Rethinking fatigue in Gaucher disease.

BACKGROUND: Gaucher disease (GD) is a rare lysosomal storage disease caused by deficiency in the enzyme beta-glucocerebrosidase. Along with visceral, hematologic, and bone manifestations, patients may experience chronic fatigue resulting in functional disability and reduced quality of life. Management of the disease includes therapeutic intervention, supportive therapies, and regular monitoring of all clinically relevant disease signs and symptoms. However, current practice guidelines do not include measurement of fatigue or therapeutic goals for fatigue. OBJECTIVE: To provide insight regarding key considerations for fatigue in GD. METHODS: We conducted a systematic PubMed literature search and an exploratory, hypothesis-generating survey regarding fatigue in GD. RESULTS: Our literature search resulted in 19 publications. Of these, 6 were identified that assessed fatigue, including 2 that used specific fatigue assessment instruments. In our survey involving 14 patients with Type 1 GD and 19 physicians, patients ascribed greater importance to fatigue than other disease parameters, while physicians placed more emphasis on objective measures of visceral and hematologic disease manifestations. CONCLUSIONS: Collectively, the results of our literature analysis and survey underscore the need for further investigation and in-office evaluation of fatigue in patients with GD, which will require a reliable, validated, and disease-specific instrument. Criteria for clinically significant fatigue in patients with GD should be established along with the development of a fatigue scale specifically designed for this patient population to provide a more objective means to potentially incorporate fatigue assessment into routine monitoring practices.

Autosomal dominant growth hormone (GH) deficiency type II: the Del32-71-GH deletion mutant suppresses secretion of wild-type GH.

Familial isolated GH deficiency type II is an autosomal dominant form of short stature, associated in some families with mutations that result in missplicing to produce del32-71-GH, a protein that cannot fold normally. The mechanism by which this mutant suppresses the secretion of wild-type GH encoded by the normal allele is not known. Coexpression of del32-71-GH with wild-type human GH in transient transfections of the neuroendocrine cell lines GH4C1 and AtT20 suppressed accumulation of wild-type GH. The suppression of wild-type GH accumulation by del32-71-GH was a posttranslational effect on wild-type GH caused by decreased stability, rather than decreased synthesis, of wild-type GH. Coexpression of del32-71-GH with human PRL did not suppress accumulation of PRL, indicating that there was not a general suppression of secretory pathway function. Accumulation of del32-71-GH protein was not necessary for the suppression of wild-type GH, because del32-71-GH did not accumulate in the neuroendocrine cell lines in which suppression of accumulation of wild-type GH was observed. Del32-71-GH did accumulate in transfected COS and CHO cells, but did not suppress the accumulation of wild-type GH in these cells. These studies suggest that del32-71-GH may cause GH deficiency in somatotropes of heterozygotes expressing both wild-type and del32-71-GH by decreasing the intracellular stability of wild-type GH.

Heritable disorders of pituitary development.

Basic and translational research achievements over the past 2 decades have disclosed the molecular mechanisms underlying several genetic forms of hypopituitarism. Disorders that are limited to the hypothalamic, pituitary, GH axis are caused by mutations in individual components of that axis. Disorders involving GH and one or more additional pituitary hormones are caused by mutations in the homeodomain transcription factors that direct embryological development of the anterior pituitary gland. Pit-1 has a POU-specific and a POU-homeo DNA-binding domain. The phenotype produced by mutations in the PIT1 gene involves deficiencies of GH, PRL, and TSH. Pituitary glands are either small or normally sized. The PROP1 gene encodes a transcription factor with a single paired-like DNA-binding domain. Persons with inactivating mutations in PROP1 have deficiencies of LH and FSH, as well as GH, PRL, and TSH. Their pituitary glands may be small, normally sized, or extremely large and show suprasellar extension. Pituitary degeneration may produce acquired deficiency of ACTH. Expression of the HESX1 gene precedes expression of PROP1 and PIT1, and it is much more widespread. The protein has a paired-like domain, and it competes with the product of PROP1 for DNA-binding. Homozygosity for inactivating mutations of HESX1 produces a complex phenotype that resembles septo-optic dysplasia. Much more needs to be learned about the role of HESX1 mutations in other forms of hypopituitarism.

Congenital hypopituitarism as a cause of undetectable estriol levels in the maternal triple-marker screen.

We are reporting a child with congenital panhypopituitarism, in whom deficient fetal steroidogenesis was suspected prenatally because of undetectable estriol levels measured in the maternal triple-marker screen. No fetal abnormalities were detected by ultrasonography. Amniocentesis demonstrated a normal 46,XX karyotype. Measurement of maternal urinary steroids failed to show elevation in the excretion of the major precursor for estriol, 16 alpha-hydroxydehydroepiandrosterone, indicating that the fetus did not have steroid sulfatase deficiency (placental sulfatase deficiency), the most common genetic cause of extremely low estriol. The steroid analysis excluded other rare single gene defects, including aromatase deficiency and 17 alpha-hydroxylase deficiency. We therefore suspected that the cause of low estriol in this fetus was adrenal insufficiency. Postnatal evaluation was consistent with panhypopituitarism, characterized by deficiency of all anterior pituitary hormones. Because this screen is now offered to more than half the pregnant women in the United States, reports of low estriol levels have become increasingly common. Therefore, it is essential that physicians be familiar with the various etiologies, perform the appropriate antenatal evaluation to determine the specific cause, and closely monitor both mother and child ante- and postnatally.

A four-year, open-label, multi-center, randomized, two-arm study of Genotropin® in patients with idiopathic short stature: comparison of an individualized, target-driven treatment regimen to standard dosing of Genotropin® - analysis of two-year data.

BACKGROUND: Several models have been developed to predict growth response to growth hormone (GH) based on auxological and biochemical parameters for children with non-GH-deficient, idiopathic short stature (ISS). OBJECTIVE: To demonstrate if an individualized, formula-based, target-driven GH regimen for children with ISS would lead to a height (Ht) gain to -1.3 SDS during the first 24 months of treatment of this 4-year study, with less variability than with standard weight-based dosing. METHODS: A 4-year, open-label, multi-center, randomized, two-arm study comparing formula-based dosing of Genotropin® GH from 0.18 to 0.7 mg/kg/week versus standard FDA-approved ISS dosing of Genotropin® (0.37 mg/kg/week). Subjects (n = 316, 89 females) were prepubertal, 3-14 years of age, bone age 3-10 years (m) and 3-9 years (f), naive to GH treatment, Ht SDS -3 to -2.25, Ht velocity <25th percentile for bone age, and peak GH >10 ng/ml. RESULTS: The majority (83%) of subjects had Ht SDS within the normal range by 2 years. All subjects displayed catch-up growth consistent with other studies of GH treatment of ISS. CONCLUSION: The formula-based therapy did not meet the primary endpoint achieving targeted gain with lower variability. No new safety concerns were found.

Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis.

BACKGROUND: Recently, growth hormone (GH) therapy for children with short stature born small for gestational age (SGA) has been approved in the USA and Europe. There have been few reports examining adverse events during GH treatment of these children. AIMS: (i) To examine glucose tolerance and insulin sensitivity during GH treatment of children born SGA in a US trial. (ii) To determine and compare adverse events reported in children born SGA with those reported in children with idiopathic short stature (ISS) enrolled in KIGS - Pfizer International Growth Database. METHODS: In the US SGA trial, an oral glucose tolerance test was performed and fasting plasma glucose, insulin and glycosylated haemoglobin (HbA(1C)) concentrations were measured at baseline and after 12 months of GH therapy. Insulin sensitivity was calculated using the homeostasis model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI). In the KIGS analysis, a retrospective audit of spontaneously logged cumulative adverse events in children born SGA and those with ISS was undertaken. Adverse events are reported per 1,000 patients. Values are expressed as mean with 10th-90th percentiles. RESULTS: In the US trial, 84 patients had complete data sets for analysis. Median birth weight was 1.78 kg (SDS, -2.5) and birth length 43 cm (SDS, -2.2) at a median gestational age of 36.5 weeks; 79% were Caucasian. At entry, median age of the patients analysed was 6.6 years, and 65% were male. Median height was 104.3 cm (SDS, -2.97), median weight 15.95 kg (SDS, -2.21) and body mass index 14.66 kg/m(2) (SDS, -0.67). No patients developed impaired glucose tolerance or overt diabetes mellitus. The 0-min glucose concentration was 81 mg/dl at baseline and 86 mg/dl at 1 year, while the 120-min glucose concentration was 90 mg/dl at baseline and 96 mg/dl at 1 year. The 0-min insulin concentrations were 2.9 mU/l at baseline and 5.3 mU/l at 1 year, while the 120-min insulin levels were 7.7 mU/l at baseline and 11 mU/l at 1 year. The proportions of HbA(1C) were 5.2 and 5.4% at baseline and 1 year, respectively. HOMA and QUICKI values were 0.59 and 0.42, respectively, at baseline, and 1.13 and 0.38 at 1 year. In KIGS, there were 1909 children born SGA aged 9.1 (3.9-13.3) years with a birth weight SDS of -2.6 (-4.0 to -1.5), birth length SDS of -2.7 (-4.3 to -1.3) and height SDS of -2.71 (-3.9 to -1.8) prior to treatment. GH doses ranged from 0.032 to 0.037 in the USA and from 0.022 to 0.023 mg/kg/day in the remaining countries in KIGS. Neither total (187 vs. 183) nor serious (14 vs. 10) adverse events occurred more commonly in the SGA group than in the ISS group. Although respiratory adverse events occurred more commonly in children born SGA (34.3 vs. 16.8; p < 0.05), endocrine (12.0 vs. 2.7; p < 0.05) and hepatobiliary (6.2 vs. 1.1; p < 0.05) adverse events occurred more commonly in children with ISS. CONCLUSIONS: As expected, a reduction in insulin sensitivity occurred during GH treatment of children born SGA; however, glucose tolerance remained normal. No adverse events were reported more commonly in children born SGA than in those with ISS. Minor differences in adverse events reporting within organ systems between children born SGA and those with ISS are probably due to variable under-reporting of adverse events. GH appears to be a safe drug to use at current doses as a growth-promoting agent in short children born SGA.

Genetic defects in the control of growth hormone secretion.

Since growth hormone deficiency (GHD) causes short stature and metabolic derangements, the processes which control its release are important physiologically. These processes can be illuminated by an understanding of genetically determined GHD. In 2 Indian Moslem cousins from a consanguineous family, GHD resistant to growth hormone releasing hormone (GHRH) stimulation was found. No mutations were found in the growth hormone gene (GH1) (J. Phillips). The receptor for GHRH (GHRHR), implicated in the dwarfism of the little mouse, thus becomes a candidate gene to explain their GHD. Amplification and sequencing a region of GHRHR homologous to that mutated in the little mouse showed a mutation (265G*T) leading to a stop codon at position 72 which would completely prevent GHRHR expression. Subsequently, Maheshwari et al. found an identical mutation in a multiplex kindred from Sindh, Pakistan, about 800 km from the place of origin of our patients. GHD is more commonly caused by recessive or dominant mutations of GH1. The latter are of great interest in understanding the mechanism of GH secretion. In a large kindred with dominant GHD we found a heterozygous 666G*A mutation replacing of Arg with His at amino acid 183. We speculate that the introduced histidine interferes with interactions necessary for correct GH secretion.

Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry.

OBJECTIVES: 1) To determine the extent of short stature in patients with Fanconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group. STUDY DESIGN: Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Research Center. The patients ranged in age from 0.1-31.9 years, with the mean age at assessment 8.6 years. RESULTS: Endocrine abnormalities were found in 44 of the 54 FA patients tested (81%), including short stature, growth hormone (GH) insufficiency, hypothyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mellitus. Twenty-one of 48 (44%) participants had a subnormal response to GH stimulation; 19 of 53 (36%) had overt or compensated hypothyroidism, while 8 of 40 participants had reduced thyroid-hormone binding. Two patients were diabetic at the time of study; impaired glucose tolerance was found in 8 of 40 patients (25%), but most surprisingly, hyperinsulinemia was present in 28 of 39 (72%) participants tested. Significantly, spontaneous overnight GH secretion was abnormal in all patients tested (n = 13). In addition, participants demonstrated a tendency toward primary hypothyroidism with serum tetraiodothyronine levels at the lower range of normal, while also having thyrotropin (thyroid-stimulating hormone) levels at the high end of normal. Sixteen patients were assigned to FA complementation group A, (FA-A), 12 to FA-C, and 5 to FA-G; 10 of the 12 participants in FA-C were homozygous for a mutation in the intron-4 donor splice site of the FANCC gene. Patients in groups FA-A and FA-G were relatively taller than the group as a whole (but still below the mean for the general population), whereas those in FA-C had a significantly reduced height for age. GH response to stimulation testing was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was more pronounced in participants belonging to complementation groups FA-C and FA-G, whereas insulin resistance was most evident in patients in FA-G, and least evident in those in FA-C. Short stature was a very common finding among the patients with a mean height >2 standard deviations below the reference mean (standard deviation score: -2.35 +/- 0.28). Patients with subnormal GH response and those with overt or compensated hypothyroidism were shorter than the group with no endocrinopathies. The heights of those participants with glucose or insulin abnormalities were less severely affected than those of normoglycemic, normoinsulinemic participants, although all were significantly below the normal mean. The mean height standard deviation score of patients with entirely normal endocrine function was also >2 standard deviations below the normal mean, demonstrating that short stature is an inherent feature of FA. CONCLUSION: Endocrinopathies are a common feature of FA, primarily manifesting as glucose/insulin abnormalities, GH insufficiency, and hypothyroidism. Although short stature is a well-recognized feature of FA, 23 patients (43%) were within 2 standard deviations, and 5 of these (9% of the total) were actually above the mean for height for the general population. Those patients with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that superimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth.