Tertiary hyperparathyroidism in patients with pseudohypoparathyroidism type 1a.

Pseudohypoparathyroidism type 1a (PHP1a) is a genetic disorder caused by heterozygous loss-of-function mutations on the maternal allele of the GNAS gene. Patients with PHP1a predominantly exhibit parathyroid hormone (PTH) resistance and physical features of Albright's hereditary osteodystrophy. We report two unrelated cases with PHP1a who developed tertiary hyperparathyroidism (HPT). Molecular analyses of the GNAS gene identified a previously known heterozygous 4-bp deletion (c. 565_568delGACT) in exon 7 in case 1 and a novel heterozygous missense mutation (p.Lys233Glu) in exon 9 in case 2. Both patients developed tertiary HPT associated with hyperfunctioning parathyroid glands during long-term treatment of hypocalcemia. Case 1 had severe osteoporosis and underwent parathyroidectomy. Case 2 was asymptomatic with no evidence of bone diseases associated with tertiary HPT. PHP1a patients are at risk of developing tertiary HPT and should be treated with sufficient doses of calcium and vitamin D to achieve serum PTH levels within the mid - normal to double the upper limit of the normal range, regardless of serum calcium levels.

Role of E148Q in familial Mediterranean fever with an exon 10 mutation in MEFV.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease caused by mutations in the MEFV gene. Mutations in exon 10 are associated with typical FMF. Most Japanese patients with typical FMF are compound heterozygotes of M694I in exon 10 and E148Q in exon 2. However, the pathogenic role of E148Q remains controversial. METHODS: We assessed symptoms and serum cytokines among patients with FMF and their family members. They were divided into three subgroups, based on MEFV mutations: individuals carrying M694I and E148Q (group A, n = 14), individuals carrying M694I, but not E148Q (group B, n = 10), and individuals carrying E148Q, but not M694I (group C, n = 11). RESULTS: All but one individual in group A had typical FMF phenotypes, whereas no individual in groups B and C exhibited any episodes of fever or serositis. The serum levels of interleukin-18 during the afebrile phase were significantly elevated in group A (2,806 ± 2,107 pg/mL), compared to those in groups B (499 ± 369 pg/mL) and C (427 ± 410 pg/mL). No difference in interleukin-6 levels was observed among the three groups. CONCLUSIONS: These findings indicated that E148Q may contribute to disease development of FMF in Japanese patients carrying the heterozygous M694I mutation in MEFV and that genetic testing of both parents would lead to better counseling for their children.

Nucleotide substitutions in CD101, the human homolog of a diabetes susceptibility gene in non-obese diabetic mouse, in patients with type 1 diabetes.

AIMS/INTRODUCTION: Although genome-wide association studies have identified more than 50 susceptibility genes for type 1 diabetes, low-frequency risk variants could remain unrecognized. The present study aimed to identify novel type 1 diabetes susceptibility genes by newly established methods. MATERIALS AND METHODS: We carried out whole-exome sequencing and genome-wide copy-number analysis for a Japanese family consisting of two patients with type 1 diabetes and three unaffected relatives. Further mutation screening was carried out for 127 sporadic cases. The functional consequences of identified substitutions were evaluated by in silico analyses and fluorescence-activated cell sorting of blood samples. RESULTS: Whole-exome sequencing and genome-wide copy-number analysis of familial cases showed co-segregation of the p.V863L substitution in CD101, the human homolog of an autoimmune diabetes gene in the non-obese diabetic mouse, with type 1 diabetes. Mutation screening of CD101 in 127 sporadic cases detected the p.V678L and p.T944R substitutions in two patients. The p.V863L, p.V678L and p.T944R substitutions were absent or extremely rare in the general population, and were assessed as 'probably/possibly damaging' by in silico analyses. CD101 expression on monocytes, granulocytes and myeloid dendritic cells of mutation-positive patients was weaker than that of control individuals. CONCLUSIONS: These results raise the possibility that CD101 is a susceptibility gene for type 1 diabetes.

Pediatric symptomatic Rathke cleft cyst compared with cystic craniopharyngioma.

INTRODUCTION: Symptomatic Rathke cleft cysts (RCCs) are rarely detected in neuroradiological screening and are less commonly found in children than in adults. However, when RCCs are observed in children, it is important to carefully distinguish a RCC from a cystic craniopharyngioma (CP) even if surgically treated or conservatively followed up. METHODS: We conducted a retrospective review of clinical data from 11 patients with symptomatic RCCs whose ages were under 18 years and compared the data with data from 15 age- and sex-matched patients with cystic CP who were treated at our institute. RESULTS: The mean age of the patients with RCCs was 12.2 years (range, 6-18). There were six males and five females. As initial symptoms, nine patients presented with headache, while two each had impaired visual function, diabetes insipidus, and activity loss. The 14 patients with CP suffered from impaired visual function. Magnetic resonance imaging (MRI) mainly showed hyperintensity on T1-weighted images (WIs) and hypointensity on T2-WI in patients with RCC. However, patients with CP had characteristic hyperintensity on T2-WI. The average maximum diameter of the RCCs was 19.0 mm on average (range, 8-33 mm). The RCCs were thus significantly smaller than CPs (34.9 mm; range, 21-54 mm). The RCCs were usually oval or dumbbell-shaped and regular in appearance, while the larger CPs were lobular and irregular. A preoperative endocrinological evaluation revealed insufficiencies in four axes in five patients with RCC. Postoperative endocrinological status improved in three patients, remained unchanged in three, and worsened in one. The gonadotropin axis was damaged in a majority (nine) of the patients with CP preoperatively. Postoperative evaluation revealed deficits in five axes in 14 patients with CP, which is a significantly different trend than observed in patients with RCC. Eight patients underwent surgical procedures (transsphenoidal surgery (TSS) in four, craniotomy in four). Two of these patients experienced a recurrence of the cysts. One of these patients subsequently underwent two craniotomies followed by radiation and other underwent TSS. Among the three conservatively treated patients, two experienced a transient worsening of their symptoms along with cyst enlargement. However, none of the three conservatively treated patients required an operation. CONCLUSIONS: When RCCs become symptomatic in children, the most common symptom they lead to is headache. The cysts are commonly small, regular, and oval in shape. Hypointensity of cyst contents on MRI is a characteristic of RCCs, which distinguishes them from CPs. Surgical intervention can be effective and lead to the relief of symptoms without a high rate of complications. However, there seems to be a relatively high recurrence rate following surgery. Thus, if the patient's symptoms remain minor, the surgical treatment option should be used only when prudent, as the patient's symptoms may improve over time.

Detection of the development of late-onset idiopathic aqueductal stenosis (LIAS) by chronological magnetic resonance imaging: a case report.

Late-onset idiopathic aqueductal stenosis (LIAS) has been recognized as one of the clinical entities of adulthood hydrocephalus for decades, although there have been no radiological reports that show normal ventricular systems before the development of LIAS. We present here an adolescent case of LIAS with a previously normal ventricular system on magnetic resonance imaging (MRI). A 17-year-old boy had been suffering from chronic headaches and mild intellectual disability (MID) since he became a teenager, and this had prevented him from leading an ordinary school life. MRIs on admission showed triventriculomegaly from the aqueductal stenosis that had not been detected on previous MRIs, at least until the age of 6. An endoscopic third ventriculostomy was successfully performed, which improved both the headache and the MID. The developmental mechanism of LIAS remains unclear, although the membranous ependymal-like tissue observed in the aqueduct suggested the preceding existence of an inflammatory process around this region. To the best of our knowledge, this case was noteworthy because the development of LIAS was clearly demonstrated on MRI for the first time.

Urinary heme oxygenase-1 as a sensitive indicator of tubulointerstitial inflammatory damage in various renal diseases.

BACKGROUND/AIMS: In oxidative stress, heme oxygenase-1 (HO-1) plays a pivotal role in maintaining renal function and protecting renal structure, especially in renal tubular epithelial cells. We examined urinary HO-1 (uHO-1) levels to assess whether uHO-1 acts as a sensitive biomarker for detecting tubulointerstitial inflammatory damage in renal diseases. METHODS: Immunohistochemical analyses and enzyme-linked immunosorbent assays for uHO-1 were performed using 61 urine samples (supernatants and sediment lysates) from healthy children and renal disease patients. RESULTS: Proximal and distal epithelial cells showed higher uHO-1 levels than squamous and urothelial cells. Inflammatory renal disease patients had higher uHO-1 levels than noninflammatory renal disease patients and controls. In IgA nephropathy, patients with interstitial cellular infiltration showed higher uHO-1 levels than those without it. Among patients with increased urinary ß(2)-microglobulin or N-acetyl-ß-D-glucosaminidase levels, uHO-1 levels increased only in those with renal disease and tubulointerstitial inflammatory damage. uHO-1 levels positively correlated with urinary interleukin-6 in inflammatory renal disease patients. CONCLUSIONS: These results indicate that uHO-1 is a potentially useful, novel, and noninvasive biomarker for evaluating the degree of tubulointerstitial inflammatory damage in renal disease.

Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome.

X-linked severe combined immunodeficiency (XSCID) is caused by mutations of the common gamma chain (gammac) and usually characterized by the absence of T and natural killer (NK) cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations. The patient carried a splice-site mutation (IVS1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual gammac expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation and result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression.