peritoneal recurrence after radical operation for gastrointestinal cancer, an intraperitoneal hyperthermic perfusion (IPHP), combined with surgical resection of recurrent tumors, intestinal by-pass anastomosis, or both, was carried out. Immediately after complete resection of the intraperitoneal recurrent tumors, a 2- to 3-hour IPHP was performed under hypothermic general anesthesia at about 32°C, using a perfusate containing 10 μg/ml or 20 μg/ml of mitomycin C (MMC) warmed at the inflow temperature of 46.6°C to 46.9°C. The apparatus used for IPHP was designed for intraperitoneal perfusion as a closed circuit. Although five of the six patients had a malignant peritoneal effusion at the time of admission, the effusion disappeared soon after IPHP, and no cancer cell was present in the lavage from Douglas' pouch. The other patient had a recurrent tumor at the anastomotic region after low anterior resection for rectal cancer and complete resection of the recurrent tumor, combined with IPHP, was carried out. One patient with a recurrent gastric cancer died of hepatic metastasis and cancerous pleuritis 5 months after this treatment, and the other five are in good health 12.8 ± 5.1 months after IPHP. On the other hand, five patients with intra-abdominal recurrent gastric cancer, who received only surgical treatment within the same period of time, died 3.0 ± 2.1 months after the surgery. Postoperatively, in the six patients with IPHP, transitory hepatic dysfunction, hypoproteinemia, and thrombocytopenia occurred. These results show that IPHP using MMC combined with surgery is a safe, reliable treatment for patients with peritoneal recurrence of gastrointestinal cancer.
To evaluate the clinical efficacy of intraperitoneal hyperthermic perfusion (IPHP) for far-advanced gastric cancer, particularly with peritoneal seeding, we investigated the survival times of 59 patients who underwent distal subtotal gastrectomy, total gastrectomy, or total gastrectomy combined with concomitant resection of some of the remaining intra-abdominal organs. In all the 30 patients given IPHP, no cancer cells were present posthyperthermically in the lavage from the Douglas pouch. The 30 patients given IPHP lived longer than the 29 patients not given IPHP (p = 0.001), with a 1-year survival rate of 80.4% in the former group compared to 34.2% in the latter. With respect to a comparison of survival time of patients with peritoneal seeding, 7 patients not given IPHP had a 6-month survival rate of 57.1% and did not survive more than 9 months, whereas 20 patients given IPHP had 1− and 2-year survival rates of 78.7% and 45.0%, respectively; here the difference was significant (p = 0.001). The IPHP and control groups without peritoneal metastasis included 10 and 22 patients, respectively, and the 1-year survival rates are 85.4% and 45.3%, respectively. The survival rates of the former exceeded those of the latter, with p = 0.015 by the generalized Wilcoxon test. Thus this combined therapy offers the promise of extended survival for patients with far-advanced gastric cancer.
Transient growth hormone deficiency (GHD) is occasionally found in prepubertal individuals, and this phenomenon has been variously interpreted. Sex steroids enhance GH secretion; however, the cut-off values of provocative GH tests are not modified according to the physiological changes. Physiological changes in sex steroid levels are thought to cause the image of transient GHD. In addition, the reproducibility of provocative GH tests makes the interpretation complicated. We experienced a case of a boy with short stature who had undergone provocative GH tests at three different times: childhood (5 and 7 years old), before puberty (12 years old), and in adolescence (15 years old). Although the responses of GH in his childhood and adolescence were within the normal range, his prepubertal GH response was extremely low, as if he had "complete" GHD (peak GH: insulin test, 0.60 ng/ml; clonidine test, 0.78 ng/ml). No morphological changes were observed in the pituitary gland or hypothalamus on MRI. The level of insulin-like growth factor 1 was in the normal range for his age at this time. Here, we report the clinical course and endocrinological data of this case, and suggest that transient GHD is caused not only by the physiological effects of sex steroids but also by certain mechanisms that actively reduce GH secretion.
Summary Purpose: Ohtahara syndrome is one of the most severe and earliest forms of epilepsy and is frequently associated with brain malformations, such as hemimegalencephaly. Recently, longer expansion of the first polyalanine tract of ARX was found to be causative for Ohtahara syndrome without brain malformation, whereas premature termination mutations of ARX were found to cause severe brain malformations, such as lissencephaly or hydranencephaly. Both are designated as ARX ‐related interneuronopathies. Methods: We investigated the molecular basis of Ohtahara syndrome in two families, comprising six male patients in two generations demonstrating X‐linked inheritance. Results: Novel frameshift mutations in the terminal exon of the ARX gene (Ala524fsX534 and E536fsX672) were identified in two patients (2 and 13 years, each) from both families. Two patients developed West syndrome, and one of these later developed Lennox‐Gastaut syndrome. Brain magnetic resonance imaging (MRI) of all patients showed no brain malformations in contrast to the patients with a premature termination mutation in other exons of ARX . Discussion: The etiology of Ohtahara syndrome is heterogeneous; however, the molecular analysis of ARX should be considered in sporadic or familial male patients with Ohtahara syndrome.
