[Rickets].

This review mainly describes on childhood vitamin D deficiency and x-linked hypophosphatemic rickets. Though nutritional state has improved dramatically, 25 (OH) D level, which is a good indicator of vitamin D status, is marginal especially in winter, and vitamin D deficiency is not rare in Japan. The PTH/Vitamin D axis does not account for the entire picture of x-linked hypophosphatemic rickets, and a new bone (osteocyte) -renal metabolic milieu has emerged and loss of PHEX, mostly expressed in osteocytes, is proposed to result in inappropriate processing of MEPE and consequent reduction in bone mineralization and an increase in circulating FGF23 to give rise to phosphaturia and hypophosphatemia.

Two patients with atypical interstitial deletions of 8p23.1: mapping of phenotypical traits.

Chromosomal 8p23 deletion syndrome is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects. The responsible gene for the heart defects in this syndrome has been identified as GATA4 on 8p23.1. Two patients with interstitial deletions of 8p23.1 were investigated; one patient showed moderate developmental delay and Ebstein anomaly, and the other showed mild delay and typical atrioventricular septum defect. The precise deletion sizes, 17 and 2.9 Mb, were determined by FISH analyses using BAC clones as probes. The latter deletion was the smallest deletion including GATA4 in the previously reported patients, and the critical regions and genes for clinical manifestation of 8p23 deletion syndrome, including facial anomalies, microcephaly, behavioral abnormality, and developmental delay, were discussed.

A posterior fossa lipoma extending into the cervical spine and subcutaneous space via a cranium bifidum.

We describe a 10-year-old boy with an intracranial lipoma in the posterior fossa. The patient had a subcutaneous tumor of the posterior neck at birth, which was gradually growing and subsequently accompanied by gait disturbance and ataxia. MR imaging revealed the intracranial lipoma in the posterior fossa extending into the cervical spinal canal and subcutaneous space via a cranium bifidum. A surgical operation was performed, but the lipoma could not be removed completely. He had had prominent obesity that might have caused not only enlargement of the intracranial lipoma but also neurological complications. Although intracranial lipomas are usually benign and asymptomatic, early detection of them is quite critical, and body weight control may help to prevent their progression.

A self adaptive hybrid enhanced artificial bee colony algorithm for continuous optimization problems.

The artificial bee colony (ABC) algorithm is one of popular swarm intelligence algorithms that inspired by the foraging behavior of honeybee colonies. To improve the convergence ability, search speed of finding the best solution and control the balance between exploration and exploitation using this approach, we propose a self adaptive hybrid enhanced ABC algorithm in this paper. To evaluate the performance of standard ABC, best-so-far ABC (BsfABC), incremental ABC (IABC), and the proposed ABC algorithms, we implemented numerical optimization problems based on the IEEE Congress on Evolutionary Computation (CEC) 2014 test suite. Our experimental results show the comparative performance of standard ABC, BsfABC, IABC, and the proposed ABC algorithms. According to the results, we conclude that the proposed ABC algorithm is competitive to those state-of-the-art modified ABC algorithms such as BsfABC and IABC algorithms based on the benchmark problems defined by CEC 2014 test suite with dimension sizes of 10, 30, and 50, respectively.

Association between AAAG repeat polymorphism in the P3 promoter of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene and adult height, urinary pyridinoline excretion, and promoter activity.

The PTH/PTHrP receptor (PTHR1) plays an essential role in skeletal development and mediates many other functions of PTH and PTHrP. Human PTHR1 gene transcription is controlled by three promoters, P1-P3. The most proximal promoter, P3, is active in bone and osteoblast-like cell lines and accounts for the majority of renal transcripts in adults. We have identified a tetranucleotide repeat (AAAG)n polymorphism in the P3 promoter. In 214 unrelated Japanese, the repeat number (n) ranged from 3-8, with the AAAG5 allele being the most frequent (59%). In 55 unrelated Caucasians, n ranged from 5-7, and the frequency of the AAAG5 allele was 78%. The most frequent genotypes in a cohort of 85 young (18-20 yr) female Japanese were 5/5, 5/6, and 6/6. The 6/6 genotype was associated with greater height (5/5 vs. 6/6; P < 0.02) and lower urinary deoxypyridinoline and pyridinoline (P < 0.02), which are markers of bone resorption. The height of an additional 71 healthy female Japanese subjects, aged 14-17 yr, having genotype 5/5, 5/6, or 6/6 was also in the order of genotype 5/5 < 5/6 < 6/6 (5/5 vs. 6/6, P < 0.05). There was no significant difference in lumbar and femoral bone mineral density between genotypes. Likewise, there was no difference in circulating intact PTH levels between groups. The activity of P3 promoter-luciferase reporter constructs in transcription assays in 2 human osteoblast-like cell-lines varied according to repeat number, with AAAG6 being the least active. In conclusion, the P3 promoter (AAAG)n polymorphism is frequent in both Japanese and Caucasians and has potential as a linkage marker for the PTHR1 locus. In addition, it may influence the expression of the receptor in target tissues and have functional consequences on the developing skeleton.

Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients.

We report on the clinical and molecular findings in 25 males and three females with Kallmann syndrome (KS) aged 10-53 yr. Ten males were from five families, and the remaining 15 males and three females were apparently sporadic cases. Molecular studies were performed for Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, also known as KAL2) by sequence analysis for all the coding exons, by PCR-based deletion analysis, and by fluorescence in situ hybridization (FISH) analysis, showing six novel and two recurrent intragenic KAL1 mutations in seven familial and four sporadic male cases and two novel intragenic FGFR1 mutations in two sporadic male cases. In addition, submicroscopic deletions at Xp22.3 involving VCX-A, STS, KAL1, and OA1 were identified in three familial cases and one sporadic male case affected by a contiguous gene syndrome. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in two males and right-side dominant renal lesion in seven males, in addition to variable degrees of hypogonadotropic hypogonadism (HH) in all the 15 males and olfactory dysfunction in 13 males. The two males with FGFR1 mutations had HH and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in one female, cleft palate in one male, cleft palate and perceptive deafness in one male, and dental agenesis and perceptive deafness in one male, in addition to a variable extent of HH and olfactory dysfunction. The results suggest the following: 1) KAL1 mutations might be more prevalent in the Japanese patients than previously estimated in the Caucasian patients and can be associated with apparently normal olfactory function; 2) FGFR1 mutations account for approximately 10% of KS patients, as previously reported in the Caucasian patients, and can result in HH and olfactory dysfunction-only phenotype; and 3) renal aplasia, which is characteristic of KAL1 mutations, and cleft palate and dental agenesis, which are characteristic of FGFR1 mutations, can occur in patients without KAL1 and FGFR1 mutations.

Familial hypophosphatemic rickets caused by a large deletion in PHEX gene.

CONTEXT: X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR) share common clinical features including high fibroblast growth factor 23 (FGF23) levels. These diseases are caused by mutations in phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and dentin matrix acidic phosphoprotein 1 (DMP1) gene respectively. It remains unclear whether these diseases can be clinically discriminated. OBJECTIVE: To clarify the underlying mechanism of patients with hypophosphatemic rickets whose parents showed no physical findings suggesting rickets. DESIGN AND PATIENTS: The proband is a 39-year-old woman. She and her 37-year-old brother show the same clinical features such as bowing of legs together with hypophosphatemia (sister: P 1.8 mg/dl, brother: P 1.6 mg/dl) and high FGF23 levels (sister: 542 pg/ml, brother: 96 pg/ml). Physical findings of their parents are normal and ARHR was suspected. RESULTS: Sequencing of all coding exons and exon-intron junctions of DMP1 and FGF23 genes showed no mutation. Subsequent analysis revealed that there is a deletion of 52 143 bp including exons 1-3 in PHEX gene in the brother. His sister was found to be a heterozygote for the same deletion indicating that they are suffering from XLH. The same deletion was detected in the mother. However, the amount of the wild-type allele was more and that of the mutant one was less in genomic DNA from the mother compared with those from the sister. Single nucleotide polymorphism (SNP) analysis indicated that the mother has three kinds of PHEX alleles suggesting a somatic mosaicism. CONCLUSION: Careful genetic analysis is mandatory for correct differential diagnosis of hypophosphatemic rickets with high FGF23 levels.

Effect of parathyroid hormone administration in a patient with severe hypoparathyroidism caused by gain-of-function mutation of calcium-sensing receptor.

Hypoparathyroidism caused by gain-of-function mutations of the calcium-sensing receptor (CaR) in the transmembrane domain is usually severe and difficult to manage. A patient with severe hypoparathyroidism, caused by CaR activating mutation F821L, was treated for 3 days (Day 1 to Day 3) with synthetic human parathyroid hormone 1-34 (teriparatide, PTH). An Ellsworth-Howard test of the patient revealed normal responses of urine phosphate and cyclic AMP excretion, indicating that the patient's renal tubules normally responded to extrinsic PTH. On Day 1 to Day 3, 0.9 microg/kg/day of PTH was administered subcutaneously twice daily at 0800 and 2000. On Day 1, the serum calcium level that was 1.8 mmol/l before PTH administration increased to 2.1 mmol/l at 1200, and gradually decreased to 1.8 mmol/l at 2000. On Days 2 and 3, the maximum calcium levels were 2.5 and 2.4 mmol/l, respectively, at 1200. At 2000, they returned to or below basal levels at 0800. On Day 4 without PTH administration, the calcium levels were maintained at the basal levels at Day 0. The urine calcium/creatinine (Ca/Cr) ratio that was high (>0.4) before PTH injection decreased after PTH administration (0.4>). Changes in the ionized calcium levels were almost parallel with the total calcium levels. The serum inorganic phosphate (IP) level decreased to 2.4 mmol/l at 1000, but gradually increased before the second PTH injection to the level at 0800 on Day 1. The minimum IP level on Days 2 and 3 was 2.1 mmol/l and 2.0 mmol/l, respectively. In contrast to the remarkable changes in the serum calcium level by PTH treatment, the serum magnesium levels showed few changes. These results indicate that PTH therapy could be effective in correcting serum and urine calcium and the phosphate levels in hypoparathyroidism caused by activating mutation of CaR.

Comparison of two assays for fibroblast growth factor (FGF)-23.

FGF-23 was recently shown to be involved in the development of several hypophosphatemic diseases, including X-linked hypophosphatemic rickets/osteomalacia (XLH) and tumor-induced rickets/osteomalacia (TIO). FGF-23 is processed between Arg179 and Ser180, and only full-length FGF-23 was shown to cause hypophosphatemia. Two assays for FGF-23 have been reported. One assay detects only full-length FGF-23. In contrast, the C-terminal assay recognizes both full-length and processed C-terminal fragment of FGF-23. However, discrepant results concerning circulatory levels of FGF-23 in patients with TIO and XLH have been reported using these two assays. We simultaneously measured FGF-23 levels in 13 patients with adult-onset hypophosphatemic osteomalacia and 29 patients with XLH by these two assays. The full-length assay indicated that FGF-23 was above the upper limit of the reference range in all patients with osteomalacia and in 24 of 29 patients with XLH. However, the C-terminal assay in dicated that FGF-23 was within the reference range in 3 of 13 patients with osteomalacia and 16 of 29 patients with XLH. In addition, there was no correlation between FGF-23 levels measured by these assays in patients with XLH whose FGF-23 was within the reference range by C-terminal assay. These results indicate that FGF-23 within the reference range by C-terminal assay does not rule out an increase in full-length FGF-23. In addition, because FGF-23 was high in most of these hypophosphatemic patients, these results support the notion that FGF-23 plays a major role in the development of hypophosphatemia in patients with TIO and XLH.

A novel gain-of-function mutation (F821L) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism.

UNLABELLED: Gain-of-function mutations of the extracellular calcium (Ca(2+)e)-sensing receptor (CaR) have been identified in patients with familial and sporadic hypercalciuric hypocalcaemia. We describe a patient with sporadic severe hypercalciuric hypocalcaemia with undetectable or very low levels of serum parathyroid hormone, carrying a de novo heterozygous missense mutation ( F821L), localized in the sixth transmembrane domain of CaR. Analysis of in vitro functional properties of the mutant receptor to measure Ca(2+)e-evoked changes in intracellular Ca(2+) revealed a leftward shift in the concentration-response curve for the mutant compared to wild-type receptor. CONCLUSION: the F821Lmutation is therefore a novel gain-of-function mutation which can cause severe hypoparathyroidism. Thiazide diuretics lowered urinary calcium excretion of the patient treated with calcium supplementation and 1alpha-hydroxyvitamin D(3.)

Three novel mutations in Japanese patients with 21-hydroxylase deficiency.

OBJECTIVE: This study analyzed the mutation of 21-hydroxylase deficiency (21-OHD) in 36 unrelated Japanese patients with congenital adrenal hyperplasia (CAH). METHODS: All the exons of the functional CYP21 gene (CYP21A2) were analyzed by polymerase chain reaction (PCR) and PCR direct sequencing. RESULTS: Apparent gene deletions and conversions were present in 23.6% of the 72 CAH alleles, in which the most frequent mutation was the IVS2-13 A/C>G (27.8%), followed by I172N (26.3%), consistent with the frequencies reported for other countries. Previously described mutations were not present in three unrelated cases. Sequence analysis of the complete functional CYP21A2 gene revealed three, not yet described mutations that represent a common pseudogene sequence. These three putative novel mutations are located in exon 1 (M1I), in exon 5 (1210-1211insT), and in exon 3 (R124H). CONCLUSIONS: In this study, we have identified three putative novel mutations. It remains to be determined whether these three mutations are responsible for the significant number of as yet uncharacterized CAH patients in Japan.

Clinical utility of thyroid ultrasonography in the diagnosis of congenital hypothyroidism.

To determine the clinical utility of thyroid ultrasonography in the diagnosis of congenital hypothyroidism (CH) before initiation of therapy, ultrasonographic images of the thyroid gland with a high-resolution transducer were obtained in 204 healthy infants aged from newborn to 12 months (Group A), and 174 infants suspected of having CH detected by neonatal mass screening (Group B). The thyroid gland was imaged by transverse scanning at the anatomic site of the thyroid gland. The maximal width of thyroid on the transverse section in the normal location was measured. By comparing with the normal thyroid gland size and location obtained from Group A, 174 infants of Group B were divided into four subgroups: 1) Normal in size (n = 117), 2) Enlarged (n = 33), 3) Small (n = 1) and 4) Invisible in the normal location (n = 23). They were compared with the final diagnoses based on the results of chemical laboratory data and scintigraphic findings. The sensitivity and the specificity for the presence or absence of the thyroid gland in the normal location were 96% (22/23) and 99% (150/151), respectively. Both subgroups of normal and enlarged sized gland included healthy infants (false positive), transient hyperthyrotropinaemia, transient hypothyroidism and CH due to dyshormonogenesis. We conclude that ultrasonography is useful for determining the presence or absence of the thyroid gland in the normal location, whereas normal and enlarged sized glands require further examination to complete the diagnosis.