Beyond the bias! Sex distribution in paediatric growth hormone deficiency reexamined.

OBJECTIVES: Various biases pertaining to stature account for a male sex predominance in growth hormone deficiency (GHD) cases diagnosed by endocrinology clinics. This manuscript will assess the sex distribution when biases are minimised. METHODS: Retrospective chart review was conducted on patients diagnosed with GHD between 3 and 16 years of age. The sex distribution of cases was ascertained according to: (1) peak GH (pGH) by groups; based on growth hormone provocative testing, (2) pituitary gland imaging results, and (3) isolated GHD (IGHD) versus multiple pituitary hormone deficiencies (MPHD). The relative frequency of each sex was compared according to these subgroups with significance evaluated at α = .05 level. RESULTS: Of the 5880 clinic referrals for short stature, there were 3709 boys (63%) and 2171 girls (37%). Of these, 20% of boys (n = 745) and 15.3% of girls (n = 332) underwent provocative testing for GHD. Of those tested, 39.2% of boys (n = 292) and 32.2% of girls (n = 107) were diagnosed with GHD, all p < .001. There was a male predominance in GHD cases based on pGH or GHD severity. Though not significant, girls were more likely than boys to have MPHD (p = .056), even across pGH groups (p = .06). Both boys and girls had a similar distribution of imaging abnormalities. CONCLUSION: Stratifying by sex, we found similar percentages of pituitary imaging abnormalities (including tumours) and the number of pituitary hormone deficiencies in boys and girls as the cause of GHD. For these classifications, we did not find the historically reported male sex predominance.

Approach to the Patient: Case Studies in Pediatric Growth Hormone Deficiency and Their Management.

CONTEXT: Pathologies attributed to perturbations of the GH/IGF-I axis are among the most common referrals received by pediatric endocrinologists. AIM: In this article, distinctive cased-based presentations are used to provide a practical and pragmatic approach to the management of pediatric growth hormone deficiency (GHD). CASES: We present 4 case vignettes based on actual patients that illustrate (1) congenital GHD, (2) childhood GHD presenting as failure to thrive, (3) childhood GHD presenting in adolescence as growth deceleration, and (4) childhood-onset GHD manifesting as metabolic complications in adolescence. We review patient presentation and a management approach that aims to highlight diagnostic considerations for treatment based on current clinical guidelines, with mention of new therapeutic and diagnostic modalities being used in the field. CONCLUSION: Pediatric GHD is diverse in etiology and clinical presentation. Timely management has the potential not only to improve growth but can also ameliorate or even mitigate adverse metabolic outcomes, which can be directly attributed to a GH deficient state.

Growth hormone after CNS tumor diagnosis: the fundamentals, fears, facts, and future directions.

Growth hormone deficiency (GHD) may occur in pediatric patients with central nervous system (CNS) tumors at initial tumor presentation or later as treatment-related sequelae. While it is well recognized that growth hormone (GH) has beneficial effects on growth and endocrinopathies, there's often hesitancy by clinicians to initiate GH therapy for GHD after CNS tumor diagnosis due to the perceived increased risk of tumor recurrence. The available data is described here and based on this review, there is no evidence of increased risk of tumor recurrence or secondary malignancy in patients treated with GH after CNS tumor diagnosis. Further understanding of tumor biology and presence of downstream GH targets including insulin-like growth factor-1 (IGF-1) and insulin receptor activity is still needed.

The utility of a random cortisol level in determining neonatal central adrenal insufficiency.

OBJECTIVES: While it has been established within the first 4 months of life that there is no circadian rhythm, what is unclear is the usefulness of a random serum cortisol (rSC) level in determining neonatal central adrenal insufficiency (CAI). The objective of the study is to determine the utility of using rSC in infants less than 4 months old in the evaluation of CAI. DESIGN AND PATIENTS: Retrospective chart review of infants who underwent a low dose cosyntropin stimulation test ≤4 months of life with rSC taken as baseline cortisol before stimulation. Infants were divided into three groups: those diagnosed with CAI, those at risk for CAI (ARF-CAI) and a non-CAI group. Mean rSC for each group was compared, and ROC analysis was used to identify rSC cut-off for the diagnosis of CAI. RESULTS: Two hundred and fifty one infants with the mean age of 50.5 ± 38.08 days, and 37% of these were born at term gestation. The mean rSC were lower in the CAI group (1.98 ± 1.88 mcg/dl) as compared to the ARF-CAI (6.27 ± 5.48 mcg/dl, p = .002) and non-CAI (4.6 ± 4.02 mcg/dl, p = .007) groups. ROC analysis identified a cut-off of rSC level of 5.6 mcg/dL is associated with 42.6% sensitivity and 100% specificity for the diagnosis of CAI in term infants. CONCLUSIONS: This study demonstrates that though an rSC can be used within the first 4 months of life, its value is best when done ≤30 days of life. Moreover, a diagnostic cut-off for CAI using rSC levels was identified for term infants.

Macimorelin Acetate for the Diagnosis of Childhood-onset Growth Hormone Deficiency.

Growth hormone provocation testing forms the cornerstone of the diagnosis of childhood growth hormone deficiency in clinical practice. Despite the widespread use of these tests, various criticisms have been levelled against them, such as the labour-intensive nature of the tests, their potential for serious adverse effects and their questionable reproducibility. Macimorelin acetate, a ghrelin mimetic approved for the diagnosis of adult growth hormone deficiency, could serve an unmet need in the diagnosis of childhood-onset growth hormone deficiency based on its good tolerability and benign side effect profile.

The necessity of magnetic resonance imaging in the evaluation of pediatric growth hormone deficiency: Lessons from a large academic center.

BACKGROUND: Current guidelines indiscriminately recommend magnetic resonance imaging (MRI) of the pituitary gland in pediatric growth hormone deficiency (GHD). The relationship between abnormal MRI, most importantly a tumor, and peak GH levels is not well known. METHODS: In this retrospective chart review, pituitary MRI results of children, ages of 3-16 years with GHD were collected and divided into 3 groups according to peak stimulated GH levels; ≤5, 5-7.4 and 7.5-10 ng/mL, Groups A, B & C respectively. Clinical and MRI findings were compared between the groups. RESULTS: A total of 399 children were included. Abnormal MRI was found in 36.9% of group A subjects, compared to group B (16.7%) and group C (17.0%), both p values =0.0002. Children with multiple pituitary hormonal deficiencies (MPHD) had a higher rate of abnormalities than those with isolated GHD. Children with isolated GHD were more likely to have abnormal MRI with peak GH level < 5 ng/mL compared to those with levels, 5-7.4 & 7.5-10 ng/mL. 4 children in group A had a craniopharyngioma. ROC analysis comparing peak GH levels with abnormal MRI findings showed an area under the curve (AUC) of 0.614 and 0.728 for IGHD and MPHD, respectively. CONCLUSION: Although abnormal MRI was found in all 3 study groups, it was more likely at GH level < 5 ng/mL and in children with MPHD. To avoid missing a tumor, the importance of imaging in children with GHD and peak GH levels <5 ng/mL cannot be overemphasized.

When They're Done Growing, Don't Forget They May Still Need Growth Hormone.

The effect of the growth hormone (GH) in promoting linear growth is well known; however, less recognized by practitioners especially pediatric, are its metabolic properties. This may be because the deleterious effects of improperly treated or untreated growth hormone deficiency (GHD) can present beyond the pediatric years. In addition, clinicians may lack familiarity with the potential issues that can arise due to inadequately treated GHD. Considering information from both the basic sciences research and clinical medicine, pediatric practitioners should be cognizant about the metabolic effects of GH. They should also be equipped to provide anticipatory guidance to patients regarding the importance of adherence to therapy in GHD and be prepared to transition patients with permanent GHD from pediatric GH supplementation to adult GH dosing. With a lack of proper transitioning, adverse outcomes may present beyond childhood.

The utility of a random growth hormone level in determining neonatal growth hormone sufficiency.

BACKGROUND: Random growth hormone (GH) levels have been used in the neonate to investigate congenital growth hormone deficiency (GHD). The cut-off value for use in this diagnosis is yet to be established. METHODS: This is a retrospective chart review of all random GH levels obtained in neonates ≤28 days of age. Neonates were divided into three groups: those diagnosed with congenital GHD, those at risk for GHD (ARF-GHD) and a non-growth hormone deficient (non-GHD) group. Mean GH levels for each group were compared, and ROC analysis was used to identify a cut-off for the diagnosis of GHD. RESULTS: The study included 138 neonates with the mean age of 9.07 ± 6.6 days, and 65% of these were born at term gestation. Mean GH levels were lower in the GHD group (2.73 ± 1.19 ng/ml) as compared to the ARF-GHD (9.4 ± 7.96 ng/ml, p = .002) and non-GHD groups (14.86 ± 14.42 ng/ml, p = .027). GH values were not significantly different between non-GHD and ARF-GHD groups. ROC analysis identified a cut-off of serum random GH level of 4.5 ng/ml that achieved 100% sensitivity and 83% specificity for the diagnosis of congenital GHD. CONCLUSION: This study demonstrates that random GH levels obtained in the first 28 days of life can be useful in diagnosing congenital GHD. Moreover, a diagnostic cut-off for congenital GHD using random GH levels was identified.

Childhood growth hormone deficiency, a diagnosis in evolution: The intersection of growth hormone history and ethics.

In 1958 the first recorded case of a patient treated with human growth hormone for growth hormone deficiency was published. Since that time, the source and availability of human growth hormone have changed. With the increased availability of growth hormone, there has been an uptrend in the level below which childhood growth hormone deficiency is diagnosed based on provocative GH stimulation testing. This increase is despite better specificity of growth hormone assays in addition to a lack of supportive evidence regarding appropriate normal values. With these trends the diagnosis of childhood growth hormone deficiency is evolving, and clinicians should be aware that this may have potential ethical implications.

For Debate: The Two Paths of Growth Hormone (Excess and Deficiency): Both Roads Uniquely Lead to Diabetes Mellitus.

Glucose dysregulation (GD), a feature of growth hormone excess, in the setting of acromegaly is well known by clinicians. However, less well known is that GD may be a feature of growth hormone deficiency. The fact that either ends of the spectrum of growth hormone (excess or deficiency) can be associated with diabetes mellitus is unique and clinicians should especially recognize that impaired glucose tolerance and even diabetes mellitus may develop in individuals predisposed to having growth hormone deficiency.

Type 2 Diabetes Mellitus, a Sequel of Untreated Childhood Onset Growth Hormone Deficiency Developing in a 17-Year-Old Patient.

In a seminal report, a 17-year-old boy with panhypopituitarism had fatty liver (FL) amelioration with growth hormone (GH). By extension, since hepatic insulin resistance (IR) is key to FL and type 2 diabetes mellitus (T2DM), GH then may ameliorate the IR of T2DM. We present a 17-year-old nonobese female with untreated childhood onset growth hormone deficiency (CO-GHD) who developed type 2 diabetes mellitus (T2DM) and steatohepatitis with bridging fibrosis. Based on height z-score of - 3.1 and a history of radiation therapy as treatment for a medulloblastoma at 7 years of age, GHD was quite likely. GH therapy was, however, not initiated at 15 years of age (when growth was concerning) based on full skeletal maturity. After she developed T2DM, GHD was confirmed and GH was initiated. With its initiation, though insulin dose decreased from 2.9 (~155 units) to 1.9 units/kg/day (~ 100 units), her T2DM was, however, not fully reversed. This illustrates the natural history of untreated CO-GHD and shows that though hepatic IR can be ameliorated by GH, full reversal of T2DM may be prevented with irreversible hepatic changes (fibrosis). Clinicians caring for pediatric patients and otherwise should remember that, even in patients beyond the cessation of linear growth, GH can have a crucial role in both glucose and lipid metabolism.

Growth Hormone Deficiency and Nonalcoholic Fatty Liver Disease with Insights from Humans and Animals: Pediatric Implications.

In addition to its growth promoting role, growth hormone (GH) has a significant effect on intermediary metabolism in the well state. Despite the latter fact, pediatric practitioners are usually focused on the growth promoting aspects of GH as opposed to those metabolic. In recent years various animal and human studies (in adults mainly) and clinical reports in children have repeatedly shown the association of GH deficiency (GHD) and fatty liver disease. Based on this well-identified association, despite a lack of studies involving children, it behooves the pediatric clinician to ensure that not only patients with GHD are appropriately treated but also that adolescents even beyond the period of linear growth should be appropriately transitioned to adult GH therapy should this be appropriate.

Myxedema Coma due to Hashimoto Thyroiditis: A Rare but Real Presentation of Failure to Thrive in Infancy.

BACKGROUND: Hashimoto thyroiditis (HT) is uncommon in infancy, and myxedema coma (MC) is even less common. While prior reports have documented these entities separately, to our knowledge, MC in combination with HT has not been reported before in this age group. METHODS/RESULTS: A 10-month-old female presented with ptosis, lethargy, dysphagia, and failure to thrive (FTT). She developed hypotension, bradycardia, hypothermia, and apnea requiring intubation. Initial thyroid-stimulating hormone was 422 µIU/mL, and free thyroxine was < 0.5 ng/dL, despite the presence of a normal thyroid newborn screen (NBS). Of note, sepsis workup was unremarkable. With the diagnosis of MC, treatment with intravenous levothyroxine was initiated, although after hydrocortisone administration to avert the possibility of an adrenal crisis, despite a random cortisol of 16.4 µg/dL. Based on positive thyroid antibodies suggesting HT, autoimmune workup later revealed positive acetylcholinesterase antibodies consistent with a diagnosis of ocular myasthenia gravis. CONCLUSION: MC may be a cause of altered mental status in infancy and may simultaneously be associated with FTT on presentation. With the presence of a normal thyroid NBS, autoimmunity should be entertained as the etiology of profound hypothyroidism, as positive thyroid antibodies may prompt an exploration for coexisting diseases which may explain other presenting features.

In iodine-induced thyrotoxicosis, steroid therapy today could keep the surgical knife at bay.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) type 2, characterized as a destructive thyroiditis, is well described in the medical literature; however, iodine-induced thyrotoxicosis (IIT) is not, though the latter has similar features and can be managed similarly. CASE PRESENTATION: We present a 17-year-old female who presented with a history of an intermittent goiter with thyroid function tests (TFTs): thyroid-stimulating hormone (TSH)<0.015 (0.4-4 µU/mL), free thyroxine (T4)≥6 (0.7-2.1 ng/dL) and total triiodothyronine (T3) 651 (50-200 mg/dL). Thyroid antibodies were all negative. Despite methimazole therapy for 6 weeks, hyperthyroidism proved refractory to medical management. 123I scan uptake was suppressed. With hyperthyroidism being recalcitrant to therapy, a nutritional history revealed consumption of an iodine supplement containing at least 7 times the recommended daily allowance (RDA) for 5 years, contributing to the Jod-Basedow phenomenon. Urinary spot and 24-hour urinary iodine were both elevated. Though a surgical consult was obtained, surgery was cancelled once TFTs improved and then normalized with steroid therapy. The TFTs and urinary iodine levels remained normal post steroid therapy. CONCLUSIONS: We suggest that in addition to the need for a thorough nutritional history, a trial of corticosteroids should be utilized in the management of IIT which can present with findings similar to AIT type 2 which is recalcitrant to thionamide therapy. If successful, corticosteroids may delay or prevent surgical management thus avoiding possible complications with the latter approach.

Severe hypertriglyceridemia at new onset type 1 diabetes mellitus.

BACKGROUND: Severe hypertriglyceridemia (HTG) as well as diabetic ketoacidosis (DKA) are complications of type 1 diabetes (T1DM). HTG is an exceedingly rare complication in the pediatric population and herein we report a case of HTG at new-onset T1DM in DKA and discuss management and potential complications. CASE PRESENTATION: An 11-year-old previously well patient with a history of fatigue and weight loss presented with: glucose >600 mg/dL, venous blood gas: pH 7.26, pCO2 20 mmHg, PO2 101 mmHg and base deficit 13 with triglyceride level 3573 mg/dL. An insulin drip was continued past criteria for discontinuation to facilitate lipoprotein lipase-based triglyceride metabolism. CONCLUSIONS: Lipemia secondary to severe HTG, though exceedingly rare, may exist in new onset T1DM with DKA. Complicating the diagnosis is the possibility of an analytical error from lipemia causing incongruence in diagnostic criteria. Clinicians should rely on clinical criteria for management and should consider HTG if laboratory data is inconsistent with the clinical picture.

Myxedema Coma Secondary to Central Hypothyroidism: A Rare but Real Cause of Altered Mental Status in Pediatrics.

BACKGROUND: Myxedema coma (MC), a medical emergency defined as severe hypothyroidism leading to altered mental status, is more common in older women with hypothyroidism. METHODS/RESULTS: A 7-year-old Caucasian male with chromosome 1q deletion presented with altered mental status preceded by milestone regression. His presenting labs results were: thyroid-stimulating hormone (TSH) 0.501 µIU/ml and free thyroxine (T4) <0.5 ng/dl. His morning cortisol level was 8.1 µg/dl with repeat testing, while TSH was 1.119 µIU/ml and free T4 was 0.5 ng/dl. Low-dose cosyntropin test showed baseline and peak cortisol levels of 1.9 and 16 µg/dl, respectively. Aside from altered mental status, heart block was present in addition to hypothermia and hypercarbia. Diffuse cerebral cortical and corpus callosum atrophy were seen on MRI. An intravenous (i.v.) stress dose of hydrocortisone was administered for 24 h prior to an i.v. loading dose of levothyroxine. His activity level subsequently returned to baseline within 48 h after treatment had been initiated. CONCLUSION: Though MC is rare, occurring mainly with noncompliance in primary hypothyroidism, it may occur at the diagnosis of secondary hypothyroidism. Based on features like hypothermia, hypoventilation, and cardiovascular instability occurring in the setting of central hypothyroidism, it should be suspected and managed urgently in order to avert the associated high mortality resulting from treatment delays.

17p13.3 microduplication including CRK leads to overgrowth and elevated growth factors: A case report.

17p13.3 microduplications classified as class I duplications involving YWHAE but not PAFAH1B1 (formerly LIS1) and class II duplications which extend to involve PAFAH1B1, are associated with diverse phenotypes including intellectual disability and structural brain malformations. We report a girl with an approximately 1.58 Mb apparently terminal gain of 17p13.3, which contains more than 20 genes including the YWHAE and CRK genes (OMIM: 164762). She had increased growth factors accompanied by pathologic tall stature. In addition to these, she developed central precocious puberty at 7 years old. In individuals with class I 17p13.3 microduplications including CRK, we recommend biochemical evaluation of the growth hormone axis. Providers caring for these patients should be aware of their possible risk for the development of central precocious puberty.

Hypercalcemia due to Milk-Alkali Syndrome and Fracture-Induced Immobilization in an Adolescent Boy with Hypoparathyroidism.

BACKGROUND: Hypercalcemia of immobilization, while rare, may occur in adolescent boys after fracture. Although not fully understood, the mechanism appears to be related to bone turnover uncoupling, in part mediated by upregulation of RANKL. Animal studies suggest that parathyroidectomy suppresses RANKL-stimulated osteoclastogenesis in immobilized bone. Thus, immobilization-induced hypercalcemia should be uncommon in patients with hypoparathyroidism. METHODS/RESULTS: We present a 15-year-old boy with well-controlled hypoparathyroidism who developed hypercalcemia and milk-alkali syndrome 5 weeks after sustaining a severe tibia/fibula fracture requiring bedrest. Milk-alkali syndrome (hypercalcemia, alkalosis, and renal insufficiency) results from chronic excessive ingestion of calcium and absorbable alkali. Prior to fracture, our patient had not experienced hypercalcemia despite high doses of supplements, necessary during puberty. Supplements were discontinued and his biochemistries normalized with saline diuresis and a dose of pamidronate. Alkaline phosphatase, which was low at presentation, returned to normal 5 weeks later with remobilization. CONCLUSIONS: Fracture and immobilization caused acute suppression of bone formation with persistent bone resorption in this rapidly growing adolescent; continuation of carbonate-containing calcium supplements resulted in the milk-alkali syndrome. Therefore, close monitoring of serum calcium with adjustments in supplementation are indicated in immobilized patients with hypoparathyroidism. © 2016 S. Karger AG, Basel.