Jose Bernardo Quintos

Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency

Background/Aims: On behalf of the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society, we sought to update the guidelines published in 2003 on the use of growth hormone (GH). Because idiopathic short stature (ISS) remains a controversial indication, and diagnostic challenges often blur the distinction between ISS, GH deficiency (GHD), and primary IGF-I deficiency (PIGFD), we focused on these three diagnoses, thereby adding recombinant IGF-I therapy to the GH guidelines for the first time. Methods: This guideline was developed following the GRADE approach (Grading of Recommendations, Assessment, Development, and Evaluation). Results: This guideline provides recommendations for the clinical management of children and adolescents with growth failure from GHD, ISS, or PIGFD using the best available evidence. Conclusion: The taskforce suggests that the recommendations be applied in clinical practice with consideration of the evolving literature and the risks and benefits to each individual patient. In many instances, careful review highlights areas that need further research.

Rare complications of pediatric diabetic ketoacidosis

The incidence of type 1 diabetes (T1D) among youth is steadily increasing across the world. Up to a third of pediatric patients with T1D present with diabetic ketoacidosis, a diagnosis that continues to be the leading cause of death in this population. Cerebral edema is the most common rare complication of diabetic ketoacidosis in children. Accordingly, treatment and outcome measures of cerebral edema are vastly researched and the pathophysiology is recently the subject of much debate. Nevertheless, cerebral edema is not the only sequela of diabetic ketoacidosis that warrants close monitoring. The medical literature details various other complications in children with diabetic ketoacidosis, including hypercoagulability leading to stroke and deep vein thrombosis, rhabdomyolysis, pulmonary and gastrointestinal complications, and long-term memory dysfunction. We review the pathophysiology, reported cases, management, and outcomes of each of these rare complications in children. As the incidence of T1D continues to rise, practitioners will care for an increasing number of pediatric patients with diabetic ketoacidosis and should be aware of the various systems that may be affected in both the acute and chronic setting.

Transient adrenal insufficiency in the premature newborn.

Purpose of reviewRelative adrenal insufficiency is a controversial phenomenon described in adults and children with critical illness, especially septic shock. In the past 2 decades, relative adrenal insufficiency has also been reported in the critically ill premature as well as term newborn. The present study will review the initial and more recent studies addressing adrenal insufficiency in the premature infant. Recent findingsStudies suggest that ‘relative adrenal insufficiency’ is a contributing factor to hemodynamic instability in the sick preterm newborn. Many ill preterm newborns have inappropriately low serum cortisol concentrations and respond to steroid administration. Adrenal insufficiency is transient and likely reflects normal adrenal physiology at younger gestational ages. There is no general consensus on its diagnosis, effective minimum dose for treatment and duration of treatment. SummaryMore large scale, multicenter, randomized, double-blind studies are needed to make the diagnosis of relative adrenal insufficiency and to determine the indication, dose, complications and outcome of glucocorticoid therapy.

Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene.

Abstract Background: Recently, whole exome sequencing identified heterozygous defects in the aggrecan (ACAN) gene in three families with short stature and advanced bone age. Objective: We report a novel frameshift mutation in ACAN in a family with dominantly inherited short stature, advanced bone age, and premature growth cessation. This is the first case of targeted sequencing of ACAN in this phenotype and confirms that ACAN sequencing is warranted in patients with this rare constellation of findings. Results: We present a 5 1/2-year-old male with a family history of short stature in three generations. The maternal grandfather stands 144.5 cm (Ht SDS –4.7), mother 147.7 cm (Ht SDS –2.6), and index case 99.2 cm (Ht SDS –2.7). Our prepubertal patient has significant bone age advancement (bone age 8 years at chronologic age 5 1/2 years) resulting in a poor predicted adult height of 142 cm (Ht SDS –5.1). DNA sequencing identified a novel heterozygous variant in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The mutation (p.Gly1797Glyfs*52) results in premature truncation and presumed loss of protein function. Conclusion: Mutations in the ACAN gene should be included in the differential diagnosis of the child with idiopathic short stature or familial short stature and bone age advancement.

Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations

Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, −2.8 standard deviation score (SDS); range, −5.9 to −0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype–phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, −2.0 SDS; range, −4.2 to −0.6). Most children with ACAN mutations had advanced bone age (bone age − chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

A novel familial 11p15.4 microduplication associated with intellectual disability, dysmorphic features, and obesity with involvement of the ZNF214 gene

We evaluated a patient with mild intellectual disability, obesity, overgrowth, and dysmorphic features. Array comparative genomic hybridization (aCGH) analysis showed a single copy number increase of a BAC clone in the 11p15.4 region. Oligonucleotide aCGH refined the duplication to approximately 2.29 megabases (Mb) in size. Testing the parents revealed that the father, who had learning disabilities and overgrowth, also had the 11p15.4 duplication, and the mother had a normal microarray. In addition, the patients brother and grandmother all share clinical features with the proband and tested positive for the duplication. The duplicated region (Chr11:6,934,067‐9,220,605) encompasses 29 genes, including the ZNF214 gene, which has been postulated to play a role in Beckwith–Wiedemann syndrome [Alders et al., 2000 ]. This three‐generation pedigree outlines features of a novel microduplication syndrome.

Autoimmune polyglandular syndrome Type 3 and growth hormone deficiency.

Quintos JB, Grover M, Boney CM, Salas M. Autoimmune polyglandular syndrome type 3 and growth hormone deficiency.

Study of Glucose Profiles with Continuous Glucose Monitoring in Adolescents with Poorly Controlled Type 2 Diabetes Mellitus

AIM To evaluate glycemic excursions in adolescents with poorly controlled type 2 diabetes mellitus (DM2). METHODS Seventeen adolescents (12 F/5 M) underwent glucose monitoring for 3 days using a continuous glucose monitoring system (CGMS). Glucose measurements were divided into periods of euglycemia, hyperglycemia, and hypoglycemia. The percentage of each period, average glucose concentration per 24 h, day and night, the number of excursions, and area under the curve (AUC) of glucose >150 mg/dl and <70 mg/dl were calculated. RESULTS On average, patients remained in euglycemia for 28.5%, hyperglycemia for 70%, and hypoglycemia 1.3% of the total day. Hyperglycemic excursions were more frequent during the day. Hypoglycemic events were more frequent during the night. 24-h average glucose, duration of glucose >150 mg/dl, and AUC >150 mg/dl correlate with HbA1c and fructosamine to varying degrees. CONCLUSION Continuous glucose monitoring provide valuable information on glucose excursions in adolescents with poorly controlled DM2 and may be helpful in improving metabolic control of poorly controlled adolescents with DM2.

Use of growth hormone and gonadotropin releasing hormone agonist in addition to L-thyroxine to attain normal adult height in two patients with severe Hashimoto's thyroiditis.

AIM We report two patients with severe acquired juvenile hypothyroidism who presented with compromised predicted adult height (PAH), and the successful use of growth hormone (GH) and gonadotropin releasing hormone agonist (GnRHa) in addition to L-thyroxine to attain normal adult height. PATIENTS AND RESULTS Patient 1: 13 year-old girl who presented with pubertal delay, short stature (height SDS -4), and marked bone age retardation (BA 8 yr). Serum T4 was undetectable and TSH level was 1,139 mIU/l. After 1 year of treatment with L-thyroxine, growth rate improved from 1.0 cm/yr to 9.8 cm/yr but puberty progressed (Tanner 3 breast) and BA accelerated by 4 years, compromising predicted adult height (PAH) (144 cm vs mid-parental target height [MTH] of 163 cm). Combined use of GH and GnRHa for one year slowed BA progression, and catch-up growth (10.4 cm/yr) continued to attain a final height (FH) of 155 cm. Patient 2: 14 year-old boy with undetectable T4, TSH of 811 mIU/l in mid-puberty with poor growth rate (1.0 cm/yr), without any bone age delay (BA 14 years) but compromised PAH (163.8 cm vs MTH 174 cm). Because of the advanced puberty and poor growth rate, treatment with GH and GnRHa was initiated. Treatment for 2 years led to improvement of growth velocity (10.6 cm/yr), slowed BA progression to attain a FH equal to MTH. CONCLUSION Combined use of GH and GnRHa improved the FH of two patients, with Hashimotos thyroiditis: one with pubertal and bone age delay and the other with normal onset of puberty and normal bone age.

PETS-D: Impact on Diabetes Management Outcomes

Objective To evaluate the efficacy of Parent Education Through Simulation–Diabetes (PETS-D; clinical trial registration NCT01517269) for parents of children <13 years old newly diagnosed with type 1 diabetes with 3 parent education vignette sessions using human patient simulation (HPS) as compared with formal parent-nurse education sessions (vignette only) regarding diabetes knowledge, problem-solving skills, hypoglycemia fear, anxiety, and self-efficacy. Design and Methods Subjects were randomized to the HPS parent diabetes education or the vignette-only arm. Using linear mixed modeling, we compared HPS and vignette-only groups at 2, 6, and 14 weeks. Effect modification of treatment by dichotomized child’s age (<6 and ≥6 years old) and parent education (≤high school and >high school) was also tested. All analyses were intent to treat and adjusted for baseline outcome level and clustering within site. Results We recruited 191 parents (116 children). Mean baseline A1C was 12%. Overall treatment-related differences were modest. There was a statistically significant effect modification of HPS by child’s age, with a larger HPS benefit among parents of younger children for several outcomes: A1C (8.16% vs 9.48% in control; P = .006), lower state anxiety (P = .0094), and higher fear of hypoglycemia (P = .03) for parents of children <6 years old in the HPS group. Conclusions Modest treatment-related differences may reflect ceiling/floor effects in many of the outcomes; we also compared HPS with another intervention rather than to usual education. Parents of younger children receiving the intervention may feel more comfortable with lower A1C levels because of management awareness gleaned from the HPS experience. Future research will include a retrospective case-control study of very young children.