A mutation of the ß-domain in POU1F1 causes pituitary deficiency due to dominant PIT-1ß expression.

BACKGROUND: POU1F1 encodes both PIT-1α, which plays pivotal roles in pituitary development and GH, PRL and TSHB expression, and the alternatively spliced isoform PIT-1ß, which contains an insertion of 26-amino acids (ß-domain) in the transactivation domain of PIT-1α due to the use of an alternative splice acceptor at the end of the first intron. PIT-1ß is expressed at much lower levels than PIT-1α and represses endogenous PIT-1α transcriptional activity. Although POU1F1 mutations lead to combined pituitary hormone deficiency (CPHD), no patients with ß-domain mutations have been reported. RESULTS: Here, we report that a three-generation family exhibited different degrees of CPHD, including growth hormone deficiency with intrafamilial variability of prolactin/TSH insufficiency and unexpected prolactinoma occurrence. The CPHD was due to a novel POU1F1 heterozygous variant (c.143-69T>G) in intron 1 of PIT-1α (RefSeq number NM_000306) or as c.152T>G (p.Ile51Ser) in exon 2 of PIT-1ß (NM_001122757). Gene splicing experiments showed that this mutation yielded the PIT-1ß transcript without other transcripts. The lymphocyte PIT-1ß mRNA expression was significantly higher in the patients with the heterozygous mutation than a control. A luciferase reporter assay revealed that the PIT-1ß-Ile51Ser mutant repressed PIT-1α and abolished transactivation capacity for the rat prolactin promoter in GH3 pituitary cells. CONCLUSIONS: We describe, for the first time, that the PIT-1ß mutation can cause CPHD through a novel genetic mechanism, such as PIT-1ß overexpression, and that POU1F1 mutation might be associated with a prolactinoma. Analysis of new patients and long-term follow-up are needed to clarify the characteristics of PIT-1ß mutations.

A 34-year-old Japanese patient exhibiting NBAS deficiency with a novel mutation and extended phenotypic variation.

Biallelic neuroblastoma amplified sequence (NBAS) gene mutations have recently been identified to cause a reduction in its protein expression and a broad phenotypic spectrum, from isolated short stature, optic nerve atrophy, and Pelger-Huët anomaly (SOPH) syndrome or infantile liver failure syndrome 2 to a combined, multi-systemic disease including skeletal dysplasia and immunological and neurological abnormalities. Herein, we report a 34-year-old patient with a range of phenotypes for NBAS deficiency due to compound heterozygous variants; one is a SOPH-specific variant, p.Arg1914His, and the other is a novel splice site variant, c.6433-2A>G. The patient experienced recurrent acute liver failure until early childhood. Hypogammaglobulinemia, a decrease in natural killer cells, and optic nerve atrophy were evident from infancy to childhood. In adulthood, the patient exhibited novel phenotypic features such as hepatic cirrhosis complicated by portal hypertension and autoimmune hemolytic anemia. The patient also suffered from childhood-onset insulin-requiring diabetes with progressive beta cell dysfunction. The patient had severe short stature and exhibited dysmorphic features compatible with SOPH, intellectual disability, and epilepsy. NBAS protein expression in the patient's fibroblasts was severely low. RNA expression analysis for the c.6433-2A>G variant showed that this variant activated two cryptic splice sites in intron 49 and exon 50, for which the predicted consequences at the protein level were an in-frame deletion/insertion, p.(Ile2199_Asn2202delins16), and a premature termination codon, p.(Ile2199Tyrfs*17), respectively. These findings indicate that NBAS deficiency is a multi-systemic progressive disease. The results of this study extend the spectrum of clinical and genetic findings related to NBAS deficiency.

High prevalence of DUOX2 mutations in Japanese patients with permanent congenital hypothyroidism or transient hypothyroidism.

BACKGROUND: Dual oxidase 2 (DUOX2) mutations are a cause of dyshormonogenesis (DH) and have been identified in patients with permanent congenital hypothyroidism (PH) and with transient hypothyroidism (TH). We aimed to elucidate the prevalence and phenotypical variations of DUOX2 mutations. METHODS: Forty-eight Japanese DH patients were enroled and analysed for sequence variants of DUOX2, DUOXA2, and TPO using polymerase chain reaction-amplified direct sequencing. RESULTS: Fourteen sequence variants of DUOX2, including 10 novel variants, were identified in 11 patients. DUOX2 variants were more prevalent (11/48, 22.9%) than TPO (3/48, 6.3%) (p=0.020). The prevalence of DUOX2 variants in TH was slightly, but not significantly, higher than in PH. Furthermore, one patient had digenic heterozygous sequence variants of both DUOX2 and TPO. CONCLUSIONS: Our results suggest that DUOX2 mutations might be the most common cause of both PH and TH, and that phenotypes of these mutations might be milder than those of other causes.

An observational study of the effectiveness and safety of growth hormone (Humatrope(®)) treatment in Japanese children with growth hormone deficiency or Turner syndrome.

This study assessed the effectiveness and safety of growth hormone (GH; Humatrope(®)) therapy in Japanese children with GH deficiency (GHD) or Turner syndrome (TS) enrolled in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). GeNeSIS is an open-label, multinational, multicenter, observational study conducted in 30 countries. In this interim report, there were 1129 GH treatment-naïve children with GHD, with a mean chronological age (± standard deviation) of 8.75 (3.32) years, and 90 girls with TS, with a mean chronological age of 8.93 (3.67) years. The mean height standard deviation score (SDS) increased from -2.73 (0.63) SD and -2.71 (0.63) SD at study entry to -2.22 (0.68) SD and -2.20 (0.60) SD after 1 year of treatment in the GHD and TS groups, respectively. In both groups, mean height SDS increased further with each year of treatment to 4 years; however, the magnitude of change in height SDS declined with time. The mean insulin-like growth factor-I SDS increased from below the mean of the reference population at study entry to a level similar to (GHD group) or higher than (TS group) the mean of the reference population during the 4-year treatment period. The incidence of serious adverse events (AEs), treatment-related AEs, and AEs related to glucose intolerance was low in both groups (0.1% to 3.0%). In conclusion, GH treatment in Japanese children with GHD or TS resulted in increased growth over a 4-year treatment period with a favorable safety profile; however, the improvements in growth declined with time.

Favorable Impacts of Growth Hormone (GH) Replacement Therapy on Atherogenic Risks in Japanese Children with GH Deficiency.

Growth hormone (GH) affects body composition and atherogenic risk factors. Severe hyperlipidemia may develop in GH-deficient adults as a consequence of continuous GH deficiency. We investigated changes in lipid profiles in 158 Japanese children (103 boys and 55 girls) with GH deficiency who had been enrolled in the Pfizer International Growth Database Japan during 3 yr of GH replacement therapy to evaluate whether GH treatment has beneficial effects on atherogenic risk factors. Total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC) and atherogenic index were evaluated before treatment and then once a year during treatment. The mean baseline TC was within the normal range in both boys and girls. Seventeen (16.5%) of the 103 boys and 18 (32.7%) of the 55 girls, however, had a TC level over 200 mg/dl before treatment. The mean TC level showed a significant decrease in girls. In a separate analysis, patients of both sexes with a TC level > 200 mg/dl showed significantly decreased TC. LDLC decreased significantly only in girls, while HDLC showed no change in either sex. The atherogenic index decreased significantly in girls. GH replacement therapy in children with GH deficiency had beneficial effects on lipid metabolism and atherogenic risk in both sexes. Early GH treatment would produce lipid metabolism benefits in these patients.

Favorable impact of growth hormone treatment on cholesterol levels in turner syndrome.

BACKGROUND: Patients with Turner syndrome (TS) are prone to having metabolic abnormalities, such as obesity, dyslipidemia, hypertension, hyperinsulinemia and type 2 diabetes mellitus, resulting in increased risks of developing atherosclerotic diseases. OBJECTIVE: To determine the effect of growth hormone (GH) therapy on serum cholesterol levels in prepubertal girls with TS enrolled in the Turner syndrome Research Collaboration (TRC) in Japan. PATIENTS AND METHODS: Eighty-one girls with TS were enrolled in the TRC, and their total cholesterol (TC) levels before GH therapy were compared with reported levels of healthy school-aged Japanese girls. TC levels after 1, 2 and 3 yr of GH treatment were available for 28 of the 81 patients with TS. GH was administered by daily subcutaneous injections, 6 or 7 times/wk, with a weekly dose of 0.35 mg/kg body weight. RESULTS: Baseline TC levels revealed an age-related increase in TS that was in contrast to healthy girls showing unchanged levels. During GH therapy, TC decreased significantly after 1 yr of GH treatment and remained low thereafter. CONCLUSIONS: Girls with untreated TS showed an age-related increase in TC that was a striking contrast to healthy girls, who showed unchanged levels. GH therapy in girls with TS brought about a favorable change in TC that indicates the beneficial impact of GH on atherogenic risk.

Efficacy and Safety of Up to 8 Years of Long-term Growth Hormone Treatment in Short Children Born Small for Gestational Age in Japan: Analysis of the Subpopulation According to the Japanese Guideline.

The efficacy and safety of 8 yr of GH treatment was assessed in 44 Japanese children with small for gestational age (SGA) short stature who met the criteria for GH treatment initiation (height SD score (SDS) <-2.5 SD) of the Japanese guidelines. Height SDS in subjects improved throughout the study period, and average height SDS improved from -3.5 to -1.6 and from -3.4 to -1.9 in the 0.033/0.067 mg and 0.067/0.067 mg groups, respectively, after 8 yr of GH treatment. Delta height SD was approximately +2 after 4 yr of treatment, and ∆ IGF-1 showed a significant positive correlation with ∆ height SD after both 1 and 2 yr (r = 0.415 and 0.488, respectively) of treatment. There was no correlation between the age at the start of treatment and age at onset of puberty, and the median age at the onset of puberty in the subjects was almost the same as that in healthy children. In conclusion, clinically significant improvements in the height SDS was confirmed in short children born SGA after 8 yr of GH treatment without any safety problems.

Identification of a novel mutation in the exon 2 splice donor site of the POU1F1/PIT-1 gene in Japanese identical twins with mild combined pituitary hormone deficiency.

CONTEXT: To date, approximately 35 different POU1F1 mutations have been described in patients with familial and sporadic combined pituitary hormone deficiency (CPHD) from different ethnic backgrounds. The majority are missense mutations clustered within the conserved POU-specific and POU-homeo domains, encoded by exons 4 and 6, respectively. OBJECTIVES: This study aimed to identify the molecular basis and clinical characteristics of a Japanese CPHD family with a novel POU1F1 mutation. DESIGN: The POU1F1 gene was sequenced in identical twin brothers with mild CPHD. The mutation identified was also evaluated in family members as well as 188 Japanese controls and then examined in functional studies. RESULTS: A novel heterozygous splice site mutation (Ex2 + 1G>T; c.214 + 1G>T) was detected. This mutation was also present in their undiagnosed mother, but not in any of the controls. In vitro splicing studies suggested this mutation to result in an in-frame skipping of exon 2, thus producing an internally deleted protein lacking most of the R2 transactivation subdomain (TAD-R2). Heterologous expression studies of the mutated POU1F1 protein showed only modest reductions in its transactivation activities in HEK293T cells, while acting as a dominant-negative inhibitor of the endogenous activities of POU1F1 in pituitary GH3 cells. CONCLUSIONS: This is the first report of a mutation at the exon 2 donor splice site of POU1F1, affecting TAD-R2. The addition of this mutation to the growing list of pathological POU1F1 mutations may provide deeper insights into clinical heterogeneity in the expressions of individual mutations and a better understanding of the structure-function relationships of POU1F1.

Long-term efficacy and safety of two doses of growth hormone in short Japanese children born small for gestational age.

BACKGROUND/AIMS: To investigate the long-term efficacy and safety of two doses (33 and 67 µg/kg/day) of growth hormone (GH) in short Japanese children born small for gestational age (SGA). METHODS: 96 children born SGA (age 3 to <8 years) were randomized to GH at 33 or 67 µg/kg/day for 104 weeks, or to an untreated control (UC) group for 52 weeks. After 52 weeks, the UC group was randomized to GH at a dose of 33 or 67 µg/kg/day for a 156-week extension study. Initial treatment groups continued unchanged for the extension phase. Efficacy was evaluated by change in height SDS for chronological age from baseline to 208/260 weeks. RESULTS: After 208 weeks, change in height SDS from baseline (least square (LS) means (SE)) was 1.01 (0.47) and 1.99 (0.67) in the UC 33 and UC 67 µg/kg/day groups, respectively. After 260 weeks, change in height SDS from baseline was 1.22 (0.51) and 2.01 (0.64) in the 33 and 67 µg/kg/day groups, respectively. Insulin-like growth factor-1 levels were significantly higher in the groups receiving 67 µg/kg/day but largely remained within normal limits (-2 to +2 SDS). CONCLUSION: Long-term continuous GH treatment was well tolerated and effective in improving height SDS. Improvements were dose-dependent and significantly higher at 67 than 33 µg/kg/day.

Proximal promoter of the cytochrome P450 oxidoreductase gene: identification of microdeletions involving the untranslated exon 1 and critical function of the SP1 binding sites.

CONTEXT: POR (cytochrome P450 oxidoreductase) is a ubiquitously expressed gene encoding an electron donor to all microsomal P450 enzymes and several non-P450 enzymes. POR mutations cause an autosomal recessive disorder characterized by skeletal dysplasia, adrenal dysfunction, and disorders of sex development. Although recent studies have indicated the presence of a CpG-rich region characteristic of housekeeping genes around the untranslated exon 1 (exon 1U) and a tropic effect of thyroid hormone on POR expression via thyroid hormone receptor-ß, detailed regulatory mechanisms for the POR expression remain to be clarified. OBJECTIVE: Our objective was to report a pivotal element of the proximal promoter of POR. RESULTS: We first studied three patients (cases 1-3) with POR deficiency due to compound heterozygosity with an p.R457H mutation and transcription failure of an apparently normal allele, by oligoarray comparative genomic hybridization and serial direct sequencing of the deletion fusion points. Consequently, a 2,487-bp microdeletion involving exon 1U was identified in case 1 and an identical 49,604-bp deletion involving exon 1U and exon 1 was found in cases 2 and 3. We next analyzed the 2,487-bp region commonly deleted in cases 1-3 by in silico analysis, DNA binding analysis, luciferase assays, and methylation analysis. The results showed a critical function of the evolutionally conserved SP1 binding sites just upstream of exon 1U, especially the binding site at the position -26/-17, in the transcription of POR. CONCLUSIONS: The results suggest that the SP1 binding sites constitute an essential element of the POR proximal promoter.

Adult height after growth hormone treatment in Japanese children with idiopathic growth hormone deficiency: analysis from the KIGS Japan database.

OBJECTIVE: To identify factors affecting adult height in Japanese patients with idiopathic growth hormone deficiency (GHD), who received growth hormone (GH) treatment during childhood. METHODS: A retrospective pharmaco-epidemiological study of the effect of GH treatment on adult height standard deviation scores (SDS) was conducted in 374 Japanese patients with idiopathic GHD. During childhood, GH (0.146 +/- 0.023 mg/kg/week) was administered for a mean of 6.4 +/- 2.6 years. RESULTS: The mean adult height was 160.6 +/- 6.3 cm (-1.75 SD; n = 232) in boys and 146.9 +/- 7.3 cm (-2.20 SD; n = 158) in girls after GH therapy. The mean increases in height SDS in boys and girls with severe GHD were 2.13 SD and 1.66 SD, respectively (p < 0.05). These increases were greater than those observed in patients with moderate GHD and mild GHD. The mean adult height of male patients with GHD and gonadotropin deficiency (166.8 cm) was significantly higher (p < 0.05) than that of isolated GHD patients who were either receiving (159.1 cm) or not receiving (160.5 cm) gonadal suppression therapy. The mean adult heights of female patients were 149.6, 146.7, and 146.9 cm, respectively, and these values did not significantly differ. CONCLUSION: Linear multiple regression analyses of Japanese patients with severe GHD (n = 61) revealed three independent variables that influenced adult height: gonadotropin deficiency, initial height SDS and height velocity during the first year after the initiation of GH therapy.

Axial spondylometaphyseal dysplasia: additional reports.

Axial spondylometaphyseal dysplasia (SMD) (OMIM 602271) is an uncommon skeletal dysplasia characterized by metaphyseal changes of truncal-juxtatruncal bones, including the proximal femora, and retinal abnormalities. The disorder has not attracted much attention since initially reported; however, it has been included in the nosology of genetic skeletal disorders [Warman et al. (2011); Am J Med Genet Part A 155A:943-968] in part because of a recent publication of two additional cases [Isidor et al. (2010); Am J Med Genet Part A 152A:1550-1554]. We report here on the clinical and radiological manifestations in seven affected individuals from five families (three sporadic cases and two familial cases). Based on our observations and Isidor's report, the clinical and radiological hallmarks of axial SMD can be defined: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and function rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on fundoscopic examination and cone-rod dystrophy on electroretinogram. The radiological hallmarks include short ribs with flared, cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. Equally affected sibling pairs of opposite gender and parental consanguinity are strongly suggestive of autosomal recessive inheritance.

Analysis of expression and structure of the rat GH-secretagogue/ghrelin receptor (Ghsr) gene: roles of epigenetic modifications in transcriptional regulation.

In the current study, to elucidate the molecular basis of cell type-specific expression of the GH-secretagogue/ghrelin receptor type 1A (GHSR1A), we characterized the structure and putative promoter region of the rat Ghsr gene. We identified an alternative 5'-untranslated first exon that contains multiple transcription start sites, and confirmed a 200-bp sequence proximal to this exon to be sufficient for basal promoter activity. A promoter-associated CpG island conserved across different species was found to be hypomethylated in Ghsr1a-expressing cell lines, while being heavily methylated in non-expressing cells. In cells with low or absent Ghsr1a expression, treatment with demethylating agents activated Ghsr1a transcription. Chromatin immunoprecipitation assays demonstrated Ghsr1a-expressing cells to display active histone modifications, whereas repressive modifications were present exclusively in other cell types. These results suggest epigenetic modifications at GHSR to play important roles in determining GHSR1A expression and abundance, and therefore the consequent sensitivity of cells to ghrelin.

Clinical characteristics of Japanese adults with growth hormone deficiency: a HypoCCS database study.

The clinical characteristics of Caucasian adults with growth hormone (GH) deficiency (GHD) have been well defined. However, no large-scale clinical practice study has examined the clinical characteristics of Japanese adults with GHD. The aim of our study was to describe the clinical characteristics of Japanese adults with GHD by reviewing the records of participants who were GH-naive at the time of enrollment in the Hypopituitary Control and Complications Study (N = 349). The majority of participants (280 of 349; 80.2%) had adult-onset rather than childhood-onset GHD. Hypothalamo-pituitary tumors were the most common cause of GHD in Japanese adults (247 of 349; 70.8%); these tumors were primarily pituitary adenomas in participants with adult-onset GHD (156 of 243; 64.2%), and germ cell tumors (19 of 40; 47.5%) and craniopharyngiomas (18 of 40; 45.0%) in participants with childhood-onset GHD. Most participants (310 of 349; 88.8%) had multiple pituitary hormone deficiencies. Dyslipidemia (195 of 349; 55.9%), visual field loss (67 of 349; 19.2%), hypertension (59 of 349; 16.9%), and liver disease (54 of 349; 15.5%) were the most common pre-existing conditions in Japanese adults with GHD. Quality of life was decreased in seven of the eight short form-36 domains in participants with GHD compared with age- and sex-matched healthy Japanese individuals. Our findings confirm that the clinical characteristics of Japanese adults with GHD are similar to those of Caucasian adults with GHD. Confirmation of these clinical characteristics will enhance the ability of clinicians to identify and treat Japanese adults with GHD.

Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature.

CONTEXT: Growth hormone-releasing hormone receptor (GHRHR) gene mutations have been identified in patients of different ethnic origins with isolated GH deficiency (IGHD) type IB. However, the prevalence of these mutations in the Japanese population has yet to be fully determined. OBJECTIVES: This study aimed to evaluate the contributions of GHRHR mutations to the molecular mechanism underlying short stature in Japanese subjects. DESIGN: The GHRHR gene was sequenced in 127 unrelated Japanese patients with either IGHD (n = 14) or idiopathic short stature (ISS; n = 113). Sequence variants were evaluated in family members and 188 controls, and then examined in functional studies. RESULTS: A novel homozygous E382E (c.1146G>A) synonymous variant, at the last base of exon 12, was identified in an IGHD family with two affected sisters. In vitro splicing studies showed this mutation to result in skipping of exon 12. In one ISS patient, a heterozygous ATG-166T>C variant was found in the distal Pit-1 P2 binding element of the GHRHR promoter. In two control subjects, a close but distinct variant, ATG-164T>C, was detected. Functional studies showed that both promoter variants diminish promoter activity by altering Pit-1 binding ability. Four missense variants were also found in both patient and control groups but had no detectable functional consequences. CONCLUSIONS: The homozygous GHRHR mutation was rare, being detected in only one Japanese IGHD family. Future research is needed to clarify the genetic contributions of heterozygous functional promoter variants to GHD, ISS and normal-stature variations.

Identification and functional analysis of novel human growth hormone secretagogue receptor (GHSR) gene mutations in Japanese subjects with short stature.

CONTEXT: Short stature (SS) is a multifactorial developmental condition with a significant genetic component. Recent studies have revealed that rare deleterious mutations in the GH-secretagogue receptor type 1A (GHSR1A) gene could be a cause of familial SS or GH deficiency. OBJECTIVE: The aim of this study was to evaluate the contribution of GHSR1A mutations to the molecular mechanism underlying SS in Japanese subjects. METHODS: We performed mutational screening of the GHSR1A gene in 127 unrelated Japanese SS patients diagnosed with either isolated GH deficiency or idiopathic SS. Identified mutations were analyzed in 188 control subjects, and their functional properties were examined in a heterologous expression system. RESULTS: Four novel heterozygous GHSR1A mutations were identified (ΔQ36, P108L, C173R, and D246A). Expression studies demonstrated that these mutations had varying functional consequences: 1) all mutations showed a loss-of-function effect on the constitutive signaling activity of GHSR1A, but the degree of loss varied widely; 2) C173R caused intracellular retention of the mutated protein, resulting in total loss of receptor function; 3) P108L resulted in a large decrease in binding affinity to ghrelin, without affecting its surface expression; 4) D246A uniquely impaired agonist- and inverse agonist-stimulated receptor signaling; and 5) ΔQ36 showed only a subtle reduction in constitutive activity. The cumulative frequency of these putative functional mutations was significantly higher in the patient group than in controls (4.72 vs. 0.53%; P = 0.019; odds ratio = 9.28; 95% confidence interval, 1.10-78.0). CONCLUSIONS: Our results suggest that GHSR1A mutations contribute to the genetic etiology of SS in the Japanese population.

5.78 Mb terminal deletion of chromosome 15q in a girl, evaluation of NR2F2 as candidate gene for congenital heart defects.

All patients with terminal deletion of chromosome 15q have been reported to show intrauterine growth retardation, postnatal growth retardation, abnormal facial appearance and developmental delay. Haploinsufficiency of IGF1R was considered to be responsible for these symptoms. However, it is difficult to explain other symptoms seen in some of the patients, such as congenital heart defects by the absence of IGF1R alone. Here, we reported a patient with congenital heart defects and a 5.78 Mb terminal deletion of chromosome 15q detected by array-CGH. Among the patients reported to share congenital heart defects and terminal deletion of chromosome 15q, our patient had the smallest deletion. Evaluating the deletion map, NR2F2 was considered a candidate gene contributing to congenital heart defects in patients with terminal deletion of chromosome 15q.

Congenital Hypothyroidism Caused by a PAX8 Gene Mutation Manifested as Sodium/Iodide Symporter Gene Defect.

Loss-of-function mutations of the PAX8 gene are considered to mainly cause congenital hypothyroidism (CH) due to thyroid hypoplasia. However, some patients with PAX8 mutation have demonstrated a normal-sized thyroid gland. Here we report a CH patient caused by a PAX8 mutation, which manifested as iodide transport defect (ITD). Hypothyroidism was detected by neonatal screening and L-thyroxine replacement was started immediately. Although (123)I scintigraphy at 5 years of age showed that the thyroid gland was in the normal position and of small size, his iodide trapping was low. The ratio of the saliva/plasma radioactive iodide was low. He did not have goiter; however laboratory findings suggested that he had partial ITD. Gene analyses showed that the sodium/iodide symporter (NIS) gene was normal; instead, a mutation in the PAX8 gene causing R31H substitution was identified. The present report demonstrates that individuals with defective PAX8 can have partial ITD, and thus genetic analysis is useful for differential diagnosis.

Single cytomegalovirus strain associated with fetal loss and then congenital infection of a subsequent child born to the same mother.

BACKGROUND: Intrauterine transmission of cytomegalovirus (CMV) can occur even in CMV-seropositive mothers. Previous studies demonstrated re-infection with a newly acquired CMV strain during pregnancy had a major role in such transmission. Although reactivation of latently infected CMV is another plausible cause, no direct evidence has been documented. OBJECTIVES: We sought to identify the route(s) and maternal risk factor of CMV infection that occurred in consecutive pregnancies and resulted in symptomatic congenital infections. STUDY DESIGN: A newborn identified with congenital CMV infection in our newborn screening program developed hearing loss and subsequent nystagmus. The mother had a history of an elective abortion due to a severe fetal CMV infection 32 months prior to delivery of this newborn. We analyzed maternal serological changes and compared CMV genomic sequences in specimens obtained from the aborted fetus and the present case. We also analyzed immunological functions of the mother. RESULTS: Our major findings were as follows: (1) the aborted fetus and the present case were infected with the same strain. (2) The congenital infection that resulted in the abortion was due to a primary infection. (3) CMV DNA was undetectable in the mother's blood from 3 months after the abortion. These results strongly suggested that maternal viral reactivation caused the congenital infection in the present case. However, we could not find impairment of immunological functions in the mother. CONCLUSIONS: Viral reactivation in an apparently immunocompetent mother can cause symptomatic congenital CMV infection.