Novel insight into nicotinamide adenine dinucleotide and related metabolites in cancer patients undergoing surgery.

Nicotinamide adenine dinucleotide (NAD +) plays a pivotal role in numerous cellular functions. Reduced NAD + levels are postulated to be associated with cancer. As interest in understanding NAD + dynamics in cancer patients with therapeutic applications in mind grows, there remains a shortage of comprehensive data. This study delves into NAD + dynamics in patients undergoing surgery for different digestive system cancers. This prospective study enrolled 99 patients with eight different cancers. Fasting blood samples were obtained during the perioperative period. The concentrations of NAD + , nicotinamide mononucleotide (NMN), and nicotinamide riboside were analyzed using tandem mass spectrometry. After erythrocyte volume adjustment, NAD + remained relatively stable after surgery. Meanwhile, NMN decreased the day after surgery and displayed a recovery trend. Interestingly, liver and pancreatic cancer patients exhibited poor postoperative NMN recovery, suggesting a potential cancer type-specific influence on NAD + metabolism. This study illuminated the behavior of NAD + in surgically treated cancer patients. We identified which cancer types have particularly low levels and at what point depletion occurs during the perioperative period. These insights suggest the need for personalized NAD + supplementation strategies, calibrated to individual patient needs and treatment timelines. Clinical trial registration jRCT1020210066.

Adipsic hypernatremia with marked hyperprolactinemia and GH deficiency in a 9-year-old boy.

Adipsic hypernatremia is typically caused by congenital dysplasia of the hypothalamus and pituitary or brain tumors. However, cases of adipsic hypernatremia without underlying organic abnormalities are rare, and some cases have been reported to be complicated by hypothalamic-pituitary dysfunction. The patient in this case was a 9-yr-old boy who was referred to our hospital because of hypernatremia. His growth chart revealed that he had rapidly become obese since infancy, with growth retardation since the age of seven. His hands and feet were very cold, and he had erythema on his abdomen, indicating possible autonomic dysregulation due to hypothalamic dysfunction. Several hormone load tests showed severe GH deficiency (GHD) and marked hyperprolactinemia (peak: 302.8 ng/mL). Magnetic resonance imaging revealed no organic abnormalities in the hypothalamus and pituitary gland. GH replacement therapy was initiated. Although his growth rate improved, obesity persisted. To the best of our knowledge, this is the first report of adipsic hypernatremia without organic intracranial abnormalities that was treated with GH. Moreover, the patient's prolactin levels were higher than those reported in previous studies. In conclusion, adipsic hypernatremia requires the evaluation of pituitary function and appropriate therapeutic interventions.

Use of time­density curves of dynamic contrast­enhanced computed tomography for determination of the histological therapeutic effects of neoadjuvant chemotherapy for pancreatic ductal adenocarcinoma.

The present study aimed to investigate the histological changes caused by neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC), and to demonstrate the use of time­density curves (TDCs) of dynamic contrast­enhanced computed tomography (CECT) for determination of the histological therapeutic effects of NAC for PDAC. A total of 96 patients with PDAC were examined; 46 underwent NAC (NAC group) and 50 did not undergo NAC (non­NAC group). Based on histological therapeutic effect and using the area of residual tumor (ART) grading system, the NAC group was divided into low­responders and high­responders. Histological analysis was used to evaluate the densities of cancer cells, cancer­associated fibroblasts (CAFs), microvessels and stromal collagen fibers in the NAC and non­NAC groups. Radiological analysis was used to evaluate the TDCs of three slopes of the NAC group, namely slopes between the non­contrast and arterial phases (δ1 and δ1'), between the arterial and portal phases (δ2 and δ2'), and between the portal and equilibrium phases (δ3 and δ3'). δ1­Î´3 were before NAC, whereas δ1'­Î´3' were after NAC. Changes in δ1, δ2 and δ3 before and after NAC were denoted as δδ1 (=δ1'­Î´1), δδ2 (=δ2'­Î´2) and δδ3 (=δ3'­Î´3). ART grading system, histological examination and radiological examination data were also statistically analyzed. Histological examination revealed a significant decrease in cancer cells and CAFs, and a significant increase in stromal collagen fibers due to NAC (P<0.01). Radiological examination revealed that δ1' was significantly higher than δ1 in low­responders (P<0.05), whereas δ2' was significantly lower than δ2 in high­responders (P<0.01). δδ2 was significantly lower and δδ3 was significantly higher in high­responders than in low­responders (P<0.01 and P<0.05, respectively). Receiver operating characteristic curve showed that δδ2 and δδ3 were effective indicators of the histological therapeutic effect of NAC. In conclusion, the TDC of dynamic CECT may be useful for determining the histological therapeutic effect of NAC for PDAC.

Necrotizing pancreatitis complicated by retroperitoneal emphysema: two case reports.

BACKGROUND: Emphysematous pancreatitis is acute pancreatitis associated with emphysema based on imaging studies and has been considered a subtype of necrotizing pancreatitis. Although some recent studies have reported the successful use of conservative treatment, it is still considered a serious condition. Computed tomography (CT) scan is useful in identifying emphysema associated with acute pancreatitis; however, whether the presence of emphysema correlates with the severity of pancreatitis remains controversial. In this study, we managed two cases of severe acute pancreatitis complicated with retroperitoneal emphysema successfully by treatment with lavage and drainage. CASE PRESENTATION: Case 1: A 76-year-old man was referred to our hospital after being diagnosed with acute pancreatitis. At post-admission, his abdominal symptoms worsened, and a repeat CT scan revealed increased retroperitoneal gas. Due to the high risk for gastrointestinal tract perforation, emergent laparotomy was performed. Fat necrosis was observed on the anterior surface of the pancreas, and a diagnosis of acute necrotizing pancreatitis with retroperitoneal emphysema was made. Thus, retroperitoneal drainage was performed. Case 2: A 50-year-old woman developed anaphylactic shock during the induction of general anesthesia for lumbar spine surgery, and peritoneal irritation symptoms and hypotension occurred on the same day. Contrast-enhanced CT scan showed necrotic changes in the pancreatic body and emphysema surrounding the pancreas. Therefore, she was diagnosed with acute necrotizing pancreatitis with retroperitoneal emphysema, and retroperitoneal cavity lavage and drainage were performed. In the second case, the intraperitoneal abscess occurred postoperatively, requiring time for drainage treatment. Both patients showed no significant postoperative course problems and were discharged on postoperative days 18 and 108, respectively. CONCLUSION: Acute pancreatitis with emphysema from the acute phase highly indicates severe necrotizing pancreatitis. Surgical drainage should be chosen without hesitation in necrotizing pancreatitis with emphysema from early onset.

Long-term Effect of Aromatase Inhibition in Aromatase Excess Syndrome.

CONTEXT: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens. OBJECTIVE: The objective was to study long-term treatment effects of an aromatase inhibitor. METHODS: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy. RESULTS: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30). CONCLUSION: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS.

[Treatment for Laterally Invasive Rectal Cancer with Robot-Assisted Surgery after Preoperative Treatment].

The patient is a 40-year-old male. He was referred to our department because, after a thorough examination, he was diagnosed with rectal cancer. Preoperative imaging showed a tumor in the rectum at the level of the seminal vesicles, and left lateral invasion was suspected. In addition, lymph node metastases in the left lateral area were suspected. We performed a robot-assisted low anterior resection plus bilateral lateral dissection plus covering ileostomy for this patient after neoadjuvant chemotherapy. The operation time was 495 minutes, and the blood loss was 50 g. The histopathological diagnosis was pT3, N3(#263), M0, pStage Ⅲc, PM0, DM0, RM0, R0, Cur A. In Japan, robotic-assisted surgery for rectal cancer has been covered by insurance since April 2018, and in our department, robotic surgery is the first option for any stage or type of surgery for rectal cancer. We believe that the greatest advantages of robotic surgery for rectal cancer are in lateral dissection, ie, the better understanding of how blood vessels and nerves travel around the internal iliac vessels and the associated anatomy of pelvic organs that comes from reliable lateral dissection. We have experienced a case of safe robotic-assisted radical resection of laterally invasive rectal cancer, which is considered to be relatively difficult, and we hereby report the usefulness of the robotic-assisted modality.

[A Case of Two Stage taTME for Perforated Rectal Cancer during Chemotherapy].

The patient was a 57-year-old male. He was diagnosed with locally advanced rectal cancer infiltrating the left levator ani muscle. Chemotherapy(S-1 plus L-OHP plus bevacizumab regimen)was started for the purpose of obtaining a negative circumferential radial margin. After the second course, he presented with perforation of the sigmoid colon for which an emergency operation was performed. The perforation was located 5 centimeters above the tumor in the sigmoid colon. We performed partial resection of the sigmoid colon to repair the perforation and create a sigmoid colostomy. CT, after the initial S-1 plus L-OHP plus bevacizumab chemotherapy regimen, revealed tumor shrinkage. Following 2 more courses of chemotherapy( S-1 plus L-OHP regimen), we performed transanal total mesenteric excision(taTME)as curative surgery. R0 resection was achieved. The combined transanal and laparoscopic approach was highly effective for a patient with pan-peritonitis.

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.

Two unrelated pedigrees with achondrogenesis type 1b carrying a Japan-specific pathogenic variant in SLC26A2.

We present two unrelated Japanese pedigrees with achondrogenesis type 1b (ACG1B), characterized by prenatally lethal fetal hydrops and severe micromelia. The affected members in these pedigrees carried a common homozygous missense point mutation in solute carrier family 26 member 2 (SLC26A2), a gene associated with ACG1B (NM_000112:c.1987G>A). This loss-of-function point mutation causes substitution of glycine 663 with arginine in a highly conserved loop domain of SLC26A2. Interestingly, only a few cases of this mutation have been registered in Japanese genomic databases, and there are no reports of this mutation in any major genomic databases outside Japan. Furthermore, we confirmed the presence of a homozygous stretch of approximately 75 kb surrounding the pathogenic variant. Our findings suggest that this missense point mutation in SLC26A2, which is likely the cause of the ACG1B phenotypes in these unrelated fetuses, is distributed exclusively in Japan.

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial.

In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia-related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, -54%, osteoid thickness, -32%, osteoid surface/bone surface, -26%, [median] mineralization lag time, -83%). Mean serum phosphorus concentration averaged across the mid-point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment-emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure-related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature.

Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

NR0B1 Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty.

NR0B1 is the causative gene for X-linked adrenal hypoplasia congenita, characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and infertility. We identified an NR0B1 frameshift mutation in a boy with precocious puberty who had no signs of adrenal insufficiency. Blood examination revealed elevated testosterone levels and gonadotropin hyperresponses to gonadotropin releasing hormone (GnRH) stimulation, together with normal adrenal hormone levels. GnRH analog treatment partially ameliorated his clinical features. Molecular analysis identified a p.Glu3fsAla*16 in NR0B1. These results expand the clinical manifestations of NR0B1 mutations to include central precocious puberty without adrenal insufficiency. NR0B1 mutations likely underlie androgen overproduction via GnRH-dependent and -independent mechanisms.

Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature.

Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1-6a and/or the CNEs result in idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3'-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX-containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father-daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis-regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation.

Spondyloepiphyseal dysplasia congenita caused by double heterozygous mutations in COL2A1.

Spondyloepiphyseal dysplasia congenita (SEDC) is a group of rare inherited chondrodysplasias characterized by short stature, abnormal epiphyses, and flattened vertebral bodies. SEDC is usually caused by substitution of glycine residue with another amino acid in the triple helical domains of alpha 1 chains, which consist of type II collagen (COL2A1). Herein, we describe a unique case of SEDC with mild coxa vara (SEDC-M) caused by double de novo COL2A1 mutations located on the same allele. One mutation, p.G504S, was previously described in patients with SEDC, whereas the other, p.G612A, was a novel mutation; both were located in the triple helical domain. Neither mutation was identified in the parents and appeared to be de novo. To the best of our knowledge, this is the first study involving a patient with a type II collagenopathy with two COL2A1 mutations on the same allele. The case was characterized by a more severe phenotype compared with previously reported cases involving a single p.G504S mutation, which may have been the result of the double mutation.

A Novel De Novo GATA Binding Protein 3 Mutation in a Turkish Boy with Hypoparathyroidism, Deafness, and Renal Dysplasia Syndrome.

Hypoparathyroidism, deafness, and renal dysplasia (HDR; OMIM 146255) syndrome is a rare disease, inherited dominantly and found to be related with GATA3 (GATA binding protein 3) gene mutations. A 13-year and 8-month-old boy who presented with hypocalcemia was diagnosed with hypoparathyroidism. He also had dysmorphic facial features, renal anomaly (pelvic kidney), and mild sensorineural hearing loss. His cranial computed tomography revealed multiple calcifications in bilateral centrum semiovale, corona radiata, and basal ganglions suggesting a persistent hypoparathyroidism. Thus, the presence of triad of HDR syndrome was considered, and genetic analysis using a next-generation sequencer identified a novel de novo missense mutation in exon 4 p.R276Q (c.827G>A) of GATA3 gene. This is the second patient who was reported to have a mutation in GATA3 gene from Turkey. In conclusion, although HDR syndrome is a rare condition, it should be kept in mind in patients with hypoparathyroidism. Classical triad can easily be identified if patients diagnosed with hypoparathyroidism are also evaluated with a urinary tract ultrasound and an audiometer.

Development of endometrial carcinoma in a patient with leprechaunism (donohue syndrome).

Leprechaunism is a rare autosomal recessive disease that is characterized by severe insulin resistance. This disease is caused by a defective insulin receptor and features abnormal glucose metabolism and retarded intrauterine and postnatal growth. However, there are few reports on the long-term course of leprechaunism. We reported the long-term clinical course and rh-IGF-1 treatment in a patient with leprechaunism. During follow-up her diabetes gradually deteriorated despite of treatment of rh-IGF-1. Furthermore, she developed endometrioid adenocarcinoma at the age of 24 yr. The development of endometrial disease must be carefully followed up in this disease.

A rare association between Rathke's cyst and hypophysitis in a patient with delayed sex development and growth failure.

We report an 18-year-old Japanese male with a lack of secondary sex characterization and growth failure caused by a rare association between Rathke's cyst and hypophysitis. He was referred to us because of delayed secondary sex characterization. Endocrinological examination showed panhypopituitarism, and the replacement of hydrocortisone, levothyroxine, and desmopressin acetate (DDAVP) was initiated. Brain magnetic resonance imaging (MRI) showed a suprasellar region and a swollen pituitary stalk. The mass was partially resected using the transsphenoidal approach. The pathological diagnosis was hypophysitis and Rathke's cyst. Follow-up MRI performed 1 year after surgery showed that the size of sellar region had not changed. After surgery, in addition to pre-operative hormonal replacement, growth hormone and testosterone were initiated. Two years later, the size of sellar region remains unchanged. In conclusion, while an association between Rathke's cyst and hypophysitis is rare, we suggest that this condition should be included in differential diagnosis of the sellar region, even in adolescents.

Early onset of liver steatosis in a Japanese girl with maturity-onset diabetes of the young type 3 (MODY3).

Maturity-onset diabetes of the young type 3 (MODY3) is caused by heterozygous mutation in the HNF1A gene. Liver adenomatosis has been reported in MODY3 patients. The patient reported in this paper is a Japanese girl who first developed hepatomegaly, fatty liver, and hepatic dysfunction at age 5 years. Liver biopsy demonstrated steatosis and degeneration of hepatocytes. At that time, blood glucose and HbA1c levels were within normal ranges. Elevated HbA1c was noticed 4 years later, but islet cell and glutamic acid decarboxylase antibodies were not detected in the serum. Therefore, MODY3 was suspected and subsequent analysis of the HNF1A gene identified a heterozygous germline splice donor-site mutation in intron 9. MODY3 patients should be screened by non-invasive liver imaging, and careful follow-up of liver disease should be performed.

Three Japanese patients with congenital pituitary hormone deficiency and ophthalmological anomalies.

The clinical phenotype of congenital pituitary hormone deficiency is variable and can be associated with a number of structural abnormalities of the central nervous system. We report three Japanese patients with congenital pituitary hormone deficiency and ophthalmological anomalies. Two of the patients initially showed strabismus and unilateral optic nerve hypoplasia. Thereafter, growth failure became evident, leading to the diagnosis of pituitary hormone deficiency. The other patient had severe congenital hypopituitarism with respiratory distress and hypoglycemia from the first day of life. In addition, he had prolonged jaundice and impaired liver function with bilateral optic nerve hypoplasia. Neuroimaging of the pituitary region in all three patients demonstrated a small anterior pituitary lobe and no pituitary stalk. Our findings indicate that clinical variability of congenital hypopituitarism must be considered. In a patient with ophthalmological symptoms, endocrine evaluation and neuroimaging of the CNS including the pituitary region should be considered.