Re-Evaluation of the Prevalence of Permanent Congenital Hypothyroidism in Niigata, Japan: A Retrospective Study.

Although newborn screening (NBS) for congenital hypothyroidism (CH) in Japan started more than 40 years ago, the prevalence of CH remains unclear. Prevalence estimations among NBS-positive CH individuals include those with transient hypothyroidism and transient hyperthyrotropinemia, and re-evaluation with increasing age is necessary to clarify the actual incidence. Thus, we re-evaluated the incidence of permanent CH. Of the 106,114 patients who underwent NBS in the Niigata Prefecture, Japan, between April 2002 and March 2006, 116 were examined further due to high thyroid-stimulating hormone levels (>8 mIU/L) and were included in the study. We retrospectively evaluated their levothyroxine sodium (LT4) replacement therapy status from the first visit to 15 years of age. Of the 116 NBS-positive patients, 105 (91%) were initially examined in our department. Of these, 72 (69%) started LT4 replacement therapy on the first visit. Subsequently, 27 patients continued LT4 replacement until 15 years of age after multiple re-evaluations. The prevalence of permanent CH in the Niigata Prefecture during this period was 1 in 2500-3500 children. Ultimately, 62.5% of patients on LT4 replacement discontinued treatment by 15 years of age. This is the first study to clarify the true prevalence of permanent CH in Japan.

Long-term follow-up study for a patient with Floating-Harbor syndrome due to a hotspot SRCAP mutation.

Floating-Harbor syndrome (FHS) is a rare autosomal dominant disorder characterized by short stature, skeletal malformations, speech delay, and dysmorphic facial appearance. Recently, mutations in SRCAP encoding a coactivator for cAMP-response element binding protein (CREB)-binding protein have been identified in small number of patients with FHS. Here, we report on long-term follow-up data of a male patient with a SRCAP mutation. The patient presented with mild hypothyroidism and renal hypouricemia, in addition to several FHS-compatible features including growth impairment, cognitive disability, facial dysmorphisms, and hypertension. He showed delayed bone age from infancy to 9 years of age and markedly accelerated bone age with the formation of cone-shaped epiphyses and early epiphysial fusions after the onset of puberty. His pubertal sexual development was almost age appropriate. Two-year treatment with growth hormone (GH) did not significantly improve the growth velocity. Molecular analysis identified a de novo heterozygous nonsense mutation (p.R2444X) in the last exon of SRCAP, which has been most common mutation detected in patients from other ethnic groups. These results indicate that perturbed skeletal maturation from infancy through adolescence is a characteristic feature in patients with SRCAP mutations. Furthermore, our data imply that GH therapy exerted only a marginal effect on the growth of this patient, and that renal hypouricemia may be a novel complication of FHS.

The occurrence of neonatal acute respiratory disorders in 21-hydroxylase deficiency.

Patients with 21-hydroxyase deficiency (21-OHD) usually do not present clinical symptoms other than female ambiguous genitalia and skin pigmentation at birth. However, we have found a case of neonatal transient tachypnea with spontaneous pneumomediastinum in a neonate with 21-OHD at birth. The purpose of this study was to investigate the occurrence of neonatal respiratory disorders in 21-OHD patients. From April 1989 to March 2009, 478,337 Japanese newborns were screened for congenital adrenal hyperplasia in Niigata prefecture. Among these newborns, 26 patients were diagnosed as having 21-OHD. We investigated the presence of neonatal respiratory disorders based on the retrospective medical records of 24 full-term patients with 21-OHD. Three of the 24 patients (12.5%) had neonatal acute respiratory disorders. Neonatal transient tachypnea developed in all patients with only oxygenation for two or three days after birth. Chest X-rays showed spontaneous pneumothorax or pneumomediastinum in two patients. In conclusion, 21-OHD patients may present with acute respiratory disorders, especially transient tachypnea with spontaneous pneumothorax, at birth. In cases of delivering mothers having other children with 21-OHD, newborns require attention regarding neonatal respiratory disorders if a prenatal diagnosis has not been performed.

A study of the etiology of congenital hypothyroidism in the Niigata prefecture of Japan in patients born between 1989 and 2005 and evaluated at ages 5-19.

BACKGROUND: The prevalence of congenital hypothyroidism (CH) increased during the period 1994-2002 in Japan. The reasons for these recently described increases in the prevalence of CH remain unclear. Moreover, the proportion of patients with different etiologies CH in the more recently diagnosed patients has not been established. In this study, we determined the etiologies of CH that were detected by neonatal screening in Niigata refecture, Japan. METHODS: A total of 100 patients having a diagnosis of CH (41 men and 59 women, aged 5-19 years old) were evaluated. To determine the etiology of CH, the patients underwent a ¹²³I thyroidal radioiodine uptake test, a scintigram, a saliva to plasma radioiodine ratio analysis, a perchlorate discharge test, thyroid ultrasonography, measurements of thyroidal function and thyroglobulin, and a thyrotropin (TSH)-releasing hormone tolerance test. RESULTS: Patients with overt CH (n=34, elevated TSH levels with low free thyroxine levels) made up 34% of the total group, 56% of the patients had subclinical CH (n=56, elevated TSH levels with normal free thyroxinelevels), and 10% had normal thyroid function. These were patients who were considered to have transient hypothyroidism or hyperthyrotropinemia. Thyroid dysgenesis was the diagnosis in 73% of patients with overt CH, and the most of these had ectopic thyroid tissue. In contrast, thyroid dysgenesis was the diagnosis in only 36% of the patients with subclinical CH. CONCLUSIONS: Only 50% of our patients with CH detected by neonatal screening had thyroid dysgenesis. With an increase in the percentage of patients with subclinical hypothyroidism, the prevalence of thyroid dyshormogenesis has increased. Studies of the frequency and etiology of CH should consider overt and subclinical CH separately.

Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin.

Resistance to TSH (RTSH [MIM 275200]) is a heterogeneous condition defined by variable degree of insensitivity to biologically active TSH. While this condition is classically caused by loss-of-function mutations of the TSH receptor gene (TSHR), several patients have exhibited RTSH-like phenotype in the apparent absence of TSHR mutations, and some of them have mutations of PAX8 or GNAS1. We identified a Japanese boy with congenital hypothyroidism who suffered from recurrent lower respiratory infection during infancy and choreoathetosis at a later age. At 14 years of age, he was diagnosed as having RTSH, on the basis of compensated hypothyroidism (TSH, 30.2 mU/L; FT4, 1.2 ng/dl), disproportionate increments of thyroid hormones and TSH during a TRH test (DeltaFT3, 0.4 pg/ml; DeltaT3, 13 ng/dl; and DeltaTSH, 88.3 mU/L), and normal ultrasound thyroid image and radioactive iodine uptakes. Molecular analysis for TITF1 revealed a novel de novo heterozygous deletion/insertion mutation (c.470_479delinsGCG,) that is predicted to lose the entire homeodomain and the NK2-specific domain. We suggest that a heterozygous loss-of-function TITF1 mutation can also cause RTSH-compatible phenotype.

Mental development of infants with congenital hypothyroidism: a longitudinal study.

The purpose of this study was to assess the relationship between the clinical findings before starting treatment and the development quotient in children treated for congenital hypothyroidism. Patients with congenital hypothyroidism (n = 129) were divided into favorable and unfavorable groups according to intellectual performance. Children with congenital hypothyroidism generally have a similar intellectual outcome to that of healthy children. However, a low birth weight, the presence of complications, and a high serum thyroid-stimulating hormone value are the risk factors for unfavorable cases, who consistently have a development quotient score of less than 100.

Longitudinal growth of the short bones of the hand in a girl with pseudohypoparathyroidism type ia.

Brachydactyly is a common feature of pseudohypoparathyroidism (PHP) type Ia. We studied the longitudinal growth of the short bones in the hand of a 15-yr-old girl with PHP type Ia who had been followed for congenital hypothyroidism. Radiographs of the hand of the patient, who had been X-rayed every year since 2 yr of age, were studied. She showed cone-shaped epiphyses of the hand at 2 yr of age before showing brachydactyly. At 4 yr of age, she showed brachydactyly and an advanced bone age, and some short bones were prematurely fused at 6 yr of age. The short bones without cone-shaped epiphyses were also short as a result of a disturbance of the longitudinal bone elongation. In conclusion, the brachydactyly of PHP type Ia is thus considered to be caused by both early epiphyseal fusion with cone-shaped epiphyses and a disturbance of the longitudinal bone elongation.

Effect of oral camostat mesilate on hematuria and/or proteinuria in children.

The effects of camostat mesilate (CM), a derivative of gabexate mesilate developed for oral use, on primary glomerulonephritis (GN) and chance hematuria and/or proteinuria were evaluated. Fourteen patients (6 males, 8 females) with a mean age of 11 years and 3 months (range 4-16 years) were enrolled. Histological and clinical diagnoses of the 14 patients were as follows: IgA nephropathy 3, non-IgA GN 2, and asymptomatic significant microscopic hematuria [more than 100 red blood cells per high-power field (x400)] with or without proteinuria 9. They were consecutively treated with oral CM (100 mg twice a day) when they were confirmed to have continuous significant microscopic hematuria and/or proteinuria after a few months of observational follow-up. Urinary findings were normalized in 10 of the 14 patients (85.7%) between 1 month 1 week and 10 months (mean 4 months) after administration of CM. Hematuria cleared in 11 of 13 patients, and proteinuria disappeared in 4 of 5 patients. The mean duration of CM administration was 21.7 +/- 9.1 months (range 4-37 months). At present, 3-12 years after discontinuation of CM therapy, their urinary findings remain normal at 9 years 10 months to 26 years 6 months of age. In conclusion, there appears to be an association between the oral use of CM and reduction in significant microscopic hematuria and/or proteinuria. Oral CM therapy could represent a practical primary care approach to chance hematuria and/or proteinuria in children.

Asymptomatic primary hyper- N-acetyl-beta-D-glucosaminidaseuria: a new clinical entity?

Urinary N-acetyl-beta-D-glucosaminidase (NAG) is excreted from renal tubular cells and increased urinary excretion reflects renal tubular damage. There are many causes for the elevation of urinary NAG; however, primary elevation of urinary NAG (primary hyper-NAGuria) has never been reported. Recently, we encountered two siblings with continuously elevated urinary NAG levels that could not been explained by any known causes. Two brothers, aged 13 and 11 years, were found to have continuously elevated urinary NAG levels that were repeatedly confirmed by urinary NAG levels (both per liter and urinary NAG/creatinine ratios). However, simultaneously measured urinary beta(2)-microglobulin levels were always within normal ranges. The elder brother is a heterozygous carrier for familial hypercholesterolemia, although this was not attributable to the urinary NAG elevation. The two patients were receiving no drugs when they were first examined at our hospital, and no nephrotoxic substances were found to be the cause for the elevation. Renal biopsy revealed no abnormal findings attributable to the abnormally high excretion of urinary NAG. Our two patients are considered to have asymptomatic primary hyper-NAGuria, which has not been previously reported. Although more cases are needed, this asymptomatic primary hyper-NAGuria is probably a new clinical entity of renal tubular disorders.

Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan.

PURPOSE: To determine the usefulness of 6-month screening for neuroblastoma. PATIENTS AND METHODS: The cumulative incidence rates (IRs) and cumulative mortality rates (MRs) of neuroblastoma in children younger than 60 months of age were analyzed for control (n = 713,025), qualitative screening (Qual Screen, n = 1,142,519), and quantitative screening (Quan Screen, n = 550,331) cohorts, and for Screened and Unscreened subgroups within screening cohorts. RESULTS: IRs (per 100,000) for infants aged 6 to 11 months were 1.12 in Control, 5.69 in Qual Screen (P <.0001), and 17.81 in Quan Screen (P <.0001); IRs for children aged 12 to 59 months were 7.29 in Control, 5.86 in Qual Screen (P =.28), and 6.36 in Quan Screen (P =.60). IRs for children aged 12 to 59 months in Unscreened or Screened subgroups remained at the same level. When patients diagnosed at younger than 6 months of age were excluded, the MR (per 100,000) under 60 months for Control was 4.21; those in Unscreened and Screened subgroups were 3.84 and 2.53 in Qual Screen (P =.30), and 3.20 and 1.97 in Quan Screen (P =.73), respectively; MRs between Control and Unscreened subgroups revealed no significant differences (P =.89 in Qual Screen, P =.85 in Quan Screen). CONCLUSION: Six-month screening resulted in a marked increase in incidence for infants with no significant decrease in incidence for children older than 1 year of age. A decrease in mortality was observed, but it was not significant. The usefulness of screening is questionable, because the decrease of mortality should be balanced against the adverse effect of overdiagnosis and the psychological burden on parents and children.