Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective.

BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.

DUOX2/DUOXA2 Mutations Frequently Cause Congenital Hypothyroidism that Evades Detection on Newborn Screening in the United Kingdom.

Background: The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 (DUOX2) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both DUOX2 and its accessory protein DUOXA2 may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort. Methods: A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. DUOX2 was sequenced in 52 patients with a bsTSH of 6-19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland in situ. DUOXA2 was sequenced in DUOX2 mutation-negative cases, and novel DUOXA2 mutations were functionally characterized. Results: A total of 26 (50%) patients harbored likely pathogenic mutations in DUOX2 (n = 20; 38%) or DUOXA2 (n = 6; 12%), including novel gene variants (DUOX2, n = 3; DUOXA2, n = 7). Two recurrent DUOX2 mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range (M = 9.3 pmol/L, range <3.9-15.8 pmol/L), Conclusions: Targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring DUOX2/DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.

Defining the Newborn Blood Spot Screening Reference Interval for TSH: Impact of Ethnicity.

CONTEXT: There is variability in the congenital hypothyroidism (CH) newborn screening TSH cutoff across the United Kingdom. OBJECTIVE: To determine the influences of year, gender, and ethnicity on screening variability and examine whether there is an optimal operational TSH cutoff. DESIGN AND SETTING: Single center, retrospective population study using blood spot TSH cards received by the Great Ormond Street Hospital Screening Laboratory between 2006 and 2012. PATIENTS: A total of 824 588 newborn screening blood spot TSH cards. INTERVENTION: Blood spot TSH results were recorded with demographic data including the Ethnic Category Code. MAIN OUTCOME MEASURES: The proportions of samples exceeding different TSH cutoffs, ranked by ethnicity. RESULTS: The proportion of samples exceeding the TSH cutoff increased over time, with the cutoff at 4 mU/L, but not at 6 mU/L. There was a consistent trend with ethnicity, irrespective of cutoff, with the odds ratio of exceeding the TSH cutoff lowest (∼1.0) in White babies, higher in Pakistani and Bangladeshi (>2.0), and highest in Chinese (>3.5). CONCLUSIONS: The blood spot TSH screening data demonstrate a clear ranking according to ethnicity for differences in mean TSH. This suggests that there may be ethnic differences in thyroid physiology. Ethnic diversity within populations needs to be considered when establishing and interpreting screening TSH cutoffs.

The Incidence and Clinical Features of Dual Thyroid Ectopia in Congenital Hypothyroidism.

CONTEXT: Congenital hypothyroidism (CH) may arise from dual foci thyroid ectopia. OBJECTIVE: To ascertain the incidence of dual ectopia in CH and compare the phenotype to single ectopia or thyroid agenesis. DESIGN AND SETTING: Single center, retrospective study of babies referred through UK Newborn Bloodspot Screening between 2006 and 2012. PATIENTS: A total of 837 377 babies were screened for CH, with 730 referred for diagnostic confirmation (134 thyroid ectopia, 73 thyroid agenesis). INTERVENTION: Thyroid isotope scans were classified as single or dual ectopia. Biochemical, clinical, and sociodemographic data were collected. MAIN OUTCOME MEASURES: The incidence of thyroid dual ectopia and comparison of clinical parameters with single ectopia and agenesis. RESULTS: Thyroid ectopia occurs with an incidence of 16 per 100 000 births. Twenty-one of 134 (15.7%) babies with thyroid ectopia had dual foci, an incidence of 2.5 per 100 000 births. Dual ectopia infants had lower mean bloodspot TSH compared to single ectopia and agenesis groups (P < .001). On venous sampling, the ectopia group differences were absent, but the difference with the agenesis group remained (TSH, P < .001; free T4, P < .001). There were no between-group differences for gestation, ethnicity, maternal age, or levothyroxine requirements at 12 months. CONCLUSIONS: Thyroid dual ectopia has an incidence of 2.5 per 100 000 births. Early functional activity in the ectopia groups with detectable serum free T4 concentrations is lost at 12 months when T4 requirements are the same as the agenesis group.

Screening for congenital hypothyroidism: comparison of borderline screening cut-off points and the effect on the number of children treated with levothyroxine.

BACKGROUND: The newborn screening programme for congenital hypothyroidism (CH) has led to the prevention of severe developmental delay associated with this condition. In the UK, thyroid-stimulating hormone (TSH) screening cut-off points have changed over time, in some instances prompted by changing methodological platforms. The use of borderline cut-off points varies throughout the country. OBJECTIVE: To use discordance in cut-off points to assess the performance of the UK Newborn Screening Programme Centre (UKNSPC) definitions. METHODS: Between January 2006 and December 2007, 223,658 newborn infants were screened by the Great Ormond Street Hospital (GOSH) for CH. All children with positive results and those with blood-spot TSH concentrations >6 mU/l on repeat screening were referred to GOSH. We compared the numbers of children detected and treated for CH using the GOSH cut-off points (>6 mU/l) and those of the national screening programme (>10 mU/l). Children were defined as transient CH if levothyroxine treatment had been discontinued by 3 years. RESULTS: Of the children screened between January 2006 and December 2007, 167 out of 223,658 fulfilled the GOSH screening criteria; 136 of these required levothyroxine treatment, but 29 (21%) of the children treated would not have been detected by the current UKNSPC guidelines. Transient CH was found in 17/47 (36%) of the treated children detected with a cut-off point >6 mU/l. Raising the cut-off point to >10 mU/l reduced the number of children treated for transient CH to 4/18 (22%). CONCLUSION: A significant number of children with true and transient CH are missed with a screening cut-off point of >10 mU/l. Our data suggests that a cut-off point of 6 mU/l is appropriate.

National audit of patient choice in pediatric GH therapy.

BACKGROUND: To assess free patient choice for pediatric patients commencing growth hormone (GH) therapy within the UK and Republic of Ireland. METHODS: A semistructured questionnaire was sent to all members of the British Society for Paediatric Endocrinology and Diabetes. RESULTS: Of 55 units responding, three do not commence patients on GH. The remaining 52 units included 21 from (all) historic growth centres, 13 from other tertiary centres, and 18 from district general hospitals. 46/52 units (89%) offer free patient choice, involving: demonstration of devices (n = 15), instructional DVDs (6), a combination of both (20), or other (3). Median (range) time spent choosing the GH device was 60 (25-150) min. Device demonstration involved: dialling up doses (39 units), assembling/dissembling (38), GH reconstitution (33), considering facilities provided by manufacturer (25), injecting patient (19), injecting parent (17), showing additional material (11), and cost consideration (4). Median (range) number of steps shown per unit was 5 (1-8), with correlation between numbers of manufacturers/devices and new patients commenced on GH per unit (R = 0.62 and 0.61, both p < 0.01), but not with time spent showing devices (R = 0.12 and 0.22, p > 0.05). CONCLUSION: Most units now offer some form of patient choice for new patients commencing GH therapy, although this involves several different methods, with larger units offering more manufacturers and more devices.

Use of combined liothyronine and thyroxine therapy for consumptive hypothyroidism associated with hepatic haemangiomas in infancy.

Hepatic haemiangiomas in infancy are rare. An association with hypothyroidism has been previously reported and is believed to be secondary to the conversion of thyroxine (fT4) to biologically inactive reverse triiodothyronine (rT3) by type 3 iodothyronine deiodinase (D3). We report a case that responded well to the combined use of liothyronine and thyroxine therapy.

Observations of nonadherence to recombinant human growth hormone therapy in clinical practice.

BACKGROUND: The effectiveness of all prescribed treatments is contingent on patient adherence. The reported levels of adherence to recombinant human growth hormone (r-hGH) therapy are highly variable, but it has been suggested that nonadherence might be as high as 36% to 49%. OBJECTIVES: This commentary discusses the factors that affect long-term adherence to injection treatment, of which r-hGH therapy is a particular challenge. It also explores potential strategies to improve adherence to injection treatments in clinical practice. METHODS: The opinion of the authors was validated and supported by published literature. A PubMed literature search was conducted in November 2006, identifying English-language articles containing key terms growth hormone, adherence, and compliance. RESULTS: This study found that factors associated with poor adherence to injection treatments include patients' lack of understanding of their disease, patient age, chronicity of the disease, complex treatment regimens, and insufficient information on the implications of nonadherence. Strengthening the patient-physician relationship by providing the patient with a clear understanding of his/her disease and the benefits of adherence, making improvements in injection devices, and eliminating subjective illness concepts, might increase adherence to SC injection treatments, thereby reducing increasing health care costs associated with nonadherence. CONCLUSIONS: Poor adherence to r-hGH therapy has a dual effect, in that it leads to reduced efficacy out-comes and increased health care costs. Implementing strategies to improve adherence with injection treatment might be of particular clinical benefit to patients undergoing r-hGH therapy.