Overall usefulness of newborn screening for congenital hypothyroidism by using free thyroxine measurement.

In Kanagawa Prefecture, Japan, simultaneous measurements of free T4 (FT4) and TSH levels are performed during newborn screening for congenital hypothyroidism (CH). FT4 measurement enables the detection of CH of central origin (CH-C), the incidence of which is estimated to be 1 in 30,833 live births in Kanagawa Prefecture. In this study, we aimed to evaluate the efficacy of FT4 screening when transient CH-C and thyroidal CH (CH-T) with delayed TSH elevation are included as screening targets. Data collected on CH-C patients using a regional survey, as well as data from a database created by a screening organization, were used. Of the 24 CH-C patients who had been born in Kanagawa Prefecture between 1999 and 2008, a positive screening result for FT4 (<0.7 ng/dL) was obtained in 13 newborns; of these, 12 were identified solely through newborn screening. Of the 113 patients for whom positive screening results were obtained during the study period, 5 and 6 were found to have transient CH-C and CH-T with delayed TSH elevation, respectively. Remarkably, 4 out of 5 patients with transient CH-C and all patients with CH-T with delayed TSH elevation were diagnosed through the evaluation of low FT4 at screening. These results indicate that the use of this FT4 screening system facilitates the identification of transient CH-C and CH-T with delayed TSH elevation, thus justifying the inclusion of these entities as screening targets.

Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency.

OBJECTIVE: To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. DESIGN: A 2-year-old girl of height 77.2 cm (-3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7 ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41 µg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81 ng/mL with insulin-induced hypoglycemia, 3.78 ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. RESULTS: Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2+3a>g mutation would lead to aberrant splicing. CONCLUSIONS: A case of isolated GH deficiency due to novel GHRHR gene mutations was identified.

Mass screening of newborns for congenital hypothyroidism of central origin by free thyroxine measurement of blood samples on filter paper.

OBJECTIVE: To evaluate the effectiveness of mass screening of newborns for congenital hypothyroidism of central origin (CH-C) by measurement of free thyroxine (FT(4)) and thyroid-stimulating hormone (TSH). DESIGN: Questionnaire-based survey of CH-C patients born between 1999 and 2008 in Kanagawa prefecture, Japan. METHODS: TSH and FT(4) levels in dried blood spots on filter paper were measured using ELISA kits, and CH-C was diagnosed at FT(4) levels below a cutoff of 0.7 ng/dl (9.0  pmol/l). Survey results were collated with the database created by the screening organizer. RESULTS: Twenty-four CH-C patients (18 males) were identified, 14 of whom had multiple pituitary hormone deficiencies (group M), eight had isolated CH-C (group I), and two had undetermined pituitary involvement (group U). In groups M, I, and U, the number of patients with FT(4) levels below the cutoff value at screening was five (36%), seven (88%), and one (50%) respectively; other patients had been diagnosed clinically. Thus, 13 patients were true positives, while nine were false negatives, yielding screening sensitivity of 59.1% and positive predictive value of 11.5%. The calculated sensitivity was 81.8% at a higher cutoff value of 0.9  ng/dl (11.6  pmol/l). The overall incidence of CH-C was estimated at 1 in 30, 833 live births, while that of CH of thyroidal origin (CH-T) is 1 in 3472 live births in Kanagawa prefecture (CH-T/CH-C, 8.9). CONCLUSIONS: Newborn screening with combined FT(4) and TSH measurements can identify a significant number of CH-C patients before manifestation of clinical symptoms, but a more appropriate FT(4) cutoff value should be considered.

Proportion of malformations and genetic disorders among cases encountered at a high-care unit in a children's hospital.

Genetic disorders and birth defects account for a high percentage of the admissions in children's hospitals. Congenital malformations and chromosomal abnormalities are the most common causes of infant mortality. So their effects pose serious problems for perinatal health care in Japan, where the infant mortality is very low. This paper describes the reasons for admissions and hospitalization at the high-care unit (HCU) of a major tertiary children's referral center in Japan. We retrospectively reviewed 900 admission charts for the period 2007-2008 and found that genetic disorders and malformations accounted for a significant proportion of the cases requiring admission to the HCU. Further, the rate of recurrent admission was higher for patients with genetic disorders and malformations than for those with acquired, non-genetic conditions. Over the past 30 years, admissions attributed to genetic disorders and malformations has consistently impacted on children's hospital and patients with genetic disorders and malformations form a large part of this facility. These results reflect improvements in medical care for patients with genetic disorders and malformations and further highlight the large proportion of cases with genetic disorders, for which highly specialized management is required. Moreover, this study emphasizes the need for involvement of clinical geneticists in HCUs at children's hospitals.