Ayako Tanae

Apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase deficiency: a possible cause of intrauterine growth retardation

A Japanese boy with apparent mineralocorticoid excess (AME) is described. He was born with intrauterine growth retardation (IUGR) and elevated serum level of creatine phosphokinase (CPK). He was studied at 2 years of age because of polyurea and polydipsia of one year’s duration and was found to have hypokalaemic alkalosis and sustained hypertension. His plasma renin activity and aldosterone levels were always low and his ratio of urinary tetrahydrocortisol plus allo‐tetrahydrocortisol to that of tetrahydrocortisone was very high. Therefore, AME due to 11β‐hydroxysteroid dehydrogenase (11β‐HSD) deficiency was diagnosed. He was successfully treated with a combination of spironolactone and nifedipine for at least 16 months. His blood pressure, plasma pH and serum potassium levels were normalized by this treatment, but serum CPK level remained high.

When and how to combine growth hormone with a luteinizing hormone-releasing hormone analogue

Tanaka T, Satoh M, Yasunaga T, Horikawa R, Tanae A, Katsumata N, Tachibana K, Nose O, Hibi I. When and how to combine growth hormone with a luteinizing hormone‐releasing hormone analogue. Acta Pædiatr 1999; Suppl 428: 85–8. Stockholm. ISSN 0803–5326

Relationships between Puberty and Growth at Adolescence in Growth-Hormone-Deficient Males: Effect of Growth Hormone and of Associated Gonadal Suppression Therapy

125 boys with idiopathic GH deficiency who received GH treatment were followed until they reached their final height. In 85 patients who had spontaneous puberty (group I), the mean final height was 151.5 +/- 6.6 cm. In 23 patients with combined GH and gonadotropin deficiency (group II) whose pubertal development was induced artificially at age 19.4 +/- 2.1 years, the mean final height was 163.7 +/- 3.9 cm (p less than 0.01 vs. group I). Final height was strongly related to height at the onset of pubertal development in combined groups I and II when the time of gonadal replacement treatment was taken as the onset of pubertal development in group II. In 17 patients (group III) who developed spontaneous puberty, gonadal suppression treatment was started at their early stage of puberty and was continued for a mean duration of 4.3 +/- 1.1 years. The mean final height in group III was 157.9 +/- 3.0 cm (p less than 0.01 vs. group I, group II). Longitudinal growth pattern analysis demonstrated that this beneficial effect on final height by gonadal suppression treatment was attributed to the elongation of pubertal growth spurt and pubertal height gain.

High‐resolution cytogenetic studies in patients with Prader‐Willi syndrome

We investigated 24 patients with Prader‐Willi syndrome by the high‐resolution banding technique. Their history and clinical findings were also examined in some detail.

A novel frameshift mutation 840delA and a novel polymorphism D203A in the steroidogenic acute regulatory protein gene in a Japanese patient with congenital lipoid adrenal hyperplasia

Congenital lipoid adrenal hyperplasia (CLAH) is an autosomalrecessive disorder characterized by impaired production of allsteroids including glucocorticoids, mineralocorticoids and sexsteroids. It has recently been reported that mutations in thesteroidogenic acute regulatory protein (StAR) gene cause CLAH. We analyzed the StAR gene in a Japanese patient with CLAH. The patient was revealed to be a compound heterozygote bearing a nonsense mutation Q258X, changing codon 258 (CAG) encoding Gln to the stop codon TAG, and a novel frameshift mutation 840delA resulting from deletion of one of the three adenosines normally present in codon 238 (AAA), thus leading to a frameshift after codon 237 (Thr) in the StAR gene. The patient was also revealed to be homozygous for a novel missense point mutation D203A, changing codon 203 (GAC) encoding Asp to GCC encoding Ala in the StAR gene. To elucidate the significance of the D203A mutation, we analyzed the StAR gene sequence in twenty normal subjects, and found that all of them were homozygous for the D203A mutation, indicating that the D203A mutation is an innocent polymorphism. In conclusion, we have identified a novel frameshift mutation 840delA which seems to cause 840delA and the first polymorphism D203A in the human StAR gene. Hum Mutat 11:331, 1998.

Normal Y sequences in Smith-Lemli-Opitz syndrome with total failure of masculinization.

We report an infant with characteristics of Smith‐Lemli‐Opitz syndrome who had anteverted nostrils, apparently low‐set ears, micrognathia, high‐arched palate, cleft palate, growth and psychomotor retardation, hypotonia, poor suck, cerebral hypotrophy and double renal pelvis and ureter. An EEG showed spike waves in the right temporal area. The patient appeared to have normal internal and external genitalia of the female type. Both ovaries were dysplastic. The karyotype was 46, XY. All of 26 loci on the Y chromosome were positive including SRY, a candidate gene for TDF.

Clinical Usefulness of Urinary Growth Hormone Measurement in Short Children

Growth hormone GH) levels in nocturnal urine were measured in 96 short children and 73 children of normal height in order to investigate whether urinary CH levels reflect spontaneous GH secretion and whether they might be used to screen short children for GH treatment. GH levels in 24‐hour urine samples were significantly correlated with urinary albumin and β2‐microglobulin levels in normal children, demonstrating an influence of renal function on urinary GH measurements. Nocturnal urinary GH levels showed significant positive correlations with mean serum GH levels during 3 hours of sleep (r= 0.26. p < 0.05) and plasma insulin‐like growth factor 1 (IGF‐I) levels, reflecting physiological GH secretion. Urinary GH levels were significantly lower in the eight children with complete GH deficiency (3.1 ± 2.3 ng/g creatinine) than in the normal children (13.8 ± 11.2 ng/g creatinine). Urinary GH levels in three other groups of short children, partial CH deficiency (11.1 ± 16.9 ng/g creatinine), impaired GH secretion during sleep (10.4 ± 12.6 ng/g creatinine) and non‐endocrine short stature (18.8 ± 19.5 ng/g creatinine), were not significantly different from those in the normal children. However, when the cut‐off point for defining GH insufficiency was set at 5 ng/g creatinine, 87.5% (21 out of 24) of the short children with low urinary GH levels were suitable subjects for GH treatment (i.e. had complete GH deficiency, partial GH deficiency or impaired GH secretion during sleep). It is concluded that urinary GH measurement, though influenced by renal function, is potentially a simple, non‐invasive and clinically useful method for screening short children for GH insufficiency. Further refinements of the technique are required before it can be widely applied.

CLINICAL SIGNIFICANCE OF GROWTH HORMONE-BINDING PROTEIN MEASUREMENTS IN CHILDREN

Abstract To investigate the role of growth hormone (GH) and its downstream axis in normal growth and growth disorders, we measured serum GH-binding protein (GHBP) levels in children by ligand-mediated immunofunctional assay (UFA). Samples were taken from 512 healthy children of normal stature, 146 healthy neonates, 153 short but otherwise normal children, and 27 patients with GH deficiency. Serum GHBP showed no significant diurnal variation. Serum GHBP levels were low in neonates, acutely rose within 6 months, and gradually increased toward midpuberty in normal children (r = 0.2, P < 0.01, assessed among subjects over 1 year old). Neither significant sexual dimorphism nor rapid pubertal changes were observed. In normal short children and patients with GH deficiency, GHBP was lower than normal, but not significant. These data suggest that one of the etiologies for growth disorder in children could be resistance to, or low efficacy for, utilization of GH.

Urinary biotinidase and alanine excretion in patients with insulin-dependent diabetes mellitus

Twenty-four-hour urine specimens from 21 juvenile insulin-dependent diabetics and 10 healthy controls were compared with respect to biotinidase activity and alanine content. Urinary biotinidase activity was analysed by a newly developed high-performance liquid chromatography (HPLC) method. It was found that the excretion of biotinidase in urine was elevated in diabetics (7.02 mU/d; p < 0.005) as compared with controls (not detectable). Alanine excretion was also found to increase (p < 0.01) in diabetics. Biotinidase excretion in diabetics was correlated with alanine excretion (rS = 0.667; p < 0.01), but not with protein, albumin or N-acetyl-beta-glucosaminidase excretion. The simultaneous elevation of urinary biotinidase and alanine excretion in juvenile diabetics suggests that changes in kidney metabolism arise in the early stages of diabetes.

Deoxyribonucleic acid and cytological detection of Y-containing cells in an XX hypospadiac boy with polyorchidism.

A hypospadiac boy with a hypoplastic penis and an apparent 46,XX karyotype in blood and testis cultures is described. Exploratory laparotomy and bilateral gonadal biopsy revealed the presence of 2 testes in the right and 1 in the left hemiscrotum, each of which only showed hypoplastic testicular tissues histologically. Uncultured testis smears showed Y chromatin in approximately 20% of the cells. Also, the Southern blot and polymerase chain reaction analyses detected a weak but distinct signal of Y chromosome-derived deoxyribonucleic acid sequences in the perineal skin but not in the blood lymphocytes. The results indicated that the boy had a small proportion of Y chromosome-containing cells in the form of mosaicism in limited tissues, such as the testes and perineal skin. This finding may have implications in the genesis of testes in some cases of XX patients, and true hermaphrodites or male pseudohermaphrodites with an apparent 46,XX karyotype. To our knowledge, this appears to be the first case of polyorchidism with an identified chromosome abnormality.