Identification of clinical factors related to antibody-mediated immune response to the subfornical organ.

OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.

Child Neurology: Pathologically Confirmed Thrombotic Microangiopathy Caused by Onasemnogene Abeparvovec Treatment for SMA.

Onasemnogene abeparvovec is an adeno-associated virus vector-based gene therapy for spinal muscular atrophy (SMA). Although several cases of drug-induced thrombotic microangiopathy due to onasemnogene abeparvovec have been reported, none has been confirmed pathologically. Here, we present renal histopathologic findings of TMA due to onasemnogene abeparvovec. On day 5 after receiving onasemnogene abeparvovec, a 23-month-old girl with SMA type 1 developed thrombocytopenia, microangiopathic hemolytic anemia, liver dysfunction, acute kidney injury, and hypertension. She was diagnosed with TMA and received an increased dose of prednisolone, antihypertensives, diuretics, packed red blood cell and platelet transfusion, a single dose of eculizumab, 4 cycles of plasmapheresis, and intermittent and continuous hemodialysis. Her TMA resolved by day 30. On day 49, renal biopsy was performed. Light microscopy revealed proliferation of glomerular mesangial cells and matrix, with mesangiolysis, endothelial cell swelling, and partial double contours of the glomerular basement membrane. Electron microscopy showed endothelial injury, with edematous changes of the subendothelial spaces and neoformation of the basement membrane, without electron-dense depositions. These findings are compatible with the recovery phase of TMA. One year after drug administration, her motor function is improved. She can hold her posture against gravity and has neither dysphagia nor respiratory disturbance, but mild hypertension persists. Physicians should be vigilant regarding TMA as a severe side effect of onasemnogene abeparvovec treatment, especially when thrombocytopenia, hemolytic anemia, increased lactate dehydrogenase, or acute kidney injury is present.

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Relapsing 6q24-related transient neonatal diabetes mellitus successfully treated with a dipeptidyl peptidase-4 inhibitor: a case report.

The most common form of transient neonatal diabetes mellitus (TNDM) is 6q24-related TNDM. Patients are treated with insulin during the neonatal period until spontaneous remission. However, diabetes often recurs in adolescence, and there is no standard therapy for patients with a relapse. A paternal duplication at the 6q24 critical region spanning the pleiomorphic adenoma gene-like 1 PLAGL1 gene was found in a Japanese patient with TNDM relapse. The patient was treated with a dipeptidyl peptidase-4 (DPP4) inhibitor, alogliptin, at a dose of 25 mg per day. Immediately after treatment initiation, his hemoglobin A1c (HbA1c) levels dropped from 7.0-7.5% (52-58 mmol/mol) to 6.0-6.5% (41-47 mmol/mol) and remained stable for over a year. We reported the successful treatment of relapsed 6q24-related TNDM with a DPP4 inhibitor. Although insulin has been the conventional treatment for such patients, treatments targeting the GLP1 pathway can be a useful alternative because these patients retain the ß cell mass and responsiveness through G protein-coupled pathways.

Childhood pheochromocytoma in a survivor of central primitive neuroectodermal tumor.

Pheochromocytoma and central nervous system primitive neuroectodermal tumor are both neural crest-derived tumors. The former is usually benign and develops mainly in adulthood and the latter brain tumor mainly occurs in childhood and has a poor prognosis. We report a case of a 15-year-old boy who developed pheochromocytoma after more than 10 years of complete remission of central primitive neuroectodermal tumor. Thus far, there have been no reports of childhood cancer survivors who developed pheochromocytoma. This quite rare occurrence of two tumors in a single patient may imply some unidentified linkage or common genetic background.

Efficacy and safety of long-term, continuous subcutaneous octreotide infusion for patients with different subtypes of KATP-channel hyperinsulinism.

OBJECTIVE: To evaluate the efficacy of long-term, continuous, subcutaneous octreotide infusion for congenital hyperinsulinism caused by mutations in the KATP-channel genes, KCNJ11 and ABCC8. PATIENTS: Fifteen Japanese patients with diazoxide-unresponsive, KATP-channel hyperinsulinism. METHODS: Molecular diagnoses were made by sequencing and multiple ligation-dependent probe amplification analysis. In patients with paternally inherited, monoallelic mutations, 18F-DOPA PET scans were performed to determine the location of the lesion. The patients were treated with continuous, subcutaneous octreotide infusion at a dosage of up to 25 µg/kg/day, using an insulin pump to maintain blood glucose levels higher than 3.33 mmol/l. Additional treatments (IV glucose, glucagon or enteral feeding) were administered as needed. The efficacy of the treatment was assessed in patients who received octreotide for 4 months to 5.9 years. RESULTS: Three patients had biallelic mutations, and 12 had monoallelic, paternally inherited mutations. Four patients with monoallelic mutations showed diffuse 18F-DOPA uptake, whereas seven patients showed focal uptake. Octreotide was effective in all the patients. The patients with biallelic mutations required a higher dosage (17-25 µg/kg/day), and two patients required additional treatments. By contrast, the patients with monoallelic mutations required a lower dosage (0.5-21 µg/kg/day) irrespective of the PET results and mostly without additional treatments. Treatment was discontinued in three patients at 2.5, 3.3 and 5.9 years of age, without psychomotor delay. Except for growth deceleration at a higher dosage, no significant adverse effects were noted. CONCLUSIONS: Long-term, continuous, subcutaneous octreotide infusion is a feasible alternative to surgery especially for patients with monoallelic KATP-channel mutations.

Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus.

BACKGROUND: In Asians, mutations in the known maturity-onset diabetes of the young (MODY) genes have been identified in only <15% of patients. These results were obtained mostly through studies on adult patients. OBJECTIVE: To investigate the molecular basis of Japanese patients with pediatric-onset MODY-type diabetes. SUBJECTS: Eighty Japanese patients with pediatric-onset MODY-type diabetes. METHODS: Mitochondrial 3243A>G mutation was first tested by the polymerase chain reaction restriction fragment length polymorphism analysis for maternally inherited families. Then, all coding exons and exon-intron boundaries of the HNF1A, HNF1B, GCK, and HNF4A genes were amplified from genomic DNA and directly sequenced. Multiplex ligation-dependent probe amplification analysis was also performed to detect whole-exon deletions. RESULTS: After excluding one patient with a mitochondrial 3243A>G, mutations were identified in 38 (48.1%) patients; 18 had GCK mutations, 11 had HNF1A mutations, 3 had HNF4A mutations, and 6 had HNF1B mutations. In patients aged <8 yr, mutations were detected mostly in GCK at a higher frequency (63.6%). In patients >9 yr of age, mutations were identified less frequently (45.1%), with HNF1A mutations being the most frequent. A large fraction of mutation-negative patients showed elevated homeostasis model assessment (HOMA) insulin-resistance and normal HOMA-ß indices. Most of the HNF1B mutations were large deletions, and, interestingly, renal cysts were undetectable in two patients with whole-gene deletion of HNF1B. CONCLUSION: In Japanese patients with pediatric-onset MODY-type diabetes, mutations in known genes were identified at a much higher frequency than previously reported for adult Asians. A fraction of mutation-negative patients presented with insulin-resistance and normal insulin-secretory capacities resembling early-onset type 2 diabetes.

Lasting 18F-DOPA PET uptake after clinical remission of the focal form of congenital hyperinsulinism.

BACKGROUND: Positron emission tomography (PET) using (18)F-DOPA is a useful tool for detecting the focal forms of congenital hyperinsulinism. (18)F-DOPA is taken up by aromatic L-amino acid decarboxylase in pancreatic ß-cells. However, the role of this enzyme in insulin secretion is unknown. SUBJECTS AND METHODS: A Japanese boy who presented with symptomatic hyperinsulinemic hypoglycemia at the age of 2 days and spontaneous resolution at 1 year and 10 months was subjected to mutational analysis and repeated (18)F-DOPA PET scans. RESULTS: Mutational analysis revealed a paternally inherited monoallelic mutation, c.4186G>T (p.D1396Y), in the ABCC8 gene, and an (18)F-DOPA PET scan revealed focal uptake in the body of the pancreas. The patient was successfully treated with frequent feeding. A follow-up PET scan revealed virtually identical uptake to that observed previously. However, in the arterial stimulation-venous sampling procedure, no significant insulin release was observed. He was placed on a normal diet, and no hypoglycemia recurrence was observed. CONCLUSION: This case demonstrates two important findings. Firstly, the uptake of (18)F-DOPA does not correlate with the insulin-secreting capacity of the lesion. Secondly, clinical remission could be a functional process not necessarily accompanied by the apoptotic death of abnormal ß-cells.

Wide phenotypic variations within a family with SALL1 mutations: Isolated external ear abnormalities to Goldenhar syndrome.

We report on wide phenotypic variations within a family with SALL1 mutations; the elder sister presented with a Townes-Brocks syndrome phenotype including external ear anomalies, preaxial polydactyly, and anteriorly placed anus, whereas the younger sister presented with a phenotype resembling Goldenhar syndrome, including atretic ear canals, mandibular hypoplasia, and right preaxial polydactyly as well as an epibulbar dermoid. The mother had abnormal external ears but was otherwise structurally normal, and the father was asymptomatic. Analysis of the SALL1 gene revealed that both daughters were heterozygous for nonsense mutation 1256T>A (L419X), that is present 5' to the region encoding the first double zinc finger. The mother was heterozygous for the L419X mutation. The younger daughter is the first patient with a SALL1 mutation to exhibit a classic Goldenhar syndrome-like phenotype with an epibulbar dermoid. The observation lends further support to the concept that Goldenhar syndrome is an etiologically heterogeneous disorder that may have a genetic basis in some cases.

Mechanisms of development and progression of cyanotic nephropathy.

Cyanotic nephropathy (CN) is often accompanied by congenital cyanotic heart diseases (CCHD). The purpose of this study was to clarify the risk factors and the mechanisms of involved in the development and progression of CN. Thirty patients with CCHD were examined. We analyzed the risk factors for the development of CN on the basis of the clinical and laboratory findings. We also examined ten renal biopsy specimens obtained from patients with CN. Patients with CN showed significantly higher hematocrit levels than those without CN (P=0.025), although there was no difference between the two groups in terms of oxygen saturation. The renal plasma flow (RPF) in patients both with and without CN was low. However, the filtration fraction (FF) was significantly lower in patients with CN than in those without CN (P=0.001). The glomeruli of biopsy specimens with significant proteinuria (n=7) were larger than those of biopsy specimens without significant proteinuria, and there were more capillaries per glomerulus in the former than in the latter (n=3) and the control specimens (n=6) (glomerular size: P<0.01; number of glomerular capillaries: P<0.01). In conclusion, hyperviscosity by polycythemia may be responsible for the development of CN. This pathological condition may induce an angiogenic increase in the glomerular capillary beds, in turn leading to glomerulomegaly. In addition, the failure of a compensatory mechanism to respond to reduced RPF by hyperfiltration may be accompanied by the development and progression of CN.