Growth hormone deficiency (GHD) is an important clinical entity which has a significant impact on a child's development unless correctly diagnosed. The studies by our group which showed that in some growth retarded children, spontaneous GH secretion could be abnormal in the face of a normal response to GH provocative studies gave birth to the concept of growth hormone neurosecretory dysfunction (GHND).
The neuroregulation of GH is extraordinarily complex involving the regulatory control of GH releasing hormone (GHRH) and somatostatin (SRIF) and several neurotransmitters. Recently, our group found that in Rhesus monkeys that had neurosurgically induced lesions of the arcuate and ventromedial nucleus (VMN) nuclei there was no significant alteration in the GH response to arginine, levodopa, and clonidine provocation after surgery but only a reduction in GH to insulininduced hypoglycemia and in spontaneous GH secretion.
GHND is a form of GHD that needs to be correctly diagnosed since it is well known that GH plays an important role in other aspects of body function including growth, i. e. in carbohydrate, lipid, and protein metabolism, and a significant lack of GH may affect a child's well-being during its entire life unless appropriately treated.

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Growth hormone neurosecretory dysfunction (GHND) is part of a spectrum of disorders of growth hormone (GH) secretion and action that range from classic GH deficiency (GHD) to partial GH insensitivity. GHND patients develop circulating levels of GH above an arbitrary level (frequently 10 ng/mL) in response to pharmacological stimuli, but have low spontaneous endogenous production of GH. However, GHND is difficult if not impossible to diagnose in the individual patient because of the inherent variability of the assessment of GH endogenous secretion and peak GH response to provocative testing. The lack of a clear linkage between long term response to GH treatment for short stature and any auxologic or biochemical parameters make the selection of short patients for treatment difficult. It is necessary to use a combination of careful auxological and biochemical assessments of short children for the appropriate selection of patients for GH treatment. Indirect ways of assessing endogenous GH metabolism such as insulin-like growth factor I (IGF-I), IGF binding protein-3 (IGFBP-3), and GH binding protein (GHBP), are more reproducible than direct GH testing, and may be useful in the definition of subtle disorders of GH secretion and action in individual patients. The diagnostic categorization of patients with short stature as GH/IGF axis dysfunction may prove to be useful.

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Growth hormone (GH) secretion in short children was evaluated by the insulin and arginine tests and by measurements of spontaneous secretion. The patients' height velocities were analysed on the basis of their GH secretory responses. The basal height velocities showed positive correlations with spontaneous GH secretion. Height velocities during the 1st year of GH therapy showed negative correlations with spontaneous secretion and the results of the insulin tests. Pharmcological tests revealed that the basal height velocity was lowest in patients with classical GH deficiency and higher values were observed in non-classical GH deficiency and non-endocrine short stature. Patients with classical GH deficiency did not always show low spontaneous secretion of GH. Inconsistent results between the pharmacological stimulation tests and spontaneous secretion were observed in 11.6 % of 129 short children. Half of these showed normal responses to the pharmacological tests and low spontaneous secretion, and half showed low GH responses to pharmacological tests and normal spontaneous secretion. It was not possible to distinguish these patients except by GH secretory studies.
It is concluded that low spontaneous secretion of GH indicates GH deficiency.

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The pituitary specific factor 1 (PIT1) gene product, pituitary transcription activator-1 (Pit-1) /growth hormone factor 1 (GHF-1), is a pituitary-specific POU-domain deoxyribonucleic acid (DNA) binding factor. Characteristics of the PIT1 gene are obtained from experiments such as transcription activation, DNA binding, solution and crystal structure analysis, in situ hybridization, and genetic analyses of combined deficiency of thyrotropin (TSH), growth hormone (GH) and prolactin (PRL). Pit-1/GHF-1 binds to and transactivates the GH, PRL, TSHβ and PIT1 genes, and is indispensable for the expression of TSH, GH, and PRL.

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Abnormalities of the pituitary-specific transcription factor-1 (Pit-1) gene cause combined deficiencies of growth hormone (GH), prolactin and thyrotropin (TSH) by altering Pit-1 protein in several different ways. The simplest are gene deletions that preclude expression of the protein. Nonsense mutations such as R172X that generate truncated proteins that lack POU specific and/or POU homeo domains and cannot bind to regulatory sites. Some missense mutations such as the Snell mouse W261C disable deoxyribnucleic acid (DNA) binding domains. Others have little effect on binding, but prevent transcriptional activation. The A158P mutation is recessive. It corresponds to “positive control” mutants in the lambda repressor that are unable to activate certain target genes, but retain the ability to silence other target genes. The R271W mutation distal to the POU homeo domain exerts dominant negative effects. Mutant proteins apparently participate in heterodimer formation and compete with active, wild type, homodimers. Alternative splicing of Pit-1 messenger ribonucleic acid (mRNA) introduces some interesting variations. Inclusion of parts of intron 1 in the protein may alter specificity of transcriptional activation. Exclusion of exon 4 bypasses the A158P and R172X mutations. If the protein encoded by this alternative splice form has a function in pituitary cell development, it may help explain the phenotypic variability seen with these mutations.

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To define clinical features of a combined deficiency of growth hormone (GH), prolactin (PRL) and thyroid stimulating hormone (TSH) due to a Pit-1 abnormality, we analyzed 16 cases (7 males, 9 females) with the disease. All cases shared complete GH and PRL deficiencies. However, TSH deficiency was various in degree among patients. Ten patients from 8 families had manifested apparent symptoms of hypothyroidism in early infancy. Seven of the 10 patients with cretinism had mild or severe psychomotor retardation, indicating requirement of immediate initiation of thyroxine therapy. The size of the anterior pituitary gland in MR imaging was extremely hypoplastic in 8 patients of 7 families and normal in 4 patients of 3 families. Birth length in patients with the disease was shorter than that in normal newborns as described in isolated GH deficiency type 1A and in Laron dwarfism patients, indicating an effect of GH/insulin-like growth factor I (GH/IGF-I) on fetal growth. Birth weight and gestational period were normal on average. Severe growth retardation with a peculiar facial appearance due to severe GH/IGF-I deficiency became more distinct in the first year of life. All patients responded well to human GH (hGH) treatment and did not produce anti-hGH antibodies. The mean final height without hGH treatment was -9.7 standard deviation (SD).

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Noonan syndrome (NS) is a syndrome with great phenotypical resemblance to Turner yndrome (TS). However, there are significant differences between the two disorders. Amongst others cardiac abnormalities in NS usually affect the right side, moderate mental retardation is freuent and hypogonadism commonly affects boys. In NS both genders are affected in equal frequency (total incidence approx. 1: 1, 000). Autosomal dominant inheritance occurs in approx. 20 %, but the molecular genetic basis is obscure. There is a disease-specific growth pattern in NS: size at birth is normal, mean height follows approximately the 5th centile of normal children, pubertal growth spurt is delayed and diminished. The pathogenesis of the growth disorder is unknown. Disease-specific growth standards are presented which are useful when evaluating the response to growth-promoting treatment.

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55 children, 34 males, 21 females, with Noonan syndrome (NS) included in the Kabi Pharmacia International Growth Study were treated with growth hormone (GH) in a median dose of 0.6 IU/kg/week. Median age at start of treatment was 10.6 years and median height standard deviation score (SDS) was-3.1. Pretreatment height velocity was 4.3 cm/year and during the first, second and third years it increased to 7.0, 6.0 and 4.8 cm/year respectively. Projected adult height with Noonan specific standard increased from -0.4 SDS to 0.3 SDS at the end of three years' treatment. No adverse reactions were reported.

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Thirty-nine children with Noonan syndrome were treated with growth hormone (GH). Prepubertal height velocity was 4.25 ± 1.31 cm/year (M ± SD) (n=38) before GH therapy, which was increased to 6.23 ± 0.87 cm/year (n=33) in the first year, to 4.92 ± 1.15 cm/year (n=22) in the second year and 4.76 ± 1.25 cm/year (n=13) in the third year. Height velocity SDS for chronological age and height velocity (SDS) for bone age were also improved in the 1st year, but declined progressively during the subsequent years. No adverse effects were observed during GH treatment.
These data indicate that GH may be effective in Noonan syndrome, but further studies are required to evaluate the efficacy of long-term GH therapy on adult height and body proportions.

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Bone ages of Japanese children aged 1.0 to 3.2 years were computed from 89 radiographs of hands and wrists. The subjects were 20 boys and 40 girls whose heights were within ±1 standard deviation (SD) of the mean for chronological age. The TW2 scoring system was used to evaluate bone age.
The RUS bone age for boys and girls was evaluated, but Carpal and 20-BONE bone ages were not useful for these ages. Carpal bone centers did not appear until 3.0 years of age. Stage B in the capitate and hamate was only seen at these ages. We conclude that RUS bone age is suitable for making a Japanese standard atlas of bone maturation. Also, in this study RUS bone age was more useful than other bone age scoring systems.

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In 80 small for gestational age (SGA) low birth weight infants (birth weight less than 2, 000 g), the relation between mental development and postnatal physical growth was investigated. At the corrected age of 24 months, infants were classified into two groups by the Enjoji Developmental Screening Test: one with normal development and the other with mental delay. There were 55 infants with normal development and 25 with mental delay. Both groups were compared in birth condition, morbidity in the neonatal period and postnatal physical growth. There was a significant relation between mental development and postnatal growth of height, but not with growth at birth, neonatal morbidity or other measurements. These results suggest that SGA infants with impaired postnatal height growth may be at increased risk for mental delay.

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We describe a 3-year-old Japanese boy with growth retardation and on empty sella turcica. He was born uneventfully by vertex delivery, birth weight 2, 890 g, length 50 cm. At the age of 3 11/12, his height was 86.7 cm (-3.3 standard deviation (SD)) and the carpal bone age was moderately delayed. Peak values of serum growth hormone and the other pituitary hormone levels by conventional stimulation tests were all within the normal range. The serum insulin-like growth factor I (IGF-I) was 29.9 ng/mL. The mean value of urinary growth hormone (GH) was 42 pg/mg Cr. Magnetic resonance imaging (MRI) showed an extremely thin and downward compressed anterior pituitary lobe with a normal pituitary stalk and posterior lobe. The skull roentgenogram showed a sella turcica of normal size. The etiology of the empty sella in the patient remained obscure. The shape of the pituitary gland in the patient is different from that due to intrinsic embryological defect in the pituitary development, indicating that an extrinsic factor might have caused the empty sella. Primary empty sella syndrome (ESS) as seen in this patient due to extrinsic factors is an important category in idiopathic GH deficiency other than perinatal injury. Careful follow up in his case is necessary to elucidate the relationship between pituitary function and empty sella

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We report a 6-year-old girl with periodic adrenocorticotropin-antidiuretic hormone (ACTH-ADH) discharge syndrome who showed accelerated height growth without pubertal signs. The levels of insulin-like growth factor I (IGF-I) and sex steroids were elevated during the spurt. Although the mechanism of hypersecretion of these hormones could not be elucidated, we speculate that it was due to extreme stimulation of the pituitary-adrenal axis or other pathway which would induce excess of adrenal sex steroid during the attack.

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We evaluated the growth, bone age and pubertal development in a boy with Addison's disease who had been followed-up over a period of 15 years. The predicted final height was acceptable, because his bone age was retarded and delayed epiphyseal closure prolonged the period of growth. Pubertal development was delayed. Endocrinological examination revealed associated partial hypogonadotropic hypogonadism.

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We report a 12-years-old boy presenting short stature, nystagmus and anemia. His growth failure became evident at the age of 7 years and progressive from then on. Routine urinalysis, which was performed every year in most of the school children in Japan, gave negative results repeatedly. When he first visited our hospital for the evaluation of short stature, he had already had azotemia and markedly increased urinary excretion of both β2 microglobulin and growth hormone (GH). Histological findings on renal biopsy led us to the diagnosis of his having familial juvenile nephronophthisis (FJN). Therefore, we should be aware that the diagnosis of FJN also has to be taken into consideration in patients with progressive growth retardation of childhood onset especially when they had marked elevation of urinary β2 microglobulin and GH. As the direct cause (s) of growth failure has not yet been fully understood in FJN, abundant urinary loss of GH and other components essential for normal growth may also have to be assessed to clarify the pathogenesis of impaired growth.

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It has recently been reported that point mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, resulting in the substitution of an arginine residue for glycine at position 380 of the mature protein, cause of achondroplasia (ACH). In the present study we analyzed the FGFR3 gene of a 6 year old Japanese girl with ACH. Genomic deoxyribonucleic acid (DNA) of the patient was isolated from whole blood. A 164-bp fragment that spans the entire transmembrane domain was amplified by the polymerase chain reaction (PCR). A heterozygous G to A transition at nucleotide 1, 138 of the complementary DNA (cDNA) was demonstrated by direct sequencing of the amplified DNA fragment, and this was confirmed by SfcI digestion of the 164-bp PCR product. The 1, 138A mutation results in the substitution of Arg for Gly at position 380 of the mature FGFR3 protein. The full role of the mutation remains to be determined.

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We report the case of a girl with a 46, XY karyotype containing the sex determining region Y gene (SRY). She was 14 years old, with the height of 131.2 cm (-4.5 SD). She had a low hair line, shield-shaped chest and multiple pigmented naevi on her face. The external genitalia were normal female. No inguinal or labial masses were found. Chromosomal analysis from blood lymphocytes and skin fibroblasts revealed a 46, XY karyotype. The basal levels of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) and their responses to LH-releasing hormone (RH) stimulation were elevated; the insulin-like growth factor-I (IGF-I), thyroid function and growth hormone (GH) secretory responses to insulin and glucagon were normal. SRY was identified on the short arm of the Y chromosome using Y-specific deoxyribonucleic acid (DNA) probes. There were no mutations in the SRY by direct sequencing analysis. Pelvic ultrasound and magnetic resonance imaging (MRI) did not reveal internal genitalia. Gonadectomy may be necessary because she has a substantial risk of developing malignant germ cell neoplasia. Two questions arise: 1) why was male sexual differentiation inhibited although she had a normal SRY, and 2) why did she have the appearance of Turner syndrome?

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Idiopathic central diabetes insipidus (CDI) is sometimes complicated with growth disturbances.
We describe 5 children (4 boys and 1 girl) with idiopathic CDI and growth hormone deficiency (GHD). They were diagnosed as sufferings from CDI by the symptoms of polydipsia and polyuria, and the result of combination tests of water deprivation and Pitressin loading. The provocation tests showed low secretory responses of GH in all cases. One patient presented with panhypopituitarism, and two with hyperprolactinemia. Magnetic resonance imaging (MRI) showed no posterior pituitary high signals in all cases. Other findings were a small anterior lobe in two cases, transection of the pituitary stalk in one case, and a thickened infundibulum in two cases. Four patients who were treated by recombinant GH showed significant and continuous improvement of their height standard deviation (SD) scores.
These patients indicate that idiopathic CDI is a heterogeneous disease which is frequently complicated with anterior pituitary dysfunction, especially GHD, and that GH replacement is effective.

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A patient with an optic glioma who had been treated by radiotherapy developed right thalamic hemorrhage 4 months after starting growth hormone (GH) therapy. This was probably due to the irradiation but the GH therapy may have contributed.

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A girl with autoimmune thyroiditis of infant-onset is described. She was very short and achieved little catch-up growth despite the adequate replacement therapy. Her bone radiographs showed a kind of skeletal dysplasia. Additionally, her mother was revealed to have the same combination of autoimmune thyroiditis and bone dysplasia. Although this combination has not been reported yet, some syndromes affecting both the immune system and the bone system are well known. So, we think that this association is not fortuitous, but a new syndrome of autosomal dominant inheritance.

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Two children with growth hormone (GH) deficiency developed hyperthyroidism during the course of their therapy with human GH (hGH). The first patient, who had been irradiated for panhypopituitarism due to suprasellar germinoma, was treated with corticosteroid, 1-deamino-8-D-arginine-vasopressin (DDAVP), l-thyroxine (T₄) and GH. Eight years after the initiation of therapy, hyperthyroidism developed without any specific symptoms. Laboratory examination revealed elevated thyroid hormone, positive thyrotropin-binding inhibiting immunoglobulin (TBII) and antimicrosomal antibody. The second patient, with optic nerve atrophy treated with GH and l-T₄, developed hyperthyroidism after 10 years of therapy. This patient also showed elevated thyroid hormone, positive anti-thyroglobulin antibody, anti-microsomal antibody and TBII. After being treated with mercazol, the thyroid function of both patients became normal.
Although diabetes mellitus (DM) and hypothyroidism are occasionally associated with GH treatment, the development of hyperthyroidism has rarely been reported. This hyperthyroidism associated with GH treatment may occur by chance. However, some other factors, which produce autoimmune antibodies, may also involve the development of hyperthyroidism. These two cases caution us that hyperthyroidism can develop even in a patient with secondary hypothyroidism during treatment with GH and l-T₄.

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A case of Klinefelter's syndrome with growth hormone (GH) deficiency is reported. He was diagnosed as GH deficiency and administration of recombinant human GH was started at the age of nine. Chromosomal analysis revealed 52, XXY, +5 mar-55, XXY, +8 mar karyotypes. Sufficient compensatory growth spurt was obtained after GH therapy. The karyotypes of Klinefelter's syndrome with short stature have been reported as 47, XXY, 48, XXYY, mosaic XY/XXY, X/Y translocation and 49, XXXXY. This is the first case of these karyotypes with GH deficiency.

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Bone mineral density (BMD) was studied in 22 young girls with Turner syndrome (5-22 year) in relation to pubertal status and karyotype. BMD of trabecular and cortical bones were evaluated by dual-energy X-ray absorptiometry of the lumbar spine (L2-4 BMD) and II metacarpal bone microdensitometry (ΣGS/D), respectively. Furthermore, 6 patients treated with growth hormone (GH) were analyzed longitudinally.
The mean Z scores of L2-4 BMD and ΣGS/D were -1.485 and -1.613, respectively. The mean Z scores of L2-4 BMD and IGS/D corrected for bone age were -1.199 and -1.104, respectively. There was no significant difference in BMD between those who eventually developed puberty and those who did not. No difference in either L2-4 BMD or ΣGS/D was found between the 14 patients with karyotype monosomy X and the 7 patients with other karyotypes. GH treatment improved the BMD of cortical bone; improvement was marked in patients treated from an early age.
These findings show that mineralization of both trabecular and cortical bone is impaired and that estrogen deficiency is not the only cause of osteopenia in this disease. Moreover, GH may be an effective treatment for osteopenia as well as for short stature.

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Total cholesterol (TC) level and percent ideal body mass index (%BMI) for age and height were measured in children with non-endocrine short stature (NESS) (n=11), partial growth hormone deficiency (PGHD) (n=4) and growth hormone neurosecretory dysfunction (GHND) (n=5) every 3 months for 2 years to evaluate the effect of growth hormone (GH) therapy. These measurements and annual growth rates were compared among three groups: group A (children who remained prepubertal during the study); group B (children who started puberty in the second year); group C (children who started puberty in the first year). There was no significant change in %BMI during the study period in the three groups and no significant correlation between %BMI and height velocity or height standard deviation (SD) before treatment or height gain after treatment. TC levels remained unchanged in groups A and B. However, there were significant decreases in group C after treatment. These results showed that the GH therapy in NESS, PGHD and GHND children had no effect on cholesterol metabolism or body composition, and that the children's nutritional status did not affect their natural growth.

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Children with Growth Hormone deficiency (GHD) are relatively obese. Adults suffering from GHD show early mortality and morbidity related to cardiovascular diseases. This study focuses on atherogenic risk factors in children with GHD. We examined changes in body composition and lipid profiles in 18 males and 6 females with GHD, aged 6-14 year; height standerd deviation score (HSDS) -4.5 to -2.0, during 12 months of treatment with GH. HSDS significantly increased by 0.41 in males and 0.47 in females after 12 months of treatment. Body weight increased in both sexes. The percentage of body fat decreased especially at 5 months of therapy in males and at 3 months in females (P<0.001). Body fat in kg decreased rapidly at 1 month in both groups (P<0.05). The lean body mass showcd a significant increase from 2 months in females and from 1 month in males until the end of the study. High density lipoprotein cholesterol (HDLC) increased in males throughout the study (P<0.05) without significant changes in total cholesterol. The atherogenic index decreased significantly at 12 months in males (P<0.01) and in females (P<0.05). We conclude that GH therapy is important in reducing atherogenic risk factors during childhood.

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Eleven growth hormone (GH) -deficient patients with delayed development composed of 10 males and one female with ages ranging from 4 to 17 years were studied. The diagnosis was cerebral palsy in 4 cases, West syndrome in 2, Prader-Willi syndrome in one and others in 4. Six patients could walk unaided, but the remaining five could not. Ten patients had mental retardation, from very severe to mild. Their parents and house staff observed their behavior and development during 3 months to 3 years of GH therapy. Some catch-up of development in gross motor function, social behavior, and speech was observed after GH therapy. In some cases, sleep disorder, feeding difficulty, and emotional state improved. Most patients became more active in daily life after therapy.
These data suggest that GH therapy is effective not only on growth but also on development and quality of life in GH-deficient patients with delayed development.

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