Propranolol is more effective than pulsed dye laser and cryosurgery for infantile hemangiomas.

UNLABELLED: Propranolol hydrochloride is a nonselective ß-blocker that is used for the treatment of hypertension, arrhythmia, and angina pectoris. In Japan, it was recently approved for the treatment of childhood arrhythmia. It has been observed to produce drastic involution of infantile hemangiomas. The aim of this prospective study was to examine propranolol's superiority to classical therapy with pulsed dye laser and/or cryosurgery in treating proliferating infantile hemangiomas. Fifteen patients between the ages of 1 and 4 months with proliferating infantile hemangiomas received grinded propranolol tablets 2 mg/kg per day divided in three doses. Twelve patients with proliferating infantile hemangiomas receiving pulsed dye laser and/or cryosurgery were enrolled as controls. Baseline electrocardiogram, echocardiogram, and chest x-ray were performed. Monitoring of heart rate, blood pressure, and blood glucose was performed every 2 weeks. Efficacy was assessed by performing blinded volume measurements and taking photographs at every visit. Propranolol induced significantly earlier involution and redness reduction of infantile hemangiomas, compared to pulsed dye laser and cryosurgery. Adverse effects such as hypoglycemia, hypotension, or bradycardia did not occur. CONCLUSION: The dramatic response of infantile hemangiomas to propranolol and few side effects suggest that early treatment of infantile hemangiomas could result in decreased disfigurement. Propranolol should be considered as a first-line treatment of infantile hemangiomas.

Oral erosive lichen planus associated with thymoma treated with etretinate.

A 68-year-old Japanese woman was referred to our hospital with a 1-year history of multiple erosions on the oral mucosa and a few pruritic, bean-sized, reddish-blue plaques on the body. Based on physical examination, pathological findings, and immunofluorescence findings, a diagnosis of lichen planus (LP) was made. Computed tomography scan revealed a thymoma. After thymectomy, cutaneous LP lesions subsided spontaneously. Oral lesions responded well to oral etretinate therapy. We speculate that direct tissue injury by CD8(+) T cells, activated by abnormal regulation of lymphocytes within the thymus, may cause LP.

[Treatment with ramelteon for sleep disturbance in severely disabled children and young adults].

OBJECTIVE: The aim of this study was to determine the efficacy and safety of ramelteon for severely disabled children and young adults who had already been treated for sleep disturbance with melatonin at a dose of 3 mg. METHODS: Eleven patients, who were aged between 3-25 years and included 4 patients with cerebral palsy, -took 3-8 mg of ramelteon at bedtime, after a one-week of washout period. Sleep states were evaluated using sleep diaries recorded by caregivers or using actigraphs. RESULTS: Ramelteon was effective in 8 out of the 11 patients. Ramelteon was tolerated well except for mild daytime sleepiness in three patients. CONCLUSIONS: This preliminary study showed the efficacy and safety of ramelteon for sleep disturbance in severely disabled children and young adults. Further trials are necessary to determine optimal dosage and safety of ramelteon in children.

Questionnaire survey on sleep habits of 3-year-old children in Asahikawa City: Comparison between 2005 and 2020.

BACKGROUND: Good sleep is essential for children's healthy growth. In 2005, we conducted a questionnaire survey on children's sleep habits and their background, targeting parents who attended health checkups for their 3-year-old children in Asahikawa City, Hokkaido. In 2020, we performed a secondary survey, including additional questions regarding media usage. We analyzed changes in children's sleep environment by comparing the results of both surveys. METHODS: Children from 500 families (n = 420; 219 males, 201 females; mean age, 3.6 years) who underwent 3.5-year-old health checkups (per the changed schedule in 2015) in Asahikawa City from July 2020 to November 2020 and their parents who had completely answered the questionnaire were included. RESULTS: The proportion of children who used childcare support system such as nursery schools or kindergarten increased from 30% in the previous survey to 95% in the present survey. The mean nocturnal sleep duration of children was 9.33 h in the present survey, 0.77 h shorter than that in the previous survey; similar to the previous survey results, it was significantly short (8.71 h) in children who went to bed after 10 PM. Moreover, it was significantly short in children who watched television for more than two hours or used media within two hours before going to bed or if parents used smartphones or watched motion pictures for >30 min/day. The rate of consulting pediatricians regarding sleep problems decreased from 3% to 2.4%. CONCLUSION: Parents' lifestyles greatly influenced children's sleep habits in 2020. Pediatricians should actively participate in managing children's sleep problems.

Arginase deficiency with parotid gland swelling and hyperamylasemia: A case report.

Arginase deficiency is a progressive neurological disorder characterized by episodic hyperammonemia crises. Our patient had been diagnosed with cerebral palsy (spastic paraplegia) in childhood and received rehabilitation. She had suffered parotid swelling since the age of 5 years, prior to liver dysfunction becoming apparent, and then developed hyperamylasemia at 8 years of age. At age 25 years, she presented with hyperammonemia and elevations of aspartate aminotransferase and alanine aminotransferase. At age 27 years, she was diagnosed with arginase deficiency due to hyperargininemia and absent arginase activity in erythrocytes. Liver cirrhosis was also present. She was hospitalized several times for management of episodic hyperammonemia due to recurrent viral infections, an unbalanced diet, and poor compliance with medications.

GRIA3 p.Met661Thr variant in a female with developmental epileptic encephalopathy.

The X-linked human glutamate receptor subunit 3 (GRIA3) gene (MIM *305915, Xq25) encodes ionotropic α amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptor subunit 3, which mediates postsynaptic neurotransmission. Variants in this gene can cause a variety of neurological disorders, primarily reported in male patients. Here, we report a female patient with developmental and epileptic encephalopathy who carries the novel de novo GRIA3 variant NM_007325.5: c.1982T > C: p.Met661Thr.

Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features.

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T>C (p.Leu60Pro) mutation occurred de novo and the c.362G>C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.

Treatment of persistent Mongolian spots with Q-switched alexandrite laser.

Mongolian spots are congenital and confluent hyperpigmented areas that are usually grayish blue in color. They are found most frequently in the sacral region in infants and typically disappear during childhood. Occasionally, they persist to adulthood. We retrospectively examined outcomes of laser treatment of persistent Mongolian spots. We used Q-switched alexandrite laser to treat persistent Mongolian spots of 16 Japanese patients at 14 years old or older. A good therapeutic outcome was achieved overall; however, postinflammatory hyperpigmentation and hypopigmentation were observed in two patients, respectively. While laser treatment was effective for all seven patients with extrasacral Mongolian spots, four out of ten patients with sacral Mongolian spots were refractory to treatment. Of these patients, two received laser irradiation only twice and abandoned treatment, simply because of unsatisfactory results without any adverse events. The other two patients received treatments at intervals of 3 months, which resulted in postinflammatory hyperpigmentation. Contrary to children, who generally show good response after two or three sessions of irradiation, we should consider more frequent irradiation, longer intervals between treatment sessions, and use of bleaching creams in the treatment of persistent sacral Mongolian spots in adults.

Wisconsin syndrome with brain volume laterality: a case report and review of the literature.

BACKGROUND: Wisconsin syndrome is a congenital anomaly caused by a 3q interstitial deletion. It is associated with characteristic facies and developmental delays. Only 33 cases with a deletion estimated to be in the associated region 3q25 have been reported. CASE REPORT: We present the case of a 5-year-old Japanese girl with a 3q24q25.2 deletion. Her facial features corresponded to the Wisconsin syndrome phenotype, and she exhibited brain volume laterality, which has not been reported previously. CONCLUSION: The clinical features of our case may contribute to narrowing down the list of candidate genes of Wisconsin syndrome.

[Three children with Rasmussen encephalitis showing marked improvement in daily life activity following the functional hemispherectomy].

We investigated seizure, intelligence quotient (IQ), and neurological outcomes including the process of motor function recovery after functional right hemispherectomy in 3 children with Rasmussen's encephalitis (RE). Before the procedure, they were unable to walk, nor sit without support due to progressive worsening of left hemiplegia and relentless epilepsia partialis continua (EPC) of the left extremities, which were refractory to antiepileptic drug and immunological treatment. After functional right hemispherectomy, EPC completely disappeared, although complete left hemiplegia was sustained. However, they recovered up to being able to walk independently with assistance devices, and to have an ordinary life with family support within 1.5 to 5 months through rehabilitation. At the same time, the interictal EEG improved on the unaffected side of hemisphere, exhibiting a posterior alpha rhythm. Their IQ also improved, and they were able to attend school. Early functional hemispherectomy should be considered before patients with RE are left in a serious condition due to progressive worsening of hemiplegia and seizures refractory to the available treatment.

Severe gastrointestinal symptoms caused by a novel DDX3X variant.

Mutations in DDX3X have recently been identified as a common cause of intellectual disability and congenital anomalies. DDX3X (Xp11.4) encodes the DEAD box RNA helicase that plays an important role in gene regulation, apoptosis, and oncogenesis. Here, we report a case of 6-year-old Japanese girl with a novel variant (NM_001193416.3: c.1574A > G; p.(Tyr525Cys), who exhibited psychomotor retardation, severe constipation, and a recurrent paralytic ileus. This is the second report of severe gastrointestinal symptoms being associated with this disease. This report expands the phenotype caused by DDX3X variants and reveals an important clinical aspect for patients and medical staff.

[Surgical management for intractable aspiration in handicapped children].

Intractable aspiration is a life-threatening medical problem. Sixteen patients with intractable aspiration underwent surgical management. Their underlying diseases were cerebral palsy (n = 6), degenerative diseases (n = 5), acquired hypoxic ischemic encephalopathy (n = 4), and congenital myopathy (n = 1). Laryngotracheal separation was performed in nine patients with median age of 2 years 6 months (range: 7 mo - 13 y 5 mo), and laryngectomy was performed in seven with median age of 7 years 4 month (range: 1 y 6 mo - 17 y 1 mo). Surgical interventions were effective in all patients with respiratory distress. The most common complication was increased drawling in six patients, who recovered within 6 months of clinical follow-up. Other complications were tracheal granulations (n = 4), bleeding (n = 2), narrowing of the tracheal hole (n = 2), tracheomalacia (n = 2), ruptured suture (n = 1), and tracheal abscess (n = 1). Considering the underlying diseases and age, surgical management for intractable aspiration should be performed at appropriate timing.

Genitopatellar syndrome: the first reported case in Japan.

Genitopatellar syndrome (GPS) is mainly characterized by an absence of patellae, congenital flexion contractures of the lower limbs, psychomotor retardation, and anomalies of the external genitalia and kidneys. We report an 18-year-old female with a novel heterozygous truncating mutation in exon 17 of the KAT6B gene [MC_000010.11:c.3603_3606 del, p.Arg1201fs]. This is the first report of typical GPS in a Japanese individual. The details of our findings may contribute to elucidating the mechanism underlying GPS-specific clinical features.

[Evaluation of social functioning ability of disabled children].

Since 1999, we have been trying to establish a reliable method for evaluating social functioning ability (SFA) of physically handicapped children, in cooperation with the Project of Comprehensive Study of Disability, Social Health, and Welfare supported by the Ministry of Health, Labor and Welfare, Japan. In this study, we investigated the reliability and accuracy of the 4th edition of "The Evaluation of SFA". This evaluation consists of 40 items in 15 areas. We examined 45 disabled patients (26 males and 19 females) aged 12-27 years (mean age, 16 years). The reliability was checked by agreement of evaluations of the same patient carried out by two examiners. The results showed good reliability (kappa value of 0.42). According to the results of questionnaires, 97% of the examiners regarded this evaluation to be useful. Although the score of SFA correlated with intelligent quotient/development quotient, the score did not correlate with motor disability level. We hope that this evaluation will be widely used to upgrade SFA of disabled children.

Clinical and genetic features of acute encephalopathy in children taking theophylline.

BACKGROUND: Theophylline has recently been suspected as a risk factor of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), although there has been no systematic study on the relationship between acute encephalopathy in children taking theophylline (AET) and AESD. METHODS: We recruited 16 Japanese patients (11 male and 5 female, median age of 2 years and 7 months) with AET from 2008 to 2013. We evaluated their clinical features, such as the duration of first seizure, biphasic clinical course and cranial CT/MRI imaging and compared them with those of AESD. We analyzed the polymorphisms or mutations of genes which are associated with AESD. RESULTS: Clinically, 12 patients had neurological and/or radiological features of AESD. Only one patient died, whereas all 15 surviving patients were left with motor and/or intellectual deficits. Genetically, 14 patients had at least one of the following polymorphisms or mutations associated with AESD: thermolabile variation of the carnitine palmitoyltransferase 2 (CPT2) gene, polymorphism causing high expression of the adenosine receptor A2A (ADORA2A) gene, and heterozygous missense mutation of the voltage gated sodium channel 1A (SCN1A) and 2A (SCN2A) gene. CONCLUSIONS: Our results demonstrate that AET overlaps with AESD, and that AET is a multifactorial disorder sharing a genetic background with AESD.

[Effects of tizanidine for refractory sleep disturbance in disabled children with spastic quadriplegia].

Tizanidine is a centrally acting alpha-2 adrenoreceptor agonist widely used in the treatment of spasticity in patients with cerebral or spinal injury, and it is causing drawsiness in some of them. Based on these drug actions, we administered tizanidine to 21 spastic quadriplegic children with severe sleep disturbance not improved by conventional therapies. All these patients were showing abnormalities of both the induction and maintenance of sleep. The dosage of tizanidine was 0.1 to 0.2 mg/kg/day, divided into two or three doses. If daytime drowsiness was severe, tizanidine admistration was restricted to just prior to bedtime. In 13 patients (61.9%), we found improvement in sleep induction and/or maintenance. Moreover, patients' families were satisfied with the treatment. There were no detectable side effects except facial pallor in two patients (9.5%) whose treatment was discontinued. Severe muscle hypertonia causes severe pain, which generates strong sympathetic nerve activity and subsequent sleep disturbance. We consider that tizanidine has direct effects on the induction of sleep, and promotes muscular relaxation bringing about good sleep. We conclude that tizanidine is useful for the treatment of refractory sleep disturbance in spastic quadriplegic patients.

A case of primary cutaneous anaplastic large cell lymphoma with prominent epidermotropism.

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is defined as anaplastic large cell lymphoma localized to the skin without extracutaneous involvement at the time of diagnosis. Histologically, PCALCL is characterized by a dense nodular infiltrate of large lymphocytes, extending into the deep dermis or subcutis. Epidermotropism is sometimes, but not frequently, seen. We herein report a case of PCALCL with prominent epidermotropism. A 63-year-old Japanese woman was referred to our hospital with a red nodule and indurated erythema in 1997. Histological findings of a skin biopsy specimen from a red nodule were typical of PCALCL, however, biopsy specimens from indurated erythema showed remarkable epidermotropism. Tumor cells were positive for CD4, and CD30, but negative for CD3 and CD8. She was diagnosed with PCALCL. In 2007, skin biopsy was performed again, which showed large atypical lymphocytes in the upper dermis with mild epidermotropism. Tumor cells expressed in both CC chemokine receptor 4 and CXC chemokine receptor 3, which may explain prominent epidermotropism in this case.

PCDH19 mutation in Japanese females with epilepsy.

PURPOSE: To determine the significance of PCDH19 mutations in Japanese females with epilepsy and to delineate their phenotypes. METHODS: PCDH19 sequencing analysis was performed in 116 females with various epilepsies, including 97 with Dravet syndrome (83.6%). They were referred for SCN1A analysis, and 52 carried SCN1A mutations. RESULTS: Seven heterozygous mutations in exon 1 were identified in 7 patients (6.0%): 2 frameshift, 2 nonsense, and 3 missense mutations. One patient was a monozygotic twin, and her sister with mild phenotype carried the same mutation. The main clinical features among these 8 patients included early seizure onset (≤25 months of age), seizure clusters (7/8), fever-associated seizures (7/8), single seizure type (6/8), and late deterioration of intellect (5/8). Seizure durations were generally up to a few minutes, and only one patient developed status epilepticus once. The main seizure types were generalized tonic-clonic (4/8), tonic (3/8) and focal seizures, with (2/8) or without secondary generalization (3/8). Myoclonic, atonic and absence seizures were extremely rare. Two patients had Dravet syndrome (25%), and this proportion was significantly smaller than that in the total subjects (p<0.01). CONCLUSION: PCDH19 mutation is a relatively frequent cause of epilepsy in Japanese females. Dravet syndrome was rare in our cohort.

Nationwide survey (incidence, clinical course, prognosis) of Rasmussen's encephalitis.

PURPOSE: Rasmussen's encephalitis (RE) is a progressive and catastrophic epileptic disorder caused by chronic localized encephalitis. We performed a nationwide survey of RE to assess the clinical picture, treatment effect, and prognosis of Japanese RE patients. SUBJECTS & METHODS: The subjects were 27 patients (male:12; female:15) from 13 medical facilities. All of them satisfied the clinical and neuroimaging criteria for RE, including 14 pathologically proven cases. RESULTS: They were divided into the childhood-onset rapidly progressive type (CORP, n=19), and late-onset slowly progressive type (LOSP, n=8). The mean age at epilepsy onset was 4 years and 4 months in CORP, and 16 years in LOSP. The mean period between the onset age of epilepsy and development of frequent seizures was 1 year and 4 months in the former, and 3 years and 4 months in the latter. The immunomodulatory treatment including high-dose steroid (n=14) and high-dose intravenous immunoglobulin therapies (IVIgG, n=12) achieved more than a 50% reduction in the seizure frequency in 5 (36%) and 4 (33%) patients, respectively. Eight and seven patients underwent focal cortical resection and functional hemispherectomy, leading to significant improvement in 5 of the 8 patients and excellent seizure control in all 7 patients, respectively. CONCLUSION: Although the high-dose steroid and IVIG therapies may have alleviated the exacerbation of seizures in those with RE, they could not halt the disease progression. Functional hemispherectomy is still the only curative therapy for RE, despite the fact that the early introduction of this procedure remains controversial.