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.

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.

A questionnaire-based survey of medical conditions in adults with Prader-Willi syndrome in Japan: implications for transitional care.

Prader-Willi syndrome (PWS) is a multisystem disorder with increased mortality predominantly due to obesity-associated complications; therefore, the management of obesity has been centric to therapeutic strategies for PWS. Although a multidisciplinary team approach has been successful for this purpose during childhood, it is generally difficult to implement during adulthood because of the lack of a structured transitional care program. A more detailed understanding of the current medical conditions of adults with PWS is needed to establish this program; however, limited information is currently available on this issue in Japan. Accordingly, we performed a questionnaire-based survey on 425 patients with PWS. There were 162 adult patients aged 18 years or older with median body mass indexes (kg/m2) of 29.4 and 30.4 in males and females, respectively. The frequencies of type 2 diabetes mellitus (T2DM) and hypertension in adults with PWS were 40.4 and 19.4%, respectively. Growth hormone (GH) therapy during childhood correlated with lower rates of T2DM and hypertension during adulthood. Among adult patients, 54% were treated by pediatricians, whereas 44% were seen by internists with an endocrinologist/diabetologist being the most prevalent. Adult patients treated with GH during childhood showed a higher rate of being seen by pediatricians than those without, demonstrating that the multidisciplinary team approach, typically applied with GH therapy, may be continuously provided even after they reach adulthood. These results emphasize the importance of the seamless provision of the multidisciplinary team approach, which is of clinical importance for establishing an optimal transitional care program for PWS.

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.

A symptomatic male carrier of Duchenne muscular dystrophy with Klinefelter's syndrome mimicking Becker muscular dystrophy.

Duchenne and Becker muscular dystrophy (DMD/BMD) are commonly inherited muscle disorders. We report a 31-year-old male who had muscle symptoms with left-right differences and intellectual disability. He was diagnosed with BMD at age 15 primarily based on muscle biopsy findings. A few years later, DMD gene analysis revealed that he was a heterozygous carrier of a normal copy of the gene and a mutated copy with an exon 45-54 deletion, which is expected to result in an out-of-frame mutation. A karyotype analysis was compatible with XXY Klinefelter's syndrome. The analysis of X-chromosome inactivation (XCI) using his skeletal muscle sample revealed a skewed XCI pattern. This is the first reported case of a symptomatic male carrier of DMD caused by skewed XCI in Klinefelter's syndrome with a genetically proven heterozygous mutation of the DMD gene. The skewed XCI pattern could also explain the left-right differences in skeletal muscle symptoms observed in this patient.

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.

Genome-wide methylation analysis in Silver-Russell syndrome, Temple syndrome, and Prader-Willi syndrome.

BACKGROUND: Imprinting disorders (IDs) show overlapping phenotypes, particularly in Silver-Russell syndrome (SRS), Temple syndrome (TS14), and Prader-Willi syndrome (PWS). These three IDs include fetal and postnatal growth failure, feeding difficulty, and muscular hypotonia as major clinical features. However, the mechanism that causes overlapping phenotypes has not been clarified. To investigate the presence or absence of methylation signatures associated with overlapping phenotypes, we performed genome-wide methylation analysis (GWMA). RESULTS: GWMA was carried out on 36 patients with three IDs (SRS [n = 16], TS14 [n = 7], PWS [n = 13]) and 11 child controls using HumanMethylation450 BeadChip including 475,000 CpG sites across the human genome. To reveal an aberrantly methylated region shared by SRS, TS14, and PWS groups, we compared genome-wide methylation data of the three groups with those of control subjects. All the identified regions were known as SRS-, TS14-, and PWS-related imprinting-associated differentially methylated regions (iDMRs), and there was no hypermethylated or hypomethylated region shared by different ID groups. To examine the methylation pattern shared by SRS, TS14, and PWS groups, we performed clustering analysis based on GWMA data. The result focusing on 620 probes at the 62 known iDMRs (except for SRS-, TS14-, and PWS-related iDMRs) classified patients into two categories: (1) category A, grossly normal methylation patterns mainly consisting of SRS group patients; and (2) category B, broad and mild hypermethylation patterns mainly consisting of TS14 and PWS group patients. However, we found no obvious relationship between these methylation patterns and phenotypes of patients. CONCLUSIONS: GWMA in three IDs found no methylation signatures shared by SRS, TS14, and PWS groups. Although clustering analysis showed similar mild hypermethylation patterns in TS14 and PWS groups, further study is needed to clarify the effect of methylation patterns on the overlapping phenotypes.

Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients.

BACKGROUND: Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype. RESULTS: Multigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS. CONCLUSIONS: We identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype.

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.

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.

Characteristic findings of skeletal muscle MRI in caveolinopathies.

Caveolinopathies, caused by CAV3 mutations, can include several phenotypes such as rippling muscle disease, limb-girdle muscular dystrophy type 1C, distal myopathy, familial hypertrophic cardiomyopathy, and idiopathic hyperCKemia. Here we present characteristic skeletal muscle imaging findings in four patients with genetically defined childhood-onset RMD caused by CAV3 mutations and in one patient with congenital generalized lipodystrophy type 4 with muscular dystrophy due to polymerase I and transcript release factor (PTRF) mutations, which may have caused secondary deficiency of caveolin-3. Muscle MRI revealed that the rectus femoris and semitendinosus muscles were most commonly affected in the rippling muscle disease patients. Peripheral changes in the rectus femoris were specific and observed even in one of the younger patients in this study. Furthermore, muscle involvement extended to the semitendinosus muscles, biceps femoris, and gracilis with disease progression or increase in its severity. Similar patterns of involvement were observed on reviewing skeletal muscle images of various previously reported phenotypes of caveolinopathy; interestingly, patients with secondary deficiency of caveolin due to PTRF mutations revealed the same pattern. Thus, primary caveolinopathies and secondary deficiency of caveolin demonstrated specific findings on skeletal muscle imaging, regardless of the broad phenotypic spectrum of these two conditions.

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.

Autistic, Aberrant, and Food-Related Behaviors in Adolescents and Young Adults with Prader-Willi Syndrome: The Effects of Age and Genotype.

The effects of age and genotype were examined, with regard to the severity of aberrant, autistic, and food-related behaviors in Prader-Willi syndrome (PWS), with an emphasis on the contrast between adolescents and young adults. The Aberrant Behavior Checklist Japanese version (ABC-J), the Food Related Problem Questionnaire (FRPQ), and the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) were administered to 65 PWS patients, including 20 adolescents (ages 12 to 17) and 45 young adults (ages 18 to 29). Significant differences (Mann-Whitney U tests) were found in ABC-J (p = 0.004) and PARS (p = 0.021), with lower scores in adolescents than in young adults. While DEL subgroups showed no significant differences between the two age groups in ABC-J (p = 0.063) and PARS (p = 0.134), mUPD subgroups showed a statistically significant difference in terms of ABC-J (p = 0.007). No significant differences were found between adolescents and young adults, in terms of FRPQ (p = 0.163). These results suggest that aberrant and autistic behaviors follow a marked worsening trend from around the age of 18. On the other hand, food-related behaviors give no sign of change at this transitory stage. Young adults with mUPD were found to be significantly more severe than adolescents with mUPD, in terms of aberrant behaviors.

Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies.

OBJECTIVE: Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have recently been associated with immune-mediated necrotizing myopathy, especially in patients with statin exposure. As the data are very limited concerning phenotypes and treatment in paediatric patients, we aimed to identify the paediatric patients positive for anti-HMGCR antibodies and clarify their features and therapeutic strategies. METHODS: We screened 62 paediatric patients who were clinically and/or pathologically suspected to have inflammatory myopathy for anti-HMGCR antibodies. We further re-assessed the clinical and histological findings and the treatment of the patients positive for anti-HMGCR antibodies. RESULTS: We identified nine paediatric patients with anti-HMGCR antibodies (15%). This was more frequent than anti-signal recognition particle antibodies (four patients, 6%) in our cohort. The onset age ranged from infancy to 13 years. Five patients were initially diagnosed with muscular dystrophy, including congenital muscular dystrophy. Most patients responded to high-dose corticosteroid therapy first but often needed adjuvant immunosuppressants to become stably controlled. CONCLUSION: Paediatric necrotizing myopathy associated with anti-HMGCR antibodies may not be very rare. Phenotypes are similar to those of adult patients, but a chronic slowly progressive course may be more frequent. Some patients share the clinicopathological features of muscular dystrophy indicating that recognizing inflammatory aetiology would be challenging without autoantibody information. On the other hand, most patients responded to treatment, especially those who were diagnosed early. Our results suggest the importance of early autoantibody testing in paediatric patients who have manifestations apparently compatible with muscular dystrophy in addition to those who have typical features of inflammatory myopathy.