PITUITARY DEFICIENCY FOLLOWING TRAUMATIC BRAIN INJURY IN EARLY CHILDHOOD: A REVIEW OF THE LITERATURE.

UNLABELLED: AIMS OF REVIEW: the intent of the current manuscript is to critically review the studies on pituitary gland dysfunction in early childhood following traumatic brain injury (TBI), in comparison with those in adults. Search of the literature: The MEDLINE database was accessed through PubMed in April 2015. Results were restricted to the past 15 years and English language of articles. Both transient and permanent hypopituitarisms are not uncommon after TBI. Early after the TBI, pituitary dysfunction/s differ than those occurring after few weeks and months. Growth hormone deficiency (GHD) and alterations in puberty are the most common. After the one to more years of TBI, pituitary dysfunction tends to improve in some patients but may deteriorate in others. GH deficiency as well as Hypogonadism and thyroid dysfunction are the most common permanent lesions. Many of the symptoms of these endocrine defects can pass unnoticed because of the psychomotor defects associated with the TBI like depression and apathy. Unfortunately pituitary dysfunction appear to negatively affect psycho-neuro-motor recovery as well as growth and pubertal development of children and adolescents after TBI. Therefore, the current review highlights the importance of closely following patients, especially children and adolescents for growth and other symptoms and signs suggestive of endocrine dysfunction. In addition, all should be screened serially for possible endocrine disturbances early after the TBI as well as few months to a year after the injury. Risk factors for pituitary dysfunction after TBI include relatively serious TBI (Glasgow Coma Scale score < 10 and MRI showing damage to the hypothalamic pituitary area), diffuse brain swelling and the occurrence of hypotensive and/or hypoxic episodes. IN CONCLUSION: There is a considerable risk of developing pituitary dysfunction after TBI in children and adolescents. These patients should be clinically followed and screened for these abnormalities according to an agreed protocol of investigations. Further multicenter and multidisciplinary prospective studies are required to explore in details the occurrence of permanent pituitary dysfunction after TBI in larger numbers of children with TBI. This requires considerable organisation and communication between many disciplines such as neurosurgery, neurology, endocrinology, rehabilitation and developmental paediatrics.

Clinical, biochemical and radiological manifestations of severe vitamin d deficiency in adolescents versus children: response to therapy.

OBJECTIVES: to compare clinical, biochemical and radiological manifestations of severe vitamin D deficiency (VDD - serum 25 OH - vitamin D level <10 ng/ml) in adolescents and children and to investigate the effects of an intramuscular injection (IM) of vitamin D3 megadose. DESIGN: in this prospective study 36 adolescents and 45 children with severe VDD were studied. An IM dose (10,000 IU/kg, max 600,000 IU) of cholecalciferol was injected and parameters of calcium homeostasis were measured at intervals of 3 months. RESULTS: at presentation, infants and young children (age 1.9 ± 0.5 years) with severe VDD had enlarged wrist joints (42/45), cranial bossing (39/45), wide anterior fontanel (27/45), Harrison's sulcus (11/45) , chest rosaries (27/45), bow legs (29/45), delayed teething (40/45), delayed motor milestones (36/45), short stature (length/height SDS <-2)(12/45), craniotabes (4/45) and hypocalcemic tetany ( 11/45). The most frequent biochemical abnormality was high alkaline phosphatase (ALP) (45/45), followed by low phosphate (PO4) (36/45) and low calcium (Ca) (8/45). Adolescents with severe VDD presented with pain in weight bearing joints, back, thighs, knees, and calves (30/36) difficulty walking and/or climbing stairs and/or running (8/36), muscle cramps and/or facial twitches and/or carpopedal spasms (2/36) and genu valgum (2/36). Biochemical serum abnormalities included high ALP (31/36), low phosphate (10/36) and low Ca (4/36). Variable radiological manifestations due to VDD were detected in all children (45/45) and in some of adolescents (19/35). Two different radiological patterns have been recognized in adolescents. Three months after injecting a mega dose of cholecalciferol all biochemical abnormalities were corrected with significant improvement of symptoms related to VDD had been reported in all children (45/45) and in the majority (33/36) of adolescents with VDD. 3-6 months after the injection, complete healing of the radiological evidence of VDD was achieved in all rachitic children and the majority of adolescents (16/19). CONCLUSION: it appears that adolescents adapt better to severe VDD compared to infants, with less severe clinical, biochemical and radiological manifestations. An IM mega dose of cholecalciferol is effective therapy for treatment of VDD in children and adolescents for 3 months but not for 6 months.;

International network on endocrine complications in thalassaemia (I-CET): an opportunity to grow.

Most of the endocrine complications in thalassaemia are attributable to iron overload which may be the result of economic circumstances (expense of the chelation therapy), late onset of chelation therapy or poor compliance with the iron chelation therapy. The major difficulties reported by hematologists or pediatric endocrinologists experienced in thalassaemias or thalassaemia syndromes in following growth disorders and endocrine complications were: lack of familiarity with medical treatment of endocrine complications (40%), interpretation of endocrine tests (30%), costs (65%), absence of paediatric endocrinologist for consultation on growth disorders and endocrine complications (27%), facilities (27%), other (e.g. lack of collaboration and on-time consultation between thalassaemic Centers supervised by hematologists and endocrinologists) (17%). Because any progress we make in research into growth disorders and endocrine complications in thalassaemia should be passed on to all those suffering from it, guaranteeing them the same therapeutic benefits and the same quality of life, on the 8th of May, 2009 in Ferrara (Italy), the International Network on Endocrine Complications in Thalassemia (I-CET) was founded. The I-CET group is planning to conduct, in Ferrara in May 2012, a workshop, "MRI and Endocrine Complications in Thalassaemia", and in Doha (Qatar) in September 2012, a 3-day intensive course entitled, "Growth disorders and Endocrine Complications in Thalassaemia", to provide interested pediatricians, physicians and hematologists from all over the world with an in-depth approach to the diagnosis and management of growth and endocrine disorders in thalassaemic patients.

Endocrine histology findings in a prepubertal thalassemic girl with multiple endocrine complications secondary to iron overload.

ß-thalassaemia major (TM) is an inherited disorder of erythropoiesis requiring regular blood transfusions and chelation therapy for the iron overload resulting from transfusions and increased gastrointestinal absorption. Endocrine dysfunctions are common in older children with TM and has been attributed to iron deposition in endocrine glands. The Authors report the clinical and histological findings of endocrine glands in a prepubertal girl with multiple endocrine complications secondary to iron overloadn died from cardiac failure. Variations in severity of the disease and therapeutic regimens may result in different incidence and types of complications It is emphasized the importance of chelating therapy to protect endocrine glands from haemosiderosis.

Spermatogenesis in young adult patients with beta-thalassaemia major long-term treated with desferrioxamine.

Since the introduction of hypertransfusion and intensive iron chelation therapy, patients with homozygous beta-thalassaemia major (TM) achieve adulthood. Many patients grow and develop normal hoping for marriage and to have a family. Therefore the question of fertility potential in this adult group of TM patients has become paramount. We report the semen parameters, the endocrine functions and serum zinc levels in 12 young adult TM patients. Their mean age was 24.8 years. Six patients (50%) had a normal sperm count, motility and morphology. While the remaining patients had oligospermia (sperm concentration <20 x 10(6)/ml) and/or asthenospermia (motility <40%). Basal serum gonadotrophins [LH and FSH], total and free testosterone and serum zinc did not differ significantly from those found in 13 normal adults with comparable testicular size. At the time of the study serum ferritin levels ranged from 240 to 3055 ng/ml (mean 1139 ng/ml). No correlations were found between semen parameters, serum total and free testosterone, plasma zinc, serum ferritin and seminal parameters. Nevertheless we observed that serum ferritin levels were lower (mean 543 ng/ml) in TM patients with abnormal seminal parameters (count and motility) compared to TM patients with normal seminal parameters (mean serum ferritin 1276 ng/ml; p<0.01). In conclusion, impairment of semen parameters may be a negative effect of intensive chelation therapy. Clearly, further investigations are required to evaluate if these adverse effects can be reduced or prevented, and if the existing spermatogenesis damage is reversible.

A rare cause of heart failure in iron-overload thalassaemic patients-primary hypoparathyroidism.

Hypocalcemia due to hypoparathyroidism (HPT) is a late complication of iron-overloaded patients with b-thalassaemia major (TM). The majority of patients have mild disease with parasthesias, while in the more severe form tetany, seizures or cardiac failure may occur. In the last 20 years we observed heart failure in 2 out of 38 (5.2%) TM patients (aged 18 and 22 years) with hypocalcemia secondary to HPT associated to iron overload. Calcium supplementation and vitamin D induced correction of hypocalcemia and resulted in an improvement of cardiac function. Calcium plays a key role in the maintenance and regulation of normal cardiac function. Extra-cellular calcium is indispensable for the contractile process since the sarcoplasmatic reticulum is unable to maintain a sufficient amount of calcium to trigger myocardial contraction. In conclusion, our observations stress the importance of a regular iron chelation therapy, adherence to treatment of endocrine complication and regular follow-up of TM patients with hypocalcemia.

Hyperparathyroidism.

Hyperparathyroidism is a disease characterized by hypercalcemia with hypophosphoremia resulting from increased secretion of parathyroid hormone (PTH). The disease may be divided into 3 forms: a) primary, b) secondary, c) tertiary (secondary refractory form). Primary hyperparathyroidism is rare in children; hyperplasia is more frequent during the early years of life (neonates and infants) and is difficult to distinguish from adenoma in children. The disease may be asymptomatic; elevated calcemia levels (>12 <13.5 mg/dl) are accompanied by anorexia, asthenia and persistent stipsis; severely elevated concentrations (>13.5 mg/dl) are accompanied by nausea, vomiting, polyuria due to osmosis, with dehydration and progressive onset of lethargy, stupor and coma. Osteopenia or osteitis fibrosa cystica may be present due to augmented bone resorption. Height and weight increases are altered due to anorexia and dehydration. Differential diagnosis includes iatrogenic causes of hypercalcemia (excessive vitamin D intake, prolonged immobilization, etc.) and idiopathic familial hypercalcemia. Emergency treatment is required in cases of extremely elevated hypercalcemia (Ca >13.5-14 mg/dl), due to risk of injury to the heart, the central nervous system, the gastrointestinal tract and the kidneys. The 4 cardinal points of treatment are: hydration, calciuresis, inhibition of bone calcium resorption, treatment of the cause underlying hyperparathyroidism. Secondary hyperparathyroidism is found in cases where chronic hypocalcemia is present, particularly in chronic renal failure, untreated deficiency rickets, chronic intestinal malabsorption, hepatobiliary disease, types I and II vitamin D-dependent rickets, tubular acidosis or Fanconi's syndrome. The tertiary form is distinguished by the autonomous nature of the parathyroid glands which have become hypertrophic/hyperplastic due to uncontrollable, chronic severe renal failure. It can also be of iatrogenic origin due to excessive intake of inorganic phosphates in familial hypophosphatemic rickets or chronic vitamin D deficiency.

Local recurrence in breast cancer after conservative surgery: timing of radiotherapy and sequencing of chemotherapy.

BACKGROUND: A randomized trial was conducted to determine (a) the role of radiotherapy and chemotherapy on local control and (b) to determine the timing of radiotherapy for early-stage breast cancer. MATERIALS AND METHODS: Five hundred and ninety patients were treated with both conservative surgery and radiotherapy (group A). The average time interval between surgery and radiation was 90 days for 452 patients and over 90 days for 138 patients. One hundred and ninety-four patients underwent adjuvant therapy based on CMF regimens (group B). RESULTS: Among 396 patients of group A, 8.1% had local failure; we observed 7.2% local recurrences in 363 patients who received therapy before 90 days and 18.2% in patients who received therapy after 90 days. Among patients of group B, 7.7% had local failure; for patients who underwent radiotherapy before 90 days, the local recurrence rate was 6.6%, compared with 12.3% for patients who underwent therapy more than 90 days after surgery. CONCLUSION: In patients who are eligible to receive chemotherapy, it is possible to administer radiotherapy after systemic treatment, while in patients who have to be treated with radiotherapy more then 90 days after breast surgery, chemotherapy can reduce the local failure rate.

Growth and puberty in thalassemia major.

Present transfusional regimen protocols increase the life expectancy of patients with beta-thalassemia major, but cause a progressive iron overload that can be prevented or limited only by appropriate iron chelation. Siderosis is responsible for the clinical complications of the disease. Short stature and hypogonadism are extremely frequent in patients with thalassemia. Many factors are responsible for short stature in patients with thalassemia, the most important of which are dysfunction of the GH-IGF-I axis and desferoxamine (DFX)-induced bone dysplasia. Hypogonadism is the most frequent endocrine complication, mostly due to gonadotrophins deficiency secondary to iron overload. Sex steroid treatment for induction of puberty and/or maintenance of sexual characteristics is necessary. Both short stature and hypogonadism are present in a significant percentage of bone marrow transplanted patients with thalassemia. Factors responsible for short stature are previous iron overload, liver impairment, DFX treatment, and toxicity of chemotherapeutic agents. In some patients absence of pubertal development is due to gonadotropin insufficiency, probably secondary to previous iron overload; other patients exhibit hypergonadotrophic hypogonadism due to the toxic effect of chemotherapeutic agents on the gonads. Both groups need hormonal replacement therapy. These data support the need for vigilant follow-up of patients with thalassemia before and after transplantation, in order to treat endocrine dysfunctions at the appropriate age.

Manganese water-soluble porphyrin senses DNA conformation.

We have determined the sites that are preferentially cleaved by Mn(T4MPyP) (where T4MPyP is the dianion of 5, 10, 15, 20, tetrakis (4-N-methylpyridine)porphyrin) on synthetic DNAs and on both intrinsically curved and average-shaped natural DNA sequences. On the basis of cleavage selectivity and of DNase I footprinting we show that the recognition specificity by this compound is based on steric properties: the preferred conformation is a DNA minor groove narrower than average and dimensionally defined. This conclusion is reached on the basis of: (i) the localization of the preferential cleavage sites at the 3' extremity of short A-tracts, known to undergo minor groove directional narrowing; (ii) the effects of temperature on cleavage specificity on curved sequences; (iii) the localization of cleavage sites in synthetic constructs whose crystal and solution structure was previously defined, and in programmed sequence variants thereoff; (iv) the effects of base substitutions on cleavage efficiency; (v) DNase I footprinting analysis. Several of these evidences argue against the possibility that Mn(T4MPyP)/DNA site selection occurs on the basis of electrostatic potential effects.Mn(T4MPyP) provides a tool for the analysis of DNA conformation whose selectivity is complementary to that of DNase I and hydroxyl radicals.

pQCT (quantitative peripheral tomography) and data evaluation of phosphocalcic metabolism in thalassaemic patients.

pQCT is a method which allows the separate determination of cortical and trabecular bone mineral density in the peripheral skeleton. 21 thalassaemic patients (8 females, 13 males) aged from 10 to 32 years, were examined using pQCT at the ultra distal radius to evaluate SSI (Stress-Strain Index). ALP, serum calcium, hydroxyproline, magnesium, IGF-I, and body surface were determined. The results show a good correlation between cortical BMD and age, concentration of hydroxyproline in urine, serum bone Gla protein, body surface index, bone density of trabecular bone and SSI. Good correlation was found between trabecular bone density and age, IGF-I, BGP and PTH, and between SSI and cortical BMD, age and BSI. The linear relationships between age and cortical and trabecular density show an increase of cortical BMD with age and a decrease of trabecular density with age. The same results were obtained considering trabecular and cortical density versus SSI.

Growth hormone secretion and bone histomorphometric study in thalassaemic patients with acquired skeletal dysplasia secondary to desferrioxamine.

An auxological and endocrinological study was performed in 21 thalassaemic patients with growth retardation and skeletal dysplasia secondary to desferrioxamine. Bone metaphyseal proximal tibial or iliac crest biopsy was performed in six patients with severe genu valgum or non-traumatic vertebral compression. GH insufficiency/deficiency (GH deficiency: peak after stimulation test below 6 ng/ml) was found in 72% of our thalassaemic patients with skeletal dysplasia, but in only 41% of patients without skeletal dysplasia. Bone histology showed abnormal chondrocytes, alteration of staining pattern of cartilage, irregular columnar cartilage and lacunae in the cartilaginous tissue. The behaviour of bone tissue was unpredictable (presence of thick or thin osteoid layer). Bone microfractures were sometimes present. The bone microstructure showed scarce mineralization, which was evenly or irregularly distributed. The bone tissue apatitic phase was quantitatively reduced. The hardness of bone tissue was remarkably lower than that of normal bone in three out of six patients. In conclusion, iron chelation therapy in patients with acquired skeletal dysplasia seems to interfere with GH secretion. The early identification of clinical and radiological abnormalities of skeletal dysplasia is of paramount importance in preventing severe bone destruction.

Short-term therapy with recombinant growth hormone in polytransfused thalassaemia major patients with growth deficiency.

Growth failure is commonly described in polytransfused thalassaemia major patients (Th) with or without growth hormone (GH) releasing hormone-GH axis impairment. We have investigated the efficacy of short-term recombinant GH (rhGH) therapy (Saizen [Serono] 0.1 IU/kg/day 6 evenings/week administered s.c. for 12 months) on growth and predicted final height in 28 (19M, 9F) regularly transfused Th with growth deficiency (aged 14.8 +/- 2.0 yr) on long term desferrioxamine s.c. therapy. All Th had no evidence of congestive heart failure, hypothyroidism or impaired glucose tolerance; in all patients the GH peak (evaluated during both insulin and clonidine test) was < or = 20 mIU/l; hypergonadotropic hypogonadism was excluded in Th with delayed puberty. At the start of therapy height age (HA)/bone age (BA) ratio was 0.92 +/- 0.12. Bone age delay was positively correlated to chronological age (CA), serum ferritin levels (mean of the last three years), the age at the start of chelation therapy, growth velocity calculated for CA during the last year; a positive correlation was also found between circulating IGF-I levels and age at the start of chelation therapy. After 1 year on rhGH therapy there was a significant increase of height calculated for CA (not for BA), of growth velocity calculated for both CA and BA and of circulating IGF-I levels; the HA variation/BA variation ratio was 1.85 +/- 1.71, without any significant difference between predicted final height at the start (-1.08 +/- 1.28 SDS) and at the end of rhGH therapy (-0.88 +/- 1.13). The variation of height calculated for CA was positively correlated to both CA and growth velocity during the last year before rhGH therapy (calculated for CA) and negatively to the height at the start (calculated for CA). There were no side effects and haematological parameters did not show significant changes. In conclusion, our data, obtained in a relatively large group of Th, confirm the emerging results of short-term (12 months) rhGH therapy on growth, as shown by the increase of both growth velocity and height calculated for CA. With regard to final height, although the mean variation of HA/variation of BA ratio was 1.85, no significant increase of the predicted final height was found between the start and the end of rhGH therapy. We are evaluating the effect of long-term rhGH therapy on growth in these patients.

Epidemiology and chelation therapy effects on glucose homeostasis in thalassaemic patients.

The incidence and prevalence of insulin-dependent diabetes mellitus (IDDM) and impaired glucose tolerance (IGT) were studied in a series of 273 patients with thalassaemia major followed in Ferrara from 1954 to 1998. It was found that the prevalence of glucose metabolism abnormalities has decreased and that the mean age of diagnosis has increased over the years. Risk factors associated with IDDM and IGT were lack of compliance with chelation therapy, iron overload and the presence of cirrhosis and severe fibrosis.

Final height and endocrine function in thalassaemia intermedia.

We present data of a detailed study of endocrine function in 50 patients (21 males, 29 females) with thalassaemia intermedia, 15-46 years old (mean age 28.7 yr), with raised serum ferritin levels (mean 1540 micrograms/l). Mean haemoglobin concentration was 8.1 g/dl. Half of them had had more than 50 transfusions in their life and had received irregular intramuscular or subcutaneous chelation therapy. Delayed puberty was one of the most frequent (36%) clinical endocrine abnormalities found in our patients. Primary amenorrhea was observed in two patients and secondary amenorrhea in four patients. Two males, aged 19 and 36 years, had hypogonadism. A poor response to GnRH, found in three females and in both males tested, suggested that pituitary dysfunction was wholly or partially responsible for hypogonadism. Gonadal function was normal in all patients studied. Glucose intolerance and primary hypothyroidism were less frequent (24 and 5.7%, respectively) and milder than in thalassaemia major patients. Two patients had low T3 and T4 and normal basal and stimulated response of TSH to TRH. This condition has been found in euthyroid sick syndrome and it is likely that it represents an adaptive response by the body to minimize catabolism when undergoing major stress. As a consequence, we believe that periodic endocrine evaluation should be carried out in subjects with beta-thalassaemia intermedia, particularly in those over 14 years old, in order to detect and to treat endocrine dysfunction.

Growth and development in thalassaemia major patients with severe bone lesions due to desferrioxamine.

UNLABELLED: Nine transfusion-dependent beta-thalassaemia major patients (seven males and two females), aged 4-15 years, with growth retardation and severe rickets-like radiological lesions due to continuous subcutaneous chelation therapy with desferrioxamine (45-75 mg/kg body weight, 6-7 time/week), were seen in our centre during the last 8 years. Serum ferritin levels ranged from 976 to 4115 micrograms/l. There was a progressive decline in growth velocity in these patients 2-3 years before the appearance of rickets-like radiological lesions. All patients underwent surgery to correct genu valgum and/or slipped capital epiphyses. The final height was below the 3rd percentile in six patients (SDS: from -2.9 to -5.2). The short stature was mainly due to a disproportion between upper and lower segments. Six of the patients had an associated sensorineural hearing loss. CONCLUSION: Our data emphasize the importance of an accurate surveillance of the toxic effects of desferrioxamine treatment and warn of the risk of overtreating patients with low iron overload and also suggest a possible individual idiosyncrasy to the adverse effects of chelation therapy.

High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin's lymphoma with partial response to front-line chemotherapy: a prospective randomized italian multicenter study.

PURPOSE: To evaluate, in a prospective multicentric study, the efficacy of a conventional salvage chemotherapy (dexamethasone, cisplatin, and cytarabine [DHAP]) versus high-dose chemotherapy (carmustine, etoposide, cytarabine, and cyclophosphamide [BEAC]) followed by autologous bone marrow transplantation (ABMT) in patients with aggressive non-Hodgkin's lymphoma (NHL) in clinical partial response (PR) after two thirds of a conventional front-line therapy. PATIENTS AND METHODS: From August 1988 to August 1991, 286 patients with aggressive NHL were randomized in seven Italian institutions to receive fluorouracil, methotrexate, cytarabine, cyclophosphamide, doxorubicin, vincristine, and prednisone (F-MACHOP) or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) as front-line therapy. Of the 286 patients enrolled onto the trial, 77 (27%) were considered in PR after two thirds of the front-line therapy, and 49 of 77 (64%) were randomized: 27 to receive DHAP chemotherapy and 22 to receive BEAC followed by ABMT. RESULTS: The response after second-line treatment was as follows: in the DHAP group, four patients (15%) achieved a complete remission (CR), 12 (44%) remained in stable PR, and 11 (41%) showed progressive disease; in the ABMT group, three patients (14%) obtained a CR, 18 (82%) obtained a stable PR, and one (4%) progressed, with an overall response (CR + stable PR) of 59% and 96% (P < .001) in the DHAP and ABMT groups, respectively. The overall survival was 59% versus 73% and the progression-free survival (PFS) was 52% versus 73% in the DHAP and ABMT groups, respectively (P, not significant). The toxicity was mild, particularly in the ABMT group, and no treatment-related deaths occurred in either group. CONCLUSION: Because of the small number of patients randomized, we were unable to determine whether ABMT or a standard salvage regimen (DHAP) is superior for PR patients. However, we confirmed that myeloablative treatment is a safe and well-tolerated procedure in this category of patients and this may enable us to evaluate its role as part of a front-line treatment in poor-risk NHL patients.

Effect of different treatment regimes on linear growth and final height in beta-thalassaemia major.

OBJECTIVE: The clinical picture of thalassaemia major has changed progressively over the years. Our study is a retrospective analysis of data on growth in a group of patients who have completed puberty spontaneously and have attained their adult height. Our objective was to evaluate the effect of different transfusion regimes and desferrioxamine administration on the growth pattern in beta-thalassaemia major. DESIGN AND PATIENTS: We studied 64 patients (28 males and 36 females). The patients were divided into three groups (A, B and C) according to the different transfusion regimes and the schedules of chelating therapy. Group A consisted of 16 patients who were transfused regularly at low haemoglobin levels (on average 8.5 g/dl) from an early age and started subcutaneous chelation therapy during adolescence. Group B consisted of 19 patients who were transfused regularly at high haemoglobin levels (on average 10 g/dl) from an early age and started subcutaneous therapy during childhood. Group C consisted of 29 patients who were transfused regularly at high haemoglobin levels (on average 10.5 g/dl) from an early age and started subcutaneous chelation therapy very early, at a mean age of 2 years. Standard auxological measurements were made at 3-monthly intervals throughout childhood and puberty until adult height was achieved. For group C patients the data on linear growth are provided only until the age of 12 years. RESULTS: Our study indicates that group A male and female patients did not grow significantly better than those in group B. Group C male and female patients, surprisingly, grew no faster than those who started chelation therapy late in childhood (group A). The most striking feature in the majority of both group A and B patients was reduced spurt in height at puberty. In addition, in both groups, a reduced sitting height due to spinal growth abnormality was found. An inverse correlation between sitting height and serum ferritin levels was observed in group A patients (r = -0.55, P < 0.05), whereas there was a direct correlation in group B patients (r = 0.42, P < 0.05). CONCLUSIONS: These data suggest that an ideal therapeutic regime has yet to be found which avoids the toxic effect of iron overload and on the other hand avoids interference with growth, secondary to desferrioxamine. Therefore we recommend that the growth of thalassaemia patients be monitored routinely at every follow-up visit and documented on growth velocity charts in order to detect early changes in their growth pattern and to establish an appropriate protocol for investigation and treatment.

Impaired response of free alpha-subunits after luteinizing hormone-releasing hormone and thyrotropin-releasing hormone stimulations in beta-thalassemia major.

In order to clarify whether the damage in gonadotropin secretion due to iron overload in patients with beta-thalassemia is of pituitary or hypothalamic origin, 14 euthyroid patients (8 females and 6 males, age 15-24 years) affected by beta-thalassemia major with hypogonadotropic hypogonadism were studied. Luteinizing-hormone (LH), follicle-stimulating hormone (FSH) and free alpha-subunit (FAS) were measured during LH-releasing hormone (LH-RH) stimulation test, and thyroid-stimulating hormone (TSH), prolactin (PRL) and FAS during thyrotropin-releasing hormone (TRH) stimulation test. During LH-RH stimulation, the mean basal LH, FSH and FAS levels were similar to those found in normal prepubertal children, but the peak values were lower than those found in such children. Also during TRH stimulation, the mean peak values of FAS were lower than those of normal prepubertal children, but the TSH response was normal. The lack of response of gonadotropins and FAS to LH-RH cannot exclude hypothalamic failure; however, the normal response of TSH to TRH, in spite of the poor response of FAS, indicates that the origin of hypogonadotropic hypogonadism is the pituitary damage concerning not only the gonadotroph but also the thyrotroph cells.