Multicentric Carpotarsal Osteolysis: a Contemporary Perspective on the Unique Skeletal Phenotype.

PURPOSE OF REVIEW: Multicentric carpotarsal osteolysis (MCTO) is an ultra-rare disorder characterized by osteolysis of the carpal and tarsal bones, subtle craniofacial deformities, and nephropathy. The molecular pathways underlying the pathophysiology are not well understood. RECENT FINDINGS: MCTO is caused by heterozygous mutations in MAFB, which encodes the widely expressed transcription factor MafB. All MAFB mutations in patients with MCTO result in replacement of amino acids that cluster in a phosphorylation region of the MafB transactivation domain and account for a presumed gain-of-function for the variant protein. Since 2012, fewer than 60 patients with MCTO have been described with 20 missense mutations in MAFB. The clinical presentations are variable, and a genotype-phenotype correlation is lacking. Osteolysis, via excessive osteoclast activity, has been regarded as the primary mechanism, although anti-resorptive agents demonstrate little therapeutic benefit. This paper appraises current perspectives of MafB protein action, inflammation, and dysfunctional bone formation on the pathogenesis of the skeletal phenotype in MCTO. More research is needed to understand the pathogenesis of MCTO to develop rational therapies.

Spinal Fusion in Pediatric Patients With Low Bone Density: Defining the Value of DXA.

BACKGROUND: Children with medical complexity are at increased risk of low bone mineral density (BMD) and complications after spinal fusion compared with idiopathic scoliosis patients. Our aim was to compare treatments and outcomes of children with medical complexity undergoing spinal fusion in those who had dual-energy x-ray absorptiometry (DXA) scans versus those who did not in an effort to standardize the workup of these patients before undergoing spinal surgery. METHODS: We conducted a retrospective review of patients with low BMD who underwent spinal fusion at a tertiary care pediatric hospital between 2004 and 2016. We consulted with a pediatric endocrinologist to create standard definitions for low BMD to classify each subject. Regardless of DXA status, all patients were given a clinical diagnosis of osteoporosis [at least 2 long bone or 1 vertebral pathologic fracture(s)], osteopenia (stated on radiograph or by the physician), or clinically low bone density belonging to neither category. The last classification was used for patients whose clinicians had documented low bone density not meeting the criteria for osteoporosis or osteopenia. Fifty-nine patients met the criteria, and 314 were excluded for insufficient follow-up and/or not meeting a diagnosis definition. BMD Z -scores compare bone density ascertained by DXA to an age-matched and sex-matched average. Patients who had a DXA scan were also given a DXA diagnosis of low bone density (≤-2 SD), slightly low bone density (-1.0 to -1.9 SD), or neither (>-1.0 SD) based on the lowest BMD Z -score recorded. RESULTS: Fifty-nine patients were analyzed. Fifty-four percent had at least 1 DXA scan preoperatively. Eighty-one percent of DXA patients received some form of treatment compared with 52% of non-DXA patients ( P =0.03). CONCLUSIONS: Patients referred for DXA scans were more likely to be treated for low BMD, although there is no standardized system in place to determine which patients should get scans. Our research highlights the need to implement clinical protocols to optimize bone health preoperatively. LEVEL OF EVIDENCE: Level II-retrospective prognostic study.

Bone Density in Transgender Youth on Gender-Affirming Hormone Therapy.

Some transgender youth are treated with gonadotropin-releasing hormone agonists (GnRHa) followed by testosterone or estradiol, which may impact bone mineral density (BMD). This cross-sectional study of transgender youth (n = 56, aged 10.4-19.8 years, 53% assigned female at birth [AFAB]) utilized total body dual-energy x-ray absorptiometry to evaluate BMD Z-scores, and associations between GnRHa duration, body mass index (BMI), and BMD. Participants on GnRHa alone (n = 19, 14 assigned male at birth [AMAB], 5 AFAB) at the time of the study visit were 13.8 [12.8, 15.3] (median [IQR]) years old, had been on GnRHa for 10 [5.5, 19.5] months, and began GnRHa at age 12 [10.4, 12.6] years. Total body BMD Z-score for individuals on GnRHa monotherapy was -0.10 [-0.8, 0.4] (AFAB, female norms) and -0.65 [-1.4, 0.22] (AMAB, male norms). AFAB participants (n = 21) on testosterone were age 16.7 [15.9, 17.8] years, had been on testosterone for 11 [7.3, 14.5] months, and started testosterone at age 16 [14.8, 16.8] years; total body BMD Z-score -0.2 [-0.5, 0] (male norms) and 0.4 [-0.2, 0.7] (female norms). AMAB participants (n = 16) were age 16.2 [15.1, 17.4] years, had been on estradiol for 11 [5.6, 13.7] months, and started estradiol at age 16 [14.4, 16.7] years; total body BMD Z-score -0.4 [-1.1, 0.3] (male norms) and -0.2 [-0.7, 0.6] (female norms). BMD Z-score was negatively correlated with GnRHa duration (male norms: r = -0.5, P = .005; female norms: r = -0.4, P = .029) and positively correlated with BMI (male norms: r = 0.4, P = .003; female norms: r = 0.4, P = .004). In this cross-sectional cohort, total body BMD Z-scores were slightly below average, but lowest in the AMAB group on GnRHa monotherapy.

Treatment of a young child with multicentric carpotarsal osteolysis exhibiting joint inflammation and dysfunctional bone formation.

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by osteolysis of the carpal and tarsal bones. Antiresorptive agents have proven ineffective and the pathogenesis of MCTO remains poorly understood. We report a young child with a novel variant in MAFB who demonstrated clinical improvement of joint symptoms following anti-rheumatic therapies. Also, radiographs from a young age suggest that dysfunctional bone formation may play a role in the skeletal phenotype of MCTO.

Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial.

Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia. Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 µg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22). Findings: Forty-two participants received TransCon CNP at doses of 6 µg (n = 10; 7 female), 20 µg (n = 11; 3 female), 50 µg (n = 10; 3 female), or 100 µg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 µg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 µg CNP/kg/week. Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 µg CNP/kg/week in the ongoing pivotal trial. Funding: Ascendis Pharma, A/S.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

Gorham's disease and diffuse lymphangiomatosis in children and adolescents.

Gorham's disease is a rare disorder of unknown etiology and variable clinical presentation that is characterized by proliferation of thin-walled vascular channels resulting in destruction and resorption of osseous matrix. The condition is frequently under recognized or misdiagnosed. There is no standard treatment defined for this disease. Here we report on eight children diagnosed with Gorham's disease at our institution over a ten-year period. Soft tissue lymphangioma was present in seven and six children had splenic involvement. Disease stabilization and improvement was observed on treatment with interferon alpha-2b and bisphosphonate therapy.

Igf-I stimulates in vivo thymopoiesis after stem cell transplantation in a child with Omenn syndrome.

CONTEXT: Children with severe combined immunodeficiency who receive a T cell-depleted hematopoietic stem cell transplantation (HSCT) have delayed immune reconstitution. OBJECTIVE: To examine the use of recombinant human insulin-like growth factor-I (rhIGF-I) therapy to stimulate thymopoiesis after HSCT. CLINICAL CASE: A child with Omenn syndrome failed T cell reconstitution 6 months after HSCT. She started rhIGF-I therapy just before age 18 months. The initial dose (40 microg/kg twice daily) was increased every 2 weeks to a maximum dose of 120 microg/kg twice daily. RESULTS: The patient's absolute T cells increased from 7 to 132/mm(3) and 662/mm(3) after 3 and 5 months of rhIGF-I therapy, respectively, and her blastogenic response to phytohemagglutinin normalized. Three months after discontinuation of rhIGF-I therapy, the T cells continued to increase (to 2,427/mm(3)) although the blastogenic response to phytohemagglutinin decreased. CONCLUSION: This is the first known use of rhIGF-I therapy to help restore thymopoiesis in a child.

Evolving central hypothyroidism in children with optic nerve hypoplasia.

BACKGROUND: Children with optic nerve hypoplasia (ONH) are at high risk for early-onset congenital central hypothyroidism (CH); however, reports of evolving, late-onset CH are rare and poorly documented. AIM: To examine the clinical and biochemical data of children with ONH who developed CH after documented normal thyroid function tests at an earlier age. PATIENTS AND METHODS: Children who developed late-onset CH were selected for review from an observational study (n = 214) that examined clinical risk factors for endocrinological abnormalities in children with ONH. RESULTS: Eight patients with ONH developed CH between the ages of 20-51 months. One child at age 28 months developed CH within 4 months of prior normal thyroid function tests. There were no associations among clinical, neuroradiographical, vision, and/or pituitary outcomes. CONCLUSIONS: Children with ONH may develop CH over time, and surveillance thyroid function tests may be necessary as frequently as every four months.

Peer mentoring for professional and personal growth in academic medicine.

Mentorship is a critical component of career development, particularly in academic medicine. Peer mentorship, which does not adhere to traditional hierarchies, is perhaps more accessible for underrepresented groups, including women and minorities. In this article, we review various models of peer mentorship, highlighting their respective advantages and disadvantages. Structured peer mentorship groups exist in different settings, such as those created under the auspices of formal career development programs, part of training grant programs, or through professional societies. Social media has further enabled the establishment of informal peer mentorship through participatory online groups, blogs, and forums that provide platforms for peer-to-peer advice and support. Such groups can evolve rapidly to address changing conditions, as demonstrated by physician listserv and Facebook groups related to the COVID-19 pandemic. Peer mentorship can also be found among colleagues brought together through a common location, interest, or goal, and typically these relationships are informal and fluid. Finally, we highlight here our experience with intentional formation of a small peer mentoring group that provides structure and a safe space for professional and social-emotional growth and support. In order to maximize impact and functionality, this model of peer mentorship requires commitment among peers and a more formalized process than many other peer mentoring models, accounting for group dynamics and the unique needs of members. When done successfully, the depth of these mentoring relationships can produce myriad benefits for individuals with careers in academic medicine including, but not limited to, those from underrepresented backgrounds.

Persistent idiopathic hyperphosphatasemia from bone alkaline phosphatase in a healthy boy.

Alkaline phosphatase (ALP) in humans comprises a family of four cell-surface phosphomonoester phosphohydrolase isozymes. Three genes separately encode the "tissue-specific" ALPs whereas the fourth gene encodes ubiquitous homodimeric "tissue-nonspecific" ALP (TNSALP) richly expressed in bone, liver, kidney, and developing teeth. TNSALP monomers have five putative N-linked glycosylation sites where different post-translational modifications account for this isozyme's distinctive physicochemical properties in different organs. Three bone-derived TNSALP (BALP) isoforms (B/I, B1, and B2) are present in healthy serum, whereas a fourth BALP isoform (B1x) can circulate in chronic kidney disease. Herein, we report a healthy boy with persistent hyperphosphatasemia due to BALP levels two- to threefold higher than age-appropriate reference values. High-performance liquid chromatography, electrophoresis, heat inactivation, catalysis inhibition, and polyethylene glycol precipitation revealed increased serum B/I, B1, and B2 differing from patterns found in skeletal diseases. B/I was ~23-fold elevated. Absence of mental retardation and physical stigmata excluded Mabry syndrome, the ALP-anchoring disorder causing hyperphosphatasemia. Routine biochemical studies indicated intact mineral homeostasis. Serum N-terminal propeptide of type I procollagen (P1NP) level was normal, but C-terminal cross-linking telopeptide of type I collagen (CTX) level was elevated. However, radiological studies showed no evidence for a generalized skeletal disturbance. Circulating pyridoxal 5'-phosphate, a TNSALP natural substrate, was not low despite the laboratory hyperphosphatasemia, thereby suggesting BALP phosphohydrolase activity was not elevated endogenously. Mutation analysis of the ALPL gene encoding TNSALP revealed no defect. His non-consanguineous healthy parents had serum total ALP activity and BALP protein levels that were normal. Our patient's sporadic idiopathic hyperphosphatasemia could reflect altered post-translational modification together with increased expression and/or impaired degradation of BALP.

Long-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation.

In this article, we describe the long-term outcomes of children who were previously reported to have developed hypophosphatemic bone disease in association with elemental formula use. An extended chart review allowed for an updated report of 34 children with regard to severity/duration of bone disease, extent of recovery, and time to correction using radiology reports and biochemical data. After implementation of formula change and/or phosphate supplementation, we found that serum phosphorus concentration increased and serum alkaline phosphatase activity decreased in all patients, normalizing by 6.6 ± 4.0 (mean ± SD) months following diagnosis. The decrease in serum alkaline phosphatase from diagnosis to the time of correction was moderately correlated with the concurrent increase in serum phosphorus (R = 0.48, P < .05). Age at diagnosis significantly correlated with time to resolution (R = 0.51, P = .01). This study supports the earlier report that bone disease associated with hypophosphatemia during elemental formula use responds to formula change and/or phosphate supplementation.

Glycogen storage disease presenting as Cushing syndrome.

Impaired growth is common in patients with glycogen storage disease (GSD), who also may have "cherubic" facies similar to the "moon" facies of Cushing syndrome (CS). An infant presented with moon facies, growth failure, and obesity. Laboratory evaluation of the hypothalamic-pituitary-adrenal (HPA) axis was consistent with CS. He was subsequently found to have liver disease, hypoglycemia, and a pathogenic variant in PHKA2, leading to the diagnosis of GSD type IXa. The cushingoid appearance, poor linear growth and hypercortisolemia improved after treatment to prevent recurrent hypoglycemia. We suspect this child's HPA axis activation was "appropriate" and caused by chronic hypoglycemic stress, leading to increased glucocorticoid secretion that may have contributed to his poor growth and excessive weight gain. This is in contrast to typical CS, which is due to excessive adrenocorticotropic hormone (ACTH) or cortisol secretion from neoplastic pituitary or adrenal glands, ectopic secretion of ACTH or corticotropin-releasing hormone (CRH), or exogenous administration of corticosteroid or ACTH. Pseudo-CS is a third cause of excessive glucocorticoid secretion, has no HPA axis pathology, is most often associated with underlying psychiatric disorders or obesity in children and, by itself, is thought to be benign. We speculate that some diseases, including chronic hypoglycemic disorders such as the GSDs, may have biochemical features and pathologic consequences of CS. We propose that excessive glucocorticoid secretion due to chronic stress be termed "stress-induced Cushing (SIC) syndrome" to distinguish it from the other causes of CS and pseudo-CS, and that evaluation of children with chronic hypoglycemia and poor statural growth include evaluation for CS.

Gynecomastia in prepubertal and pubertal men.

PURPOSE OF REVIEW: Gynecomastia is often benign, but it can be the sign of serious endocrine disease and the source of significant embarrassment and psychological stress. Understanding its pathogenesis is crucial to distinguish a normal developmental variant from pathological causes. RECENT FINDINGS: There is a growing list of potential causes of gynecomastia. Rare and unique case reports continue to supplement the literature to augment our understanding of this common physical finding. However, the exact basis for the pathogenesis of gynecomastia remains unknown. There appears to be a local imbalance between estrogen stimulation and the inhibitory action of androgens on breast tissue proliferation. Gynecomastia in a prepubertal boy is rare and should prompt an immediate evaluation for possible endocrine disorder. Pubertal gynecomastia, on the contrary, is common and usually physiological, with sympathetic reassurance and watchful waiting the mainstays of treatment. There is some evidence that early pharmacological intervention with antiestrogens may diminish persistent pubertal gynecomastia, but treatment with an aromatase inhibitor has not been shown to be more effective than placebo. SUMMARY: Treatment of gynecomastia is geared toward its specific cause. Currently, there are insufficient data to recommend medical therapy in children with idiopathic gynecomastia.

Comprehensive nutritional and metabolic assessment in patients with spinal muscular atrophy: Opportunity for an individualized approach.

Optimal nutrition support is recommended for patients with spinal muscular atrophy (SMA). In a prospective study, we performed comprehensive nutritional assessments with the aim to guide best nutritional strategies for patients with SMA types II and III. We recorded a) anthropometry; b) macro- and micronutrient intakes; c) measured resting energy expenditure by indirect calorimetry; and d) body composition including dual X-ray absorptiometry. We enrolled a cohort of 21 patients aged 3 to 36 years of which 13 were female; 19 had SMA type II and 2 had SMA type III. The body mass index z-score ranged from -3 to 2.4. Forty-five percent of the cohort was either underfed or overfed, based on the difference between actual energy intake and measured resting energy expenditure. Vitamin D, E, K, folate and calcium intakes were low in a majority of the cohort. Forty-five percent of the cohort was either hypometabolic or hypermetabolic. Fat mass index (kg/m2) was significantly higher and lean body mass index (kg/m2) was significantly lower in the study cohort compared to population normalized values. Bone mineral density was low in 13 of 17 patients. In summary, we have described the prevalence of malnutrition, suboptimal feeding and alterations in body composition in children with SMA. A comprehensive nutritional assessment could guide individualized nutrition therapy in this vulnerable population.

Risk Factors for Fractures in Children Hospitalized in Intensive and Intermediate Care Units.

BACKGROUND AND OBJECTIVES: Fragility fractures are increasingly recognized in hospitalized children. Our study aim was to identify risk factors for fracture in children hospitalized in intensive and intermediate care units. METHODS: We conducted a retrospective, case-control study comparing the clinical characteristics of children with fractures (cases) to children without fractures (controls) matched for age, sex, hospital unit, admission quarter and year, ICU length of stay, severity of illness, and resource utilization. Bivariate comparisons and matched multivariable logistic regression modeling were used to determine associations between potential risk factors and fracture. RESULTS: Median age at fracture for the 35 patients was 5.0 months (interquartile range 2.0 to 10.0 months) and at a comparable interval for the 70 matched controls was 3.5 months (interquartile range 2.0 to 7.0 months). In bivariate analyses, factors associated with fracture included: primary diagnosis of tracheoesophageal fistula, esophageal atresia and stenosis; diagnosis of kidney disease; and per 5-day increase in median cumulative ICU days at risk. In the final model, a respiratory disease diagnosis (odds ratio 3.9, 95% confidence interval 1.1-13.7) and per 5-day increase in median cumulative ICU days at risk (odds ratio 1.3, 95% confidence interval 1.0-1.6) were significant independent risk factors for fracture. CONCLUSIONS: Children prone to fracture in the hospital are young, medically complex patients who require extended periods of intensive level medical care and potentially life-sustaining treatment modalities. The children who would benefit most from fracture reduction efforts are those with respiratory disease and prolonged ICU stays.

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.

Brief Report: Scurvy as a Manifestation of Food Selectivity in Children with Autism.

Scurvy was diagnosed in seven children at Boston Children's Hospital. All of the children had a developmental disorder and autism was the most common. They had a long-standing history of food selectivity with diets devoid of fruits and vegetables, and none of the children were supplemented with a multivitamin. They presented with limp, and an elaborate panel of tests and procedures were undertaken before the diagnosis of scurvy was made. Treatment with vitamin C led to rapid recovery of symptoms. This report emphasizes the importance of considering nutritional causes of musculoskeletal symptoms in children with autism and restrictive diets.