Growth After Menarche in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Growth impairment in pediatric patients with pediatric onset inflammatory bowel disease (IBD) is multifactorial. Reports on the effect of age at menarche on adult stature in this population are limited. This study investigated the impact of age at menarche, disease-associated factors, and mid-parental height on growth from menarche to final height (FHt) in pediatric patients with Crohn disease (CD) and ulcerative colitis (UC) and IBD unclassified (IBD-U). METHODS: Subjects were enrolled from a prospectively maintained pediatric IBD database when IBD preceded menarche and dates of menarche and FHt measurements were recorded. RESULTS: One hundred forty-six patients: CD 112 and UC 30/IBD-U 4. Mean age (years) at diagnosis (10.9 vs 10.1), menarche (14.4 vs 14.0), and FHt (19.6 vs 19.7). CD and UC/IBD-U patients showed significant association between Chronological age (CA) at menarche and FHt (cm, P < 0.001) but not FHt z score (FHt-Z) < -1.0 (P = 0.42). FHt-Z < -2.0 occurred in only 5 patients. Growth impairment (FHt-Z < -1.0) was associated with surgery before menarche (P = 0.03), jejunal disease (P = 0.003), low mid-parental height z score (MPH-Z) (P < 0.001), hospitalization for CD (P = 0.03) but not UC, recurrent corticosteroid, or anti-tumor necrosis factor alpha (anti-TNFα) therapy. CONCLUSIONS: Early age of menarche was associated with greater potential for linear growth to FHt but not FHt-Z (P < 0.05). Surgery before menarche, jejunal disease, hospitalization for CD, low MPH, and weight z score were associated with FHt-Z < -1.0.

Metabolic Consequences of Pediatric Obesity: A Review of Pathophysiology, Screening, and Treatment.

The prevalence of pediatric obesity has been increasing during the last 30 years, and the subsequent metabolic consequences of obesity, which were mainly seen in adults, are now presenting in childhood. Type 2 diabetes, prediabetes, metabolic syndrome, and nonalcoholic fatty liver disease are serious metabolic ramifications of pediatric obesity; pediatricians need to be familiar in screening and treatment of these metabolic issues. This review will discuss the inflammation and insulin resistance involved in obesity that can lead to these conditions. We will explore the pathophysiology of type 2 diabetes and prediabetes, metabolic syndrome, and nonalcoholic fatty liver disease and review screening and treatment modalities. Finally, we will highlight other important endocrine related comorbidities in pediatric obesity, including polycystic ovary syndrome, precocious puberty, and early accelerated growth. [Pediatr Ann. 2023;52(2):e62-e67.].

Dilemmas in Vitamin D Management in Children and Adolescents.

The importance of vitamin D and its role in several biological processes has been a topic of interest in recent years. Vitamin D is an essential nutrient that is needed for metabolic bone health and for maintaining bone calcium homeostasis. It is primarily synthesized in the skin on exposure to sunlight. Of late, vitamin D deficiency has been associated with conditions such as obesity, poor control of asthma and other autoimmune diseases, which has led to questions about its potential role in causation and management of these conditions. Given the increase in data about this topic, providers may often have questions about whom to screen and what to tell patients. In this article, we address screening guidelines for vitamin D in children and adolescents, management of vitamin D deficiency, and current literature on the role of vitamin D in conditions such as obesity, asthma, and type 1 diabetes mellitus. [Pediatr Ann. 2019;48(8):e298-e303.].

A Phenotypic Female Adolescent with Primary Amenorrhea and Dysmorphic Features.

We report on a case of a 14-year-old phenotypic female with a microdeletion at 13q31.1-q31.3, dysmorphic facial and limb features, and neurologic symptoms. She presented to her pediatrician with concerns for delayed puberty, and laboratory analysis revealed hypergonadotropic hypogonadism. She was found to have an XY karyotype and streak gonads. Further genetic studies did not reveal another cause for her gonadal dysgenesis and, to our knowledge, an association with her known 13q-microdeletion has not yet been reported. Given the risk of malignancy with XY gonadal dysgenesis, the patient had surgery to remove the gonads and had no postoperative complications after a 6-month follow-up visit. We also discuss the role of the pediatrician in cases of delayed puberty, from initial diagnosis to definitive management. [Pediatr Ann. 2019;48(12):e495-e500.].

Intractable early childhood obesity as the initial sign of insulin resistant hyperinsulinism and precursor of polycystic ovary syndrome.

OBJECTIVE: We report that intractable early childhood obesity may be associated with severe insulin resistance syndromes (pseudo-Cushing's syndrome and pseudo-acromegaly) and precede polycystic ovary syndrome (PCOS). STUDY DESIGN/RESULTS: Patient 1 had prepubertal obesity followed by early puberty and was diagnosed with pseudo-Cushing's syndrome and insulin resistance at 10.3 years. Oligomenorrhea, androgen excess, and type 2 diabetes mellitus (DM2) emerged at 13.5 years. Patient 2 developed intractable prepubertal obesity followed by atypical true sexual precocity and pseudo-Cushing's syndrome in early childhood. By 11.3 years, oligomenorrhea, androgen excess, and DM2 had appeared. Patient 3 had prepubertal overgrowth in weight and height and was diagnosed with pseudo-acromegaly, menstrual irregularity, androgen excess, and impaired glucose tolerance at 14.3 years of age. Patient 4 had prepubertal overgrowth that evolved into pseudo-acromegaly, insulin resistance, secondary amenorrhea, and androgen excess at 15.6 years. CONCLUSIONS: Intractable prepubertal obesity was recognized to culminate in early childhood pseudo-Cushing's syndrome or pseudo-acromegaly, which are manifestations of insulin-resistant hyperinsulinism, and to herald adolescent PCOS.

An adolescent with Graves' disease and thymic hyperplasia.

A 14-year-old female presented to our hospital for a second opinion regarding a recent diagnosis of Graves' disease and a mediastinal mass. Four months prior to presentation, the patient developed difficulty with concentration. Historically she had been an A/B student; however, her school performance worsened suddenly, and she almost failed the eighth grade. One month later, she began complaining of increased sweating, diarrhea, difficulty with balance, jitteriness, and difficulty sitting still. During the previous 2 months, she had an increased appetite along with a 10-lb weight gain, increased hair loss, fatigue, and dry skin. Two weeks prior to her presentation, her mother noted that she had a "large neck mass." At that time, the patient complained of dysphagia and tenderness of the anterior neck on palpation, but she had no respiratory difficulties. In addition, she had no symptoms of fever or night sweats.

Unique mode of lipogenic activation in rat preputial sebocytes.

Lipoprotein delivery of fatty acids and cholesterol is linked with peroxisome proliferator-activated receptor (PPAR) activation in adipocytes and macrophages. We postulated that similar interactions exist in sebaceous epithelial cells (sebocytes) in which PPAR activation induces differentiation. High-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) markedly enhanced sebocyte differentiation above that found with PPAR agonists and were more potent than explicable by their lipid content. The PPARγ antagonist GW5393 reduced sebocyte differentiation to all PPAR isoform agonists, HDL and VLDL, suggesting that the lipoprotein effect on differentiation occurs partially through activation of PPARγ. Furthermore, we found that sebocytes expressed a unique pattern of lipogenic genes. Our results demonstrate that HDL and VLDL are the most potent inducers of sebocyte differentiation tested to date, and these actions are partially inhibited by PPAR antagonists. This suggests that substrates provided by lipoproteins are targeted to sebocytes and affect their own disposition via PPAR activation.

Evidence of a mechanism for isodicentric chromosome Y formation in a 45,X/46,X,idic(Y)(p11.31)/46,X,del(Y)(p11.31) mosaic karyotype.

Abnormalities involving sex chromosomes account for approximately 0.5% of live births. The phenotypes of individuals with mosaic cell lines having structural aberrations of the X and Y chromosomes are variable and hard to accurately predict. Phenotypes associated with sex chromosome mosaicism range from Turner syndrome to males with infertility, and often present with ambiguous genitalia. Previous studies of individuals with an 45,X/46,X,idic(Y)(p11) karyotype suggest that the presence of both cell lines should result from an intermediate, 46,XY cell line. Here we report a 2.5 year old female with phenotypic features of Turner syndrome with an isodicentric Y chromosome and a cell line with a deleted Y with a final karyotype of 45,X/46,X,idic(Y)(p11.31)/46,X,del(Y)(p11.31). Fluorescence in situ hybridization (FISH) mapping of the Y chromosome breakpoint revealed very low percentages of the deleted Y cells, but suggested a potential mechanism for the formation of the isodicentric Y chromosome. To our knowledge, the 46,X,del(Y) intermediate cell line in our patient has not been previously reported in individuals with mosaic sex chromosome structural abnormalities.

The nuclear receptor corepressors NCoR and SMRT decrease peroxisome proliferator-activated receptor gamma transcriptional activity and repress 3T3-L1 adipogenesis.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a central regulator of adipogenesis and recruits coactivator proteins in response to ligand. However, the role of another class of nuclear cofactors, the nuclear receptor corepressors, in modulating PPARgamma transcriptional activity is less clear. Such corepressors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT). Our data suggest that PPARgamma recruits SMRT and NCoR in the absence of ligand and that these corepressors are capable of down-regulating PPARgamma-mediated transcriptional activity. The addition of the PPARgamma ligand pioglitazone results in dissociation of the PPARgamma-corepressor complex. To define the role of SMRT and NCoR in PPARgamma action, 3T3-L1 cells deficient in SMRT or NCoR were generated by RNA interference. When these cells are exposed to differentiation media, they exhibit increased expression of adipocyte-specific genes and increased production of lipid droplets, as compared with control cells. These data suggest that the nuclear receptor corepressors decrease PPARgamma transcriptional activity and repress the adipogenic program in 3T3-L1 cells.

An intact DNA-binding domain is not required for peroxisome proliferator-activated receptor gamma (PPARgamma) binding and activation on some PPAR response elements.

Peroxisome proliferator-activated receptor gamma (PPARgamma) interacts with retinoid X receptor (RXR) on PPAR response elements (PPREs) to regulate transcription of PPAR-responsive genes. To investigate the binding of PPARgamma and RXR to PPREs, three mutations were constructed in the DNA-binding domains of PPARgamma; two of the mutants maintained the structure of zinc finger I (PPARgamma-GS and PPARgamma-AA), and a third mutation disrupted the protein structure of zinc finger I (PPARgamma-CS). Results indicated that the mutations of PPARgamma that maintained intact zinc fingers were capable of binding to a variety of PPREs in the presence of RXR and could activate transcription on several PPREs. In parallel, a mutation was created in the DNA-binding domain of RXRalpha that maintained the structure of the zinc fingers (RXR-GS) but did not bind DNA and was transcriptionally inactive. Examination of the 3' half-site of several PPREs revealed that variations from the consensus sequence reduced or abolished transcriptional activity, but conversion to consensus improved transcriptional activity with PPARgamma-GS and PPARgamma-AA. Examination of the 5' half-site indicated that the upstream three nucleotides were more important for transcriptional activity than the downstream three nucleotides. Our data demonstrated that stringent binding of RXR to the 3' half-site of a PPRE is more influential on the binding of the PPARgamma/RXR heterodimer than the ability of PPARgamma to bind DNA. Thus, unlike RXR, PPARgamma exhibits promiscuity in binding on a PPRE, suggesting that the definition of a PPRE for PPARgamma may need to be expanded.