Hyperglycemia in Turner syndrome: Impact, mechanisms, and areas for future research.

Turner syndrome (TS) is a common chromosomal disorder resulting from complete or partial absence of the second sex chromosome. Hyperglycemia, ranging from impaired glucose tolerance (IGT) to diabetes mellitus (DM), is common in TS. DM in individuals with TS is associated with an 11-fold excess in mortality. The reasons for the high prevalence of hyperglycemia in TS are not well understood even though this aspect of TS was initially reported almost 60 years ago. Karyotype, as a proxy for X chromosome (Xchr) gene dosage, has been associated with DM risk in TS - however, no specific Xchr genes or loci have been implicated in the TS hyperglycemia phenotype. The molecular genetic study of TS-related phenotypes is hampered by inability to design analyses based on familial segregation, as TS is a non-heritable genetic disorder. Mechanistic studies are confounded by a lack of adequate TS animal models, small and heterogenous study populations, and the use of medications that alter carbohydrate metabolism in the management of TS. This review summarizes and assesses existing data related to the physiological and genetic mechanisms hypothesized to underlie hyperglycemia in TS, concluding that insulin deficiency is an early defect intrinsic to TS that results in hyperglycemia. Diagnostic criteria and therapeutic options for treatment of hyperglycemia in TS are presented, while emphasizing the pitfalls and complexities of studying glucose metabolism and diagnosing hyperglycemia in the TS population.

Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency.

INTRODUCTION: The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin-like growth factor (IGF)-binding proteins 3 and 5 to release bioactive IGF-I from its ternary complex. Patients with mutations in PAPP-A2 have growth failure and low free IGF-I despite elevated total IGF-I. We describe 5-year treatment response to recombinant human IGF-1 (rhIGF-1) in a patient with PAPP-A2 deficiency, and the phenotype of PAPP-A2 deficiency in three siblings. METHODS: Two siblings (P2, P3) with PAPP-A2 deficiency were recruited for rhIGF-1 therapy at 120 µg/kg subcutaneous twice daily, along with a third sibling (P1) for phenotyping. We evaluated efficacy and safety of rhIGF-1 therapy, including effect on metabolic measures and bone mineral density (BMD). RESULTS: Treatment with rhIGF-1 was started in 10.4-year- (P3) and 14.5-year (P2)-old brothers. P2 discontinued therapy due to pseudotumor cerebri. P3 continued rhIGF-1 for 5 years; height velocity increased (3.0 cm/year at baseline; 5.0-7.6 cm/year thereafter) as did height SDS (+0.6). P3's pubertal onset was at 12.4 year. BMD height-adjusted Z-score modestly improved for lumbar spine (+0.4), and decreased in forearm (-0.2) and hip (-0.3). All siblings had hyperinsulinemia. Impaired glucose tolerance (IGT) resolved in P1. P2 showed worsening glucose tolerance (2-h glucose: 225 mg/dL). Impaired fasting glucose and hyperinsulinemia initially resolved for P3, but IGT (2-h glucose: 152 mg/dL) developed during puberty. CONCLUSION: Therapy with rhIGF-1 modestly improved linear growth in one patient with PAPP-A2 deficiency, but without true catch-up. Therapy was associated with pseudotumor cerebri in a sibling. Initial improvement in BMD and glycemic pattern on rhIGF-1 was not sustained during puberty.

Improving Anxiety Screening in Patients with Turner Syndrome.

INTRODUCTION: Turner syndrome (TS) results from a complete or partial loss of the X chromosome and affects 25-50 per 100,000 females. These individuals have characteristic neurocognitive and psychological profiles with an increased lifetime prevalence of mood disorders, such as depression and anxiety. Consensus guidelines recommend the use of psychometrically robust tools to screen for these conditions [Eur J Endocrinol. 2017;177(3):G1-G70 and Gynecol Endocrinol. 2004;19(6):313-9]. We propose a sustainable and informative approach to routine anxiety screening in individuals with TS and describe the prevalence of anxiety, genotype-phenotype associations, and impact of comorbidities on anxiety. METHODS: We pilot the use of a self-administered version of the validated Pediatric, Parent Proxy, and Adult Patient-Reported Outcomes Measurement Information System (PROMIS®) Anxiety tool during routine visits to the Cincinnati Children's Hospital Medical Center (CCHMC) TS clinic from October 2019 to March 2020. RESULTS: Ninety-two eligible TS females, ages 8-62 years, received the PROMIS® Anxiety measure. Elevated anxiety scores, ≥1 standard deviation above the T-score mean, were present in 65% of patients (38% mild, 19% moderate, and 8% severe). Results were discussed during the clinic visit, and referral for further evaluation and treatment was offered. There was no apparent genotype-phenotype association among females with anxiety; however, there appeared to be elevated anxiety symptoms (T-score >60) in those with hearing deficits and also in individuals with three or more medical comorbidities. Of the 55% of patients who filled out the acceptability survey, 88% found the process helpful and ∼50% felt that screening should be performed at least every 6 months. CONCLUSION: Our study demonstrated a high prevalence of anxiety symptoms within a cohort of 92 females with TS. In alignment with current guidelines, these findings indicate the importance of routine neuropsychological assessments for timely recognition and subsequent management of anxiety, especially as milder presentations may otherwise go unnoticed. We have shown that screening tools, such as the PROMIS® Anxiety measure, can be easily utilized by nonmental health care providers (i.e., endocrinologists) who may see TS patients more frequently and be able to initiate impactful discussions surrounding mental health and further referral to subspecialists for expert management.

Clinical phenotype and musculoskeletal characteristics of patients with aggrecan deficiency.

Aggrecan is a proteoglycan within the physeal and articular cartilage. Aggrecan deficiency, due to heterozygous mutations in the ACAN gene, causes dominantly inherited short stature and, in many patients, early-onset osteoarthritis and degenerative disc disease. We aimed to further characterize this phenotypic spectrum with an emphasis on musculoskeletal health. Twenty-two individuals from nine families were enrolled. Histories and examinations focused on joint health, gait analysis, joint specific patient reported outcomes, and imaging studies were performed. All patients had dominantly inherited short stature, with the exception of a de novo mutation. Short stature was worse in adults versus children (median height -3.05 SD vs. -2.25 SD). ACAN mutations were not always associated with bone age advancement (median advancement +1.1 years, range 0 to +2 years). Children had subtle disproportionality and clinically silent joint disease-25% with osteochondritis dissecans (OD). Adults had a high prevalence of joint symptomatology-decline in knee function, disability from spinal complaints, and lower physical activity on outcome measures. Osteoarthritis (OA) and OD was detected in 90% of adults, and orthopedic surgeries were reported in 60%. Aggrecan deficiency leads to short stature with progressive decline in height SD, mild skeletal dysplasia, and increasing prevalence of joint pathology over time. Optimal musculoskeletal health and quality of life can be attained with timely identification of pathology and intervention.

Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human Growth Hormone: 1-Year Response.

CONTEXT: Patients with aggrecan (ACAN) deficiency present with dominantly inherited short stature, often with advanced skeletal maturation and premature growth cessation. There is a paucity of information on the effects of growth-promoting interventions. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) therapy on linear growth in children with ACAN deficiency. METHODS: Open-label, single-arm, prospective study at Cincinnati Children's Hospital Medical Center. Ten treatment-naïve patients were recruited. Inclusion criteria were a confirmed heterozygous mutation in ACAN, age ≥2 years, prepubertal, bone age (BA) ≥chronological age (CA), and normal insulin-like growth factor I concentration. Treatment was with rhGH (50 µg/kg/day) over 1 year. Main outcomes measured were height velocity (HV) and change in (Δ) height SD score (HtSDS). RESULTS: Ten patients (6 females) were enrolled with median CA of 5.6 years (range 2.4-9.7). Baseline median HtSDS was -2.5 (range -4.3 to -1.1). Median baseline BA was 6.9 years (range 2.5-10.0), with median BA/CA of 1.2 (range 0.9-1.5). Median pretreatment HV was 5.2 cm/year (range 3.8-7.1), increased to 8.3 cm/year (range 7.3-11.2) after 1 year of therapy (P = .004). Median ΔHtSDS after 1 year was +0.62 (range +0.35 to +1.39) (P = .002). Skeletal maturation did not advance inappropriately (median ΔBA/CA -0.1, P = .09). No adverse events related to rhGH were observed. CONCLUSION: Treatment with rhGH improved linear growth in a cohort of patients with short stature due to ACAN deficiency.

Treatment-Induced Neuropathy of Diabetes in Youth: Case Series of a Heterogeneous and Challenging Complication.

Treatment-induced neuropathy of diabetes (TIND) is a small fiber neuropathy precipitated by rapid correction of hyperglycemia. Literature on TIND in pediatric diabetes is scarce. We present 7 cases of TIND in children and young adults, increasing awareness of this condition in pediatric diabetes and broadening the scope of published knowledge.

Algorithm-Driven Electronic Health Record Notification Enhances the Detection of Turner Syndrome.

Early diagnosis of Turner syndrome enhances care, but in routine practice, even within larger referral centers, diagnosis is delayed. Our study examines the utility of an electronic health record algorithm in identifying patients at high risk for Turner syndrome. Six percent of those identified had missed diagnoses of Turner syndrome.