Chutaro Yamanaka

Unfavorable effects of growth hormone therapy on the final height of boys with short stature not caused by growth hormone deficiency

A group of 18 boys with non-growth hormone (GH)-deficient short stature without GH therapy (group A) and another group of 9 boys with non-GH-deficient short stature with GH therapy in doses of 0.5 IU (0.17 mg)/kg per week administered 5 to 6 times weekly (group B) were observed until they reached their final height. The mean duration of GH therapy was 4.2 years (range 3.2 to 5.0 years). These two groups were matched with respect to their standard deviation score (SDS) for bone age at the start of observation. Mean +/- SD of the final height for group A and group B was 162.0 +/- 5.4 cm and 154.2 +/- 4.2 cm, respectively. During the prepubertal period, height SDS for bone age of these two groups was not affected by GH therapy. During the pubertal period, however, height SDS for bone age remained constant for group A but decreased gradually for group B. Our observation indicates that for boys with non-GH-deficient short stature GH therapy does not improve height SDS for bone age during the prepubertal period, and in fact reduces it during the pubertal period, possibly resulting in a shorter final height than might have been attained naturally.

Acquired growth hormone deficiency due to pituitary stalk transection after head trauma in childhood

Two patients are reported with growth hormone deficiency due to head trauma in childhood. Although their injuries were outwardly only slight and there was no loss of consciousness and no subsequent neurological deficits, they exhibited gradual growth retardation from the time of the trauma. Provocative endocrinological tests showed growth hormone deficiency and MRI showed transection of the pituitary stalk. These findings suggest that ordinary head trauma, as well as perinatal insult and congenital abnormalities, could be a cause of growth hormone deficiency.

Serum Copper and Zinc Levels in Epileptic Children with Valproate Treatment

Summary: Valproate (VPA) induces zinc (Zn) deficiency in experimental animals, but whether VPA treatment induces deterioration of serum trace metal homeostasis in humans is uncertain. We measured serum copper (Cu) and Zn levels in epileptic children treated with VPA and/or other antiepileptic drugs (AEDs). Patients treated with VPA monotherapy had significantly lower levels of serum Cu (82.2 ± 16.6 μg/dl) than normal controls (97.3 ± 23.0 μg/dl). Patients treated with VPA in addition to some other AED also had significantly lower levels of serum Cu (84.8 ± 20.0 μg/dl). Serum Cu concentrations in patients treated with AEDs except for VPA (87.7 ± 19.1 pg/dl) were not statistically different from those of control subjects. In contrast to the reported results of animal experiments, serum Zn levels were not altered in patients with VPA treatment. Although none of our patients showed any symptoms of Cu deficiency, we should pay attention to potential Cu deficiency in patients with VPA treatment.

Uniparental and functional X disomy in Turner syndrome patients with unexplained mental retardation and X derived marker chromosomes.

We analysed parental origin and X inactivation status of X derived marker (mar(X)) or ring X (r(X)) chromosomes in six Turner syndrome patients. Two of these patients had mental retardation of unknown cause in addition to the usual Turner syndrome phenotype. By FISH analysis, the mar(X)/r(X) chromosomes of all patients retained the X centromere and the XIST locus at Xq13.2. By polymorphic marker analysis, both patients with mental retardation were shown to have uniparental X disomy while the others had both a maternal and paternal contribution of X chromosomes. By RT-PCR analysis and the androgen receptor assay, it was shown that in one of these mentally retarded patients, the XIST on the mar(X) was not transcribed and consequently the mar(X) was not inactivated, leading to functional disomy X. In the other patient, the XIST was transcribed but the r(X) appeared to be active by the androgen receptor assay. Our results suggest that uniparental disomy X may not be uncommon in mentally retarded patients with Turner syndrome. Functional disomy X seems to be the cause of mental retardation in these patients, although the underlying molecular basis could be diverse. In addition, even without unusual dysmorphic features, Turner syndrome patients with unexplained mental retardation need to be investigated for possible mosaicism including these mar(X)/r(X) chromosomes.

Short stature with normal growth hormone and elevated IGF-I

We report on a Japanese girl with short stature, malar hypoplasia, up-slanting palpebral fissures, blue sclerae and thin, stiff and slightly brownish hair. Short stature started in utero and her psychomotor development was normal. Menarche appeared at 13 years 8 months. Height at 14 years 5 months was 132 cm (−4.6 SD). Her growth hormone (GH) sleep pattern and responses to insulin,l-dopa, arginine, propranolol-glucagon and growth hormone-releasing hormone were normal. Plasma insulin-like growth factor I (IGF-I) was high (2170–4860 units/l) and increased from 4860 to 7080 units/l 20 h after biosynthetic GH injection. Gel infiltration patterns of the free and protein-bound IGF-I in plasma from the patient were not different from the controls; IGF-I fraction of the high and low molecular weight binding protein and the non-protein bound fraction were 75.5%, 15.8% and 8.7%, respectively. IGF-I from the patient showed normal bioactivities when determined by [35S]sulphate and [3H]thymidine uptake into cultured rat chondrocytes, and by [3H]thymidine and [3H]α-aminoisobutyric acid uptake into the patients skin fibroblasts. IGF-I binding to cultured skin fibroblasts from the patient was comparable to that of controls. These results suggest that tissue specific defects of IGF-I receptors may be the cause of increased IGF-I levels in the patient.

Normal mutation frequencies of somatic cells in patients receiving growth hormone therapy

The number of reported cases of malignancy developing in growth hormone (GH) users worldwide has increased to more than 40. However, the causal relationship between GH administration and the occurrence of malignancies is still uncertain. We investigated somatic cell mutation frequencies (Mfs) or variant frequency (Vf) at three gene loci in patients with pituitary dwarfism receiving GH therapy to clarify the genetic effect of GH. Eighty-eight patients receiving GH therapy for at least 3 months and 42 age-matched healthy controls were studied. Mfs at hypoxanthineguanine phosphoribosyltransferase (HPRT) and T-cell receptor (TCR) loci in GH users were not significantly higher than in the controls. Although a few patients seemed to have a slightly increased Vf at the glycophorin A (GPA) locus, the difference was not statistically significant. In addition, there was no tendency for the Mfs (Vf) at these loci to increase with the duration of the GH therapy. These data seem to exclude the possibility that GH induces genetic instability in patients with pituitary dwarfism who are receiving GH therapy.

Type 3 GM I gangliosidosis: clinical and neuroradiological findings in an 11-year-old girl

An 11-year-old Japanese girl was diagnosed as having type 3 GM1 gangliosidosis by clinical symptoms and enzyme assay. She was the youngest among the patients with type 3 GM 1 gangliosidosis whose clinical and neuroradiological findings have been documented. Clumsiness since early infancy and dystonia since early childhood which progressed slowly without mental deterioration and dysmorphism led us to the diagnosis of type 3 GM1 gangliosidosis. Genotype determination showed point mutation in exon 2 of the ß-galactosidase gene, which is common among the patients reported in Japan. T2-weighted MRI demonstrated bilateral symmetrical hypointensity in the putamen and globus pallidus. Single photon emission computed tomography using99mTc-HMPAO showed bilateral hyperperfusion in the basal ganglia which decreased gradually during 1 year of observation. Twenty-two patients with type 3 GM1 gangliosidosis reported in the literature whose onset was at under 15 years of age were reviewed.

Analysis of the SRY gene in Turner syndrome patients with Y chromosomal material

Editor—Turner syndrome is one of the most common chromosomal abnormality syndromes affecting 1 in 2500 liveborn females. The syndrome is characterised by short stature, gonadal dysgenesis, congenital heart disease, renal anomalies, and a variety of somatic features including neck webbing, cubitus valgus, short neck, and widely set nipples. Nearly half of the patients have a classical 45,X karyotype while others have structurally abnormal sex chromosomes (for example, 46,X,i(Xq)) or are mosaics with other cell lines with normal (46,XX) or abnormal sex chromosomes.1-4 Among these, patients with Y chromosomal material require specific attention since many of these 45,X/46,XY Turner syndrome patients develop gonadoblastoma or dysgerminoma later in life.5 6 Conventional chromosomal analysis indicates that 4-20% of patients with Turner syndrome have a Y chromosome or its derivatives.1-4 These figures could be even higher, since the more sensitive PCR based analysis has shown that 15-60% of cytogenetically 45,X females have Y chromosomal material.7-9 These findings mean that 10-50% of all Turner syndrome patients have Y chromosomal material and therefore are, to some extent, at risk of developing gonadoblastoma. A more precise understanding of the mechanism leading to generation of a 45,X/46,XY karyotype is therefore important for providing better care for these patients. Karyotypes such as 45,X/46,XY are presumably caused by mitotic loss of the Y chromosome from the originally 46,XY fetus. It is not known, …

Leukaemia in children with growth hormone deficiency not treated with growth hormone

Sir: A small number of cases with Gaucher disease who are symptomatic in the neonatal period and who show ichthyotic skin changes have been described [1, 2, 5]. This association appears to be typical for neonatal Gaucher disease [4, 5]. We wish to report another case. A 2580 g female infant was born vaginally at 37 weeks gestation to a 23-yearold, gravida 3, para 1 mother who was a second degree relative of the father. Her first pregnancy ended in spontaneous abortion. Her second pregnancy resulted in the delivery of a boy who had ichthyosis, hepatosplenomegaly, cardiac defects and died 2 days after birth. The present pregnancy, labour and delivery were uneventful. The baby had a collodion skin and ectropion, eclabinm, generalized joint contractures, gross hepatosplenomegaly, jaundice, petechiae and purpura. Laboratory investigations revealed thrombocytopenia, conjugated hyperbilirubinaemia and elevated liver enzymes. The patients clinical condition deteriorated on the 3rd day and she died on the 8th day with severe septicaemia and disseminated intravascular coagulation. At postmortem examination, large macrophages, histochemically and morphologically consistent with Gancher cells were found in the liver, spleen, lymph nodes, bone marrow and thymus (Fig. 1). The parents were later tested for glucocerebrosidase activity which was 50% of normal in both. To our knowledge eight cases of neonatal Gancher disease associated with ichthyosis have been reported [1-5]. Although the reason for this association is not clear, it appears that the enzyme deficiency may be directly responsible for the skin changes in these neonates [5]. Thus, Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis. In our case the diagnosis was established after the death of the second child. Recognition of this distinct Gaucher Fig. 1 A typical Gaucher cell in the lymph node parenchyma (H & E x 770)

Wilms tumour in a patient with growth hormone replacement therapy

Wilms tumour was found in a Japanese boy aged 5 years 9 months with isolated growth hormone (GH) deficiency and some congenital anomalies. He had received pituitary GH replacement therapy from the age of 2 years 1 month to 4 years 7 months and after a 1 year interval he received biosynthetic GH for 2 months until the tumour became clinically apparent. This was the sixth known patient with GH deficiency to develop a malignant neoplasm during or after GH replacement therapy and the first with a solid tumour in Japan since 1975, when treatment with pituitary GH for patients with GH deficiency was introduced.