A case report of odonto-hypophosphatasia with a novel variant in the ALPL gene.

OBJECTIVES: Hypophosphatasia (HPP) is a rare skeletal dysplasia caused by variants in the alkaline phosphatase (ALPL) gene. More than 400 pathogenic variants of the ALPL gene have been registered in the ALPL gene variant database. Here, we describe the case of a Japanese child with odonto-hypophsphatasia (odonto-HPP) and a novel ALPL variant. CASE PRESENTATION: At the age of 2 years and 1 month, he prematurely lost one deciduous tooth, with the root intact, when he fell and hit his face lightly. Three months later, he lost another adjacent deciduous tooth without incentive. His serum alkaline phosphatase (ALP) level was 72 U/L. His urine phosphoethanolamine (PEA) level was extremely high at 938 µmol/mg·Cre. The serum pyridoxal 5'-phosphaye (PLP) level was 255.9 nmol/L. Based on the clinical symptoms and laboratory findings, the patient was clinically diagnosed with odonto-HPP. Genetic analysis of the ALPL gene revealed a heterozygous variant (NM_000478.6:c.1151C>A, p.Thr384Lys). CONCLUSIONS: We report a case of odonto-HPP with a novel variant in the ALPL gene. HPP is a rare disease, and the heterozygous mutation in the ALPL gene highlights the novelty of this case.

Dexamethasone to prednisolone rotation relieved hiccups in colorectal cancer patient continuing teleworking during anticancer therapy.

We present a case of chemotherapy-induced hiccups that were alleviated by steroid rotation. Hiccups are often overlooked, but they have an impact on the patient's quality of life. In the COVID-19 era, web-based teleworking has become an important tool, hiccups during a teleconference should be noted as a concern for patients.

Perinatal and neonatal characteristics of Prader-Willi syndrome in Japan.

BACKGROUND: Prader-Willi syndrome (PWS) is suspected at birth if extreme hypotonia, difficulty in feeding, hypogonadism, and failure to thrive are present. Genetic diagnosis of PWS can generally be made within the first few months of life; however, a delayed diagnosis of PWS is frequently reported. Although the clinical characteristics of perinatal and neonatal patients with PWS have been reported, there are no such reports on the clinical characteristics of these patients in Japan. METHODS: This retrospective, single-center study involved 177 Japanese patients with PWS and their medical data regarding the perinatal and neonatal periods were evaluated. RESULTS: The median maternal age at birth was 34 years; 12.7% of the mothers had a history of assisted reproductive technology (ART). Of the mothers, 13.5% reported polyhydramnios and 4.3% had oligohydramnios. Decreased fetal movement during pregnancy was reported by 76% of the mothers. A total of 60.5% of patients were born by cesarean section. Genetic subtypes included deletions (66.1%), uniparental disomy (31.0%), imprinting defects (0.6%), and other or unknown subtypes (2.3%). The median birth length was 47.5 cm and the median birthweight was 2476 g. Of the 160 patients, 14 (8.8%) were classified as small for gestational age. Most patients had hypotonia (98.8%), and 89.3% required gavage feeding at birth. Breathing problems, congenital heart disease, and undescended testis were noted in 33.1%, 7.0%, and 93.5% of patients, respectively. CONCLUSION: In our study, higher rates of ART, polyhydramnios, decreased fetal movements, cesarean section, hypotonia, feeding difficulties, and undescended testis were observed in PWS.

Negative effects of rivaroxaban observed in a patient with multiple common risks triggered by a bicycle accident.

The negative effects of anticoagulants are well-known in patients with renal impairment, drug-drug interaction, lower physical conditions, and multiple comorbidities. We highlight that even in patients with controllable multiple risks for rivaroxaban use, add-on inevitable risks will lead to negative effects greater than those expected.

Three pediatric cases of symptomatic hyponatremia in Prader-Willi syndrome.

OBJECTIVES: A recent large retrospective cohort study of cases of hyponatremia in Prader-Willi syndrome (PWS), conducted at nine reference centers, showed that severe hyponatremia was rare in PWS (0.5%); furthermore, all cases involved adults. Here, we describe three pediatric cases of severe hyponatremia in PWS, with neurological symptoms. CASE PRESENTATION: The cases involved two girls and one boy, and only one patient showed uniparental disomy. All patients had hyponatremia during infancy and presented with clinical symptoms, such as convulsions. All three patients improved with intravenous fluids and fluid restriction, with no sequelae. CONCLUSIONS: We report three pediatric cases of symptomatic hyponatremia of unknown cause in PWS. In patients with PWS, especially those with neurological symptoms such as convulsions, it is necessary to take hyponatremia into consideration.

Relationship Between Sensory Processing and Autism Spectrum Disorder-Like Behaviors in Prader-Willi Syndrome.

The relationship between sensory processing and ASD-like and associated behaviors in patients with Prader-Willi Syndrome (PWS) remains relatively unexplored. Examining this relationship, 51 adults with PWS were administered the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), Short Sensory Profile (SSP-J), Food-Related Problem Questionnaire (FRPQ), and Aberrant Behavior Checklist (ABC-J). Based on SSP-J z-scores, participants were classified into three severity groups. Analysis of variance was performed to compare the behavioral scores of these three groups. Statistically significant group differences were observed in PARS (p = .006, ηp2 = .194) and ABC-J (p = .006, ηp2 = .193) scores. Our findings suggest that the level of sensory processing may predict ASD-like and aberrant behaviors in adults with PWS, implying the importance of a proper assessment for early intervention.

Psychiatric behavioral effect and characteristics of type 2 diabetes mellitus on Japanese patients with Prader-Willi syndrome: a preliminary retrospective study.

OBJECTIVES: In recent years, research on behavioral and psychiatric problems of adults with Prader-Willi syndrome (PWS) has gained attention. However, no report is available regarding the relationship between psychiatric illness and type 2 diabetes mellitus (T2DM) in patients with PWS. Therefore, we evaluated a behavioral assessment to address the lack of data on the association between psychiatric behavior and T2DM. METHODS: This was a retrospective single-center study of patients with PWS. Patients with PWS whose blood tests were performed in our hospital between January 2018 and December 2019 and aged >10 years were included. We evaluated the data, including the behavioral patterns of Japanese PWS patients with T2DM. RESULTS: Overall, 114 patients were evaluated; 33 patients (28.9%) developed T2DM. The age of T2DM onset was 18.0 years (interquartile range [IQR], 14.6-21.4 years). The median body mass index at T2DM onset was 33.7 kg/m2 (IQR, 30.0-37.4 kg/m2). Between-group comparisons of the intelligence quotient, Food-Related Problem Questionnaire (FRPQ), and Japanese versions of the Short Sensory Profile and Aberrant Behavior Checklist showed a significant difference only in FRPQ scores (p=0.003). CONCLUSIONS: The occurrence of T2DM among Japanese patients with PWS remains high. Only the FRPQ was significantly different between the T2DM and the non-T2DM group.

Subtle Cardiovascular Abnormalities in Prader-Willi Syndrome Might Begin in Young Adulthood.

Objective Patients with Prader-Willi syndrome (PWS) are known to have a high mortality rate. However, little is known about the exact reason for this, particularly in adults, because so few reports have been published. The present study examined cardiovascular abnormalities to determine the cause of death in adults with PWS. Methods From September 2017 to April 2019, a total of 18 adults with PWS, and, no history of cardiovascular diseases, were enrolled. We investigated the levels of the cardiovascular biomarkers: high-sensitivity C-reactive protein (hs-CRP) and troponin T (TnT). To estimate the cardiac function, we measured the left ventricular ejection fraction (LVEF), global longitudinal systolic strain (GLS) of the left ventricle, ratio of peak early mitral filling velocity (E) to early diastolic mitral annular velocity (E/e' ratio), mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) using standard and tissue Doppler echocardiography. Results The mean patient age was 28±9 years old. There were 11 men, and the mean body mass index was 45.1 kg/m2. Dyslipidemia (82%), diabetes mellitus (82%) and hypertension (83%) were commonly found as comorbidities. Most patients had elevated levels of hs-CRP (mean 1.007±0.538 mg/dL). The LVEF (mean 61%±5%) showed normal values, while the GLS (mean 15.0%±3.0%) was decreased. The TAPSE was mildly reduced (mean 16±3 mm). Conclusion These results suggest that subtle cardiovascular abnormalities have already begun in young adults with PWS. We need to manage obesity and the resultant obesity-related disorders in order to prevent heart failure and coronary atherosclerosis in PWS patients.

Transdermal Fentanyl Usage in Working-age Patients Undergoing Cancer Treatment: Prescription Pattern Analysis Using Large Claims Data in Japan.

The number of working-age individuals undergoing cancer treatment has been increasing. In these patients, transdermal fentanyl is the preferred treatment. However, it is known to have (1) pharmacodynamic interactions with benzodiazepines and (2) fever-induced pharmacokinetic variations. The aim of this study is to clarify the frequency of co-administration of benzodiazepine and the predictors for fever among working-age patients with cancer using transdermal fentanyl. We used a large claims data source including over 3.6 million patients. Finally, 759 working-age patients aged 20 to 60 years undergoing cancer treatment, in whom transdermal fentanyl was initiated, were analyzed. The proportion of patients receiving co-administration of benzodiazepines with the first administration of transdermal fentanyl was 16.5% (n = 125). This increased to 39.3% (n = 298) within 30 days. Predictive factors for fever using patients' baseline characteristics were male sex, gastrointestinal cancer, hematological cancer, and renal disease. To provide adequate pharmacotherapy to working-age patients undergoing cancer treatment with transdermal fentanyl, medical staff should pay attention to (1) avoid adding benzodiazepines easily and (2) monitor patients having predictors for fever to avoid fentanyl-related adverse events.

Growth hormone treatment and bone mineral density in pediatric patients with Prader-Willi syndrome.

OBJECTIVES: Previous reports indicate that growth hormone (GH) treatment for Prader-Willi syndrome (PWS) improves bone mineral density (BMD) only when initiated at a young age and not when initiated in adulthood. However, there are no data on BMD during long-term GH treatment of Japanese children and adolescents with PWS. Thus, this study aimed to investigate BMD changes among patients with PWS, who were undergoing GH treatment from childhood to adolescence. METHODS: Sixty-seven pediatric patients with PWS who had GH treatment initiated during childhood between January 2003 and June 2020 were evaluated. To avoid underestimation, we used total body BMD, which was evaluated using dual-X-ray absorptiometry adjusted for the BMD z-score using patient height, sex, and age. RESULTS: In both sexes, age was negatively correlated with the BMD-standard deviation score (SDS) (male: r=-0.156 [p=0.042]; female: r=-0.197 [p=0.043]), which started to decrease in childhood. CONCLUSIONS: The BMD-SDS of patients with PWS decreases gradually despite GH treatment. As there are no clear recommendations about monitoring of bone health in patients with PWS, further studies are needed to improve the guidelines for screening of BMD and treatment of patients with PWS.

Successful treatment of Gaucher disease type 1 by enzyme replacement therapy over a 10-year duration in a Japanese pediatric patient: A case report.

The prevalence of Gaucher disease (GD) in Japan is much lower than that in Western countries; therefore, data on Japanese pediatric patients with GD type 1 are currently limited. The present study reports on the case of a Japanese pediatric patient with GD type 1 who was diagnosed when she presented with hepatosplenomegaly, thrombocytopenia and slight anemia at the age of 2 years. Serology tests revealed high levels of acid phosphatase (ACP) and angiotensin-converting enzyme (ACE). A bone marrow biopsy revealed the presence of Gaucher cells. Abdominal MRI indicated huge hepatosplenomegaly. Erlenmeyer flask deformity was observed on X-ray examination. MRI of the femora featured a high-intensity area within the diaphysis region. The enzymatic activity of leukocyte ß-glucosidase, the measurement of which is necessary for a definitive diagnosis of GD, had decreased to 186.7 nmol/h/mg (reference range, 1,424.0-2,338.0 nmol/h/mg). Based on these results, the patient was clinically diagnosed with GD. Glucocerebrosidase gene analysis identified the compound heterozygote mutation of F213I (c.754T>A) on exon 7 and L444P (c.1448T>C) on exon 11. Enzyme replacement therapy (ERT) along with an intravenous infusion of 60 U/kg of imiglucerase every other week was initiated following diagnosis. Hemoglobin levels and the platelet count gradually improved and normalized after two years. ACP and ACE levels, biomarkers of the progression of GD, also improved. Abdominal MRI at six months after the initiation of ERT revealed a decrease in the size of the liver and spleen, which normalized after 1 year. Conversely, MRI of the femora indicated no improvement in the high-intensity area within the diaphysis region for 10 years.

Predictive factors associated with bleeding in atrial fibrillation patients treated with anti-coagulant drugs using a large claims database.

OBJECTIVE: To identify risk factors for bleeding in atrial fibrillation (AF) patients treated with anti-coagulants such as warfarin, apixaban, edoxaban, dabigatran, rivaroxaban using a large claims database. METHODS: A claims database for 8926 AF patients from 2004 to 2016 was obtained from JMDC. Inc. We performed a retrospective cohort study in 2796 Japanese AF patients with 4-month screening and 12-month observation periods. Polypharmacy was defined as prescription of over six drugs. Logistic regression analysis was conducted after stratification based on the presence and absence of cerebrovascular diseases to detect the predictive factors for bleeding. RESULTS: Polypharmacy was observed in 815 of 2796 (29.1%) patients. A total of 371 AF patients (13.3%) experienced bleeding in the 12-month observation period. Bleeding risk assessment using multiple logistic regression analysis revealed that the odds ratio for the number of co-administered drugs in the elderly (age for ≥60, ≤74) was not significant in those without and with cerebrovascular diseases (1.05 [0.99-1.12], N.S. and 1.10 [0.96-1.27], N.S.). In contrast, in the young (age for <60), the number of co-administered drugs was a significant predictive factor in those without and with cerebrovascular diseases (1.09 [1.03-1.16], p = 0.0054 and 1.20 [1.05-1.36], p = 0.0059). Other observed predictors were"history of bleeding" in young and elderly, but "polypharmacy" and "start from warfarin" were observed in only young. CONCLUSION: We determined the bleeding risk in the clinical setting using a large claims database. Physicians and pharmacists need to monitor patients for the initial bleeding signs, particularly in those with these predictive risk factors.

Effects of growth hormone treatment on thyroid function in pediatric patients with Prader-Willi syndrome.

It is unclear whether hypothyroidism is present in patients with Prader-Willi syndrome (PWS). This study aimed to clarify the state of the hypothalamic-pituitary-thyroid axis and the effects of growth hormone (GH) treatment on thyroid function in pediatric patients with PWS. We retrospectively evaluated thyroid function in 51 patients with PWS before GH treatment using a thyroid-releasing hormone (TRH) stimulation test (29 males and 22 females; median age, 22 months). We also evaluated the effect of GH therapy on thyroid function by comparing serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels at baseline, 1 year, and 2 years after GH therapy. TSH, fT4, and fT3 levels were 2.28 µU/ml (interquartile range [IQR]; 1.19-3.61), 1.18 ng/dl (IQR; 1.02-1.24), and 4.02 pg/dl (IQR; 3.54-4.40) at baseline, respectively. In 49 of 51 patients, the TSH response to TRH administration showed a physiologically normal pattern; in two patients (4.0%), the pattern suggested hypothalamic hypothyroidism (delayed and prolonged TSH peak after TRH administration). TSH, fT4, and fT3 levels did not change significantly during 1 or 2 years after GH treatment. The TSH response to TRH showed a normal pattern in most patients, and thyroid function did not change significantly during the 2 years after initiating GH treatment.

(Epi)genetic defects of MKRN3 are rare in Asian patients with central precocious puberty.

We sequenced MKRN3, the major causative gene of central precocious puberty in Western countries, in 24 Japanese or Chinese patients and examined the DNA methylation and copy-number statuses of this gene in 19 patients. We identified no (epi)genetic defects except for one previously reported mutation. These results, together with reports from Korea, indicate that MKRN3 defects are rare in Asian populations. The ethnic differences likely reflect Western country-specific founder mutations and the rarity of de novo mutations.

Early adiposity rebound in patients with Prader-Willi syndrome.

Background Prader-Willi syndrome (PWS) is associated with marked obesity that can lead to severe complications such as diabetes mellitus. Early adiposity rebound (AR) is associated with future obesity and an increased risk of diabetes mellitus and metabolic syndrome. Previous reports have shown that the onset of AR occurred earlier in diseases that cause obesity. However, there have been no studies focusing on the timing of AR in PWS, or on the effect of growth hormone (GH) treatment on AR. The aim of this study was to explore AR in PWS patients and to analyze the effect of GH treatment on AR. Methods This retrospective study evaluated 48 patients, with 16 of the patients found to have AR prior to GH treatment. AR was constructed for each patient using Microsoft Excel, and the exact point of the nadir of body mass index (BMI) following the initial peak was determined. We additionally analyzed the relationship between GH treatment and the timing of AR onset. Results AR onset for patients found to have AR before starting GH treatment was 16.0 (13.0-21.0) months. In contrast, AR onset for patients found to have AR after starting GH treatment was 27.5 (23.8-36.3) months. The difference between the two groups was statistically significant (p=0.0001). A positive correlation was found between the GH treatment period and AR (p=0.00013). Conclusion The median age of AR onset in PWS patients was 16.0 (13.0-21.0) months, and GH treatment might delay the early AR onset.

Delayed peak response of cortisol to insulin tolerance test in patients with Prader-Willi syndrome.

Deaths among children with Prader-Willi syndrome (PWS) are often related to only mild or moderate upper respiratory tract infections, and many causes of death remain unexplained. Several reports have hypothesized that patients with PWS may experience latent central adrenal insufficiency. However, whether PWS subjects suffer from alteration of the hypothalamus-pituitary-adrenal (HPA) axis remains unclear. This study aimed to explore the HPA axis on PWS. We evaluated the HPA axis in 36 PWS patients (24 males, 12 females; age range, 7 months to 12 years; median age 2.0 years; interquartile range [IQR], 1.5-3.4 years) using an insulin tolerance test (ITT) in the morning between 08:00 and 11:00. For comparison, ITT results in 37 age-matched healthy children evaluated for short stature were used as controls. In PWS patients, basal levels of adrenocorticotropic hormone (ACTH) were 13.5 pg/ml (IQR, 8.3-27.5 pg/ml) and basal levels of cortisol were 18.0 µg/dl (IQR, 14.2-23.7 µg/dl). For all patients, cortisol levels at 60 min after stimulation were within the reference range (>18.1 µg/dl), with a median peak of 41.5 µg/dl (IQR, 32.3-48.6 µg/dl). Among control children, basal level of ACTH and basal and peak levels of cortisol were 10.9 (IQR, 8.5-22.0 pg/ml), 15.6 (IQR, 11.9-21.6 µg/dl), and 27.8 µg/dl (IQR, 23.7-30.5 µg/dl), respectively. Basal and peak levels of cortisol were all within normal ranges, but peak response of cortisol to ITT was delayed in the majority of PWS patients (64%). Although the mechanism remains unclear, this delay may signify the existence of central obstacle in adjustment of the HPA axis.

Aberrant, autistic, and food-related behaviors in adults with Prader-Willi syndrome. The comparison between young adults and adults.

This study aims to explore the differences of age as well as genotype in regards to the severity of behavioral symptoms in Prader-Willi syndrome (PWS), with emphasis on the comparison between youngadults and adults.The Food Related Problem Questionnaire (FRPQ), the Aberrant Behavior Checklist Japanese Version (ABC-J), and the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) were administered to 46 PWS patients, including 33 young adults (ages 18-28) and 13 adults(ages 30-45). To examine the differences between young adults and adults, Mann-Whitney U tests were conducted. Statistically significant differences were found in ABC-J (p = .027) and PARS (p = .046), with higher scores in young adults than adults. Such differences between the two age groups were still true for the subgroups having a paternal chromosome 15q deletion (DEL) for ABC-J (p = .050) and part of PARS ("Problematic behavior"; p = .007). By contrast, there was no significant differences between young adults and adults regarding FRPQ (p = .65).These results suggest that aberrant behaviors decline from around the ages of thirty, in PWS patients in general and in DEL subgroups in particular, while food-related behaviors give no indication of diminishing in spite of developmental growth.

Partial lipodystrophy in patients who have undergone hematopoietic stem cell transplantation during childhood: an institutional cross-sectional survey.

Partial lipodystrophy (PD), a condition similar to metabolic syndrome without obesity, is one of the late complications of hematopoietic stem cell transplantation (HSCT) performed during childhood. We aimed to investigate the prevalence and risk factors of PD. A cross-sectional survey was performed in a children's hospital, targeting patients treated for a malignancy or hematological disorder, and who were disease-free for > 24 mo. PD was defined as gluteal lipoatrophy and lipohypertrophy of the cheeks or neck associated with diabetes and/or fatty liver disease. In total, 65 patients were enrolled. Six patients (9.2%) were judged to have PD, all of whom had received 10-14 Gy total body irradiation. Compared with the patients without PD, patients with PD were older at investigation (P < 0.01), had a longer elapsed time following HSCT (P < 0.01), had more frequent disease recurrence (P < 0.05), and were more likely to have undergone multiple HSCT (P < 0.05). In addition, they had higher blood pressure and showed higher levels of low-density lipoprotein-cholesterol and triglycerides, whereas their adiponectin levels were significantly lower. In conclusion, a large number of patients developed PD following HSCT, with unfavorable metabolic profiles at a later age, especially when they experienced a complex disease course.