Growth hormone deficiency in Dubowitz syndrome

Severe short stature as a result of intra-uterine growth retardation is one of the characteristics of Dubowitz syndrome. There have been few reports elaborating growth hormone secretory status in this syndrome. A child with Dubowitz syndrome, who was found to have complete growth hormone (GH) deficiency and who responded to growth hormone therapy, is described. This appears to be the first documentation of GH deficiency in this syndrome.     

Long-term hormone replacement therapy in two patients with Kabuki syndrome and growth hormone deficiency

The Kabuki syndrome is characterized by mental retardation (mild-to-moderate), skeletal anomalies, typical facial appearance and post-natal growth deficiency. The authors describe two patients with Kabuki syndrome and proven growth hormone deficiency. The first patient has been on GH replacement therapy for 4 years; the second for 11 years. On the basis of a sufficiently long follow-up period the Authors discuss the advisability of replacement therapy with growth hormone in patients with Kabuki syndrome.     

Robinow syndrome with growth hormone deficiency: treatment with growth hormone.

We describe a 5 years and nine months old boy who presented with facial features, vertebral anomalies and dwarfism consistent with Robinow syndrome. Investigations revealed growth hormone (GH) deficiency to be the cause of his dwarfism. We reviewed data on four other patients with Robinow syndrome from the Genentech National Cooperative Growth Study (NCGS). Results of GH testing on three out of four were available and showed GH deficiency. Recombinant human GH therapy in our patient and the three patients from the NCGS resulted in a significant increase in the growth rate per year. The cause of dwarfism in children with Robinow syndrome has hitherto not been studied. We propose its association with GH deficiency and that treatment with rhGH can result in a significant increase in the growth rate of these children.     

Smith-Magenis syndrome and growth hormone deficiency

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome including physical and neurobehavioural features. The disease is commonly associated with a ca. 3.7 Mb interstitial deletion of chromosome 17p11.2, while a 1.1 Mb critical region has been identified, containing about 20 genes expressed in multiple tissues. Haploinsufficiency of one of them, RAI1, seems to be responsible for the neurobehavioural, craniofacial and otolaryngological features of the syndrome, but not for short stature, commonly seen in SMS patients with chromosome deletion, implying the role of other genes in the 17p11.2 region. Growth failure is a final result of several different mechanisms involving decreased growth hormone (GH) production, reduced tissue response to GH, or impaired activity of epistatic factors. To our knowledge, the association of GH deficiency with SMS has never been reported and rarely investigated, despite the very short stature of SMS patients. We describe a girl with a full SMS phenotype and a typical 3.7 Mb deletion of 17p11.2 who also has GH deficiency. After starting replacement therapy, growth has significantly improved, her stature being now above both the 10th percentile and her genetic target. Conclusion:we suggest that an investigation of both growth hormone secretion and function is carried out in patients with Smith-Magenis syndrome and 17p11.2 deletion.Abbreviations FISH fluorescent in situ hybridisation - GH growth hormone - SMS Smith-Magenis syndrome     

Insulin secretion in children with growth retardation

The effect of tolbutamide administration on insulin secretion was studied in 69 children with growth retardation. Diminished insulin secretion was found in all the patients, compared to the control group. This insulin deficit was most evident in patients with isolated, total GH deficiency and least evident in children with idiopathic short stature. Intermediate values were found in dwarfism due to isolated, partial GH deficiency.These results favour the hypothesis that hypoinsulinism contributes to the somatotropin deficiency in causing growth retardation.Abbreviations PD pituitary dwarfism - FSS familial short stature - GR growth retardation - GH growth hormone - ISS idiopathic short stature - tbt tolbutamide - GHtd isolated, total GH deficiency - GHpd isolated, partial GH deficiency     

Long-lasting catch-up growth under bio-methionyl growth hormone treatment in an infant with isolated growth hormone deficiency type 1A.

This case report concerns a 7-month-old infant with severe height retardation (-5.0 SD), typical growth hormone (GH)-deficient phenotype, and undetectable GH serum levels in response to three pharmacological stimuli. Diagnosis of isolated GH deficiency type 1A was confirmed by restriction endonuclease analysis of genomic DNA which pointed out GH-N gene deletion. The introduction of bio-methionyl-GH therapy in this patient was followed by a transient and clinically irrelevant appearance of low binding capacity GH antibodies as well as by a long-lasting catch-up growth (42.2 cm) which is continuing 44 months after beginning of treatment. This atypical pattern confirms that immune and growth response to exogenous GH in isolated GH deficiency 1A may be very heterogeneous.     

Growth hormone deficiency in a child with Williams-Beuren syndrome. The response to growth hormone therapy

Pre- and postnatal growth retardation of unknown pathogenesis is a common clinical feature in patients with Williams-Beuren syndrome (WBS). However, growth hormone deficiency (GHD) has not been considered a major cause of growth retardation. There is only one patient in the literature with confirmed GHD who responded well to human growth hormone (hGH) therapy. We report a female infant with confirmed WBS who, through provocative testing, was found to have GHD and who responded satisfactorily to hGH therapy. Height SDS was -4.2 at the age of 12 months when hGH was initiated and increased to -0.8 at the age of 4.25 years. The pathogenesis of GHD in our patient is unclear. Nevertheless, the elevated levels of prolactin and the response of hGH to growth hormone releasing hormone (GHRH) administration are indicative of a hypothalamic rather than pituitary defect. In conclusion, GH deficiency might contribute to the growth failure in a number of patients with WBS and in such cases hGH therapy will most likely improve final height.     

Hajdu-Cheney syndrome with growth hormone deficiency and neuropathy

A Hajdu-Cheney syndrome is a very rare congenital dysplastic bone disease including acro-osteolysis, short stature, characteristic facies, osteopenia, abnormalities of spine, skull and long bones. A 9 year-old boy presented at our clinic with a chief complaint of short stature and frequent lower respiratory tract infections. He had typical physical and radiographic features of Hajdu-Cheney syndrome associated with growth hormone (GH) deficiency and peripheral motor neuropathy. To our knowledge, this is the first report describing GH deficiency and neuropathy in Hajdu-Cheney syndrome.     

Partial growth hormone insensitivity

Partial growth hormone (GH) insensitivity can be defined as the clinical and biochemical features of IGF-I deficiency without GH deficiency and in the absence of the dysmorphic features of Laron syndrome. There is good evidence that this form of GH insensitivity exists, both in the context of severe GH resistance, and also in some patients with idiopathic short stature. The series of GH insensitivity patients in the European study shows a spectrum of clinical and biological defects, with several patients at the milder end of the spectrum having normal facies. The report of the presence of heterozygous mutations of the GH receptor in patients with idiopathic short stature has been confirmed by documentation of dominantly inherited mutations in familial short stature. Molecular screening in our unit of a group of 31 children with idiopathic short stature and normal GHBP, failed to identify mutations of the intracellular domain of the GH receptor. Consequently, although partial GH insensitivity is a proven entity, the clinical and biochemical identification of patients with GH resistance should precede molecular analysis. The analysis of individual patients and their families is more likely to reveal mutations, rather than a strategy of blanket molecular screening.     

Endocrinological study on growth retardation in Rett syndrome

Aim: To determine whether primary or secondary growth hormone (GH) deficiency has a causative role in linear growth retardation, a key feature in Rett syndrome (RTT). Methods: In 38 patients with Rett syndrome a variable set of investigations was performed including assays of growth and thyroid hormones, gonadotropins, gonadal and adrenal steroids and determination of bone age. Not all measurements were attainable from all patients. In three patients the 24-h growth hormone secretion profile was evaluated using the pulsar method. Results: The bone age determined in 24 patients was found to be normal in 8, retarded in 9 and accelerated in 7 patients. Insulin-like growth factor (IGF)-1 was low in 8 out of 23 patients. IGF-binding protein (IGFBP)-3 and insulin and arginine-stimulated growth hormone secretion were both normal, indicating normal GH secretion in the majority of patients. The 24-h GH secretion profile in the first patient showed a normal day/night rhythm and a normal increase in nocturnal GH secretion. The second patient's overall GH secretion was normal but there was no day/night rhythm. The third patient showed borderline low GH secretion. Normal age-appropriate plasma values were found for the thyroid hormones (T4, TSH), TSH-night rhythm, oestradiol, prolactin and cortisol (08.00, 18.00).

Conclusion: Our study provides no evidence that growth retardation in RTT is caused by growth hormone deficiency. A disturbed hypothalamic control cannot be excluded but it is unlikely that this is the major cause of growth retardation in RTT.     

Amelogenesis imperfecta with growth hormone deficiency in a 12 year-old boy

Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders that are characterized by a defect in the formation of the tooth enamel and a high degree of clinical diversity. X-linked, autosomal dominant and recessive inheritance have been demonstrated. Growth hormone (GH) has an effect on bone and soft tissue development. Dental and facial abnormalities associated with pituitary dwarfism have been reported, but GH deficiency with AI is very rare. We describe a 12 year-old pre-pubertal boy who was referred to our hospital with teeth deformities and growth retardation. His teeth had brown-yellow pigmented surfaces, and dental examination showed extensive enamel deficiency in his permanent teeth. He also had severe growth retardation; height SDS was -3.6. Laboratory examinations showed reduced GH levels, and he was diagnosed as having idiopathic isolated GH deficiency and AI.     

Fanconi's anemia with growth hormone deficiency.

The association of Fanconi's anemia (FA) and growth hormone (-gh) deficiency is not commonly reported. These children may have the typical features of the FA syndrome, or may exhibit much variability in clinical and hematological findings. In a single family, members may have FA with or without GH deficiency. The genetic basis for this heterogeneity is unknown. We describe here two siblings with FA, one of whom had dwarfism due to GH deficiency. Combined treatment with GH and androgen (oxymetholone) resulted in strikingly greater acceleration of growth than did the use of GH alone. Pancytopenia was not influenced by hormone therapy.     

Growth hormone deficiency, brain development, and intelligence.

Twenty-nine patients with growth hormone (GH) deficiency were selected according to the following criteria: no evidence of reversible GH deficiency, onset of growth retardation in early childhood, and no evidence of pituitary tumors or other direct pituitary trauma. Fourteen patients had evidence of multiple hormone deficiencies, 14 had isolated GH deficiency, and one patient questionable isolated GH deficiency. Psychometric testing showed a normal IQ distribution. The GH deficiency was not associated with deficiencies in specific mental abilities. Likewise, GH treatment in later childhood and adolescence did not seem to influence intelligence. Patients with multiple hormone deficiencies had somewhat lower IQs than patients with isolated GH deficiency when socioeconomic status was controlled. We conclude that GH deficiency itself does not seem to affect human brain development and intelligence.     

Prediction of the growth response in children with various growth disorders treated with growth hormone: analyses of data from the Kabi Pharmacia International Growth Study

Analyses to predict the growth response to recombinant human growth hormone (GH) in prepubertal children during the first year of treatment were performed on data from 472 patients with idiopathic GH deficiency (IGHD), 202 children with Turner's syndrome, 327 children with idiopathic short stature (ISS) and 135 children with intrauterine growth retardation (IUGR). In IGHD, 56% of the variability of the response could be predicted from a model based on six variables. These variables could be ranked in order of importance as follows: target height SDS minus height SDS, chronological age, frequency of GH injections, dose of GH, weight-for-height index, and birth weight SDS. When the model for IGHD was applied to Turner's syndrome, ISS and IUGR, there was a high degree of similarity between the predicted and achieved growth response in ISS and IUGR. However, an uneven distribution within the plot of Studentized residuals in ISS and IUGR suggested heterogeneity within these populations. Prediction of growth in Turner's syndrome was greatly exaggerated by the model for IGHD, suggesting a different pathogenesis as the basis of the growth disorder. Specific prediction models were therefore developed for Turner's syndrome, ISS and IUGR. In all three disorders, the dose of GH was found to be the most important predictor, suggesting that, in contrast to IGHD, first-year growth is governed less by the difference between height and the presumed genetically determined target height. Again, in contrast to IGHD, this suggests that catch-up phenomena are not involved. As the predictability of the variation in growth response in Turner's syndrome, ISS and IUGR did not exceed 32% (for ISS), the search for new predictors should continue in these disorders.     

Physiological and pathological growth hormone secretion

Growth hormone (GH) secretion is normally episodic, with discrete bursts of GH super-imposed on a minimal basal level of production. This pattern of GH production yields a dynamic state between a low baseline and intervening peaks, posing a challenge for the clinician attempting to understand the 'true GH status' in a specific patient. This pulsatile pattern is maintained throughout the day, but there are clear differences between different segments of the day, with approximately two-thirds of the total daily secretion produced at night. The dynamic nature of GH production has led many investigators to suggest that when evaluating short stature, parameters of spontaneous GH production be applied rather than the GH response to artificial stimulation. GH secretory patterns in healthy control populations are compared to those in patients with several conditions seen by the pediatric endocrinologist (classical GH deficiency, GH neurosecretory dysfunction, acute lymphoblastic leukemia, hypothyroidism, small for gestational age, Russell-Silver syndrome, constitutional delay of growth and puberty and Fanconi's anemia) and variables used for analysis of these patterns are described. Inferences made from comprehensive evaluations of the GH axis in Fanconi's anemia provide unique insight into general GH pathophysiology.     

Evaluation of growth hormone secretion and insulin-like growth factor-1 in prepubertal children with thalassemia.

Growth retardation is a clinical feature of patients with thalassemia major, and endocrine studies have frequently revealed the presence of normal growth hormone (GH) secretion. The present study was undertaken in 14 prepubertal thalassemic children (9 males and 5 females), aged 2(2/12) to 10(3/12) years, with the aim of evaluating GH response to i.v. arginine, oral L-dopa stimulation and insulin-like growth factor-1 (IGF-1) levels. Eleven patients had peak serum GH levels less than 7 ng/ml and two patients had peak serum GH levels of 7-10 ng/ml with arginine. Similarly, 10 patients had peak levels less than 7 ng/ml and one patient had a peak level of 7-10 ng/ml with L-dopa. Thus, nine of the patients had GH deficiency and two had partial GH deficiency. Three patients had elevated basal GH values. The serum IGF-1 levels in the patients were not statistically different from the levels in the controls, but three patients had low IGF-1 values. These findings suggest a defect in the regulatory mechanisms of GH secretion.     

Growth hormone for short stature not due to classic growth hormone deficiency

The advent of recombinant DNA technology has resulted in potentially unlimited supplies of growth hormone. Sufficient quantities are now available not only for the long-term, uninterrupted treatment of GH-deficient children but potentially for the treatment of non-GH-deficient patients with other short stature or growth attenuating disorders. Short-term studies have demonstrated an improvement in the growth rates of subjects with isolated short stature, Turner syndrome, and chronic renal failure; and additional studies are under way to assess the efficacy of GH therapy of other short stature syndromes. However, the long-term efficacy and possible adverse effects of GH treatment in these situations is not known. Until there has been more experience, GH deficiency should remain the primary indication for GH treatment. Growth hormone should not be considered routine therapy for other conditions associated with or resulting in short stature. However, research should continue in these areas to define which children may benefit from GH treatment.     

Clinical and genetic characteristics and effects of long-term growth hormone therapy in a girl with Floating-Harbor syndrome

The established facts to date relating to Floating-Harbor syndrome (FHS) are its characteristic typical triangular facies with bulbous nose and thin lips, short stature, delayed bone age, and mild mental retardation with delay in expressive speech; its sporadic occurrence without Mendelian inheritance; and its unknown cause. Little is known about the growth hormone-insulin-like growth factor 1 (GH-IGF-1) axis and the effect of GH treatment in children with this syndrome. We report on a 9-year-old girl born small for gestational age (SGA, birth length -2.2 standard deviation score) with persistent short stature who has been treated with GH from 3.5 years onward with a modest growth response. Revision of the case led to the diagnosis of FHS. No abnormalities were found in the sequence or copy number of IGF-1 receptor or in the genomic single-nucleotide polymorphism array. GH treatment led to an increase in serum IGF-1 in the upper normal range, but the growth response was modest, suggesting a defect in IGF-1 signaling. Early recognition of this entity is important, as it enables specific diagnostic tests targeted at other abnormalities associated with FHS.