Growth hormone deficiency associated with methylmalonic acidemia.

Poor growth is a common finding in patients with organic acidemias. Growth hormone (GH) therapy has been considered in the management of these disorders as a mode to enhance anabolism and lower the high levels of methylmalonic acid. We report two patients with methylmalonic acidemia (mut(o)) and GH deficiency. Both patients had persistently elevated serum concentrations of methylmalonic acid, which failed to respond to conventional therapy. In anticipation of using GH therapy to reduce high methylmalonic acid concentrations, the first patient underwent GH testing utilizing a provocative glucagon stimulation test and was found to be deficient. He was subsequently treated with GH and demonstrated improved growth, but his methylmalonic acid concentrations remain elevated. The second patient was also found to be GH deficient. These findings suggest that GH deficiency may be an etiologic factor in the poor growth seen in patients with organic acidemia.

Advances in the recognition and treatment of endocrine complications in children with chronic illness.

Children with chronic illness live with the specific consequences of their illness, as well as secondary endocrine abnormalities that further compromise growth and pubertal development. These secondary abnormalities may significantly add to their physiologic and psychological burden. Although these endocrine abnormalities theoretically arise as adaptations to the chronic illness, they may have deleterious effects if they persist untreated. Children with HIV infection and other wasting disorders, for example, show growth suppression out of proportion to the severity of their primary illness as a result of growth hormone resistance and enhanced cortisol secretion. In hematologic conditions such as sickle cell anemia, thalassemia, or bone marrow transplant, damage to the hypothalamus and/or pituitary may lead to growth hormone deficiency, gonadal insufficiency, and hypothyroidism. Growth and pubertal delay are also common among children with cystic fibrosis, along with insulin-dependent diabetes mellitus caused by pancreatic fibrosis. Similarly, children receiving long-term steroid therapy have delays in growth and pubertal development, accompanied by risk for osteoporosis, whereas chronic renal disease is associated with growth and pubertal delay, as well as secondary hyperparathyroidism. Recognition of potential endocrinopathies in children with chronic illness is an important aspect of the care of these children because the disturbances are frequently amenable to treatment, permitting full or partial restoration of normal growth and development in these children. In this chapter, the endocrine consequences of common chronic conditions of childhood are reviewed, as well as the etiology of the endocrine disturbance, the clinical consequences, and recommendations for treatment.

Studies of 3 beta-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated delta 5-steroid levels.

Classic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) deficiency congenital adrenal hyperplasia (CAH) results from a mutation in the type II 3 beta HSD gene encoding adrenal and gonadal 3 beta HSD. We investigated the type II and type I 3 beta HSD gene sequences in 15 infants and children with premature pubarche (PP; mean/range of age at PP, 4/0.08-9 yr) and elevated ACTH-stimulated delta 5 precursor steroid levels. Compared to Tanner I control subjects of similar age, ACTH-stimulated hormonal levels were at 2.3-10.7 SD for 17-hydroxypregnenolone (delta 5-17P) in all PP subjects, at 2.2-17 SD for dehydroepi-androsterone (DHEA) and 2.4-5.6 SD for the delta 5-17P/cortisol (F) ratio in all PP subjects except 1 infant, and at 2.3-10 SD for the DHEA/ androstenedione (delta 5-A) ratio in 8 PP subjects. Compared to Tanner II normal children, the hormonal levels were at 3-8 SD for delta 5-17P in all 13 PP children, at 2.3-4.7 SD for the delta 5-17P/F ratio in 6 PP children, and at 2.3-6.5 SD for DHEA and 3.5-9 SD for the DHEA/delta 4-A ratio in 7 PP children. Type II 3 beta HSD gene sequences, including regions of a putative promoter, all exons (I, II, III, and IV), and exon-intron boundaries, were normal in all subjects. Sequences of the type I 3 beta HSD gene encoding extraadrenal and extragonadal 3 beta HSD were normal in the 6 patients tested. The ACTH-stimulated delta 5-17P levels and delta 5-17P/F ratios in the PP children without type II 3 beta HSD gene mutation were exceedingly lower than the respective reported hormonal data for children with 3 beta HSD deficiency CAH with proven type II 3 beta HSD gene mutation. The ACTH-stimulated DHEA levels and DHEA/delta 4-A ratios were not exceedingly different between the children with and without type II 3 beta HSD gene mutation. These findings suggest that the degree of ACTH-stimulated delta 5 precursor steroid abnormality, such as delta 5-17P levels up to 10 SD above the normal mean level found in our PP patients, is not caused by a mild variant of 3 beta HSD deficiency CAH resulting from type II or type I 3 beta HSD gene mutation. The hormonal criterion for ACTH-stimulated delta 5-17P levels in patients with mild variant 3 beta HSD deficiency, therefore, is predicted to be higher than 10 SD above the normal mean value.

Advances in the treatment of precocious puberty.

The development of immunoassay techniques for accurately measuring serum gonadotropins and gonadal steroids allows distinction between central (GnRH-dependent) and peripheral (GnRH-independent) precocious puberty in children. Previously (see case 3) it was not possible to do this, and a rational approach to therapy could not be designed. Significant advances in the synthesis of superagonists of gonadotropin-releasing hormone have allowed effective treatment for children with CPP. Such treatment has only been possible for the past 10 to 15 years, and GnRHa have been approved for use in the United States for this indication only since 1992. Long-term studies are still needed to determine what effect, if any, such treatment has on fertility, because only a few patients, even from the earliest studies, have reached child-bearing age. All indications, however, suggest that treatment with GnRHa is reversible, as well as safe and efficacious. More challenging is the effective treatment of PPP, for which innovative approaches involving inhibition of gonadal steroid synthesis or action have met with some success. Again, long-term studies or efficacy and safety are needed.

Mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene in a patient with classic salt-wasting 3 beta-hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia.

Inherited adrenal and gonadal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is most likely caused by a mutation of the type II 3 beta-HSD gene. Cloning and sequencing of exons I-II, III, and IV and portions of the adjacent introns, amplified by polymerase chain reaction using primers specific for the type II gene, in one male pseudohermaphrodite with salt-wasting classic 3 beta-HSD deficiency congenital adrenal hyperplasia revealed the same mutation in all nine clones of exon IV consisting of a missense mutation at codon 248 [GTC(Val)-->AAC(Asn)] followed by a frameshift mutation at codon 249 [CGA (Arg)-->TA], resulting in a stop codon TAG, and normal sequences of exon I-II and III and the adjacent portions of introns. The same codon 248 and 249 mutations were found on one clone of his mother's DNA, but two other clones revealed normal sequences. These data indicate a homozygous combined missense/frameshift mutation in exon IV of the type II 3 beta-HSD gene resulting in severe salt-wasting adrenal and gonadal 3 beta-HSD deficiency in the patient.

Developing therapeutic relationships in multicultural settings.

The expertise of native peoples as well as resources drawn from humanities, education, and arts organizations in Arizona contributed to an educational program to heighten the cultural sensitivity of health care professionals at the Children's Health Center of St. Joseph's Hospital. The sentiment expressed by Kraut that "respect for the cultural preferences and taboos of more traditional medical systems thus renders American physicians more effective and in the long run more efficient" is supported by our experience with this program.

Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment of children with central precocious puberty.

OBJECTIVE: To assess the efficacy and safety of a long-acting gonadotropin-releasing hormone analogue (GnRHa), leuprolide acetate for depot suspension (Lupron Depot), in the treatment of central precocious puberty in children, and to determine the reversibility of GnRHa therapy after it has been discontinued. RESEARCH DESIGN: Children with documented central precocious puberty were treated with Lupron Depot for 1.6 to 3.5 years. Their course of pubertal development, growth rate, skeletal maturation, and response to gonadorelin hydrochloride testing were compared before and during treatment. For those girls who finished treatment, an assessment of the reversibility of the GnRHa was performed by documenting a return to pubertal responses to gonadorelin testing, and by documenting menarche at an appropriately mature bone age. SETTING: Community teaching hospital. PATIENTS: Ten girls with central precocious puberty defined as pubertal maturation statistically advanced for age combined with a pubertal gonadotropin response to gonadorelin testing. Children who had been treated for less than 1.5 years were excluded, as were those with congenital adrenal hyperplasia. Patients who finished treatment have been followed up for up to 5 years, and will continue in follow-up throughout their reproductive life. SELECTION SAMPLE: A consecutive group of children with documented central precocious puberty was studied. INTERVENTIONS: Lupron Depot was administered as a single monthly subcutaneous injection to each patient. Treatment was usually discontinued by 10 to 11 years of age, at which time pubertal progression was allowed to resume. MEASUREMENT AND RESULTS: Mean peak serum concentrations of follicle-stimulating and luteinizing hormone responses to gonadorelin testing decreased significantly after the initial dose (from 21.8 +/- 4.5 [+/- SEM] to 2.4 +/- 0.2 IU/L for follicle-stimulating hormone and from 50.1 +/- 11.2 to 5.0 +/- 0.8 IU/L for luteinizing hormone) and remained suppressed for the duration of treatment. The progression of puberty slowed or reversed in all patients. Mean growth rate for chronologic age was significantly increased initially by 3.9 SDs and decreased to 0.9 SDs during treatment. The mean rates of skeletal maturation divided by the change in chronologic and height age changes over time were advanced (1.4 +/- 0.1 and 1.1 +/- 0.15, respectively) at the onset of therapy and decreased significantly to 0.7 +/- 0.1 and 0.8 +/- 0.1, respectively, on treatment. There was an increase in mean predicted height of 3.4 cm for all patients, and this was statistically significant. Thus, treatment with Lupron Depot at least maintained the predicted height at the onset of therapy. Girls who completed their course of treatment had pubertal gonadotropin responses to gonadorelin testing within 2 to 6 months, and menarche within the first year if skeletal maturation reached 13.0 to 13.5 years. No significant side effects of therapy were noted. CONCLUSIONS: Treatment of central precocious puberty in children using Lupron Depot is safe and efficacious. Its effects are readily reversible after treatment is discontinued, and menarche occurs at a normal bone age. Measurement of serum luteinizing hormone concentrations using an assay that is specific for the beta-subunit is necessary to monitor chemical suppression of luteinizing hormone during treatment. Longer-term studies, including reproductive history, will be needed before the potential effects of treatment on fertility can be assessed.

Cerebral salt wasting in children. The need for recognition and treatment.

OBJECTIVES: To describe a salt-wasting syndrome in children with central nervous system (CNS) insults and to differentiate it from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and diabetes insipidus so that it may be more readily diagnosed and treated. DESIGN: Case reports. SETTING: Community teaching hospital. PATIENTS: Two inpatients with CNS insults (closed head trauma in one and seizure disorder, spastic diplegia, mental retardation, and hydrocephalus in the other). SELECTION CRITERIA: Evidence of hyponatremia accompanied by elevated urine sodium concentration and excessive urine output. INTERVENTIONS: Volume-for-volume urine replacement with 0.9% and/or 3% sodium chloride. Oral salt supplementation was required for brief periods to maintain normal plasma sodium concentration after discharge from the hospital. MEASUREMENTS AND MAIN RESULTS: Both patients had hyponatremia, high urine sodium concentrations, hypovolemia, and excessive urine output while receiving maintenance fluids. They also had elevated plasma atrial natriuretic hormone (ANH) concentrations, decreased aldosterone concentrations, and decreased [corrected] plasma renin activity for their degree of hyponatremia and negative fluid balance. Both patients maintained normal serum electrolyte concentrations with appropriate treatment. CONCLUSIONS: These patients showed true salt wasting associated with acute or chronic CNS injury, with hormonal patterns consistent with "inappropriate" ANH secretion and distinct from the SIADH. It is important to distinguish cerebral salt wasting (CSW) from the two other major disturbances of water metabolism seen following CNS injury (ie, SIADH and diabetes insipidus), because incorrect diagnosis and treatment could greatly increase morbidity in CSW. The etiologic roles of ANH or brain natriuretic peptide in CSW need to be further elucidated.

Diabetes in pregnancy: rationale and guidelines for care.

The management of pregnancy in a woman with diabetes is directed toward insuring a normal outcome for the mother and her newborn baby. There is ample evidence from studies in both humans and animals that maintenance of a normal maternal metabolic environment, particularly blood glucose concentrations, can avoid or ameliorate the complications of pregnancy responsible for increased morbidity and mortality in the mother and her baby. It is essential that this metabolic normalcy be achieved preconceptionally if congenital malformations, the leading cause of death in IDMs, are to be avoided. Thus, preconceptional care, intensive regulation of maternal glucose metabolism and fetal surveillance throughout pregnancy are critical. The use of the multidisciplinary team to optimize care has led to significant reductions in maternal and perinatal morbidity/mortality in IDMs, and is thus essential to successful outcomes in pregnancies complicated by diabetes.

Suppression of gonadotropin secretion by a long-acting gonadotropin-releasing hormone analog (leuprolide acetate, Lupron Depot) in children with precocious puberty.

The GnRH analog leuprolide acetate has been shown to be effective in the treatment of precocious puberty when given as a daily sc injection. We studied the effectiveness of a single im dose of a new depot form of leuprolide in suppressing estradiol and gonadotropin secretion in children with precocity. Five girls with previously untreated precocity showed significant decreases in basal serum estradiol and FSH levels and in peak LH levels (after GnRH testing) 30 days after a single im dose of leuprolide acetate for depot suspension. Mean peak FSH levels also fell greatly, but the difference was not significant. No adverse effects were noted during the first 4-6 months of monthly im injections. Depot im leuprolide appears to be effective in suppressing estradiol and gonadotropin secretion, and may be a useful method of treating children with central precocious puberty.

Efficacy of leuprolide therapy in children with central precocious puberty.

Eight girls with central precocious puberty were treated with the long-acting gonadotropin releasing hormone analogue leuprolide acetate (Lupron) for a period of six to 18 months. Suppression of gonadotropin and estradiol secretion and regression of secondary sexual characteristics and menses were observed while patients received a subcutaneous dose of 35 to 40 micrograms/kg/d. Growth velocity was slowed in all but one patient, and the rate of skeletal maturation was slowed even more, resulting in a stabilization or improvement in predicted adult height. There were no major side effects. Although the long-term effects of leuprolide therapy cannot be determined with this study, it appears to be efficacious in the treatment of central precocious puberty.