Pubertal induction in Turner syndrome without gonadal function: A possibility of earlier, lower-dose estrogen therapy.

Delayed and absent puberty and infertility in Turner syndrome (TS) are caused by primary hypogonadism. A majority of patients with TS who are followed at hospitals during childhood will not experience regular menstruation. In fact, almost all patients with TS need estrogen replacement therapy (ERT) before they are young adults. ERT in TS is administered empirically. However, some practical issues concerning puberty induction in TS require clarification, such as how early to start ERT. The present monograph aims to review current pubertal induction therapies for TS without endogenous estrogen production and suggests a new therapeutic approach using a transdermal estradiol patch that mimics incremental increases in circulating, physiological estradiol. Although evidence supporting this approach is still scarce, pubertal induction with earlier, lower-dose estrogen therapy more closely approximates endogenous estradiol secretion.

Knowns and unknowns about congenital hypothyroidism: 2022 update.

Several excellent guidelines and expert opinions on congenital hypothyroidism (CH) are currently available. Nonetheless, these guidelines do not address several issues related to CH in detail. In this review, the authors chose the following seven clinical issues that they felt were especially deserving of closer scrutiny in the hope that drawing attention to them through discussion would help pediatric endocrinologists and promote further interest in the treatment of CH. 1. How high should the levothyroxine (L-T4) dose be for initial treatment of severe and permanent CH? 2. What is the optimal method for monitoring treatment of severe CH? 3. At what level does maternal iodine intake during pregnancy affect fetal and neonatal thyroid function? 4. Does serum thyroglobulin differ between patients with a dual oxidase 2 (DUOX2) variants and those with excess iodine? 5. Who qualifies for a genetic diagnosis? 6. What is the best index for distinguishing transient and permanent CH? 7. Is there any cancer risk associated with CH? The authors discussed these topics and jointly edited the manuscript to improve the understanding of CH and related issues.

Factors affecting prepubertal and pubertal bone age progression.

Bone age (BA) is a clinical marker of bone maturation which indicates the developmental stage of endochondral ossification at the epiphysis and the growth plate. Hormones that promote the endochondral ossification process include growth hormone, insulin-like growth factor-1, thyroid hormone, estrogens, and androgens. In particular, estrogens are essential for growth plate fusion and closure in both sexes. Bone maturation in female children is more advanced than in male children of all ages. The promotion of bone maturation seen in females before the onset of puberty is thought to be an effect of estrogen because estrogen levels are higher in females than in males before puberty. Sex hormones are essential for bone maturation during puberty. Since females have their pubertal onset about two years earlier than males, bone maturation in females is more advanced than in males during puberty. In the present study, we aimed to review the factors affecting prepubertal and pubertal BA progression, BA progression in children with hypogonadism, and bone maturation and deformities in children with Turner syndrome.

Congenital hypogonadotropic hypogonadism complicated by neuroblastoma.

A 3-mo-old male infant was referred to our hospital with micropenis. Since his serum LH, FSH, and testosterone levels were low (< 0.3 mIU/mL, 0.08 mIU/mL, and < 0.03 ng/mL, respectively), Kallmann syndrome/normosmic hypogonadotropic hypogonadism was suspected. In the process of searching for complications of Kallmann syndrome/normosmic hypogonadotropic hypogonadism, a right adrenal gland tumor was incidentally discovered. The patient was diagnosed with stage 1 neuroblastoma. A homozygous p.P147L (c.C440T) mutation in the KISS1R gene was detected as a cause of the congenital hypogonadotropic hypogonadism. KISS1-KISS1R signaling, which is essential for GnRH secretion, exhibits anti-metastatic and/or anti-tumoral roles in numerous cancers. High KISS1 expression levels reportedly predict better survival outcomes than low KISS1 expression levels in neuroblastoma. Therefore, decreased KISS1-KISS1R signaling may have played a role in the neuroblastoma in this patient.

Association of autosomal-recessive-type distal renal tubular acidosis and Glanzmann thrombasthenia as a consequence of runs of homozygosity.

We report the case of a Filipino girl with autosomal-recessive-type distal renal tubular acidosis and Glanzmann thrombasthenia caused by homozygous variants in the genes SLC4A1 and ITGA2B within the long homozygous DNA region on chromosome 17q21.31. This haplotype may be retained among individuals of Filipino descent.

Predictive effect of antithyroid antibody for relapse of Graves' disease.

BACKGROUND: The remission rate in children with Graves' disease (GD) after 2-6 years of antithyroid drug (ATD) treatment is 40-50%. It has been reported that it is difficult to predict the GD prognosis based on the thryroid stimulating hormone (TSH) receptor antibody (TRAb) level at the cessation of ATD treatment. We studied whether the persistence of negative TRAb at ATD treatment cessation increased the remission rate in pediatric patients with GD. METHODS: We included 22 patients diagnosed with GD who discontinued ATD treatment after confirmation of negative TRAb on two or more consecutive tests. Remission was defined as the maintenance of normal thyroid function, including serum TSH level, with negative TRAb more than 2 years after ATD discontinuation. RESULTS: Of the 22 patients, 12 achieved remission (remission rate 54.5%), with no significant between-group difference in the median duration of ATD treatment in the remission and relapse groups (4.4 vs 3.9 years). Of the 10 patients who relapsed, four (40.0%) relapsed within 2 years after ATD discontinuation, and 4 (40.0%) relapsed more than 5 years after ATD discontinuation. CONCLUSIONS: The persistence of negative TRAb at ATD treatment cessation might indicate prolonged duration of remission but does not increase the final remission rate in patients with childhood-onset GD.

Hypereosinophilia with Hepatic Nodule Formation Caused by Ganoderma lucidum.

A 61-year-old man who underwent surgery for rectal adenocarcinoma developed multiple hepatic nodules. The nodules were 1-3 cm without a capsular structure or contrast enhancement on computed tomography/magnetic resonance imaging, findings that were atypical for adenocarcinoma metastases. A biopsy showed the aggregation of eosinophils without larval bodies, ova, or granulomas. Laboratory tests showed a marked increase in eosinophils and a slight liver enzyme elevation. He had been taking the commercial herbal medicine Ganoderma lucidum for his liver function. After discontinuing G. lucidum, the eosinophil counts and liver enzyme levels rapidly resolved, and the nodules disappeared completely. This is a rare case of hypereosinophilia with hepatic nodules reactive to herbal medicine rather than a parasitic infection.

A Gas-forming Liver Abscess with Massive Bleeding into the Abscess Cavity Due to a Ruptured Inferior Phrenic Artery.

An 88-year-old woman developed a huge abscess, forming an air-fluid level in the right lobe of the liver. A pigtail catheter was placed and drained thick pus with putrid odor from the abscess cavity. Gram-positive rods were detected in the pus, which were subsequently determined to be Clostridium perfringens by culture. She developed hemorrhaging in the abscess cavity when the right inferior phrenic artery was damaged by inflammation that had spread from the abscess. Emergency transarterial embolization with gelatin sponges was performed, and the bleeding ceased. We herein report a rare case of liver abscess that caused inferior phrenic artery injury, resulting in bleeding.

Bone age in prepubertal children with nonfamilial or familial idiopathic short stature and prepubertal short-stature children born small for gestational age: a longitudinal data analysis.

This retrospective study aimed to clarify the characteristics of bone maturation using longitudinal data in short-stature prepubertal children. Children with chronological ages (CAs) of 4.5-10.5 yr with nonfamilial idiopathic short stature (ISS, n = 95), familial ISS (FSS, n = 21), and short-stature children born small for gestational age (SGA, n = 23) were selected, of which 435 left-hand plain radiographic images were evaluated. Bone age (BA) delay was defined as BA minus CA. In the ISS group, there was a statistically significant difference in median BA delay among the CA groups (P < 0.001), as median BA delay gradually increased from 5- to 9-yr-old groups (-1.06 [range, -2.17 to 0.27] and -2.45 [range, -4.35 to -0.32] yr, respectively). In the FSS group, median BA delays were approximately -1 yr in all CA groups. In the SGA group, median BA delay gradually decreased from 7- to 10-yr-old groups (-1.96 [range, -2.99 to 0.56] and -0.04 [range, -2.44 to 0.92] yr, respectively), but with no significant difference (P = 0.647). The heavier weight of children with FSS and the probable earlier onset of adrenarche in children born SGA compared to those with ISS could have affected bone maturation.

Immunoglobulin G4-Related Hepatic Inflammatory Pseudotumor Diagnosed with Endoscopic Ultrasound-Guided Fine-Needle Biopsy.

A 71-year-old man with obstructive jaundice was referred to our department. He underwent cholangiojejunostomy 15 years ago for palliative drainage. At that time, he had obstructive jaundice caused by an unresectable pancreatic head tumor. Contrast-enhanced computed tomography (CE-CT) now revealed a mass with low enhancement in the hepatic hilum that occluded the hilar bile duct and infiltrated extensively along the portal vein and hepatic artery. CE-CT also showed marked atrophy of the left hepatic lobe. No swelling or tumors were observed in the pancreas. Serum immunoglobulin G4 (IgG4) levels were as high as 465 mg/dL. Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) was performed targeting the hepatic hilar lesion. Immunohistological results of the biopsy specimens suggested that the lesion was an IgG4-related hepatic inflammatory pseudotumor (IPT) with no atypical cells. Steroid treatment resulted in rapid clinical improvement. This case suggested the usefulness of EUS-FNB for diagnosing IgG4-related hepatic hilar IPT.

ACTH-cortisol dissociation in patients with Kawasaki disease: a retrospective study.

ACTH-cortisol dissociation is recognized in patients with critical illnesses. Cytokines, including tumor necrosis factor-α and interleukin-6 induce hypercortisolemia by enhancing the ACTH-independent synthesis and secretion of cortisol and by reducing cortisol breakdown. Subsequently, hypercortisolemia suppresses ACTH secretion by negative feedback inhibition. ACTH-cortisol dissociation in patients with systemic inflammatory diseases has not been reported. Here, we examined whether ACTH-cortisol dissociation is recognized in patients with Kawasaki disease (KD) associated with hypercytokinemia, as well as the possible cytokine involvement in ACTH-cortisol dissociation, retrospectively. The levels of serum cortisol, plasma ACTH, and cytokine-induced proteins, i.e., plasma C-reactive protein (CRP), serum ferritin, and urinary ß2-microglobulin (U-ß2MG), in 232 patients with KD were measured at diagnosis. Quartile groups based on cytokine-induced protein levels were formed (Q1, Q2, Q3, and Q4). We found a low median plasma ACTH [median (range): 8.9 (<2.0-332.0) pg/mL] but a high median serum cortisol level [median (range): 25.8 (1.4-99.8) µg/dL] in the entire study population. The median serum cortisol levels were significantly higher in the CRP-Q4, ferritin-Q4, and U-ß2MG-Q4 groups than in the CRP-Q1, ferritin-Q2, and U-ß2MG-Q1 groups, respectively (p < 0.01; p < 0.01; p < 0.001). The median plasma ACTH levels were significantly lower in the CRP-Q4 and ferritin-Q4 groups than in the CRP-Q1 and ferritin-Q1 groups, respectively (p < 0.001; p < 0.001). ACTH-cortisol dissociation was identified in patients with KD. Our findings suggest that inflammatory cytokines are involved in ACTH-independent hypercortisolemia in patients with KD. ACTH-cortisol dissociation in other systemic inflammatory diseases needs further investigation.

Retrospective study of the renal function using estimated glomerular filtration rate and congenital anomalies of the kidney-urinary tract in pediatric Turner syndrome.

Although Turner syndrome (TS) is frequently associated with congenital anomalies of the kidney-urinary tract (CAKUT), which is a major cause of pediatric chronic kidney disease, renal function in TS is usually considered normal. The present study aimed to analyze the frequency of renal dysfunction and CAKUT in pediatric patients with TS. Our study included 122 patients with TS between the ages of 2 and 18 years from 30 hospitals across Japan. Clinical data related to renal function and CAKUT were retrospectively collected. The estimated glomerular filtration rate (eGFR) was calculated using the serum creatinine-based formula recommended by the Japanese Society for Pediatric Nephrology. An eGFR <90 mL/min/1.73 m2 for two consecutive years was defined as renal dysfunction. Fifteen (13.5%) of 122 patients had CAKUT, and four patients had renal dysfunction (3.2%, 95% confidence interval: 0%-6.7%). Three of the four did not have CAKUT. Of the CAKUT manifestations, horseshoe kidney, renal hypodysplasia, and multicystic dysplastic kidney were seen in nine, two, and one patient, respectively. Eight of the nine patients with horseshoe kidney had a normal renal function; however, the remaining patient with renal hypodysplasia had renal dysfunction. A small percentage of patients with pediatric TS may had an eGFR below 90 mL/min/1.73 m2 which was not necessarily associated with CAKUT.

A Biliary Mucinous Cystic Neoplasm with Intrahepatic and Lymph Node Metastases.

A 51-year-old woman who presented with a large cystic liver tumor with mural nodules in the lateral segment developed Trousseau's syndrome. A mural nodule directly invaded her liver parenchyma. Metastatic nodules were detected in the right lobe and portal/paraaortic lymph nodes. The pathological findings showed mucin-producing adenocarcinoma cells to have invaded the fibrous stroma forming a micropapillary cluster. She developed obstructive jaundice due to tumor progression and subsequently died of hepatic failure. Invasive biliary mucinous cystic neoplasm (MCN) is a rare form of a malignant tumor with a relatively favorable prognosis. This is a very rare case biliary MCN with invasive carcinoma that showed intrahepatic and lymph node metastases.

Levothyroxine Dosage as Predictor of Permanent and Transient Congenital Hypothyroidism: A Multicenter Retrospective Study in Japan.

BACKGROUND: Congenital hypothyroidism (CH) can be divided into 2 types, transient CH (T-CH) and permanent CH (P-CH), depending on the requirement of levothyroxine (LT4) for life-long treatment. Several studies have recently reported that the LT4 dosage is useful for predicting the LT4 requirement, but none of the studies followed their patients to puberty. OBJECTIVE: To determine the cutoff value for the LT4 dosage as a predictor of the LT4 requirement after puberty in patients with CH. METHODS: The LT4 dosage and clinical data on 99 patients with CH who were followed at the participating hospitals from the neonatal period to 15 years of age or older were retrospectively analyzed. Based on their LT4 requirement at their last hospital visit, the participants were divided into the P-CH group (n = 75), who were treated with LT4, and the T-CH group (n = 24), who were not. RESULTS: At age 1 year, a higher LT4 dosage was required for the P-CH group (median 3.75 vs. 2.88 µg/kg/day; p < 0.001). When the LT4 dosage cutoff value at age 1 year was set at 4.79 and 1.74 µg/kg/day, the specificity of P-CH and T-CH (for denying T-CH and P-CH, respectively) was 100 and 97%, respectively. CONCLUSIONS: An LT4 dosage above 4.7 µg/kg/day and below 1.8 µg/kg/day at age 1 year may help predict P-CH and T-CH, respectively.

Language delay and developmental catch-up would be a clinical feature of pseudohypoparathyroidism type 1A during childhood.

Pseudohypoparathyroidism type 1A (PHP1A) is characterized by resistance to multiple hormones, the Albright Hereditary Osteodystrophy phenotype, obesity, and developmental delay. Developmental delay usually appears prior to hypocalcemia due to parathyroid hormone resistance and could be a clinically important feature for early diagnosis of PHP1A. To date, however, the details have not been documented. With regard to developmental delays, we conducted a multicenter retrospective study of 22 PHP1A patients from 18 families who were diagnosed clinically or genetically from 2005 to 2015. For quantitative analysis of their development, we calculated the ratios of the milestone ages of the patients to those in normal reference data. The ratio of the ages with respect to speech development, i.e., speaking a first meaningful word (median: 1.67), was significantly higher than that for gross motor development, walking unassisted (median: 1.34). The ratio of age at stringing a two-word sentence (median: 1.32) was significantly lower than that of saying a first word (median: 1.84). Ten out of 11 (91%) patients exhibited two or three of the following clinical phenotypes: developmental delay, obesity, and hyperthyrotropinemia. These results suggest two possible clinical features of developmental delays in PHP1A patients: developmental delay is more obvious in speech acquisition than in gross motor skills, and speech delays could be attenuated during later childhood. Further, the presence of multiple of three clinical symptoms could be an important indicator to differentiate the diagnosis of PHP1A during early childhood.

Effect of treatment with epoprostenol and endothelin receptor antagonists on the development of thyrotoxicosis in patients with pulmonary arterial hypertension.

Thyroid disease is known to be associated with pulmonary arterial hypertension (PAH). We investigated the prevalence of thyroid disease in patients with idiopathic PAH (IPAH) or heritable PAH (HPAH), and the factors affecting the pathogenesis of thyroid disease. We retrospectively evaluated 59 patients with IPAH or HPAH who had been diagnosed with PAH before the age of 20 years. Thyrotoxicosis was detected in 12 of the 59 patients (6 patients with Graves' disease, 3 with hashitoxicosis, and 3 with silent thyroiditis) after the start of PAH treatment. The proportion of patients who received epoprostenol in the thyrotoxicosis group was significantly higher than that in the euthyroid group (12/12 vs. 27/47, p=0.015). In the 39 patients treated with epoprostenol, the proportion of patients who received combination therapy with epoprostenol and an endothelin receptor antagonist (ERA) in the thyrotoxicosis group was significantly lower than that in the euthyroid group (5/12 vs. 23/27, p=0.016). Logistic regression analysis revealed that thyrotoxicosis development was significantly associated with administration of epoprostenol (odds ratio [OR] 8.22, 95% confidence interval [CI] 1.26-53.74, p=0.028) and non-administration of ERA (OR 5.33, 95% CI 1.29-22.06, p=0.021). The prevalence of thyrotoxicosis was high in patients with IPAH or HPAH. The onset of thyrotoxicosis might be promoted by epoprostenol and inhibited by ERA.

Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2.

Here, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 (DUOX2) occurring along with concurrent missense mutations in thyroid peroxidase (TPO), leading to transient congenital hypothyroidism (CH). Three Japanese boys with nonconsanguineous parents were diagnosed with CH during their neonatal screenings. All patients presented with moderate-to-severe neonatal hypothyroidism and were diagnosed with transient CH after re-evaluation of thyroid function. Two siblings were compound heterozygous for p.[R1110Q]+[Y1180X] in DUOX2; one of them was also heterozygous for p.[R361L] in TPO. The third patient was compound heterozygous for p.[L1160del]+[R1334W] in DUOX2 and heterozygous for p.[P883S] in TPO. This is the first report of a de novo L1160del mutation affecting the DUOX2 gene and of the novel mutations Y1180X in DUOX2 and R361L in TPO. R1110Q and L1160del were found to reduce H2O2 production (5%-9%, p<0.01), while Y1180X, which introduces a premature stop codon, did not confer detectable H2O2 production (-0.7%±0.6%, p<0.01). Moreover, R1334W, a missense mutation possibly affecting electron transfer, led to reduced H2O2 production (24%±0.9%, p<0.01) in vitro, and R1110Q and R1334W resulted in reduced protein expression. Y1180X was detected in a 120 kDa truncated form, whereas L1160del expression was maintained. Further, R361L, a novel missense mutation in TPO, caused partial reduction in peroxidase activity (20.6%±0.8%, p=0.01), whereas P883S, a missense variant, increased it (133.7%±2.8%, p=0.02). The protein expression levels in the case of R361L and P883S were maintained. In conclusion, we provide clinical and in vitro demonstrations of different functional defects and phenotypic heterogeneity in the same thyroid hormonogenesis pathway.

Bone age: assessment methods and clinical applications.

The main bone age assessment methods are the Greulich-Pyle and Tanner-Whitehouse 2 methods, both of which involve left hand and wrist radiographs. Several other bone age assessment methods have been developed, including ultrasonographic, computerized, and magnetic resonance (MR) imaging methods. The ultrasonographic method appears unreliable in children with delayed and advanced bone age. MR imaging is noninvasive; however, bone age assessment using MR imaging is relatively new, and further examinations are needed. An automated method for determining bone age, named BoneXpert, has been validated for Caucasian children with growth disorders and children of various ethnic groups. Sex hormones are necessary for bone growth and maturation in children with a bone age corresponding to normal pubertal age, and estrogen is essential for growth plate closure. Bone age is an effective indicator for diagnosing and treating various diseases. A new method for adult height prediction based on bone age has been developed using BoneXpert, in addition to the commonly used Bayley-Pinneau and Tanner-Whitehouse mark II methods. Furthermore, bone age may become a predictor for the timing of peak height velocity and menarche.