Endometrial Cancer Diagnosed at an Early Stage during Lynch Syndrome Surveillance: A Case Report.

Lynch syndrome is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair genes, resulting in multi-organ cancer. Annual transvaginal ultrasonography and endometrial biopsy are recommended for endometrial cancer surveillance in patients with Lynch syndrome in several guidelines; however, evidence is limited. Here, we present the case of a 51-year-old woman with endometrial cancer who underwent robot-assisted laparoscopic simple hysterectomy at an early stage detected by Lynch syndrome surveillance. The patient was a 51-year-old gravida zero woman without any medical history or symptoms. Her sister suffered from bladder, breast, rectal, and endometrial cancer and was diagnosed with Lynch syndrome using a hereditary cancer panel test (VistaSeq®). During gynecologic surveillance, the patient's endometrial cytology was classified as Papanicolaou class III. Therefore, she underwent endometrial curettage with hysteroscopy and was diagnosed with atypical endometrial hyperplasia. Robot-assisted hysterectomy was performed with a final pathological diagnosis of endometrial cancer (endometrioid carcinoma, Grade 1), stage 1A. She has remained disease-free for more than 12 months. Owing to advances in genetic medicine, prophylactic and therapeutic surgeries for hereditary cancers are increasing. To achieve an early diagnosis and treatment of Lynch syndrome-associated cancers, the importance of Lynch syndrome surveillance should be more widely recognized.

Long-term response to olaparib in a patient with metastatic pancreatic cancer associated with hereditary breast and ovarian cancer syndrome.

BRCA mutations are associated with an increased risk of pancreatic cancer (PC). Olaparib, an oral poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, has been approved for the treatment of metastatic PC with a germline BRCA mutation. In this report, we present the case of a metastatic PC harboring a germline BRCA2 mutation, and the daughter of the patient, who had bilateral breast cancers harboring the same germline mutation, suggesting that the PC was associated with hereditary breast and ovarian cancer syndrome. Although PC is an aggressive disease and has poor prognosis, olaparib was administered as maintenance therapy following modified FOLFIRINOX, providing clinical benefits for >12 months.

An Asymptomatic Case With MEN1 Slipping Through Genetic Screening by SNV-dependent Allelic Dropout.

Context: Genetic testing is useful not only for the diagnosis of the MEN1 proband but also for determining the putative asymptomatic variant carriers to improve the prognosis or to avoid unnecessary medical intervention. However, we must be aware of the putative pitfalls of polymerase chain reaction (PCR)-based genetic testing in specific conditions that lead to medical mismanagement. Objective: To warn of the putative pitfalls of PCR-based genetic testing, we report an overlooked case of MEN1 due to PCR allelic dropout. Methods: A 69-year-old man was clinically diagnosed with MEN1, and genetic testing revealed that he had a pathogenic variant in the MEN1 gene. His 36-year-old son was completely asymptomatic. As the son was 50% at risk of MEN1, he was willing to undergo genetic testing himself after genetic counseling. Results: Genetic testing was carried out in 2 independent laboratories. Although laboratory A showed that he carried a pathogenic variant, laboratory B showed that he had the wild-type genotype of MEN1. The discrepancy in these results was due to PCR allelic dropout by single-nucleotide variations of the MEN1 gene in the 5' region. The surveillance revealed that he had asymptomatic primary hyperparathyroidism and a neuroendocrine tumor of the pancreas. Conclusion: PCR-dependent genetic analysis may be susceptible to PCR allelic dropout in an SNV-specific manner. We must be careful when genetically testing individuals of relatives with clinical MEN1 disease.

Familial Pseudohypoparathyroidism Type IB Associated with an SVA Retrotransposon Insertion in the GNAS Locus.

Loss of methylation (LOM) at GNAS-A/B:TSS-differentially methylated regions (DMRs) in the GNAS locus is observed in pseudohypoparathyroidism type 1B (PHP1B). Many PHP1B cases are sporadic, but autosomal dominant-PHP1B has a deletion involving NESP55 expressed from the maternal allele or STX16 located upstream of the GNAS locus on the maternal allele. We report the possible first familial PHP1B cases with retrotransposon insertion in the GNAS locus on the maternal allele. To our knowledge, they are the possible first cases with imprinting disorders caused by retrotransposon insertion. The two sibling cases experienced tetany and/or cramps from school age and had hypocalcemia and an increased serum intact parathyroid hormone (PTH) level together with overweight, round face, and normal intellectual levels. Methylation analysis for DMRs in the GNAS locus showed only LOM of the GNAS-A/B:TSS-DMR. Copy number abnormalities at STX16 and the GNAS locus were not detected by array comparative genomic hybridization. Whole-genome sequencing and Sanger sequencing revealed an approximately 1000-bp SVA retrotransposon insertion upstream of the first exon of A/B on the GNAS locus in these siblings. Whole-genome methylome analysis by Enzymatic Methyl-Seq in the siblings showed normal methylation status in the region surrounding the insertion site and mild LOM of the GNAS-A/B:TSS-DMR. We conducted transcriptome analysis using mRNA from skin fibroblasts and induced pluripotent stem cells (iPSCs) derived from the siblings and detected no aberrant NESP55 transcripts. Quantitative reverse-transcriptase PCR (qRT-PCR) analysis in skin fibroblasts showed increased A/B expression in the patients and no NESP55 expression, even in a control. qRT-PCR analysis in iPSCs showed decreased NESP55 expression with normal methylation status of the GNAS-NESP:TSS-DMR in the patients. The retrotransposon insertion in the siblings likely caused decreased NESP55 expression that could lead to increased A/B expression via LOM of the GNAS-A/B:TSS-DMR, subsequent reduced Gsα expression, and finally, PHP1B development. © 2022 American Society for Bone and Mineral Research (ASBMR).

Bilateral Pheochromocytoma with Germline MAX Variant without Family History.

Recently, the genetic background of pheochromocytomas/paragangliomas (PPGLs) has been rapidly revealed. These tumors have been referred to as the "ten percent tumor"; however, the frequency of genetic variants of PPGLs has turned out to be more common than expected. PPGLs are potentially hereditary tumors and appear clinically sporadic. Here, we report a case of bilateral pheochromocytoma (PCC) with a variant in the MYC-associated factor X (MAX) gene (c.295 + 1G > A). A male patient was diagnosed with adrenal pheochromocytoma (PCC) and underwent a left adrenalectomy at the age of 40. A new tumor in the right adrenal gland was detected at the age of 43. Urinary metanephrine and normetanephrine concentrations gradually increased. The size of the right adrenal PCC continued to increase one year after detection. Genetic testing of the peripheral blood revealed the presence of a pathogenic variant in MAX. The natural history of adrenal PCCs with the MAX variant has not yet been clarified, because the number of reported cases is not sufficient. Thus, clinicians should consider a MAX variant when they find bilateral or multiple PCCs.

High-dose fludrocortisone therapy was transiently required in a female neonate with 21-hydroxylase deficiency.

For salt-wasting 21-hydroxylase deficiency (21OHD), fludrocortisone (FC) is usually supplemented at 0.05-0.2 mg/d dose. To date, no report has described 21OHD neonates requiring > 0.4 mg/d of FC. Our female 21OHD patient was lethargic and experienced weight loss with hyponatremia (133 mEq/L), hyperkalemia (6.5 mEq/L), and elevated active renin concentration (ARC, 1942.2 pg/mL) at 6 days of life. Hydrocortisone and FC replacement were initiated. FC dose was gradually increased to 0.4 mg/d at 21 days of life, but her hyperkalemia (6.4 mEq/L) and high ARC (372.3 pg/mL) persisted. We increased FC to 0.6 mg/d and used a low-potassium and high-sodium formula. Hyperkalemia subsequently improved. At 33 days of life, the ARC decreased to 0.6 pg/mL and FC dosage was gradually decreased. At 3 months of age, the low-potassium and high-sodium formula was discontinued, but the serum potassium level was normal and ARC remained low at 0.1 mg/d of FC. We speculated that severe mineralocorticoid resistance was the reason why her hyperkalemia persisted even with 0.4 mg/d of FC; however, the pathophysiology of transiently severe resistance to FC in this patient is unknown. In conclusion, 21OHD neonates may show severe salt-wasting that transiently require > 0.4 mg/d of FC.

Retroperitoneal paraganglioma with loss of heterozygosity of the von Hippel-Lindau gene: a case report and review of the literature.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease related to germline mutations in VHL. In VHL disease, pheochromocytoma develops in 10%-20% of patients because of germline mutations and loss of heterozygosity of VHL. However, the rate of paraganglioma associated with VHL is low compared with that of pheochromocytoma, and the reason is unknown. In this study, we performed germline and somatic mutation analyses of retroperitoneal paraganglioma that developed in a patient with clinically diagnosed VHL disease and investigated the tumorigenic mechanism of paraganglioma. The patient was a 25-year-old woman who was considered to have VHL disease on the basis of her family history. She was referred to our clinic to investigate a tumor at the bifurcation of the common iliac artery. The tumor was diagnosed as retroperitoneal paraganglioma by clinical evaluations. A left renal cell carcinoma was also suspected. Polymerase chain reaction direct sequencing analysis and polymorphic microsatellite analysis within the VHL locus suggested that loss of heterozygosity of VHL was associated with paraganglioma and renal cell carcinoma. Multiplex ligation-dependent probe amplification analysis showed a loss of the copy number of VHL exons in paraganglioma. These results suggest that VHL disease contributes to the development of paraganglioma. A literature review showed no reported common missense variants involved in the progression of paraganglioma. The loss of heterozygosity of VHL can be a tumorigenic mechanism of retroperitoneal paraganglioma in VHL disease. However, the low rate of paraganglioma compared with pheochromocytoma is not explained by their genetic background alone.

Bezafibrate induces hypothyroidism in a patient with resistance to thyroid hormone ß due to a G347R variant.

OBJECTIVE: A unique clinical course was observed in a patient with resistance to thyroid hormone ß (RTHß) caused by a variant of the THRB gene leading to the replacement of glycine with arginine in codon 347 (p.G347R). He presented with the syndrome of inappropriate secretion of thyrotropin (TSH) (free T4 [fT4]: 32.43 pmol/L, TSH: 4.67 mIU/L), but slowly developed progressive hypothyroidism (fT4: 8.37 pmol/L, TSH: 100.90 mIU/L) that resolved after suspending bezafibrate (BZ) treatment (fT4: 32.18 pmol/L, TSH: 7.14 mIU/L). This study clinically and experimentally evaluated this interesting phenomenon. METHODS: A retrospective cohort analysis of non-RTHß patients was performed at Kyoto University Hospital. Data before BZ treatment were compared to the first data after treatment. Using reporter assays of iodothyronine deiodinases (DIO1, DIO2, DIO3) in HEK293T cells, we performed functional analyses of mutant thyroid hormone receptor ß with p.G347R (G347R TRß). Mice with G347R TRß were generated by hydrodynamic gene delivery. RESULTS: In non-RTHß patients (n = 7), BZ treatment did not change serum free T3 and TSH but significantly increased fT4 (p = .008). BZ administration increased DIO3 reporter activity in the context of G347R TRß, whereas did not change DIO1 and DIO2 reporter activity. In the livers of mice with G347R TRß, BZ administration increased reverse T3 content, which corresponded to an increase in Dio3 messenger RNA. CONCLUSIONS: While hypothyroidism associated with BZ treatment did not occur in non-RTHß patients, it was observed in a patient with RTHß due to the p.G347R variant. Liver DIO3 upregulation might involve this hypothyroidism.

Identification of a homozygous c.1039C>T (p.R347C) variant in CYP17A1 in a 67-year-old female patient with partial 17α-hydroxylase/17,20-lyase deficiency.

17α-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by pathogenic mutations in CYP17A1. Impaired 17α-hydroxylase and 17,20-lyase activities typically induce hypertension, hypokalemia, sexual infantilism, and amenorrhea. Most patients with 17OHD are diagnosed in adolescence. Here, we report a female (46, XX) patient with 17OHD who was diagnosed at the age of 67 years. Genetic analysis was performed using direct DNA sequencing of polymerase chain reaction (PCR) products and multiplex ligation-dependent probe amplification (MLPA) analysis. Direct DNA sequencing revealed a homozygous c.1039C>T in CYP17A1, corresponding to a p.R347C amino acid change. MLPA probe signals showed that the CYP17A1 mutation was present in the homozygous carrier state. The patient's dehydroepiandrosterone sulfate and androstenedione levels were extremely low, despite elevated adrenocorticotropic hormone (ACTH) and normal cortisol levels. A corticotropin-releasing hormone (CRH) test showed no response of cortisol, despite a normal response of ACTH. Rapid ACTH injection resulted in elevations in the deoxycorticosterone, corticosterone, aldosterone, and 17-hydroxypregnenolone levels, but not in the cortisol level. These results suggested that 17α-hydroxylase/17,20-lyase activities were partially impaired. Computed tomography revealed bilateral adrenal hyperplasia and a hypoplastic uterus. A high basal plasma ACTH level and a discrepancy between ACTH and cortisol responses in a CRH test may provide a definitive diagnostic clue for this disease.

Comparisons of plasma aldosterone and renin data between an automated chemiluminescent immunoanalyzer and conventional radioimmunoassays in the screening and diagnosis of primary aldosteronism.

Determining values of plasma renin activity (PRA) or plasma active renin concentration (ARC), plasma aldosterone concentration (PAC), and aldosterone-to-renin ratio (ARR) is essential to diagnose primary aldosteronism (PA), but it takes several days with conventional radioimmunoassays (RIAs). Chemiluminescent enzyme immunoassays for PAC and ARC using the Accuraseed® immunoanalyzer facilitated the determination, but relations between Accuraseed® immunoanalyzer-based and RIA-based values in samples of PA confirmatory tests and adrenal venous sampling remained to be elucidated. We addressed this issue in the present study. This is a prospective, cross-sectional study. ARC and PAC values were measured by the Accuraseed® immunoanalyzer in samples, in which PRA and PAC values had been measured by the PRA-FR® RIA and SPAC®-S Aldosterone kits, respectively. The relations between Accuraseed® immunoanalyzer-based and RIA-based values were investigated with regression analyses. The optimal cutoff of Accuraseed® immunoanalyzer-based ARR for PA screening was determined by the receiver operating characteristic analysis. After log-log transformations, linear relations with high coefficients of determination were observed between Accuraseed® immunoanalyzer-based and RIA-based data of renin and aldosterone. Following the PA guidelines of Japan Endocrine Society, Accuraseed® immunoanalyzer-based cutoffs were calculated from the regression equations: the basal PAC for PA screening >12 ng/dL, PAC for the saline infusion test >8.2 ng/dL, ARC for the furosemide-upright test <15 pg/mL, and ARR for the captopril challenge test >3.09 ng/dL per pg/mL. The optimal cutoff of Accuraseed® immunoanalyzer-based ARR for PA screening was >2.43 ng/dL over pg/mL not to overlook bilateral PA patients. The present study provided conversion formulas between Accuraseed® immunoanalyzer-based and RIA-based values of renin, aldosterone, and ARR, not only in basal samples but also in samples of PA confirmatory tests and adrenal venous sampling. Although validation studies are awaited, the present study will become priming water of harmonization of renin and aldosterone immunoassays.

Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia.

BACKGROUND: Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. The previous studies indicate that this condition is mediated by parthenogenetic activation and is free from a specific phenotype ascribed to unmaking of a maternally inherited recessive variant in the parthenogenetic cell lineage. RESULTS: We examined a 28-year-old Japanese 46,XX female with Silver-Russell syndrome and idiopathic hypersomnia. The results revealed (1) predominance of maternally derived alleles for all the differentially methylated regions examined; (2) no disease-related copy-number variant; (3) two types of regions for all chromosomes, i.e., four BAF (B-allele frequency) band regions with single major microsatellite peaks of maternal origin and single minor microsatellite peaks of non-maternal (paternal) origin, and six BAF band regions with single major microsatellite peaks of maternal origin and two minor microsatellite peaks of maternal and non-maternal (paternal) origin; (4) an unmasked extremely rare PER2 variant (c.1403G>A:p.(Arg468Gln)) with high predicted pathogenicity; (5) mildly affected local structure with altered hydrogen bonds of the p.Arg468Gln-PER2 protein; and (6) nucleus-dominant subcellular distribution of the p.Arg468Gln-PER2 protein. CONCLUSIONS: The above findings imply that the second polar body retention occurred around fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei, and that the homozygous PER2 variant in the parthenogenetic cells is the likely causative factor for idiopathic hypersomnia.

A case of retinitis pigmentosa homozygous for a rare CNGA1 causal variant.

Retinitis pigmentosa (RP) is a heterogenous hereditary disorder leading to blindness. Despite using next-generation sequencing technologies, causal variants in about 60% of RP cases remain unknown. The heterogeneous genetic inheritance pattern makes it difficult to pinpoint causal variants. Besides, rare penetrating variants are hardly observed in general case-control studies. Thus, a family-based analysis, specifically in a consanguineous family, is a clinically and genetically valuable approach for RP. We analyzed a Japanese consanguineous family with a member suffering from RP with a typical autosomal recessive pattern. We sequenced five direct descendants and spouse using Whole-exome sequencing (WES) and Whole-genome sequencing (WGS). We identified a homozygous pathogenic missense variant in CNGA1 (NM_000087.3, c.839G > A, p.Arg280His) in the proband, while we found no homozygous genotypes in the other family members. CNGA1 was previously reported to be associated with RP. We confirmed the genotypes by the Sanger sequencing. Additionally, we assessed the homozygous genotype in the proband for the possibility of a founder mutation using homozygosity analysis. Our results suggested the two copies of the variant derived from a founder mutation. In conclusion, we found the homozygotes for c.839G > A in CNGA1 as causal for RP.

Parameters of captopril challenge test can predict results of other confirmatory tests for primary aldosteronism and propose the next test to be done.

In Japan, primary aldosteronism (PA) is diagnosed if any one of the captopril challenge test (CCT), saline infusion test (SIT), furosemide-upright test (FUP), and oral salt-loading test (OST) is positive. The present study aimed to investigate if parameters of CCT, the safest confirmatory test, could predict decisions of other tests and propose the next test to diagnose PA in CCT-negative patients. In a cross-sectional design, 142 patients, who were referred to our hospital for the scrutiny of PA and underwent at least two confirmatory tests, were enrolled. While 123 patients underwent all of the CCT, SIT, and FUP, the OST was successfully done in only six patients and excluded from further analyses. CCT parameters showing correlations of higher degrees with SIT and FUP parameters were selected, and their powers to predict SIT and FUP decisions were investigated by receiver operating characteristic analyses. Proposals of the next test based on the CCT parameters were validated with SIT and FUP decisions in subsets of CCT-negative patients divided by cut-offs of the CCT parameters. The plasma aldosterone concentration and plasma renin activity 60 min after the load of CCT (CCT60-PAC and CCT60-PRA) were selected, and CCT60-PAC ≤59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h could predict negativities of SIT and FUP, respectively, with >95% specificities. Based on the validation, the present study suggested the SIT as the next test to be done if the CCT-negative patient belonged to the subset with CCT60-PAC >59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h, otherwise the FUP should be selected.

[A Case of Enterocutaneous Fistula Caused by Cytomegalovirus Enteritis after Gastrectomy Successfully Treated with Antiviral Therapy-A Case Report].

Cytomegalovirus(CMV)infection is a well-recognized complication of immunodeficiency. We present the case of a 90- year-old female admitted due to gastric cancer. Fifty-seven days after gastrectomy, intestinal juice was observed from the umbilical wound, which was suspected of anastomotic failure or gastrointestinal perforation. Abdominal computed tomography didn't reveal gastrointestinal perforation. CMV enteritis was diagnosed by transanal double-balloon endoscopy from the cecum to the oral side 15 cm of the ileum. Enterocutaneous fistula was considered to be caused by CMV enteritis. The intestinal fluid outflow from the wound disappeared treated with ganciclovir, and the ulcer in the intestinal tract disappeared, too. We report this case to reinforce the importance of considering CMV infection as a differential diagnosis in gastrointestinal perforation of compromised patients.

ARMC5 Alterations in Primary Macronodular Adrenal Hyperplasia (PMAH) and the Clinical State of Variant Carriers.

CONTEXT: Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. ARMC5 is one of the responsible genes for PMAH. OBJECTIVES: This study was performed to identify the genotype-phenotype correlation of ARMC5 in a cohort of Japanese patients. PATIENTS AND METHODS: Fourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for ARMC5 gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied. RESULTS: Of fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of ARMC5. We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the ARMC5 pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the ARMC5 gene was evident. The ARMC5 variant-positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the ARMC5 variant-positive group. CONCLUSIONS: ARMC5 pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of ARMC5 variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of ARMC5 in the tumor tissues was evident. The ARMC5 variant-positive mutant group showed a higher basal cortisol level than the negative group.

A case of combined 21-hydroxylase deficiency and CHARGE syndrome featuring micropenis and cryptorchidism.

BACKGROUND: 21-hydroxylase deficiency (21-OHD) is caused due to CYP21A2 gene variant. In males, the excess androgens produce varying degrees of penile enlargement and small testes. CHARGE syndrome (CS) has a broad spectrum of symptoms. In males, genital features such as micropenis and cryptorchidism are found in 48% of CS. There are no reports of patients with combined 21-OHD and CS; therefore, it is unknown whether the external genitalia shows penile enlargement or micropenis with/without cryptorchidism. CASE: A boy, born at 37 weeks and 5 days of gestational age with no consanguineous marriage, was admitted to our hospital due to congenital cleft lip, cleft palate, micropenis, cryptorchidism, and a ventricular septal defect. He had severe hyponatremia and hyperkalemia on day 10. He was diagnosed to have 21-OHD and CS. His external genitalia demonstrated both cryptorchidism and micropenis, but not penile enlargement. METHODS: DNA was extracted from peripheral leukocytes using standard procedures. Sanger sequence was performed in CYP21A2. Exome sequence was performed, and then, Sanger sequence was performed around variant in CHD7. RESULTS: Genetic screening for CYP21A2 gene was performed and compound heterozygous variants of c.293-13A/C>G (IVS2-13A/C>G) and c.518T>A (p.I172N) were detected in chromosome 6p21.3. His mother had been heterozygous variant of c.293-13A/C>G, and his father had been heterozygous variant of c.518T>A. Simultaneously, a de novo splicing acceptor alteration in c.7165-4 A>G, in chromodomain helicase DNA binding protein-7 (CHD7), located in chromosome 8q12 was detected, and the patient was diagnosed with 21-OHD and CS. CONCLUSION: Although these two disorders exhibit different modes of inheritance and their co-morbidity is extremely rare, we encountered one male patient who suffered from both 21-OHD and CS.

Familial congenital choanal atresia with GATA3 associated hypoparathyroidism-deafness-renal dysplasia syndrome unidentified on auditory brainstem response.

Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder primarily caused by GATA3 haploinsufficiency and is challenging to diagnose in early childhood. We report a Japanese family with HDR syndrome and congenital choanal atresia. The 6-year-old female proband was diagnosed with epilepsy at the age of three. Under carbamazepine monotherapy, the patient presented hypoparathyroidism accompanied by severe hypocalcemia. Subsequently, renal ultrasound analysis revealed bilateral multicystic dysplastic kidneys. Because she had difficulty hearing, we sequenced GATA3 and determined that she had a c.708_709insC (p.Ser237Glnfs*66) allelic variant in exon 3. As a result, we found a family of this disease. Each family member, including her grandfather, mother, and two siblings, had HDR syndrome of varying clinical penetrance. We found a craniofacial anomaly, congenital choanal atresia, which was inherited as an autosomal dominant trait. Hypocalcemia coupled with vitamin D deficiency, triggered by carbamazepine treatment, ultimately revealed the proband's childhood- onset HDR syndrome. Pure-tone audiometry revealed different severities of deafness as well as the progression of sensory hearing loss. However, auditory brainstem response for hearing screening is probably insufficient for ascertaining HDR syndrome in the early stages of life. We presented new clinical clues to diagnose the HDR syndrome.

Lung squamous cell carcinoma associated with hypoparathyroidism with sensorineural deafness and renal dysplasia syndrome: a case report.

Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome is an autosomal dominant condition caused by mutations of the gene encoding the dual zinc-finger transcription factor, GATA3. A previous study identified some patients with GATA3 gene variants and breast cancer, suggesting that GATA3 variants may contribute to tumorigenesis in estrogen receptor 1-positive breast tumors; however, these patients did not have HDR syndrome. A 32-year-old nonsmoking Japanese woman was histologically diagnosed with lung squamous cell carcinoma associated with HDR syndrome and a c.C952T>C (p.C318R) germline mutation in GATA3. This is the first report describing cancer in a patient with HDR syndrome. Our data indicates that GATA3 mutations may be a potential therapeutic target for lung cancer.

Importance of the Average Glucose Level and Estimated Glycated Hemoglobin in a Diabetic Patient with Hereditary Hemolytic Anemia and Liver Cirrhosis.

Glycated hemoglobin (HbA1c) is a widely used marker of glycemic control but can be affected by hemolytic anemia. Glycated albumin (GA) is also affected in patients with liver cirrhosis. We herein report the assessment of glycemic control in a 41-year-old man with dehydrated hereditary stomatocytosis and a PIEZO1 gene mutation complicated by diabetes mellitus and liver cirrhosis due to hemochromatosis. The estimated HbA1c calculated from the average glucose level obtained by continuous glucose monitoring or by self-monitoring of blood glucose was useful for evaluating the glycemic control in this patient, as HbA1c and GA were unreliable due to the coexisting conditions.