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.     

Therapeutic optimization of growth hormone deficiency in children and adolescents

More than 40 years after the introduction of growth hormone (GH) treatment, many questions remain unanswered. Clearly, with the availability of rhGH and with current treatment protocols, treatment efficacy has improved. However, it still remains unclear whether current treatment protocols are the best possible. Before GH deficiency was recognized as a chronic disease, children only received treatment until normal adult height had been reached. However, it has recently been shown that not all GH-dependent body structures and functions normalize in parallel with height. Furthermore, in adolescents with GH deficiency, the interruption of GH substitution leads to severe hormone deficiency symptoms in adulthood. In the case of an adolescent who meets the biochemical criteria for GH deficiency in adulthood, but does not show alterations of metabolism, body structure, or emotional state, should GH treatment be started in adolescence, or only if and when the clinical syndrome becomes apparent? This is a difficult question to which there is not yet any clear answer, and we suggest that there is a need for further studies in this area. Furthermore, it will be necessary to re-evaluate the situation of patients who have completed their growth, and definitive conclusions will require controlled studies.     

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.     

Borjeson-Forssman-Lehmann syndrome and multiple pituitary hormone deficiency

We describe two brothers with Borjeson-Forssman-Lehmann syndrome and the 22A-->T (Lys8X) PHF6 mutation, who presented with the symptoms and signs of multiple pituitary hormone deficiency. Biochemical investigations and radiology confirmed growth hormone (GH), thyroid stimulating hormone (TSH) and adrenocorticotrophic hormone (ACTH) as well as gonadotrophin deficiency. They were also found to have optic nerve hypoplasia. This family suggests that the BFL gene product may play an important role in midline neuro-development including the hypothalamo-pituitary axis.     

Growth hormone treatment in a girl with Prader Willi syndrome

Prader Willi syndrome (PWS) is a rare endocrine-metabolic disorder that is characterised by neonatal hypotonia, hyperphagia, marked obesity, short stature, hypogonadism and behavioural problems. 7-20% percent of these children develop diabetes mellitus. A large number of individuals with PWS show growth hormone (GH) deficiency. Recent studies indicate beneficial effects of GH replacement therapy not only for their linear growth but also for correction of metabolic dysfunction. In the present communication this article details about the therapeutic outcome in a girl with PWS who received recombinant growth hormone (rGH), Genotropin. Some carry-over therapeutic benefits have been observed even after discontinuation of rGH.     

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.     

Genetic studies in idiopathic short stature

Idiopathic short stature (ISS) refers to a heterogeneous group of children with marked growth failure of unknown cause, and encompasses familial short stature and constitutional delay of growth. It has been postulated that specific genetic mutations may explain certain cases of growth failure. Some patients with growth hormone (GH) deficiency have mutations in the GH-releasing hormone receptor or GH gene, whereas patients with GH insensitivity syndrome have mutations in the GH receptor or insulin-like growth factor-I gene. It appears that heterozygous mutations of the GH receptor may cause partial GH insensitivity in a subset of patients with ISS. Defects in the short stature homeobox-containing gene (SHOX) in the pseudoautosomal region of the sex chromosomes may cause the growth failure seen in the Leri-Weill and Turner syndromes, and in some familial cases of ISS. Further research into stature-related genes will likely contribute to our understanding of this population.     

Two years of growth hormone treatment in the first growth hormone deficient patient with cerebrofaciothoracic dysplasia

We recently reported two siblings, a sister and a brother, with intrauterine growth retardation, microcephaly, short stature, mental retardation, facial dysmorphism and multiple costovertebral malformations. These features fit most with the diagnosis of cerebrofaciothoracic dysplasia, or Pascual-Castroviejo syndrome. The second sibling, our index patient, presented also with cleft palate and growth hormone (GH) deficiency, suggesting that endocrinological assessment should be performed in short patients with this syndrome, especially if midline defects are present. We present the results of 2 years GH treatment of this first GH deficient patient with cerebrofaciothoracic syndrome and compare the results to those observed in other genetic syndromes with GH deficiency.     

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     

Gender and hormonal regulation of growth

Puberty is the transitional period between childhood and adulthood when substantial growth, sexual maturation, and reproductive capacity is attained. The onset of puberty is triggered by the combined action of the somatotropic (GH-IGF-I) and gonadotropic (GnRH-LH/FSH-sex steroid) hormone axes, the latter of which stimulates the former to produce the pubertal growth spurt. Studies of GH secretion in boys and girls, in Turner's syndrome, in hypogonadal girls, and in androgen-deficient boys have revealed estrogen-dependent mechanisms controlling GH production, age-dependent response to and control of GH, and gender-dependent differences in response to GH therapy. The interplay between the somatotropic and gonadotropic hormone axes during puberty has profound implications on the treatment of adolescent patients in need of hormone replacement therapy for growth deficiency or hypogonadism.     

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.     

Growth hormone treatment in Noonan syndrome

Growth responses to growth hormone (GH) treatment in Noonan syndrome are compared with those in short children with the other growth disorders. The responses in Noonan syndrome are much less than those in children with GH deficiency, a little less than those in children with non-endocrine short stature and almost the same as those in children with Turner syndrome. As it is speculated that GH induces puberty earlier that expected in Noonan Syndrome, the efficiency of GH treatment for final height in Noonan syndrome is not promising.     

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.     

Johanson-blizzard syndrome: loss of glucagon secretion response to insulin-induced hypoglycemia

Johanson-Blizzard syndrome is a rare autosomal recessive disorder characterized by aplasia of the alae nasi, aplasia cutis, dental anomalies, postnatal growth retardation and pancreatic exocrine aplasia. Some endocrinological dysfunctions--growth hormone (GH) deficiency, hypothyroidism, and diabetes mellitus--are known to complicate this syndrome. We report here a Japanese infant with Johanson-Blizzard syndrome presenting with failure to thrive. Endocrinological examination by insulin-induced hypoglycemia showed not only the presence of GH deficiency, but also the loss of the glucagon secretion response to hypoglycemia. This complication suggests abnormal input of autonomic nerves to the islets of pancreas in Johanson-Blizzard syndrome.     

Growth response to growth hormone therapy following cranial irradiation

The growth response to growth hormone (GH) therapy has been studied in 12 children who received irradiation to the cranium alone either for brain gliomas, distant from the hypothalamic-pituitary axis, or as prophylaxis against CNS leukaemia. Seven children have completed GH treatment (mean duration 4 years) and five are presently on GH (mean duration 1.2 years). This response has been compared to that seen in 14 children with isolated idiopathic GH deficiency (IGHD), following GH therapy. Before treatment, the cranially irradiated patients (C-PRGHD) had higher standard deviation scores (SDS) for standing height, sitting height and leg length, and less bone age (BA) retardation, but started treatment at a similar age, and with a similar pre-treatment growth velocity and GH peak to standard provocative tests, compared to IGHD patients. GH produced a significant and similar increase in growth velocity (cm/year and SDS for BA) over the first 2 years' treatment in both groups. However C-PRGHD patients entered puberty and thus completed growth earlier than the IGHD group. As a result, cranially-irradiated children showed no change in height SDS with GH therapy, compared to catch-up growth in IGHD. Nevertheless, GH has enabled C-PRGHD patients to maintain their centile position and to achieve a more acceptable final height.Abbreviations GH growth hormone - IGHD idiopathic growth hormone deficiency - C-PRGHD post cranial-irradiation growth hormone deficiency - SDS standard deviation score - BA bone age - ALL acute lymphatic leukaemia - TSH thyroid stimulating hormone - CA chronological age - HA height age     

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.     

Growth hormone treatment in a child with Williams-Beuren syndrome: a case report

Growth retardation is a consistent finding in Williams-Beuren syndrome. The cause of short stature in this syndrome is unknown. Endocrine studies have failed to reveal abnormalities in the growth hormone – insulin-like growth factor I axis. We report a boy with confirmed Williams-Beuren syndrome, who was found to have classical growth hormone deficiency and responded well to growth hormone therapy. Conclusion Although growth hormone deficiency is not likely to be a common cause of short stature in Williams-Beuren syndrome, we nevertheless recommend evaluation of the growth hormone – insulin-like growth factor I axis in all cases. Received: 14 February 1998 / Accepted in revised form: 4 April 1998     

Transition of childhood-onset growth hormone-deficient patients to adult healthcare

In patients with childhood-onset growth hormone (GH) deficiency who have reached adult height, the transition from pediatric to adult healthcare is an appropriate time for reassessment of GH status. For patients in whom persistent GH deficiency (GHD) is established by appropriate testing, reinstitution of GH therapy or its continuation can improve quality of life, optimize body composition and bone mineral density, as well as reduce cardiovascular risks associated with GHD. Ongoing GH therapy should be individualized with attention paid to changes in serum insulin-like growth factor (IGF)-I concentrations, body composition, and occurrence of adverse effects such as edema and arthralgia. GH deficient patients who discontinue childhood GH replacement therapy and are not restarted as adults should undergo long-term surveillance to detect possible adverse consequences (e.g. reduced bone mineral density) typically associated with interruption of GH treatment.     

Is there a place for combined therapy with GnRH agonist plus growth hormone in improving final height in short statured children?

The availability of recombinant human growth hormone (GH) and the optimization of substitutive therapy have improved final growth in children with GH deficiency, but despite this some of them fail to grow to their genetic potential. In particular, this may occur in patients who started the substitutive therapy too late and/or in whom bone age progressed too fast during GH administration. In these patients, with unfavorable auxological characteristics, the administration of a GnRH agonist in combination with GH may slow down bone maturation and prolong prepubertal growth, mimicking, to some extent, the growth pattern of patients with GH + Gn deficiency who grow better than children with isolated GHD. A different condition in which such a combined therapy might be used is the short normal child. As they are short but normally-growing children, the onset of puberty is in general appropriate for their chronological age but precocious for their height age. Thus, slowing down pubertal maturation may increase the time available for growth. GH would sustain growth during both GnRHa administration and after its withdrawal, when puberty starts again. Our preliminary results suggest that the administration of GH + GnRHa in combination may have a positive effect on final height in selected children with isolated GHD and in short normal children.