Invited Review- Children with idiopathic short stature (ISS): an expanding role for genetic investigation in their medical evaluation.

Short stature in children is a common reason for referral to a pediatric endocrinologist. A myriad of genetic, nutritional, psychological, illness-related, and hormonal causes must be excluded before labeling as idiopathic. However, idiopathic short stature (ISS) is not a diagnosis, but rather describes a large, heterogeneous group of children, who are short and often growing at the lower limit of the normal range. As new testing paradigms become available, the pool of patients labeled as idiopathic will shrink, although most will still have a polygenic cause. Given that many of the new diagnoses are involved in growth plate biology, physical examination should assess for subtle dysmorphology or disproportion of the skeleton that may indicate a heterozygous mutation that in its homozygous state would be apparent. When laboratory evaluations are negative, one may consider genetic testing, such as targeted gene or gene panel, comparative genomic hybridization (cGH), or whole exome or whole genome sequencing (WES or WGS, respectively). With a known genetic diagnosis, targeted therapy may be possible rather than the use of recombinant human growth hormone (rhGH), where response is generally poorer than that for children with growth hormone (GH) deficiency, because the variety of diagnoses may have varying GH sensitivity. A firm diagnosis has heuristic value to truncate further diagnostic evaluation, alert the clinician to other possible co-morbidities, inform the family for genetic counseling, and direct appropriate targeted therapy, if available. Short stature in children is a common reason for referral to a pediatric endocrinologist. To begin a discussion about the evaluation of short children with particular reference to idiopathic short stature (ISS), an instructive patient is presented.

Testicular Dysfunction in Male Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: The male reproductive task force of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative performed a comprehensive review that included a meta-analysis of publications reporting radiation dose-volume effects for risk of impaired fertility and hormonal function after radiation therapy for pediatric malignancies. METHODS AND MATERIALS: The PENTEC task force conducted a comprehensive literature search to identify published data evaluating the effect of testicular radiation dose on reproductive complications in male childhood cancer survivors. Thirty-one studies were analyzed, of which 4 had testicular dose data to generate descriptive scatter plots. Two cohorts were identified. Cohort 1 consisted of pediatric and young adult patients with cancer who received scatter radiation therapy to the testes. Cohort 2 consisted of pediatric and young adult patients with cancer who received direct testicular radiation therapy as part of their cancer therapy. Descriptive scatter plots were used to delineate the relationship between the effect of mean testicular dose on sperm count reduction, testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) levels. RESULTS: Descriptive scatter plots demonstrated a 44% to 80% risk of oligospermia when the mean testicular dose was <1 Gy, but this was recovered by >12 months in 75% to 100% of patients. At doses >1 Gy, the rate of oligospermia increased to >90% at 12 months. Testosterone levels were generally not affected when the mean testicular dose was <0.2 Gy but were abnormal in up to 25% of patients receiving between 0.2 and 12 Gy. Doses between 12 and 19 Gy may be associated with abnormal testosterone in 40% of patients, whereas doses >20 Gy to the testes were associated with a steep increase in abnormal testosterone in at least 68% of patients. FSH levels were unaffected by a mean testicular dose <0.2 Gy, whereas at doses >0.5 Gy, the risk was between 40% and 100%. LH levels were affected at doses >0.5 Gy in 33% to 75% of patients between 10 and 24 months after radiation. Although dose modeling could not be performed in cohort 2, the risk of reproductive toxicities was escalated with doses >10 Gy. CONCLUSIONS: This PENTEC comprehensive review demonstrates important relationships between scatter or direct radiation dose on male reproductive endpoints including semen analysis and levels of FSH, LH, and testosterone.

Categorization of a Universal Coding System to Distinguish Use of Durable Medical Equipment and Supplies in Pediatric Patients.

Importance: Although durable medical equipment and supplies (DMES) are commonly used to optimize the health and function in pediatric patients, little is known about the prevalence of use and spending on DMES. Objective: To categorize the Healthcare Common Procedure Coding System (HCPCS) for distinguishing DMES types, and to measure the prevalence and related spending of DMES in pediatric patients using Medicaid. Design, Setting, and Participants: This study is a cross-sectional analysis of the 2018 Merative Medicaid Database and included 4 569 473 pediatric patients aged 0 to 21 years enrolled in Medicaid in 12 US states from January 1 to December 31, 2018. Data were analyzed from February 2019 to April 2023. Exposure: DMES exposure was identified with the Centers for Medicare & Medicaid Services HCPCS codes. Three pediatricians categorized HCPCS DMES codes submitted by vendors for reimbursement of dispensed DMES into DMES types and end-organ systems; 15 expert reviewers refined the categorization (2576 DMES codes, 164 DMES types, 14 organ systems). Main Outcomes and Measures: The main outcome was DMES prevalence & Medicaid spending. The χ2 test was used to compare DMES prevalence and Wilcoxon rank sum tests were used to compare per-member-per-year (PMPY) spending by complex chronic conditions (CCC). Results: Of the 4 569 473 patients in the study cohort, 49.3% were female and 56.1% were aged 5 to 15 years. Patients used 133 of 164 (81.1%) DMES types. The DMES prevalence was 17.1% (95% CI, 17.0%-17.2%) ranging from 10.1% (95% CI, 10.0%-10.2%) in patients with no chronic condition to 60.9% (95% CI, 60.8%-61.0%) for patients with 2 or more CCCs. The PMPY DMES spending was $593, ranging from $349 for no chronic condition to $4253 for 2 or more CCCs. Lens (7.9%), vision frames (6.2%), and orthotics for orthopedic injury (0.8%) were the most common DME in patients with no chronic condition. Enteral tube / feeding supplies (19.8%), diapers (19.2%), lower extremity orthotics (12.3%), wheelchair (9.6%), oxygen (9.0%), and urinary catheter equipment (4.2%) were among the most common DMES in children with 2 or more CCCs. Conclusions and Relevance: In this cross-sectional study, HCPCS distinguished a variety of DME types and use across pediatric populations. Further investigation should assess the utility of the HCPCS DMES categorization with efforts to optimize the quality and safety of DMES use.

Management of childhood cancer survivors at risk for thyroid function abnormalities: A Delphi study.

BACKGROUND: Thyroid function abnormalities can occur after treatment for childhood cancer. Evidence for the management of thyroid dysfunction among asymptomatic childhood cancer survivors (CCS) is lacking. We used a Delphi consensus methodology to expand guidelines for screening asymptomatic CCS at risk for thyroid dysfunction and explore recommendations for the clinical management of abnormal results. PROCEDURE: A Delphi panel of 40 expert physicians representing oncology, endocrinology, and primary care participated in three rounds of anonymous, iterative questionnaires formatted as clinical scenarios. Consensus is defined as ≥ 90% of panelists agree with recommendation and disagreement as < 70% agree. RESULTS: Panelists reached consensus that CCS treated with radiation including neck, total body, whole brain, brain including the hypothalamic-pituitary axis (HPA), and therapeutic meta-iodobenzylguanidine (MIBG) should have annual, lifelong screening using serum thyroid-stimulating hormone (TSH) and free T4 starting within one year off-treatment (98%). Panelists disagreed on continuing to screen CCS for thyroid dysfunction after immunotherapy associated with acute thyroid injury (31%-50%). There was also disagreement on indications for brain (17%-43%) or thyroid (50%-65%) imaging, laboratory tests to assess the HPA (29%-75%), and TSH threshold to initiate treatment of subclinical hypothyroidism. Lack of evidence was the most frequent rationale panelists offered for not recommending additional testing or medications. Panelists' recommendations did not vary by geography, specialty, or survivorship clinical experience. CONCLUSIONS: Consensus was reached on most recommendations for screening and management of cancer treatment-related thyroid dysfunction. Screening after completion of thyroid-toxic immunotherapy, indications for imaging, and treatment of subclinical hypothyroidism are areas of disagreement for further investigation.

Metformin for treatment of cytopenias in children and young adults with Fanconi anemia.

Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Hyperglycemia during induction therapy for acute lymphoblastic leukemia is temporally linked to pegaspargase administration.

BACKGROUND: Chemotherapy regimens containing glucocorticoids and pegaspargase are associated with hyperglycemia; however, the pattern and underlying risk factors are not well characterized. We determined the pattern of hyperglycemia and associated factors in children with acute lymphoblastic leukemia (ALL) receiving glucocorticoids and pegaspargase during induction. METHODS: Retrospective analysis of patients treated between 2010 and 2020 at a single institution. Pretreatment data, glucose values, and insulin regimens were abstracted from the record. Hyperglycemia was defined as two or more random glucose measurements ≥200 mg/dl. Analyses of demographic and clinical factors were conducted with logistic regression. RESULTS: Two hundred thirteen patients, median age 6 years (range 1.0-18.9 years), 47% female, were included. The prevalence of hyperglycemia was 23% (n = 48). Mean glucose levels peaked 3 days following administration of pegaspargase. In multivariable analysis, age ≥10 years (odds ratio [OR] 6.2, 95% confidence interval [CI]: 2.9-13.4), female sex (OR 2.7, 95% CI: 1.2-6.2), and family history of diabetes (OR 3.2, 95% CI: 1.4-7.3) were predictive of hyperglycemia. Age ≥10 years (OR 19.4, 95% CI: 5.5-68.4), family history of diabetes (OR 8.2, 95% CI: 2.7-25.3), and higher body mass index (BMI) (OR 1.8, 95% CI: 1.1-2.9) were associated with insulin treatment. CONCLUSIONS: Onset of hyperglycemia in children receiving induction chemotherapy for ALL is temporally linked to administration of pegaspargase. Older age, female sex, and family history of diabetes are predictive of hyperglycemia during induction; older age, family history of diabetes, and higher BMI are associated with insulin treatment. Frequent glucose monitoring is indicated during induction therapy for ALL.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Growth Hormone Deficiency and Treatment in Childhood Cancer Survivors.

Growth hormone (GH) deficiency is a common pituitary hormone deficiency in childhood cancer survivors (CCS). The identification, diagnosis, and treatment of those individuals at risk are important in order to minimize associated morbidities that can be ameliorated by treatment with recombinant human GH therapy. However, GH and insulin-like growth factor-I have been implicated in tumorigenesis, so there has been concern over the use of GH therapy in patients with a history of malignancy. Reassuringly, GH therapy has not been shown to increase risk of tumor recurrence. These patients have an increased risk for development of meningiomas, but this may be related to their history of cranial irradiation rather than to GH therapy. In this review, we detail the CCS who are at risk for GHD and the existing evidence on the safety profile of GH therapy in this patient population.

Juvenile Granulosa Cell Tumor as the Presenting Feature of McCune-Albright Syndrome.

INTRODUCTION: GNAS mutations have been reported in both McCune-Albright syndrome (MAS) and juvenile granulosa cell tumors (JGCT) but have never been reported simultaneously in the same patient. CASE PRESENTATION: A 15-year-old girl developed secondary oligomenorrhea. Laboratory studies revealed suppressed gonadotropin levels with markedly elevated estradiol and inhibin B levels. Pelvic ultrasound showed a 12-cm heterogeneous right adnexal mass; pelvic magnetic resonance imaging to further characterize the mass displayed heterogeneous bilateral femoral bone lesions initially concerning for metastatic disease. Positron emission tomography/computed tomography showed minimal 18F-fluorodeoxyglucose (FDG) uptake in the pelvic mass but unexpectedly revealed FDG uptake throughout the skeleton, concerning for polyostotic fibrous dysplasia in the context of MAS. The adnexal mass was excised and pathology confirmed a JGCT. The patient's affected bone and JGCT tissue revealed the same pathogenic GNAS p.R201C mutation, while her peripheral blood contained wild-type arginine at codon 201. CONCLUSION: This mutation has been previously reported in cases of MAS and JGCT but never simultaneously in the same patient. This demonstration of a GNAS mutation underlying both JGCT and MAS in the same patient raises questions about appropriate surveillance for patients with these conditions.

Novel predictive scoring system for morbid hypothalamic obesity in patients with pediatric craniopharyngioma.

PURPOSE: To identify the independent risk factors for developing morbid hypothalamic obesity, to propose a predictive scoring system for morbid hypothalamic obesity, and to propose an algorithm for management in order to minimize the risk of developing morbid hypothalamic obesity in patients with pediatric craniopharyngioma. METHODS: A retrospective analysis of all pediatric craniopharyngioma patients diagnosed and treated at Boston Children's Hospital (BCH) between 1985 and 2017. Analysis of the data was conducted using IBM SPSS Statistics. RESULTS: We identified 105 patients, 90 (47 males and 43 females) fulfilled the inclusion criteria. The median age of patients at time of diagnosis was 8.4 years. The median follow-up was 10.6 years. Morbid hypothalamic obesity was evident in 28 (31.1%) patients at the last follow-up visit. Age of patients at time of diagnosis > 10 years (P = 0.023), preoperative body mass index (BMI) > 95th percentile (P = 0.006), and preoperative papilledema (P < 0.001) were the independent risk factors for developing morbid hypothalamic obesity. CONCLUSION: We developed a unique predictive scoring system in order to differentiate between patients with and without high risk for developing morbid hypothalamic obesity.

Undernutrition and Pubertal Timing in Female Survivors of Medulloblastoma and Other Embryonal Tumors.

CONTEXT: Children with brain tumors may have pubertal onset at an inappropriately young chronologic age. Hypothalamic-pituitary irradiation ≥18Gy has been found to be a risk factor; age at irradiation is associated with pubertal timing. However, the underlying mechanisms are unknown. OBJECTIVE: To determine the impact of body mass index (BMI) and catch-up growth on pubertal timing in females treated for medulloblastoma and other embryonal tumors. DESIGN, SETTING, AND PATIENTS: Retrospective cohort analysis of 90 female patients treated for medulloblastoma and other embryonal tumors at Dana-Farber Cancer Institute/Boston Children's Hospital from 1996 to 2016. Eighteen individuals met inclusion criteria, with a mean ± SD follow-up period of 11.9 ± 3.4 years. MAIN OUTCOME MEASURES: Multiple linear regression models for age at pubertal onset and bone age discrepancy from chronologic age at pubertal onset assessed the joint influences of age at irradiation, hypothalamic irradiation dose, undernutrition duration, BMI standard deviation score (SDS) at pubertal onset, and catch-up BMI SDS. RESULTS: The mean ± SD age of pubertal onset was 9.2 ± 1.3 years and hypothalamic radiation dose was 31.9 ± 9.9 Gy. There was a direct relationship between age at irradiation and age at pubertal onset (ß = 0.323 ± 0.144 [standard error] year per year; P = 0.04) that was significantly attenuated after adjusting for BMI SDS at pubertal onset (P = 0.5) and catch-up BMI SDS (P = 0.08), suggesting that BMI is a mediator. CONCLUSIONS: Both absolute and catch-up BMI SDS at pubertal onset are significant mediators of pubertal timing and bone age discrepancy in pediatric medulloblastoma and other embryonal tumors, and thus, are targetable risk factors to optimize pubertal timing.

Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.

Clinical Course of Nonfunctional Pituitary Microadenoma in Children: A Single-Center Experience.

CONTEXT: Pituitary lesions consistent with microadenomas are increasingly discovered by MRI. Sparse data are available on the long-term clinical and imaging course of such lesions in children. OBJECTIVE: The aim of this study was to define the clinical and imaging course of pituitary lesions representing or possibly representing nonfunctioning microadenomas in children to guide clinical management. DESIGN: Retrospective observational study. METHODS: The clinical data warehouse at a tertiary care academic children's hospital was queried with the terms "pituitary" AND "microadenoma" and "pituitary" AND "incidentaloma." The electronic health records of the identified subjects were reviewed to extract data on the clinical and imaging course. RESULTS: A total of 78 children had nonfunctioning pituitary lesions incidentally discovered during clinical care, of which 44 (56%) were reported as presumed or possible microadenomas. In the children with microadenoma (median age 15 years, interquartile range 2), a majority (70%) underwent imaging for nonendocrine symptoms, the most common being headache (n = 16, 36%). No significant increase in the size of the microadenoma or cysts or worsening of pituitary function was seen over the average clinical follow-up of 4.5 ± 2.6 years. Four cases of drug-induced hyperprolactinemia resolved with discontinuation of the offending medication. CONCLUSIONS: Asymptomatic pituitary lesions representing cysts, microadenomas, or possible microadenomas follow a benign course in children. In the absence of new endocrine or visual symptoms, repeat MRI may not be needed, and if performed, should be done in no less than a year. When possible, it is prudent to discontinue hyperprolactinemia-inducing medications before imaging.

Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline.

Objective: To formulate clinical practice guidelines for the endocrine treatment of hypothalamic-pituitary and growth disorders in survivors of childhood cancer. Participants: An Endocrine Society-appointed guideline writing committee of six medical experts and a methodologist. Conclusions: Due to remarkable improvements in childhood cancer treatment and supportive care during the past several decades, 5-year survival rates for childhood cancer currently are >80%. However, by virtue of their disease and its treatments, childhood cancer survivors are at increased risk for a wide range of serious health conditions, including disorders of the endocrine system. Recent data indicate that 40% to 50% of survivors will develop an endocrine disorder during their lifetime. Risk factors for endocrine complications include both host (e.g., age, sex) and treatment factors (e.g., radiation). Radiation exposure to key endocrine organs (e.g., hypothalamus, pituitary, thyroid, and gonads) places cancer survivors at the highest risk of developing an endocrine abnormality over time; these endocrinopathies can develop decades following cancer treatment, underscoring the importance of lifelong surveillance. The following guideline addresses the diagnosis and treatment of hypothalamic-pituitary and growth disorders commonly encountered in childhood cancer survivors.

GH Therapy in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis.

Background: GH deficiency (GHD) is common among childhood cancer survivors (CCSs) with history of tumors, surgery, and/or radiotherapy involving the hypothalamus-pituitary region. We aimed to evaluate the effects of GH therapy (GHT) in CCSs on adult height, risk of diabetes mellitus, abnormal lipids, metabolic syndrome, quality of life, secondary tumors, and disease recurrence. Methods: We searched multiple databases for randomized and observational studies. Pairs of reviewers independently selected studies and collected data. Random effects meta-analysis was used to pool outcomes across the studies. Results: We included 29 observational studies at moderate to high risk of bias. Sixteen studies compared CCSs on GHT with those not on GHT (512 patients, GH dose: 0.3 to 0.9 IU/kg/week). GHT was significantly associated with height gain [standard deviation score, 0.61; 95% CI, 0.08 to 1.13] and was not significantly associated with the occurrence of secondary tumors [odds ratio (OR), 1.10; 95% CI, 0.72 to 1.67] or tumor recurrence (OR, 0.57; 95% CI, 0.31 to 1.02). Thirteen studies compared CCSs on GHT with normal age- or sex-matched controls or controls with idiopathic GHD or short stature. GHT was associated with either improved or unchanged risk of diabetes, lipid profiles, and metabolic syndrome. GHT was associated with improvements in quality of life. Conclusion: CCSs treated with GHT gain height compared with the untreated controls. GHT may improve lipid profiles and quality of life and does not appear to increase the risk of diabetes or the development of secondary tumors, although close monitoring for such complications remains warranted due to uncertainty in the current evidence.

Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers.

Background: Limited guidance exists for selecting a laboratory method for diagnosing GH deficiency (GHD) when it occurs as a late effect of radiotherapy in childhood cancer survivors (CCSs). Methods: We searched Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus for studies evaluating GHD that used IGF-1 or IGF-binding protein 3 (IGFBP-3) measurements compared with GH dynamic testing. Results: We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients. Comparator tests varied widely. Overall, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy but were strongly correlated. The use of both tests simultaneously in the same cohort did not improve the diagnostic accuracy. Despite high variability in the testing protocols, dynamic tests remained the most accurate for appropriately identifying patients with GHD. The insulin tolerance test (ITT) appears to be the most accepted reference test when used alone or in combination with arginine; however, standardized testing strategies among practice groups are absent. GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT. Insufficient data were available to assess the accuracy of serial GH testing (nocturnal or over 24 hours). Conclusion: The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population.

Endocrine Late Effects in Childhood Cancer Survivors.

Endocrine complications are highly prevalent in childhood cancer survivors. Approximately 50% of survivors will experience at least one hormonal disorder over the course of their lives. Endocrine complications often are observed in survivors previously treated with radiation to the head, neck, or pelvis. We provide an overview the most common endocrine late effects seen in survivors, including hypothalamic-pituitary dysfunction, primary thyroid dysfunction, obesity, diabetes mellitus, metabolic syndrome, and decreased bone mineral density. Primary gonadal injury is discussed elsewhere in this series. Given a variable latency interval, a systematic approach where individuals are periodically screened on the basis of their risk factors can help to improve health outcomes by prompt diagnosis and treatment of evolving endocrinopathies. These recommendations must be revised in the future given changes and improvements in cancer treatment over time.