Lisa Swartz Topor

Variation in Methods of Predicting Adult Height for Children With Idiopathic Short Stature

OBJECTIVE: Recombinant human growth hormone (GH) is approved for treatment of children with idiopathic short stature, and endocrinologists often depend on algorithms to predict adult height. Because algorithm performance often is included in treatment decisions, we sought to evaluate agreement among height prediction formulas. METHODS: We identified 3 commonly used algorithms for height prediction, the Bayley-Pinneau, Roche-Wainer-Thissen, and Khamis-Roche methods. We constructed simulated samples of children with typical distributions of ages, heights, weights, bone ages, and parental heights seen in patients with idiopathic short stature, and we applied the algorithms to the simulated sample to determine whether predicted adult height was <160 cm for boys or <150 cm for girls (<1.2nd height percentiles for adults). RESULTS: We found substantial disagreement among algorithms in the proportions of simulated cases with predicted adult heights of <1.2nd percentile, a cutoff value that may influence GH treatment decisions. With the Bayley-Pinneau formula, 43% of boys and 81% of girls had predicted adult heights below this threshold; with the Khamis-Roche method, only 3% of boys and 0.2% of girls had predicted heights of <1.2nd percentile. Roche-Wainer-Thissen predictions were between those values. Overall agreement of the methods was poor (κ = 0.21) for boys and negative for girls. CONCLUSIONS: Wide variation exists among formulas used to predict adult heights. Because these algorithms may be used in decisions regarding whether to initiate GH treatment and assessment of the efficacy of GH in research trials, it is important for parents, pediatricians, and investigators to recognize the considerable variation involved in height predictions.

Unexpected Widespread Hypophosphatemia and Bone Disease Associated with Elemental Formula Use in Infants and Children

OBJECTIVE Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. METHODS A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. RESULTS Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. CONCLUSION The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop.

Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2 (UCP2).

Context The rarest genetic form of congenital hyperinsulinism (HI) has been associated with dominant inactivating mutations in uncoupling protein 2 (UCP2), a mitochondrial inner membrane carrier that modulates oxidation of glucose vs amino acids. Objective To evaluate the frequency of UCP2 mutations in children with HI and phenotypic features of this form of HI. Design We examined 211 children with diazoxide-responsive HI seen at The Childrens Hospital of Philadelphia (CHOP) between 1997 and October 2016. Setting CHOP Clinical and Translational Research Center. Results Of 211 cases of diazoxide-responsive HI, we identified 5 unrelated children with UCP2 mutations (5 of 211; 2.4%). All 5 were diagnosed with HI before 6 months of age; diazoxide treatment was only partly effective in 3 of the 5. Among the 5 cases, 4 unique mutations (3 missense and 1 splicing) were identified. Three mutations were novel; 1 was previously reported. In vitro functional assays showed 30% to 75% decrease in UCP2 activity. Two of the children, when not taking diazoxide, developed hypoketotic-hypoglycemia after fasting 15 to 20 hours; a similar trend toward hypoglycemia after fasting 24 hours occurred in 4 adult carriers. In contrast, both children and 2 of the 4 carriers developed symptomatic hypoglycemia 4 hours following oral glucose. Unusual oscillating glucose and insulin responses to oral glucose were seen in both cases and carriers. Conclusions These data indicate that dominant UCP2 mutations are a more important cause of HI than has been recognized and that affected individuals are markedly hypersensitive to glucose-induced hypoglycemia.

Fractures Among Inpatients in a Pediatric Hospital

OBJECTIVE Fractures occurring in hospitalized children may be an underrecognized preventable harm with implications for current and future bone health, but few data exist regarding the clinical characteristics of these pediatric patients. We describe the clinical characteristics of patients who sustained fractures during hospitalization over a 4.5-year period at a single tertiary care center. METHODS We retrospectively identified subjects who experienced inpatient fractures using a voluntary safety event reporting system and computer-assisted keyword search of the electronic medical record. We used the medical record to collect clinical characteristics, laboratory data, and survival status. RESULTS The safety event reporting system and keyword search identified 57% and 43% of subjects, respectively. Fifty-six subjects sustained 128 fractures while hospitalized, most frequently at the femur (33 fractures) and humerus (30 fractures). Twenty-seven subjects sustained multiple fractures. Common clinical characteristics included age ≤1 year (64%); preterm birth (53%); admission to an ICU (90%); immobilization (88%); and weight-for-age z score less than or equal to -2.0 (52%). Sixteen (29%) subjects died, and the mortality rate varied by primary diagnosis. CONCLUSIONS Critically ill, immobilized infants under 1 year of age and who were often born preterm sustained the majority of fractures occurring during hospitalization. A voluntary reporting system was insufficient to identify all inpatient fractures. Future studies should explore optimal fracture screening strategies and the relationship among fractures, severity of illness and mortality in hospitalized children.

Turner syndrome and pituitary adenomas: a case report and review of literature.

Abstract Background: Turner syndrome (TS) is the most common sex chromosome abnormality in females, typically associated with primary amenorrhea and premature ovarian failure due to gonadal dysgenesis. The association of TS with hypopituitarism is an uncommon finding. The objective of the study was to describe an adolescent with TS with hypergonadotropic hypogonadism and subsequent hypogonadotropic hypogonadism. Case presentation: A 16-year-old female with primary amenorrhea was diagnosed with TS based on karyotype 45,XO. Other laboratory values included FSH 45.52 IU/L, LH 17.4 IU/L, undetectable estradiol, and prolactin 1.08 nmol/L. Two months later and before treatment, she presented with severe headache and a new left cranial nerve VI palsy. Brain MRI showed a 2.7-cm hemorrhagic pituitary macroadenoma expanding the sella. Laboratory evaluation showed FSH 5.9 IU/L, LH 0.9 IU/L, prolactin 0.09 nmol/L, and GH 1.03 ng/mL. She underwent transphenoidal hypophysectomy, and pathology revealed pituitary adenoma with immunohistochemical staining positive for growth hormone and prolactin. She subsequently developed multiple pituitary hormone deficiencies. Review of the literature identified eight case reports of women with TS who developed pituitary adenomas. Conclusions: This case illustrates an uncommon co-occurrence of TS and pituitary macroadenoma. Sequential gonadotropin measurements demonstrate the evolution of hypergonadotropic hypogonadism into hypogonadotropic hypogonadism due to hemorrhagic pituitary macroadenoma.

Case 3: Emesis and Oral Hyperpigmentation in a 17-year-old Girl

1. Meghan E. Fredette, MD* 2. Lisa Swartz Topor, MD, MMSc* 1. *Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, RI A 17-year-old girl presents for evaluation of persistent emesis and an unintentional 13.2-lb (6-kg) weight loss during the past 3 months. Emesis occurs daily in the mornings and is nonbloody and nonbilious. Nausea improves throughout the day and with hot showers. She denies diarrhea. When eating, she prefers salty foods such as pickles. She reports daily marijuana use. She feels that marijuana has stained her lips and tongue, as they appear darker to her. She notes fatigue, epigastric pain, weakness, and dizziness. She denies fevers, dysuria, or headaches. On physical examination she is afebrile, with a heart rate of 140 beats/min, respiratory rate of 18 breaths/min, blood pressure of 86/52 mm Hg, and oxygen saturation of 98%. Her weight is 91 lb (41.3 kg) (<1st percentile), height is 59 in (150 cm) (2nd percentile), and body mass index is 18.3 (14th percentile). Patchy hyperpigmentation is noted on the lips, buccal mucosa, and palate. Bowel sounds are hyperactive, and abdominal examination is without tenderness, rebound, or guarding. There are no masses or hepatosplenomegaly. Laboratory evaluation reveals a low serum sodium level of 130 mEq/L (130 mmol/L), with a normal potassium level of 3.8 mEq/L (3.8 mmol/L). Urine pregnancy test result is negative. The results of thyroid function testing, liver enzymes, lipase, complete blood cell count, and inflammatory markers are within normal limits. Abdominal radiograph is normal. Additional laboratory testing reveals the diagnosis. Random serum cortisol and corticotropin samples were sent in the setting of hypotension and tachycardia, and a stress dose of …

Craniosynostosis as the Presenting Feature of X-linked Hypophosphatemic Rickets

With these cases, we describe primary craniosynostosis as the presenting feature of XLH and highlight that craniosynostosis can develop in infancy in children with XLH. Craniosynostosis is the premature closure of cranial sutures. Primary, or congenital, craniosynostosis is often sporadic but may be associated with genetic or chromosomal abnormalities. Secondary craniosynostosis presents after gestation, and can occur in metabolic bone diseases, including rickets. We describe the first reported cases of primary craniosynostosis in 2 unrelated, term infants with X-linked hypophosphatemic rickets (XLH). The diagnosis of XLH in both patients was confirmed by genetic testing. At the time craniosynostosis was detected, the patient in the first case did not have any other clinical features of XLH. The second patient developed clinical findings of craniosynostosis, followed by rickets. These are the earliest reported cases of craniosynostosis in XLH and demonstrate that craniosynostosis may be a presenting feature of this disease.

Nephrolithiasis: A complication of pediatric diabetic ketoacidosis: AGRAWAL et al.

To determine the frequency of nephrolithiasis as a complication of diabetic ketoacidosis (DKA) in pediatrics.

Central precocious puberty in Boston boys: A 10-year single center experience

Objective Recent studies in the US and abroad suggest that boys are undergoing puberty at a younger age. It is unknown if this secular trend extends to boys with central precocious puberty (CPP), who sit at the extreme end of the pubertal spectrum, and if neuroimaging should remain a standard diagnostic tool. Study design Retrospective chart review of all boys with CPP seen by Endocrinology at a US pediatric hospital from 2001–2010. Results Fifty boys had pubertal onset at an average age of 7.31 years (95CI 6.83–7.89), though many did not present until nearly one year thereafter, by which time 30% were mid-to-late pubertal. Boys were predominantly non-Hispanic White and 64% were overweight/obese. The majority (64%) of boys had neurogenic CPP (CNS-CPP) with neurofibromatosis type I being the most common diagnosis. Diagnosis of CPP led to discovery of a neurogenic lesion in only 3 of 32 (9%) CNS-CPP cases. The remaining boys, with idiopathic CPP (36%), were indistinguishable from those with CNS-CPP aside from four boys who endorsed a family history of PP (22% vs. 0% among CNS-CPP cases). Importantly, there was no change in the incidence of male CPP after accounting for the increase in clinic volume during this time period. Conclusion In this contemporary Boston-based cohort of 50 boys with CPP, most cases were neurogenic, consistent with older literature. Several idiopathic cases had a family history of PP but were otherwise indistinguishable from CNS-CPP cases. Thus, neuroimaging remains a critical diagnostic tool. We find no evidence for an increase in the prevalence of male CPP.

The Efficacy of Anastrozole and Growth Hormone Therapy on Adult Height in Six Adolescent Males with Growth Hormone Deficiency or Idiopathic Short Stature

Background. Data on adult height outcomes of the use of Anastrozole and Growth Hormone (GH) in pubertal males with Growth hormone deficiency (GHD) and Idiopathic short stature (ISS) are limited. Objective. We examined the effect of Anastrozole and GH therapy on near adult height (NAH) with pubertal males with GHD or ISS. Methods. Retrospective review of 419 charts from 2008 to 2015. The primary outcomes are NAH compared to mid-parental target height (MPTH) and predicted adult height (PAH). Results. We identified 23 patients (5 SGA/IUGR, 1 Noonan syndrome, 6 GHD, and 11 ISS). Six patients (4 GHD; 2 ISS) achieved NAH. Prior to Anastrozole treatment, the mean chronological age was years (range 13.7–14.4), bone age was years (range 12.5–14), mean height SDS was (range −0.8 to −2.3), and mean PAH was cm (range 153.5–168.6). MPTH was 173.6 cm ± 7 (range 161.8–181.6). Patients received Anastrozole for an average of 30.5 months (range 19–36 months). At NAH, the mean chronological age was years (range 15.9–18.1 years) and height was cm (range 168.5–173.4 cm). The mean height SDS improved to (range