Aggressive immunotherapy combined with bortezomib and rituximab for membranous nephropathy associated with enzyme replacement therapy in Pompe disease.

BACKGROUND: Pompe disease (PD) is a lysosomal glycogen storage disorder caused by a deficiency in acid α-glucosidase (GAA) activity. Various organs, including the skeletal muscle, cardiac muscle, and liver, are commonly involved. Early initiation of enzyme replacement therapy (ERT) with recombinant human α-glucosidase (rhGAA) can improve the outcome. However, some patients experience a poor clinical course despite ERT because of the emergence of anti-rhGAA antibodies that neutralize rhGAA. Treatment against anti-rhGAA antibodies is challenging. CASE-DIAGNOSIS/TREATMENT: A 14-year-old boy with late-onset PD was referred to our hospital with proteinuria detected by school urinalysis screening. He was diagnosed with PD at the age of 4 years based on muscle biopsy and decreased GAA activity. Treatment with rhGAA was initiated, but anaphylaxis occurred frequently. Anti-rhGAA antibodies were detected and immune tolerance therapy was therefore given, but his antibody titer remained high. Kidney biopsy revealed stage II membranous nephropathy. Immunohistochemistry staining revealed anti-rhGAA antibody/rhGAA immune complexes along the glomerular capillary loop. Aggressive immunotherapy combined with bortezomib and rituximab was then initiated. Serum levels of anti-rhGAA antibodies decreased significantly and his proteinuria finally resolved. CONCLUSIONS: There have been few reports of membranous nephropathy associated with ERT for PD. We clarified the cause in the current patient. Bortezomib and rituximab effectively suppressed anti-rhGAA antibody production resulting in the resolution of proteinuria and maintenance of ERT efficacy.

Progressive Left Ventricular Outflow Tract Stenosis in a Noonan Syndrome Patient With Severe Hypertrophic Cardiomyopathy During Growth Hormone Treatment.

Short stature is a main problem in Noonan syndrome (NS). Recombinant human growth hormone (GH) has been used to safely improve the growth rate in NS patients with short stature. However, there is little information about GH therapy for NS associated with hypertrophic obstructive cardiomyopathy. We present the case of a seven-year-old NS patient with severe hypertrophic obstructive cardiomyopathy. The patient received GH therapy for six months, at which time progressive left ventricular outflow tract stenosis was apparent.

Quantification of serum thyroid hormones using tandem mass spectrometry in patients with Down syndrome.

Thyroid dysfunction is common in patients with Down syndrome (DS), the most common chromosomal disorder. Thyroid hormones (THs) are important for normal growth, neurodevelopment, and metabolism, highlighting the importance of quantifying the levels in patients with DS. However, current methods possess cross-reactivity that results in inaccuracies in quantification. We aimed at developing a new analytical method for quantifying the total 3,3',5-triiodo-l-thyronine (TT3), total 3,3',5,5'-tetraiodo-l-thyronine (TT4), 3,3',5'-triiodo-l-thyronine, and reverse T3 (rT3) levels using LC-MS/MS. Repeatability and reproducibility with coefficient of variation values of 2-9 and 3-13%, respectively, were acceptable, suggesting that the assay was suitable for measuring serum THs. We measured the serum TH levels of patients with DS but without thyroid dysfunction (age, 3-20 years) and compared the levels to those of controls (patients with idiopathic short stature; age, 3-17 years). When TH levels were summarized by age group, the serum TT4 concentrations were not significantly different between the controls and patients with DS across all age groups. Meanwhile, the serum TT3 concentrations differed according to age. In addition, the serum rT3 concentrations were significantly higher in patients with DS than in controls, except for those in the 12-14 age group. We also calculated the T3/T4 and rT3/T4 ratios to elucidate the reason for the higher rT3 in patients with DS; however, no useful findings were obtained. Thus, further investigation is needed to clarify our findings.

Metreleptin worked in a diabetic woman with a history of hematopoietic stem cell transplantation (HSCT) during infancy: further support for the concept of 'HSCT-associated lipodystrophy'.

A 17-year-old woman with a history of childhood leukemia and hematopoietic stem cell transplantation (HSCT), preceded by total body irradiation, developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance. Based on Dunnigan phenotype, HSCT-associated lipodystrophy was suspected. Because of rapid deterioration of diabetes control, metreleptin was introduced at 23 years of age upon receipt of her caregiver's documented consent. This trial was initially planned as a prospective 18 month-long study, with regular assessments of the patient's physical activity, food intake, and body composition analysis. However, because an abrupt and transient attenuation of the metreleptin effect occurred 16 months after the treatment initiation, the entire course of 28 months is reported here. Over the period, her HbA1c decreased from 10.9% to 6.7% despite no significant increase of physical activity and with a stable food intake. Decreased levels of triglyceride and non-HDL cholesterol were found. Her liver function improved, indicating the amelioration of fatty liver. In addition, a 25% reduction in the subcutaneous fat area at umbilical level was found, accompanied by a decrease in fat percentage of both total-body and trunk. The formation of neutralizing antibodies to metreleptin may be responsible for the transient loss of efficacy, considering a sudden elevation in her serum leptin level. In conclusion, metreleptin is useful for the management of HSCT-associated lipodystrophy, supporting the concept that adipose tissue dysfunction is responsible for diverse post-HSCT metabolic aberrations.

Severe in utero under-virilization in a 46,XY patient with Silver-Russell syndrome with 11p15 loss of methylation.

Background Silver-Russell syndrome (SRS) is characterized by growth retardation and variable features including macrocephaly, body asymmetry, and genital manifestations such as cryptorchidism in 46,XY patients. Case presentation The patient was born at 39 weeks with a birth weight of 1344 g. Subtle clitoromegaly warranted a thorough evaluation, which disclosed 46,XY karyotype, bilateral undescended testes, and a rudimentary uterus. Because of severe under-virilization, the patient was assigned as female. Failure to thrive, macrocephaly, and body asymmetry led to the diagnosis of SRS, confirmed by marked hypomethylation of H19/IGF2 intergenic differentially methylated region (IG-DMR). From age 9 years, progressive virilization occurred, which necessitated luteinizing hormone-releasing hormone analog (LHRHa) treatment. Gonadal resection at 15 years revealed immature testes with mostly Sertoli-cell-only tubules. Panel analysis for 46,XY-differences of sex development (DSD) failed to detect any pathogenic variants. Conclusions This is the second reported case of molecularly proven 46,XY SRS accompanied by severe under-virilization. SRS should be included in the differential diagnosis of 46,XY-DSD.

Spontaneous virilization around puberty in NR5A1-related 46,XY sex reversal: additional case and a literature review.

A heterozygous NR5A1 mutation is one of the most frequent causes of 46,XY DSD (disorders of sex development). We here reported a NR5A1-related 46,XY DSD patient, who first received endocrinological attention at 10 years of age for clitoromegaly. The patient had been reared as a girl, and no signs of virilization had been detected before. On examination, her clitoris was 35 mm long and 10 mm wide, with Tanner 3° pubic hair. Urogenital sinus and labial fusion was absent, while her uterus was found to be severely hypoplastic. Her basal testosterone level was 94.8 ng/dL, suggesting the presence of functioning Leydig cells. Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia. Novel heterozygous Arg313Leu substitution in NR5A1 was identified in the patient. Literature search confirmed twelve other cases of this scenario, namely, severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD. Of interest, Leydig cell hyperplasia was documented in 6 out of 9 patients for whom testicular histology was available. To keep in mind about the possible restoration of Leydig cell function around puberty, even in patients without discernible in utero androgen effect, may be of clinical significance, because it will give a great impact on the judgement about sex assignment.

Fluctuation of blood glucose levels in an infant with an ileostomy on continuous glucose monitoring: A case report.

Infants with an ileostomy can be at high risk of hypoglycemia because of inadequate nutritional intake; however, there are no reports investigating blood glucose (BG) in infants with ileostomy. We experienced a case of an extremely low birth weight infant who was born at 24 wk of gestation and weighted 623 g. He received an ileostomy because of an intestinal perforation. After the ileostomy, he had recurrent hypoglycemia. Continuous glucose monitoring showed fluctuation of BG levels (postprandial BG elevations and subsequent declines) and non-fasting hypoglycemia, which were undetectable with intermittent fasting BG measurement. The fluctuation of BG levels and non-fasting hypoglycemia improved after closure of the ileostomy. Patients with ileostomy may present with hypoglycemia that is undetectable with intermittent fasting BG measurement. In this case, continuous glucose monitoring was very useful for detecting fluctuation of BG levels and hypoglycemic episodes. Therefore, we recommend that continuous glucose monitoring be performed in infants with an ileostomy to confirm whether they have hypoglycemia or a fluctuation in BG levels. Further studies on the postprandial dynamics of various hormones in infants with ileostomy are required.

Partial lipodystrophy in patients who have undergone hematopoietic stem cell transplantation during childhood: an institutional cross-sectional survey.

Partial lipodystrophy (PD), a condition similar to metabolic syndrome without obesity, is one of the late complications of hematopoietic stem cell transplantation (HSCT) performed during childhood. We aimed to investigate the prevalence and risk factors of PD. A cross-sectional survey was performed in a children's hospital, targeting patients treated for a malignancy or hematological disorder, and who were disease-free for > 24 mo. PD was defined as gluteal lipoatrophy and lipohypertrophy of the cheeks or neck associated with diabetes and/or fatty liver disease. In total, 65 patients were enrolled. Six patients (9.2%) were judged to have PD, all of whom had received 10-14 Gy total body irradiation. Compared with the patients without PD, patients with PD were older at investigation (P < 0.01), had a longer elapsed time following HSCT (P < 0.01), had more frequent disease recurrence (P < 0.05), and were more likely to have undergone multiple HSCT (P < 0.05). In addition, they had higher blood pressure and showed higher levels of low-density lipoprotein-cholesterol and triglycerides, whereas their adiponectin levels were significantly lower. In conclusion, a large number of patients developed PD following HSCT, with unfavorable metabolic profiles at a later age, especially when they experienced a complex disease course.

Potential utility of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism: a case report.

We report a Japanese pedigree with familial primary hyperparathyroidism due to a CDC73 mutation. To our knowledge, this is the first report of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism. The proband had severe psychomotor retardation and received laryngotracheal separation surgery. At 19 yr of age, he developed acute pancreatitis. Hypercalcemia (12.2-13.8 mg/dL), elevated levels of intact PTH (86-160 pg/mL), and a tumor detected upon neck ultrasonography led to the diagnosis of primary hyperparathyroidism. Family history and biochemical examinations revealed that three family members (the proband's mother, elder brother, and maternal grandfather) had primary hyperparathyroidism. We identified a novel heterozygous mutation, c.240delT, p.Glu81Lysfs*28, in the CDC73 gene in three affected family members, excluding the proband's elder brother who refused genetic testing. Parathyroidectomy for the proband was considered as high-risk, because the tumor was located close to the tracheostomy orifice. After receiving approval from the institutional review board and obtaining the consent, we initiated cinacalcet treatment. At 22 yr of age, treatment with 100 mg of cinacalcet maintained serum calcium levels below 11.0 mg/dL with no apparent side effects. Our report presents the potential efficacy of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism, in particularly inoperative cases.

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1.

BACKGROUND: Recent reports have indicated that loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1, OMIM 300888) cause congenital central hypothyroidism with macroorchidism. METHODS: We conducted a next-generation sequencing-based comprehensive mutation screening for pituitary hormone deficiencies to elucidate molecular mechanisms other than anatomical abnormalities of the pituitary that might be responsible for multiple anterior hormone deficiency in a male patient who originally visited our institute complaining of short stature. He was born large for gestational age (4,370 g, +3.0 SD) after an obstructed labour. Endocrinological evaluation revealed growth hormone and thyroid-stimulating hormone deficiency. Magnetic resonance imaging showed a discontinuity of the pituitary stalk with an ectopic posterior lobe and a hypoplastic anterior lobe, likely explaining multiple anterior pituitary hormone deficiency. RESULT: We identified a novel hemizygous IGSF1 mutation (c.1137_1138delCA, p.Asn380Glnfs*6) in the patient. In reviewing the literature, we noticed that all reported Japanese male IGSF1 mutation carriers were born larger than mean standards for gestational age (mean birth weight SD score of +2.0, 95% confidence interval 1.0-3.0). CONCLUSION: This case suggests that more attention should be paid to intrauterine growth and birth history when patients are suspected of having an IGSF1 mutation.

The ratio of serum free triiodothyronine to free thyroxine in children: a retrospective database survey of healthy short individuals and patients with severe thyroid hypoplasia or central hypothyroidism.

BACKGROUND: The ratio of serum free triiodothyronine (FT3) to free thyroxine (FT4) has been shown to be constant in healthy adults. However, this ratio has been found to be decreased in athyreotic adult patients on levothyroxine (L-T4) supplementation. In order to better evaluate thyroid-related pathologies in children as well as to establish a reference range, we investigated the FT3/FT4 ratio in a pediatric population. Furthermore, we evaluated this ratio in children with congenital hypothyroidism as well as those with central hypothyroidism. METHODS: A reference range for the FT3/FT4 ratio was obtained from 129 Japanese children (3-17 y) with idiopathic short stature who were designated as the 'Control' group. Patients with congenital hypothyroidism due to athyreosis or severe thyroid hypoplasia (designated as 'A/Hypoplasia'), as well as patients with central hypothyroidism ('Central'), were recruited from the institutional database. For each group, the mean FT3/FT4 ratio was obtained. RESULTS: In the Control group, the FT3/FT4 ratio was 3.03 ± 0.38 10(-2) pg/ng (mean ± standard deviation) with no age or gender differences. A/Hypoplasia patients showed a significantly decreased mean FT3/FT4 ratio (2.17 ± 0.33, P < 0.001) compared to Control patients, with decreased FT3 and elevated FT4 levels. The Central group also showed a significantly decreased FT3/FT4 ratio (2.55 ± 0.45, P < 0.001) compared to the Control group, with decreased FT3 and equivalent FT4 levels. CONCLUSIONS: The FT3/FT4 ratio appears to be constant between the ages of 3-17 y. Children on L-T4 due to congenital thyroid a/hypoplasia or central hypothyroidism have a decreased FT3/FT4 ratio compared to short normal children.

Clinical manifestations and enzymatic activities of mitochondrial respiratory chain complexes in Pearson marrow-pancreas syndrome with 3-methylglutaconic aciduria: a case report and literature review.

Pearson marrow-pancreas syndrome (PS) is a rare mitochondrial disorder. Impaired mitochondrial respiratory chain complexes (MRCC) differ among individuals and organs, which accounts for variable clinical pictures. A subset of PS patients develop 3-methylglutaconic aciduria (3-MGA-uria), but the characteristic symptoms and impaired MRCC remain unknown. Our patient, a girl, developed pancytopenia, hyperlactatemia, steatorrhea, insulin-dependent diabetes mellitus, liver dysfunction, Fanconi syndrome, and 3-MGA-uria. She died from cerebral hemorrhage at 3 years of age. We identified a novel 5.4-kbp deletion of mitochondrial DNA. The enzymatic activities of MRCC I and IV were markedly reduced in the liver and muscle and mildly reduced in skin fibroblasts and the heart. To date, urine organic acid analysis has been performed on 29 PS patients, including our case. Eight patients had 3-MGA-uria, while only one patient did not. The remaining 20 patients were not reported to have 3-MGA-uria. In this paper, we included these 20 patients as PS patients without 3-MGA-uria. PS patients with and without 3-MGA-uria have similar manifestations. Only a few studies have examined the enzymatic activities of MRCC. CONCLUSION: No clinical characteristics distinguish between PS patients with and without 3-MGA-uria. The correlation between 3-MGA-uria and the enzymatic activities of MRCC remains to be elucidated. WHAT IS KNOWN: • The clinical characteristics of patients with Pearson marrow-pancreas syndrome and 3-methylglutaconic aciduria remain unknown. WHAT IS NEW: • No clinical characteristics distinguish between Pearson marrow-pancreas syndrome patients with and without 3-methylglutaconic aciduria.

Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation.

Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C>T; p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient's mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD.

Neonatal case of classic maple syrup urine disease: usefulness of (1) H-MRS in early diagnosis.

We describe a male neonate with classic maple syrup urine disease (MSUD) in metabolic crisis. On day 7 of life, he was referred to hospital because of coma and metabolic acidosis with maple syrup odor. On day 4 after admission, brain magnetic resonance imaging findings were consistent with encephalopathy due to MSUD. Proton magnetic resonance spectroscopy ((1) H-MRS) showed a large methyl resonance peak at 0.9 p.p.m. The diagnosis of MSUD was confirmed on low branched-chain α-keto acid dehydrogenase complex activity in lymphocyte. (1) H-MR spectra were obtained in 10 min, while it took at least several days to obtain the results of other diagnostic examinations. In convalescence, the peak at 0.9 p.p.m. decreased. The large methyl resonance peak at 0.9 p.p.m. in brain (1) H-MRS would be one of the earliest clues to the diagnosis of classic MSUD in the neonatal period, especially in metabolic crisis.

Association between graves' disease and renal coloboma syndrome: a case report.

Renal coloboma syndrome is an autosomal dominant condition characterized by renal lesions and optic nerve abnormalities. We report an 11-yr-old Japanese girl with familial renal coloboma syndrome, who also had Graves' disease. Four affected family members had a previously reported heterozygous mutation (c.76dupG, p.Val26Glyfs*28) in the PAX2 gene. We hypothesized that PAX2 mutations may increase the risk of autoimmune diseases through alterations of human ß-defensin 1 expression.