Halley Wasserman

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.

Use of dual energy X-ray absorptiometry in pediatric patients

Dual Energy X-ray Absorptiometry (DXA) is a vital tool for assessing bone health in patients at risk for fragility fractures. In pediatric patients, this technology is used in conjunction with clinical fracture history to diagnosis osteoporosis and monitor treatment response. Childhood and adolescence is characterized by linear growth and bone mass accrual; thus there are important differences in the interpretation of bone measurements obtained by DXA in these young patients. This review aims to explore the current indications for DXA use and interpretation of DXA in the pediatric age group using currently available reference databases. Limitations of DXA in pediatric patients, specifically in children with short stature, will be explored. We will review several pathophysiologic mechanisms that may lead to low bone density in children, discussing representative diseases and the recommendations for monitoring bone health with DXA in these conditions. Finally, we will highlight new methods by which DXA imaging can gather additional information on bone health in children and may improve our ability to predict fractures and osteoporosis.

Pharmacokinetics of IGF-I in PAPP-A2 Deficient Patients, Growth Response, and Effects on Glucose and Bone Density.

Context The pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulinlike growth factor binding proteins 3 and 5, releasing free insulinlike growth factor 1 (IGF-1). Homozygous mutations in PAPP-A2 result in growth failure with elevated total but low free IGF-1. Objective To determine the 24-hour pharmacokinetic (PK) profile of free and total IGF-1 after a dose of recombinant human insulinlike growth factor 1 (rhIGF-1). We describe the growth response and effects on glucose metabolism and bone mineral density (BMD) after 1 year of rhIGF-1 therapy. Design and Patients Three affected siblings, their heterozygous parents, and two healthy controls participated. The subjects received a dose of rhIGF-1, followed by serial blood samples collected over 24 hours. The two younger siblings were started on rhIGF-1 treatment. An oral glucose tolerance test and dual-energy X-ray absorptiometry scans were obtained at baseline and after 1 year of treatment. Results Subcutaneous administration of rhIGF-1 increased the concentration of free and total IGF-1 in patients with PAPP-A2 deficiency. The PK profile was comparable in all participants. At baseline, all three subjects demonstrated insulin resistance and below-average BMD. Treatment with rhIGF-1 is ongoing in the youngest patient but was discontinued in his brother because of the development of pseudotumor cerebri. The treated patient had an increase in height velocity from 3.0 to 6.2 cm/y, resolution of insulin resistance, and an increase in total body BMD. Conclusions rhIGF-1 at standard dosages resulted in similar PK characteristics in patients with PAPP-A2 deficiency, heterozygous relatives, and healthy controls. The youngest affected patient experienced a modest growth response to therapy with rhIGF-1, as well as beneficial effects on glucose metabolism and bone mass.

Low bone mineral density and fractures are highly prevalent in pediatric patients with spinal muscular atrophy regardless of disease severity

Patients with Spinal Muscular Atrophy (SMA) are at risk for poor bone health. The prevalence of fractures, low areal bone mineral density (aBMD; Z-score ≤-2.0) of the lateral distal femur and of osteoporosis by SMA subtype is not known. We aimed to describe the natural history of bone health in patients with SMA prior to bisphosphonate treatment. We reviewed data from 85 eligible patients with SMA ages 12 months to 18 years, seen at a single institution between January 2005 and July 2016. Fracture history was reported at annual clinic visits. aBMD was obtained from dual energy x-ray absorptiometry scans of the lumbar spine, total body, and lateral distal femur. 85% of patients had aBMD Z-scores ≤-2.0 SD and were progressively lower with worsening SMA severity. Longitudinal aBMD Z-scores of the lateral distal femur decreased with age. Fractures occurred in 38% (32/85) of patients with the femur being the most common location (25 of 57 fractures). Thirteen percent of patients fulfilled criteria for osteoporosis. Low aBMD and femur fractures are highly prevalent in all SMA subtypes from a young age; however, few patients met the criteria for osteoporosis. Poor bone health may be an under-recognized comorbidity of SMA.

Bilateral cataracts in a 6-yr-old with new onset diabetes: a novel presentation of a known INS gene mutation.

The prevalence of diabetes‐related cataracts during childhood is less than 1%. When cataracts occur, it is often in adolescent females with prolonged symptoms and significant hyperglycemia. Cataracts are not a classic feature of monogenic diabetes. We report a case of a 6‐yr‐old, previously healthy Caucasian male, who presented with bilateral acquired cataracts and was subsequently diagnosed with new onset diabetes. Additional symptoms at presentation included a several year history of polyuria and polydipsia, mild hepatomegaly, and short stature. Pertinent negatives include acanthosis nigricans, lipoatrophy, deafness, muscle weakness, or neuropathy. HbA1c was significantly elevated at diagnosis (>14%, 129.5 mmol/mol) without evidence of ketosis. Autoantibody testing was negative. Features of Mauriac syndrome (short stature, hepatomegaly) as well as acquired cataracts indicated long‐standing hyperglycemia with sufficient insulin production to prevent ketone production and development of diabetic ketoacidosis. Whole exome sequencing was conducted and a de novo heterozygous mutation in the INS gene (c.94G>A; p.Gly32Ser) was identified. INS gene mutations are common causes of permanent neonatal diabetes but rare causes of antibody‐negative diabetes in children. Importantly, INS gene mutations have not been previously associated with acquired cataracts. Knowledge of a monogenic cause of diabetes allows clinicians to tailor counseling and screening of diabetes‐related comorbidities. In summary, this case highlights the need to consider testing for monogenic diabetes, specifically INS gene mutations, in pediatric patients with antibody‐negative diabetes, especially if complications of prolonged hyperglycemia are present at diagnosis.

Bone fragility in Turner syndrome: Fracture prevalence and risk factors determined by a national patient survey

Osteoporosis is considered a comorbidity of adult women with Turner syndrome (TS). Limited data are available on fracture prevalence in girls and women with this diagnosis. We aimed to determine the prevalence of fractures in individuals with TS in the United States and identify risk factors for fracture.

Outcome of Isolated Absent Septum Pellucidum Diagnosed by Fetal Magnetic Resonance Imaging (MRI) Scan

Improved fetal imaging has resulted in increased diagnosis of isolated absent septum pellucidum without other intracranial abnormalities. There is little literature regarding outcomes for these fetuses. This study hypothesized the majority of infants diagnosed by fetal magnetic resonance imaging (MRI) with isolated absent septum pellucidum would retain this diagnosis postnatally. Specifically, in the absence of postnatal endocrine or ophthalmologic abnormalities, postnatal imaging would find no additional related findings, and fetuses would be at low risk for developmental delay. Two of 8 subjects met postnatal criteria for septo-optic dysplasia; remaining subjects had normal postnatal endocrine and ophthalmologic evaluations and no significant related findings on postnatal MRI. One subject without septo-optic dysplasia had delays on developmental screening; all others had normal screening (range of follow-up 8-72 months). Our study questions the necessity of postnatal imaging for prenatally diagnosed isolated absent septum pellucidum. Majority of fetuses with isolated absent septum pellucidum retained this diagnosis postnatally.

Bone Mineralization and Fracture Risk Assessment in the Pediatric Population

Identifying children most susceptible to clinically significant fragility fractures (low trauma fractures or vertebral compression fractures) or recurrent fractures is an important issue facing general pediatricians and subspecialists alike. Over the last decade, several imaging technologies, including dual-energy X-ray absorptiometry and peripheral quantitative computed tomography, have become useful to identify abnormal bone mineralization in children and in adolescents. This review aimed to summarize the latest literature on the utility of these modalities as they pertain to use in pediatrics. In addition, we review several disease states associated with poor bone health and increased fracture risk in children, and discuss the implications of low bone mineral density in these patients. Finally, we will highlight the gaps in knowledge with regard to pediatric bone health and make recommendations for future areas of research.