Screening and counseling for nicotine use in youth with diabetes.

OBJECTIVE: To assess current practice patterns and identify knowledge gaps among pediatric endocrinologists in the United States regarding screening and counseling for combustible tobacco and e-cigarette use in youth with diabetes. INTRODUCTION: Electronic cigarettes (e-cigarettes) are the most used tobacco product among adolescents and may be associated with an increased risk of progression to combustible cigarette smoking, cardiovascular disease, and stroke. Diabetes mellitus is a known risk factor for cardiovascular disease, and nicotine products can increase this risk. We sought to assess current practice patterns and identify knowledge gaps among pediatric endocrinologists in the United States regarding screening and counseling for combustible tobacco and e-cigarette use in youth with diabetes. RESEARCH DESIGN AND METHODS: We conducted an anonymous, online-based survey of Pediatric Endocrine Society members who provide care to youth with Type 1 or Type 2 diabetes. The survey collected information about provider demographics and smoking habits, knowledge and attitudes regarding screening and counseling for combustible tobacco and e-cigarette use, and current practice patterns. RESULTS: The survey was completed by 106 individuals of whom 64 reported providing care to youth with diabetes mellitus and ever asking about combustible tobacco or e-cigarette use. The majority of respondents were female, attending providers, and working in academic medical centers. None reported a history of formal training in e-cigarette counseling but recognized the harms of e-cigarette use. Nearly all (98%) who ever screen for nicotine use reported routinely screening for combustible tobacco use, while 18% never screen for e-cigarette use (p < 0.01). Over 80% of respondents reported feeling confident or very confident about discussing the harms of combustible tobacco, compared to 58% reporting the same confidence in discussing harms of e-cigarette use (p < 0.0001). Over 90% of respondents agreed that pediatric endocrinology providers should ask about nicotine use with over half agreeing that counseling reduces the risk of initiating nicotine product use, and 30% reported lack of change with counseling as a barrier to discussing nicotine use. Lack of visit time was the most reported barrier to discussing nicotine use. More providers cited lack of knowledge regarding e-cigarettes compared to combustible tobacco as a barrier to discussing its use. CONCLUSIONS: Pediatric endocrinology providers recognize the harms of e-cigarette use, but more frequently ask about combustible tobacco use compared to e-cigarette use. This may be related to lower reported confidence and provider knowledge in counseling about e-cigarette use. Increased utilization of existing resources and expanding opportunities for providers to learn more about e-cigarettes may increase provider confidence and comfort in screening and counseling.

Self-reported insulin pump prescribing practices in pediatric type 1 diabetes.

INTRODUCTION: Disadvantaged and minority youth with type 1 diabetes are less likely to be on insulin pump therapy compared to the majority population. Little is known about how pediatric endocrinology providers determine eligibility for insulin pump. We aimed to identify provider factors influencing the decision to initiate insulin pump therapy. METHODS: We conducted a survey of Pediatric Endocrine Society members who prescribe insulin pump therapy to pediatric patients with type 1 diabetes. The survey collected information about prescriber characteristics, use and adherence to guidelines, eligibility criteria, and objective and subjective factors that influence insulin pump prescription. RESULTS: The survey was completed by 192 individuals who met eligibility criteria (14.1% response rate). The majority of respondents were attending providers, and were white, non-Hispanic females. A minority of providers (22%) reported following written insulin pump guidelines, and many (70%) reported using personal guidelines to guide patient selection. Most providers had no objective eligibility criteria, aside from standard glucose monitoring. Providers identified patient lifestyle and increased risk of hypoglycemia, as well as patient and family factors such as motivation, realistic expectations of insulin pump use, ability to demonstrate carbohydrate counting, patient request, and ability to communicate as important in the decision to initiate insulin pump. CONCLUSION: Pediatric endocrinology providers place significant importance on subjective factors and utilize few objective criteria in determining eligibility for insulin pump. In the setting of the known disparities in insulin pump use, providers should utilize objective, consistent criteria to determine which patients are safe to initiate insulin pump.

PARTIAL HOSPITALIZATION: AN INTERVENTION FOR YOUTH WITH POORLY CONTROLLED DIABETES MELLITUS.

Objective: To examine the efficacy of an integrated medical/psychiatric partial hospitalization program (PHP) to improve glycemic control in youth with both diabetes mellitus and mental health disorders. Methods: This retrospective chart review is of patients admitted to a PHP between 2005-2015 with concerns about diabetes mellitus care. Clinical characteristics, laboratory data, diabetic ketoacidosis hospitalizations, and outpatient clinic visit frequency were collected from the year prior to the year after PHP admission. Results: A total of 43 individuals met inclusion criteria: 22 (51%) were female, 40 (93%) had type 1 diabetes, the mean age was 15.2 ± 2.3 years, and the mean diabetes mellitus duration was 4.6 ± 3.6 years. Of those individuals, 35 of these patients had hemoglobin A1c (HbA1c) data available at baseline, 6 months, and 1 year after PHP. The average HbA1c before PHP admission was 11.3 ± 2.3% (100.5 ± 25 mmol/mol), and decreased to 9.2 ± 1.3% (76.7 ± 14.8 mmol/mol) within 6 months of PHP admission (P<.001). The average HbA1c 1 year after PHP was 10.7 ± 1.7 % (93.3 ± 19.1 mmol/mol). Overall, 24 patients (68%) had lower HbA1c, and 75% of those with improvement maintained an HbA1c reduction of ≥1% (≥10 mmol/mol) at 1 year compared to before PHP. Conclusion: Most patients demonstrated improved glycemic control within 6 months of PHP admission, and many of those maintained a ≥1% (≥10 mmol/mol) reduction in HbA1c at 1 year following PHP admission. This program may represent a promising intervention that could serve as a model for intensive outpatient management of youth with poorly controlled diabetes mellitus. Abbreviations: ADA = American Diabetes Association; DKA = diabetic ketoacidosis; EMR = electronic medical record; HbA1c = hemoglobin A1c; ICD-9 = International Classification of Diseases, 9th revision; PHP = partial hospitalization program.

Pediatric Diabetic Ketoacidosis With Hyperosmolarity: Clinical Characteristics and Outcomes.

OBJECTIVE: Studies of hyperglycemic emergencies with hyperosmolality, including hyperglycemic hyperosmolar state (HHS) and "mixed presentation" with features of diabetic ketoacidosis (DKA) and HHS, are lacking in children. Objectives were to determine the incidence of DKA, HHS, and mixed presentation in a pediatric population, to characterize complications, and to assess accuracy of associated diagnosis codes. METHODS: Retrospective cohort study of 411 hyperglycemic emergencies in pediatric patients hospitalized between 2009 and 2014. Hyperglycemic emergency type was determined by biochemical criteria and compared to the associated diagnosis code. RESULTS: Hyperglycemic emergencies included: 333 DKA, 54 mixed presentation, and 3 HHS. Altered mental status occurred more frequently in hyperosmolar events ( P<.0001), and patients with hyperosmolarity had 3.7-fold greater odds of developing complications compared to those with DKA ( P = .0187). Of those with DKA, 98.5% were coded correctly. The majority (81.5%) of mixed DKA-HHS events were coded incorrectly. Events coded incorrectly had 3.1-fold greater odds of a complication ( P = .02). CONCLUSION: A mixed DKA-HHS presentation occurred in 13.8% of characterized hyperglycemic emergencies, whereas HHS remained a rare diagnosis (0.8%) in pediatrics. Hyperosmolar events had higher rates of complications. As treatment of hyperosmolarity differs from DKA, its recognition is essential for appropriate management. ABBREVIATIONS: AMS = altered mental status; DKA = diabetic ketoacidosis; EMR = electronic medical record; HHS = hyperglycemic hyperosmolar state; ICD-9 = International Classification of Diseases, Ninth Revision; ISPAD = International Society of Pediatric and Adolescent Diabetes; NODM = new-onset diabetes mellitus; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

Intervention Fidelity: Monitoring Drift, Providing Feedback, and Assessing the Control Condition.

BACKGROUND: Measurement of intervention fidelity is an essential component of any scientifically sound intervention trial. However, few papers have proposed ways to integrate intervention fidelity data into the execution of these trials. OBJECTIVE: The purpose of this article is to describe the intervention fidelity process used in a randomized controlled trial of a human patient simulator intervention and how these data were used to monitor drift and provide feedback to improve the consistency of both intervention and control delivery over time in a multisite education intervention for parents of children with newly diagnosed Type 1 diabetes. METHODS: Intervention fidelity was measured for both the intervention and control condition by direct observation, self-report of interventionist delivery, and parent participant receipt of educational information. Intervention fidelity data were analyzed after 50%, 75%, and 100% of the participants had been recruited and compared by group (treatment and control) and research site. RESULTS: The sample included 191 parents of young children newly diagnosed with Type 1 diabetes. Observations scores in both intervention and control groups indicated a high level of intervention fidelity. Treatment receipt was also high and did not differ by treatment group. The teaching session attendance rates by site and session were significantly different at Time Point 1 (50% enrollment); following study staff retraining and reinforcement, there were no significant differences at Time Point 3 (100% enrollment). IMPLICATIONS: Results demonstrate the importance of monitoring intervention fidelity in both the intervention and control condition over time and using these data to correct drift during the course of a multisite clinical trial.

AUTONOMOUSLY FUNCTIONING THYROID NODULES IN PATIENTS <21 YEARS OF AGE: THE RHODE ISLAND HOSPITAL EXPERIENCE FROM 2003-2013.

OBJECTIVE: This study evaluates the clinical characteristics, workup, treatment, and outcomes of pediatric patients diagnosed with an autonomously functioning thyroid nodule (AFTN) in a large cohort of patients presenting for evaluation of a thyroid nodule. There are few prior studies on AFTN in pediatrics, with limited data on treatment and outcomes. Rates of malignancy in AFTN are perceived as low, but prior studies have varying reports. METHODS: This is a retrospective chart review of patients less than 21 years of age at Rhode Island Hospital over an 11-year period (2003-2013). We reviewed 354 charts, which yielded 242 patients with a diagnosis of thyroid nodule and 17 patients with AFTN. RESULTS: The prevalence of AFTN in patients presenting with thyroid nodules was 7%. Mean age of patients was 15.8 years at diagnosis, and mean nodule size was 3.3 cm. There was female predominance. Thyroid-stimulating hormone levels were suppressed at diagnosis in 87% of patients. Six patients were treated with surgery, 5 patients with radioactive iodine therapy (RAI), 2 patients with medication, and 1 patient was observed without treatment. Three patients treated with RAI required subsequent treatment for hypothyroidism or continued hyperthyroidism. One patient had papillary thyroid carcinoma based on final surgical pathology. CONCLUSION: Our study found a higher prevalence of AFTN compared to the reported prevalence in adults. We concur with the new guidelines on management of thyroid nodules in recommending surgery for treatment of AFTN, based on the variability of outcomes after treatment with RAI.

Resistance to Thyroid Hormone Beta in a Patient Born to a Mother With Undiagnosed Graves' Disease.

Background/Objective: Graves' disease is an autoimmune disease associated with high levels of circulating thyroid hormones (THs). Resistance to thyroid hormone beta (RTHß) caused by mutations in the thyroid hormone receptor beta (THRB) gene also can lead to high TH levels. Here, we describe 2 related cases, one of a woman with Graves' disease, and her newborn with RTHß. Case Report: The woman was 27 years of age, with free thyroxine (T4) (FT4) >7.7 ng/dL (0.8-1.8), triiodothyronine of 1350 ng/dL (90-180), and undetectable thyrotropin (TSH), but no symptoms of thyrotoxicosis. She also had thyroglobulin antibodies of 65 (2-38). She was treated with methimazole and atenolol. The newborn neonatal screen showed a TSH of 43 mU/L [upper limit of normal 20 mU/L] and total T4 of 21.8 µg/dL (upper limit of normal 15). At 6 days of age, the newborn had a FT4 of 12.3 ng/dL (0.9-2.3), and unsuppressed TSH. The infant, at 3.5 months of age, was identified to harbor a THRB mutation (R438H) inherited from her father, but the brothers and mother had no THRB mutation. The newborn had tachycardia and delayed growth and was treated with atenolol and supplemental feeding, resulting in weight gain and reduced heart rate. Discussion: The perinatal high FT4 and tachycardia could have been influenced by the elevated TH levels of the mother and the fetal RTHß. Conclusion: It is difficult to evaluate the etiology of neonatal hyperthyroidism when fetal RTHß and maternal Graves' disease are not diagnosed early at birth.

Normal Adult Height in an Untreated Boy With McCune-Albright Syndrome Presenting With Precocious Puberty.

Background/Objective: We present a boy with McCune-Albright syndrome (MAS)-associated precocious puberty (PP) who achieved normal adult height without treatment. Case Report: The patient presented at 10 years of age with PP and fibrous dysplasia of the right humerus. Examination showed a height 148.7 cm, Tanner 2 pubic hair and 12-15 cc testes. The Bone age (BA) was 13 years with a predicted adult height of 175 cm vs. mid parental target height of 173 cm. Laboratory parameters were as follows: luteinizing hormone (LH) 0.745 mIU/mL (0.2-4.9 mIU/mL), follicle stimulating hormone (FSH) 0.933 mIU/mL (1.8-3.2 mIU/mL), testosterone 42 ng/dL (18-150 ng/dL), inhibin B 436.6 pg/mL (41-238 pg/mL) and AMH 36.1 ng/mL (45.26-191.34 ng/mL). The DNA testing result of tissue from the right humerus was positive for GNAS p. R201C mutation confirming a diagnosis of MAS. Pubertal progression with growth spurt occurred over the next 3 years: growth velocity (GV) 12 cm/y, testosterone 116 ng/dL, LH 0.715 mIU/mL and FSH 1.3 mIU/mL at 10.6 years; GV 10.3 cm/y, BA 13 to 13.6 years, testosterone 450 ng/dL, LH 1.7 mIU/mL and FSH 1.4 mIU/mL at 11.7 years; and GV 3.8 cm/y, BA 17 years, Testosterone 668 ng/dL and LH 4.2 µIU/mL at 13.3 years. Height was 171.2 cm. Discussion: PP is reported in approximately 15% of boys with MAS. PP leads to BA advancement and reduction in final adult height. Our patient achieved normal adult height without treatment in the absence of excess growth hormone. Conclusion: Boys with MAS and PP with slow BA advancement may achieve normal adult height without treatment even in the absence of excess growth hormone.

Incidence, Severity, and Presentation of Type 2 Diabetes in Youth During the First and Second Year of the COVID-19 Pandemic.

OBJECTIVE: To describe the evolving impact of the coronavirus disease 2019 pandemic on the incidence and presentation of new-onset pediatric type 2 diabetes. RESEARCH DESIGN AND METHODS: Retrospective medical record review of youth with new-onset type 2 diabetes comparing the prepandemic period (1 January 2017-29 February 2020) with the first (1 March 2020-31 December 2020) and second pandemic year (1 January 2021-31 December 2021). RESULTS: The annualized incidence of type 2 diabetes increased nearly threefold during the pandemic versus prior, with a 61% increase in the 2nd versus 1st year. BMI increased during the pandemic versus prior (129% of 95th percentile vs. 141%, P = 0.02). In the 1st year, patients were younger (12.9 years vs. 14.8, P < 0.001), with higher incidence of diabetic ketoacidosis and/or hyperglycemic hyperosmolar syndrome (20% vs. 3.5%, P = 0.02) versus prior. CONCLUSIONS: Providers should be aware of the escalating incidence of youth-onset type 2 diabetes to avoid delays in diagnosis and inform educational programs to combat the continued impact of the pandemic on health outcomes.

Thyroid function tests of iodine deficiency goiter can mimic thyroid hormone resistance alpha.

OBJECTIVES: Iodine deficiency goiter can develop in children on a restrictive diet and most have normal thyroid function. We report a 6-year-old girl with iodine deficiency goiter with thyroid function studies mimicking thyroid hormone resistance alpha. Thyroid hormones mediate its effects through thyroid hormone receptors alpha and beta. Biochemical picture of low/low-normal T4 and high/high-normal T3 levels, variably reduced reverse T3 and normal TSH is characteristic of thyroid hormone resistance alpha. CASE PRESENTATION: A 6-year-old girl, born out of non-consanguineous marriage presented with goiter of 1.5 years duration. She was without symptoms of thyroid dysfunction. The patient was evaluated at one year of age for macrocephaly with cranial ultrasound which was normal. She had normal growth and development. Patient was vegan and was not on any medications or supplements. Laboratory work up showed TSH 5.03 uIU/mL (0.34-5.5), FT4 0.3 ng/dL (0.58-1.2), FT3 5.3 pg/mL (2.5-3.9), total T3 258 ng/dL (94-241), reverse T3 <5.0 ng/dL (8.3-22.9) and negative thyroglobulin antibody and thyroid peroxidase antibody. Thyroglobulin level was 1,098.8 ng/mL (<13 ug/L), and urine iodine 15.8 ug/L (<100 ug/L) confirming a diagnosis of iodine deficiency goiter. Patient was started on iodine supplements, 150 ug daily and repeat work up 3 months later were TSH: 2.717 uIU/mL, T3, total 182 ng/dL, T4, total 9.3 ug/dL, FT 4 2.1 ng/dL. CONCLUSIONS: Iodine deficiency goiter may present with low FT 4, elevated T3 and normal TSH mimicking thyroid hormone resistance alpha and should be considered in children on restrictive diet.

Acute Hepatitis due to Hepatic Glycogenosis After Insulin Overdose and Oral Glucose Administration in an Adolescent.

BACKGROUND: Hepatic glycogenosis (HG) has been reported after intravenous (IV) dextrose administration to treat insulin overdose. We describe a case of HG in a patient with type 1 diabetes mellitus (T1DM) due to insulin overdose treated with oral glucose administration. CASE PRESENTATION: An adolescent boy with T1DM on a basal bolus insulin regimen presented with abdominal discomfort, nausea, vomiting, and hypoglycemia of a few hours. His glucose was 71 mg/dL, aspartate transaminase (AST) 119 U/L, and alanine transaminase (ALT) 65 U/L. Hypoglycemia was treated with juice, and 12 hours later AST and ALT were 979 U/L and 700 U/L, respectively. Workup for infectious, autoimmune, metabolic, and toxic causes of hepatitis was negative. The transaminases improved by the next day and normalized within 3 weeks. Two weeks after discharge the patient returned with hypoglycemia, nausea, and right-sided abdominal pain of 13 hours. Hypoglycemia persisted despite multiple courses of glucose tablets and juice. Laboratory studies showed glucose of 58 mg/dL, AST of 776 U/L, ALT of 496 U/L, negative toxicology studies, and normal abdominal ultrasound. His serum insulin level was 249.7 mU/L and, C-peptide was less than 0.1 ng/mL, consistent with insulin overdose. He received IV fluids with dextrose, and insulin was held. Transaminases improved by the following day. Repeat serum insulin while on home regimen was normal. CONCLUSION: Along with other diagnoses, HG should be considered in patients treated with insulin who present with hypoglycemia and acute hepatitis. HG can occur in cases of insulin overdose treated with repeated oral glucose administration.

Lack of Catch-Up Growth with Growth Hormone Treatment in a Child Born Small for Gestational Age Leading to a Diagnosis of Noonan Syndrome with a Pathogenic PTPN11 Variant.

BACKGROUND: Growth hormone (GH) treatment increases the adult height of short children born small for gestational age (SGA). Catch-up growth is associated with a younger age, shorter height, and prepubertal status at the onset of GH treatment. We report a 12 11/12-year-old girl born SGA who received GH for 5 years without catch-up growth and was diagnosed with Noonan Syndrome (NS). RESULTS: A 5-year-and-9-month-old 46, XX girl born SGA was started on GH treatment at a dose of 0.32 mg/kg/week. Her midparental target height is 158.6 cm. Endocrine work up showed an IGF-1 level 69 ng/ml (Normal (N): 55-238 ng/ml), IGFBP3 2.6 mg/L (N: 1.9-5.2 mg/L), TSH 3.2 mIU/L (N: 0.35-5.5 mIU/L), and a normal skeletal survey. Height was 96 cm (0.1%; Ht SDS -2.9), weight 14 kgs (1%; Wt SDS -2.3), and Tanner 1 breast and pubic hair were observed. Due to the poor catch-up growth on GH treatment, she was referred to Genetics to elucidate genetic or syndromic causes of short stature. She was noted to have posteriorly rotated ears and slight down slanting of the palpebral fissures. Genetic findings showed a heterozygous pathogenic variant in PTPN11 (c.922A > G (p.Asn308Asp)) diagnostic for NS. This finding is de novo given negative parental testing. She was noted to have a heterozygous missense variant of unknown significance (VUS) in FGFR3: c.746C > A (p.Ser249Tyr). FGFR3 is associated with multiple skeletal dysplasias including thanatophoric dysplasia, achondroplasia, and Crouzon syndrome and hypochondroplasia. Clinical correlation is poor for these syndromes. CONCLUSION: Diminished catch-up growth and response to GH treatment in a child born SGA led to the diagnosis of NS. The concomitant diagnosis of SGA and NS may have affected the responsiveness of this child to the growth promoting effect of GH treatment.

Anastrozole Improves Final Adult Height in Severe Hypothyroidism With Rapid Pubertal Progression.

Severe prolonged hypothyroidism due to Hashimoto thyroiditis may lead to rapid pubertal progression and compromised adult height after initiation of levothyroxine (LT4) therapy. There are no reports of aromatase inhibitor use to augment height in these patients. We describe a patient with severe hypothyroidism and growth failure who experienced rapid pubertal and bone age maturation on initiation of LT4 therapy. Anastrozole was added after 2 years to delay epiphyseal fusion. A boy aged 12 years and 1 month presented to the endocrine clinic with short stature and a markedly delayed bone age of 6 years. Brain magnetic resonance imaging showed a 1.5 × 1.0 × 1.2-cm enlarged lobular anterior pituitary. On examination, his height was -3.5 SD score (SDS) and weight was -2.87 SDS. Laboratory studies showed elevated thyrotropin (TSH) 850.6 µIU/mL, low free thyroxine 0.25 ng/dL, and elevated antithyroid antibodies. LT4 was initiated with normalization of TSH after 6 months. After 2 years of treatment he demonstrated catch-up growth with rapid bone age maturation, and his predicted adult height was compromised at 164.6 cm vs a midparental target height of 175.4 cm. Anastrozole 1 mg once daily was initiated. After 1.5 years of anastrozole treatment, the rate of his bone age advancement had slowed and his linear growth remained robust. The patient's near-final height (167 cm) was 2.4 cm taller than his height prediction prior to starting anastrozole. Anastrozole slowed the rate of bone age advancement in a patient with severe hypothyroidism and rapidly progressive puberty during treatment with LT4, leading to improvement in near-final height.

The Incidence of Erosive Esophagitis as a Complication of Pediatric Diabetic Ketoacidosis.

INTRODUCTION: Gastrointestinal (GI) symptoms commonly occur during diabetic ketoacidosis (DKA) and typically resolve with treatment. However, GI complications can persist after DKA resolves. The incidence of upper GI bleeding during DKA in adults has been described, with erosive esophagitis one of the most common lesions. The incidence of GI bleeding or erosive esophagitis in children with DKA has not been previously reported. We performed a retrospective chart review of DKA admissions in children 0 to <18 years with type 1 diabetes mellitus (T1DM) at a pediatric hospital between January 2009 and July 2016. Among 395 episodes of DKA over 7.5 years, erosive esophagitis occurred during two DKA admissions (0.5%) and there were no episodes of GI bleeding. Case presentations. Both episodes of erosive esophagitis occurred in adolescent males with known T1DM who presented with severe DKA. Both developed odynophagia after resolution of DKA and were readmitted for DKA recurrence. Upper endoscopy for both patients showed erosive esophagitis. Biopsies were negative for infection, though candida was found during one patient's endoscopy. Both had resolution of their esophagitis symptoms with medication management; neither has had recurrence. CONCLUSION: Erosive esophagitis, a rare complication of pediatric DKA, can manifest with odynophagia or substernal chest pain. This complication can lead to DKA recurrence, likely due to increased insulin resistance from inflammation and pain and from reduced oral intake and insulin administration. Patients with odynophagia associated with DKA should be monitored closely to allow timely evaluation and treatment of esophagitis.

Severe Dental Disease as a Presenting Sign of Relapsed 6q24-Related Transient Neonatal Diabetes Mellitus.

Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes that presents in infancy and is characterized by intrauterine growth restriction and hyperglycemia without ketones on urinalysis. Patients are treated with insulin until remission, usually within the first year. Relapse to a permanent state may occur later in life, with a mean age of 14 years. The most common cause of TNDM is a chromosome 6q24 mutation that affects pancreatic ß-cell function. Reports of relapse have been limited. We describe a case of an adolescent female with TNDM due to 6q24 hypomethylation who relapsed at 15 years of age with severe dental disease as the presenting sign.

NOVEL XRCC4 MUTATIONS IN AN INFANT WITH MICROCEPHALIC PRIMORDIAL DWARFISM, DILATED CARDIOMYOPATHY, SUBCLINICAL HYPOTHYROIDISM, AND EARLY DEATH: EXPANDING THE PHENOTYPE OF XRCC4 MUTATIONS.

OBJECTIVE: Microcephalic primordial dwarfism (MPD) is a group of clinically and genetically heterogeneous disorders which result in severe prenatal and postnatal growth failure. X-ray repair cross-complementing protein 4 (XRCC4) is a causative gene for an autosomal recessive form of MPD. The objective of this report is to describe novel XRCC4 mutations in a female infant with MPD, dilated cardiomyopathy, and subclinical hypothyroidism. METHODS: Genetic testing was performed using a comprehensive next generation sequencing panel for MPD, followed by targeted XRCC4 gene sequencing. RESULTS: We report the case of a 970-gram, 35-cm, female infant (weight z score -5.05, length z score -4.71) born at 36 weeks and 3 days gestation. Physical examination revealed triangular facies, micrognathism, clinodactyly, and second and third toe syndactyly. Initial echocardiogram at birth was normal. Follow-up echocardiogram at 60 days of life revealed dilated cardiomyopathy with moderate left ventricular systolic dysfunction (ejection fraction was 40 to 45%), and anticongestive therapy was initiated. Thyroid testing revealed subclinical hypothyroidism with elevated thyroid-stimulating hormone of 13.0 µIU/mL (reference range is 0.3 to 5.0 µIU/mL) and normal free thyroxine by dialysis of 1.6 ng/dL (reference range is 0.8 to 2.0 ng/dL). Levothyroxine was initiated. Postnatal growth remained poor (weight z score at 3 months -4.93, length z score at 3 months -6.48), including progressive microcephaly (head circumference z score at 3 months -10.94). Genetic testing revealed novel compound heterozygous XRCC4 variants in trans: c.628A>T and c.638+3A>G. The child ultimately had cardiopulmonary arrest and died at 6 months of life. CONCLUSION: Molecular diagnosis in MPD is key to defining the natural history, management, and prognosis for patients with these rare disorders.

Individualized care for patients with intersex (disorders/differences of sex development): Part 3.

The focus of this article is to review the complex determinants of gender assignment in a child with a disorder of sex development using four different clinical cases. While the care of patients with DSD may be shared across several specialties and opinions regarding their management may vary, this may be further complicated by psychosocial, cultural and economic factors. In this regard, access to behavioral health specialists with experience and specialization in the treatment of patients with DSD should be a foundational component of the standard of care and can greatly assist in the complex decision-making regarding gender assignment. We recommend an individualized approach by a multidisciplinary team utilizing a range of evolving strategies, including outcome data (or lack thereof) to support families during the decision-making process.