Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina.

Importance: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal genetic disorder in which an accumulation of very long-chain fatty acids leads to inflammatory demyelination in the central nervous system and to adrenal cortex atrophy. In 2016, X-ALD was added to the US Recommended Uniform Screening Panel. Objective: To evaluate the performance of a single-tier newborn screening assay for X-ALD in North Carolina. Design, Setting, and Participants: This diagnostic screening study was of all newborn dried blood spot specimens received in the North Carolina State Laboratory of Public Health between January 2 and June 1, 2018, excluding specimens of insufficient quantity or quality. A total of 52 301 specimens were screened for X-ALD using negative ionization high-performance liquid chromatography tandem mass spectrometry to measure C24:0- and C26:0-lysophosphatidylcholine concentrations. Sanger sequencing of the adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene was performed on screen-positive specimens. Exposures: A medical and family history, newborn physical examination, sequencing of ABCD1 on dried blood spot samples, and plasma analysis of very long-chain fatty acids were obtained for all infants with screen-positive results. Main Outcomes and Measures: The prevalence of X-ALD in North Carolina and the positive predictive value and false-positive rate for the first-tier assay were determined. Results: Of 52 301 infants tested (47.8% female, 50.6% male, and 1.7% other or unknown sex), 12 received screen-positive results. Of these 12 infants, 8 were confirmed with a genetic disorder: 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, 1 female infant with a peroxisome biogenesis disorder, and 1 female infant with Aicardi-Goutières syndrome. Four infants were initially classified as having false-positives results, including 3 female infants who were deemed unaffected and 1 male infant with indeterminate results on confirmatory testing. The positive predictive value for X-ALD or other genetic disorders for the first-tier assay was 67%, with a false-positive rate of 0.0057%. Conclusions and Relevance: This newborn screening pilot study reported results on 2 lysophosphatidylcholine analytes, identifying 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, and 3 infants with other disorders associated with increased very long-chain fatty acids. These results showed successful implementation in a public health program with minimal risk to the population. The findings will support other state laboratories planning to implement newborn screening for X-ALD and related disorders.

Brief Clinical Report: Hypophosphatasia-Diagnostic Considerations and Treatment Outcomes in an Infant.

Hypophosphatasia (HPP) is a rare, inherited metabolic bone disorder characterized by low serum alkaline phosphatase activity and impaired bone mineralization. Clinical manifestations and severity of symptoms vary widely in HPP, ranging from in utero death to isolated dental manifestations in adults. Treatment with enzyme replacement therapy has been reported to improve outcomes in perinatal, infantile, and childhood forms of HPP. Here, we present a case of a boy with poor linear growth, mild limb bowing, and radiographic rickets who was diagnosed with HPP before 6 months of age. Treatment with enzyme replacement therapy was initiated at 7 months of age, after which significant improvements in radiographic findings and linear growth were demonstrated. This case highlights several important challenges in the diagnosis, classification, and management of HPP.

Short Stature Homeobox-Containing Haploinsufficiency in Seven Siblings with Short Stature.

Deficiency of the short stature homeobox-containing (SHOX) gene is a frequent cause of short stature in children (2-15%). Here, we report 7 siblings with SHOX deficiency due to a point mutation in the SHOX gene. Index case was a 3-year-old male who presented for evaluation of short stature. His past medical history and birth history were unremarkable. Family history was notable for multiple individuals with short stature. Physical exam revealed short stature, with height standard deviation score (SDS) of -2.98, as well as arm span 3 cm less than his height. His laboratory workup was noncontributory for common etiologies of short stature. Due to significant familial short stature and shortened arm span, SHOX gene analysis was performed and revealed patient is heterozygous for a novel SHOX gene mutation at nucleotide position c.582. This mutation is predicted to cause termination of the SHOX protein at codon 194, effectively causing haploinsufficiency. Six out of nine other siblings were later found to also be heterozygous for the same mutation. Growth hormone was initiated in all seven siblings upon diagnosis and they have demonstrated improved height SDS.

Etiological and clinical characteristics of central diabetes insipidus in children: a single center experience.

BACKGROUND: Central diabetes insipidus (CDI) results from a number of conditions affecting the hypothalamic-neurohypophyseal system to cause vasopressin deficiency. Diagnosis of CDI is challenging, and clinical data and guidelines for management are lacking. We aim to characterize clinical and radiological characteristics of a cohort of pediatric patients with CDI. METHODS: A chart review of 35 patients with CDI followed at North Carolina Children's Hospital from 2000 to 2015 was undertaken. The frequencies of specific etiologies of CDI and characteristic magnetic resonance imaging (MRI) findings were determined. The presence of additional hormone deficiencies at diagnosis and later in the disease course was ascertained. Patient characteristics and management strategies were evaluated. RESULTS: The cohort included 14 female and 21 male patients with a median age of 4.7 years (range, less than 1 month to 16 years) at diagnosis. Median duration of follow-up was 5 years (range, 2 months to 16 years). The cause of CDI was intracranial mass in 13 patients (37.2 %), septo-optic dysplasia in 9 patients (25.7 %), holoprosencephaly in 5 patients (14.2 %), Langerhans cell histiocytosis in 3 patients (8.6 %), isolated pituitary hypoplasia in 2 patients (5.7 %), and encephalocele in 1 patient (2.9 %). Patients were symptomatic for a mean of 6.3 months (range, less than 1 month to 36 months) prior to diagnosis of CDI. Growth hormone (GH), thyrotropin (TSH), adrenocorticotropic hormone (ACTH), and gonadotropin deficiencies were present at diagnosis in 34, 23, 23, and 6 % of patients, respectively. GH, TSH, ACTH, and gonadotropin deficiencies were diagnosed during follow-up in 23, 40, 37, and 14 % of patients, respectively. In patients with structural CNS abnormalities, development of additional hormone deficiencies occurred anywhere from 2 months to 13 years after the time of initial presentation. CONCLUSIONS: All patients in our cohort had an underlying organic etiology for CDI, with intracranial masses and CNS malformations being most common. Therefore, MRI of the brain is indicated in all pediatric patients with CDI. Other pituitary hormone deficiencies should be investigated at diagnosis as well as during follow-up.

Effects of Diabetic Ketoacidosis on Visual and Verbal Neurocognitive Function in Young Patients Presenting with New-Onset Type 1 Diabetes.

OBJECTIVE: To evaluate the effects of diabetic ketoacidosis (DKA) on neurocognitive functions in children and adolescents presenting with new-onset type 1 diabetes. METHODS: Newly diagnosed patients were divided into two groups: those with DKA and those without DKA (non-DKA). Following metabolic stabilization, the patients took a mini-mental status exam prior to undergoing a baseline battery of cognitive tests that evaluated visual and verbal cognitive tasks. Follow-up testing was performed 8-12 weeks after diagnosis. Patients completed an IQ test at follow-up. RESULTS: There was no statistical difference between the DKA and non-DKA groups neither in alertness at baseline testing nor in an IQ test at follow-up. The DKA group had significantly lower baseline scores than the non-DKA group for the visual cognitive tasks of design recognition, design memory and the composite visual memory index (VMI). At follow-up, Design Recognition remained statistically lower in the DKA group, but the design memory and the VMI tasks returned to statistical parity between the two groups. No significant differences were found in verbal cognitive tasks at baseline or follow-up between the two groups. Direct correlations were present for the admission CO2 and the visual cognitive tasks of VMI, design memory and design recognition. Direct correlations were also present for admission pH and VMI, design memory and picture memory. CONCLUSION: Pediatric patients presenting with newly diagnosed type 1 diabetes and severe but uncomplicated DKA showed a definite trend for lower cognitive functioning when compared to the age-matched patients without DKA.

Adult and near-adult height in patients with severe insulin-like growth factor-I deficiency after long-term therapy with recombinant human insulin-like growth factor-I.

BACKGROUND: Treatment with recombinant human insulin-like growth factor-I (IGF-I) stimulates linear growth in children with severe IGF-I deficiency (IGFD). AIMS: To evaluate the efficacy and safety of treatment with IGF-I in patients with severe IGFD treated until adult or near-adult height. METHODS: Twenty-one children with severe IGFD were treated until adult or near-adult height under a predominantly open-label design. All patients were naive to IGF-I. Recombinant human IGF-I was administered subcutaneously in doses between 60 and 120 µg/kg twice daily. Nine patients received additional therapy with gonadotropin- releasing hormone (GnRH) analog for a mean period of 2.9 ± 1.8 years. RESULTS: Mean duration of treatment was 10.0 years. Mean height velocity increased from 3.1 cm/year prior to treatment to 7.4 cm/year during the first year of treatment. Height velocities during the subsequent years were lower, but remained above baseline for up to 12 years. Cumulative mean Δ height SD score at (near) adult height was +2. The observed mean gain in height was 13.4 cm more than had been expected without treatment. The adult height achieved by the patients also treated with GnRH analog was not different from those who received IGF-I therapy alone. There were no new safety signals identified in these patients, a subset of those previously reported. CONCLUSION: Long-term therapy with IGF-I improves adult height of patients with severe IGFD. Most patients did not bring their heights into the normal adult range.

Autoimmune polyendocrinopathy associated with ring chromosome 18.

Phenotypic and clinical features of individuals with ring chromosome 18 [r(18)] vary with the extent of deletion of the short (18p-) or long arm (18q-). Most patients with r(18), therefore, demonstrate a clinical spectrum of both 18p- and 18q- deletions. Short stature, microcephaly, mental and motor retardation, craniofacial dysmorphism and extremity abnormalities are the most commonly reported features in patients with r(18). Abnormalities of chromosome 18, especially 18p- syndrome, are often reported with autoimmune thyroid disease and growth hormone deficiency, but reports of endocrine abnormalities associated with r(18) are rare. Here, we report a case of an African-American female with hyperthyroidism, type 1 diabetes mellitus, vitiligo and IgA deficiency associated with a r(18) chromosome complement. This patient additionally had mild intellectual disability and dysmorphic features. Karyotype analysis showed a de novo ring chromosome 18 (deletion 18q23-18qter and deletion 18p11.3-18pter). Although this unique association of autoimmune polyglandular endocrinopathy with ring chromosome 18 could be coincidental, we speculate that a gene or genes on chromosome 18 might play a role in the autoimmune process.

Vitamin D-dependent rickets type 1: a rare, but treatable, cause of severe hypotonia in infancy.

Vitamin D-dependent rickets type 1 is an autosomal recessive disorder caused by an inactivating mutation of the 25-hydroxyvitamin-D-1α-hydroxylase (CYP27B1) gene. Clinical presentation is characterized by early onset of severe rickets and can include severe hypotonia. Here, we report a 16-month-old white male who presented with severe muscle weakness, failure to thrive, renal tubular dysfunction, and skeletal deformities, including osteopenia and multiple fractures. At presentation, he had severe hypocalcemia, hypophosphatemia, hypomagnesemia, and elevated alkaline phosphatase and parathyroid hormone levels, although normal 25-hydroxyvitamin D levels. DNA sequencing of the CYP27B1 gene revealed a novel mutation in exon 2 (c286_300de115) and a previously reported mutation in exon 7 (c.1166G>A). Once calcitriol therapy was initiated, the patient showed significant improvement in muscle strength and linear growth. Serum calcium, phosphorous, and alkaline phosphatase returned to normal range. Organic aciduria resolved and aminoaciduria significantly improved 2 months after parathyroid hormone levels normalized.

HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/γc(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells.

OBJECTIVE: Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing ß-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS: We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γc(null)/HLA-A*0201 (NOD-scid/γc(null)/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γc(null)/A2 mice after transfer. RESULTS: Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γc(null)/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γc(null)/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8(+) T cells among the islet infiltrates. CONCLUSIONS: We show that insulitis is transferred to NOD-scid/γc(null)/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8(+) T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γc(null)/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes.

Hemoglobin Raleigh results in factitiously low hemoglobin A1c when evaluated via immunoassay analyzer.

BACKGROUND: Glycosylated hemoglobin (HbA1c) is commonly used to assess long-term blood glucose control in patients with diabetes mellitus. Numerous conditions including hemoglobinopathies can alter HbA1c measurements and cause misleading results. OBJECTIVE: To report a 13-year-old male with Type 1 diabetes mellitus who had low HbA1c measurements, despite persistent hyperglycemia. DESIGN/METHODS: HbA1c was initially measured by immunoassay. Hb electrophoresis was then employed to assess potential Hb variants. Electrospray ionization (ESI) tandem mass spectrometry of isolated Hb and gene sequencing of the Hbß gene were used to specifically identify the Hb variant. RESULTS: HbA1c measurement by immunoassay revealed an unusually low HbA1c of 3.9%. Hb electrophoresis revealed an aberrant Hb. The ESI mass spectrum of the intact Hb sample revealed a variant ß-chain of 15,881 Da, 14 Da heavier than the mass of the normal Hb ß-chain (15,867 Da). Sequence analysis of the 965.45 Da peptide suggested a substitution of valine (Val) to acetylated alanine (Ala). The DNA sequence of the patient's Hbß gene revealed a single-base heterozygous mutation (GTG to GCG) at Base 2 of the codon of the first amino acid, producing a Val→Ala substitution, previously termed Hb-Raleigh. Because the acetylated N-terminal amino acid of the Hb-Raleigh ß chain cannot be glycated, the HbA1c immunoassay will result in falsely low HbA1c levels. CONCLUSION: In managing diabetic patients, knowledge of hemoglobinopathies influencing HbA1c determination methods is essential because hemoglobin variants may cause mismanagement of diabetes. Unusual results should prompt further analysis for a hemoglobinopathy as the potential cause of aberrant results.

Alternative strategies for the treatment of classical congenital adrenal hyperplasia: pitfalls and promises.

Despite decades of different treatment algorithms, the management of congenital adrenal hyperplasia (CAH) remains clinically challenging. This is due to the inherent difficulty of suppressing adrenal androgen production using near physiological dosing of glucocorticoids (GC). As a result, alternating cycles of androgen versus GC excess can occur and may lead to short stature, obesity, virilization, and alterations in puberty. Novel therapeutic alternatives, including new and more physiological means of GC delivery, inhibitors at the level of CRH or ACTH secretion and/or action, as well as "rescue strategies", such as GnRH analogs, anti-androgens, aromatase inhibitors, and estrogen receptor blockers, are available; many of these agents, however, still require active investigation in CAH. Bilateral adrenalectomy is effective but it is also still an experimental approach. Gene therapy and stem cells, to provide functional adrenal cortical tissue, are at preclinical stage but provide exciting avenues for a potential cure for CAH.

Cushing Syndrome in a 6-Month-Old Infant due to Adrenocortical Tumor.

Cushing syndrome is rare in infancy and usually due to an adrenocortical tumor (ACT). We report an infant with Cushing syndrome due to adrenocortical carcinoma. The patient presented at six months of age with a three-month history of growth failure, rapid weight gain, acne, and irritability. Physical examination showed obesity, hypertension, and Cushingoid features. Biochemical evaluation showed very high serum cortisol, mildly elevated testosterone, and suppressed ACTH. Abdominal MRI revealed a heterogeneous right adrenal mass extending into the inferior vena cava. Evaluation for metastases was negative. The tumor was removed surgically en bloc. Pathologic examination demonstrated low mitotic rate, but capsular and vascular invasion. She received no adjuvant therapy. Her linear growth has improved and Cushingoid features resolved. Hormonal markers and quarterly PET scans have been negative for recurrence 24 months postoperatively. In conclusion, adrenocortical neoplasms in children are rare, but should be considered in the differential diagnosis of Cushing syndrome.

Hyperthyroidism and lupus-like syndrome in an adolescent treated with minocycline for acne vulgaris.

Minocycline is a tetracycline antibiotic commonly used in the treatment of acne. While it is generally considered to be a safe medicine, a number of side effects have been associated with its use. We describe an adolescent boy who developed hyperthyroidism and a drug-induced lupus-like syndrome following minocycline treatment for his acne.

Continuous subcutaneous glucose monitoring in children with type 1 diabetes mellitus: a single-blind, randomized, controlled trial.

BACKGROUND: Tight glycemic control delays the long-term complications of type 1 diabetes mellitus (T1DM) but increases the risk for hypoglycemia. The continuous glucose-monitoring system (CGMS) provides blood glucose (BG) readings every 5 min, and its accuracy and reliability has been established in adults. However, there are limited data on its efficacy and safety in children. The purpose of this study was to determine if CGMS use improves metabolic control in children with T1DM. METHODS: Twenty-seven children (12 male) with T1DM participated in this single-blind, randomized, controlled trial. Participants (age: 11.4 +/- 3.7 (mean +/- SD) yr, range: 7-17 yr) were randomized to an intervention group (n = 18) or a control group (n = 9). Both groups wore the CGMS for 72-h periods at 0, 2, and 4 months. Adjustments in therapy for the intervention group were based on both CGMS and self-monitoring of BG (SMBG) data, while only SMBG data were used for the control group. Hemoglobin A1c (HbA1c) was determined at 0, 2, 4, and 6 months. The change in HbA1c from 0 to 6 months (HbA1c(Delta1-4)) and mean daily area under the CGMS curve for glucose <70 mg/dL area under the curve (AUC(<70)) were compared between groups. RESULTS: At study entry, HbA1c levels were similar in the intervention and control groups (8.4 +/- 0.98 and 8.8 +/- 0.86%, respectively; p = 0.12) but were significantly lower in the intervention group compared with the control group at study completion (7.8 +/- 0.88 and 8.6 +/- 0.95%, respectively; p = 0.02). The decrease in HbA1c of 0.61 +/- 0.68% in the intervention group was statistically significant (p = 0.03), whereas the decrease in HbA1c of 0.28 +/- 0.78% in the control group was not. Nonetheless, the differences in HbA1c(Delta1-4) between groups did not reach statistical significance (p = 0.13). There was no statistically significant difference in AUC(<70) between study groups (p = 0.18). CONCLUSION: CGMS use may improve metabolic control in children with T1DM without increasing the risk for hypoglycemia.

A new challenge in pediatric obesity: pediatric hyperglycemic hyperosmolar syndrome.

OBJECTIVES: To describe four adolescents with hyperglycemic hyperosmolar syndrome, an uncommon presentation of type 2 diabetes in pediatric patients. DESIGN: Case report. SETTING: Two tertiary pediatric intensive care units in university teaching hospitals. PATIENTS: Four obese adolescents with hyperglycemic hyperosmolar syndrome associated with type 2 diabetes mellitus. INTERVENTIONS: Isotonic fluid resuscitation and insulin. MEASUREMENTS AND MAIN RESULTS: Two of the four patients died. The first patient died within the first 24 hrs of hyperglycemic hyperosmolar syndrome presumably due to hypovolemic shock. The second patient, who died, developed rhabdomyolysis and multiple-system organ failure after a prolonged intensive care unit stay. The third and fourth patients were discharged from the hospital in good health. None of the patients had cerebral edema on head computed tomography, despite differences in fluid and insulin management. CONCLUSIONS: Pediatric patients with hyperglycemic hyperosmolar syndrome have a high mortality rate and may experience multiple complications such as rhabdomyolysis and hypovolemic shock. Treatment strategies to reduce mortality are unclear and warrant further investigation.

Novel mutation in the SLC19A2 gene in an African-American female with thiamine-responsive megaloblastic anemia syndrome.

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is an autosomal recessive disorder characterized by diabetes mellitus (DM), progressive sensorineural deafness, and thiamine-responsive anemia. Mutations in the SLC19A2 gene encoding a high-affinity thiamine transporter protein THTR-1 are responsible for the clinical features associated with TRMA syndrome. We report an African-American female with TRMA-syndrome associated with thyroid disease and retinitis pigmentosa caused by a novel mutation in the SLC19A2 gene. The patient presented at 12 months of age with paroxysmal atrial tachycardia and hepatosplenomegaly. One month later, she developed DM requiring intermittent insulin therapy. At 2-1/2 years of age, profound sensorineural hearing loss was discovered. By 4 years of age, daily insulin therapy (0.5 U/kg/day) was instituted and her insulin requirement gradually increased to 1.0 U/kg/day by 9 years of age. She developed optic atrophy, retinitis pigmentosa, and visual impairment by 12 years of age with severe restriction of peripheral vision by 16 years. At age 19, a thiamine-responsive normocytic anemia was discovered. She was diagnosed with autoimmune thyroiditis at 20 years and she experienced a psychotic episode associated with a mood disorder at age 21. With oral thiamine therapy, her insulin requirement decreased by 30% over a 20 month period. Molecular analysis revealed that the patient is homozygous for a missense mutation (C152T) in exon 1 of the SLC19A2 gene.

Obesity and type 2 diabetes mellitus: a population-based study of adolescents.

A cross-sectional, population-based study was conducted on 1,647 Turkish adolescents to determine the prevalence of obesity, impaired fasting glucose (IFG) and type 2 diabetes mellitus (DM2), and to determine whether the recent increase in DM2 prevalence in some countries is applicable to this population. Information was gathered through a questionnaire. All children were screened with physical examination and fasting plasma glucose. 10.7% of adolescents were overweight (BMI 85-95th percentile) and 3.6% were obese (BMI > or =95th percentile). Mean BMI was 20.25 +/- 3.31 kg/m2 with maximum BMI 35.88 kg/m2. No child was diagnosed with DM2; 1.96% had IFG (110-126 mg/dl). No significant relationship was found between IFG and obesity, socio-economic status (SES) or family history of DM. The risk of obesity was increased among children with family history of DM or obesity, and among those who had low physical activity and were of high SES level. This analysis represents the population-based data upon which future studies will be based.