Quality of life and socioeconomic and educational status in patients with congenital hypothyroidism.

BACKGROUND: The aim of this study was to investigate the influence of primary congenital hypothyroidism (CH) on quality of life, level of education and socioeconomic status (SES). METHODS: Two independent study cohorts, a national and a regional, were collected from Finnish national registers and patient records. Data on social security benefits, SES, marital status, and education were collected from Statistics Finland. Health-related quality of life (HRQoL) was studied in the regional patient cohort with the standardized 15D and 16D instruments. RESULTS: There were no statistically significant differences in education level, marital status, or SES between CH patients (n = 40) and their matched controls at the age of 25 years. The mean 15D score was both statistically significantly and clinically importantly lower in CH patients (n = 29) than controls (0.904 vs. 0.953, p = 0.008). CH patients reported significantly lower scores across various dimensions of physical and mental HRQoL, including breathing, sleeping, speech, excretion, mental function, distress, and vitality. The mean 16D score was lower in CH patients compared to controls (0.917, vs. 0.947), but without statistical significance. CONCLUSION: SES of CH patients did not differ from matched controls. Thus, most CH patients integrate well into society, but their HRQoL is impaired. IMPACT: Most patients with primary congenital hypothyroidism integrate well into society. In the current study, their socioeconomic and marital status did not differ from matched controls at the age of 25 years. However, health-related quality of life measured using 15D instrument was impaired. Every fourth patient reported that congenital hypothyroidism influenced everyday life.

Incidence of primary congenital hypothyroidism over 24 years in Finland.

BACKGROUND: A rise in the incidence of congenital hypothyroidism (CH) has been reported worldwide. This nationwide study aimed to describe the secular trends and current incidence of CH in Finland. METHODS: Two independent study cohorts, a national and a regional, were collected from national registers and patient records. The national cohort represents all CH cases born in Finland between 1994 and 2017. Birth data, results of the screening test, and the incidence of CH were reviewed. RESULTS: Between 1994 and 2017, 1,400,028 children were born in Finland. Of these children, 503 were diagnosed with primary CH (incidence 1:2783). Male-to-female sex ratio was 1:2.0. The nationwide incidence was 33 cases per 100,000 live births between 1994 and 1999, 38 cases per 100,000 live births between 2000 and 2005, 40 cases per 100,000 live births between 2006 and 2011, and 33 cases per 100,000 live births between 2012 and 2017. In the regional cohort (n = 139), the incidence of transient CH was 3.6%. The incidence of mild, moderate, and severe CH remained constant. CONCLUSIONS: In Finland, the incidence of CH has not changed during the 24-year study period. IMPACT: As opposed to recent reports worldwide, the incidence of congenital hypothyroidism has not changed between 1994 and 2017 in Finland. The proportions of mild, moderate, and severe congenital hypothyroidism did not change significantly over the study period. Lowering the TSH cut-off limit or increasing immigration did not affect the incidence rate of primary congenital hypothyroidism in Finland.

Serum testosterone and oestradiol predict the growth response during puberty promoting treatment.

OBJECTIVE: The influence of androgens and oestrogens on growth is complex, and understanding their relative roles is important for optimising the treatment of children with various disorders of growth and puberty. DESIGN: We examined the proportional roles of androgens and oestrogens in the regulation of pubertal growth in boys with constitutional delay of growth and puberty (CDGP). The study compared 6-month low-dose intramuscular testosterone treatment (1 mg/kg/month; n = 14) with per oral letrozole treatment (2.5 mg/day; n = 14) which inhibits conversion of androgens to oestrogen. PATIENTS: Boys with CDGP were recruited to a randomized, controlled, open-label trial between 2013 and 2017 (NCT01797718). MEASUREMENTS: The patients were evaluated at 0-, 3- and 6-month visits, and morning blood samples were drawn. Linear regression models were used for data analyses. RESULTS: In the testosterone group (T-group), serum testosterone concentration correlated with serum oestradiol concentration at the beginning of the study and at 3 months, whereas in the letrozole group (Lz-group) these sex steroids correlated only at baseline. Association between serum testosterone level and growth velocity differed between the T and Lz groups, as each nmol/L increase in serum testosterone increased growth velocity 2.7 times more in the former group. Serum testosterone was the best predictor of growth velocity in both treatment groups. In the Lz-group, adding serum oestradiol to the model significantly improved the growth estimate. Only the boys with serum oestradiol above 10 pmol/L had a growth velocity above 8 cm/year. CONCLUSIONS: During puberty promoting treatment with testosterone or aromatase inhibitor letrozole, growth response is tightly correlated with serum testosterone level. A threshold level of oestrogen appears to be needed for an optimal growth rate that corresponds to normal male peak height velocity of puberty. Serum testosterone 1 week after the injection and serum testosterone and oestradiol 3 months after the onset of aromatase inhibitor treatment can be used as biomarkers for treatment response in terms of growth.

Increased referrals for congenital hyperinsulinism genetic testing in children with trisomy 21 reflects the high burden of non-genetic risk factors in this group.

BACKGROUND: Hyperinsulinism results from inappropriate insulin secretion during hypoglycaemia. Down syndrome is causally linked to a number of endocrine disorders including Type 1 diabetes and neonatal diabetes. We noted a high number of individuals with Down syndrome referred for hyperinsulinism genetic testing, and therefore aimed to investigate whether the prevalence of Down syndrome was increased in our hyperinsulinism cohort compared to the population. METHODS: We identified individuals with Down syndrome referred for hyperinsulinism genetic testing to the Exeter Genomics Laboratory between 2008 and 2020. We sequenced the known hyperinsulinism genes in all individuals and investigated their clinical features. RESULTS: We identified 11 individuals with Down syndrome in a cohort of 2011 patients referred for genetic testing for hyperinsulinism. This represents an increased prevalence compared to the population (2.5/2011 expected vs. 11/2011 observed, p = 6.8 × 10-5 ). A pathogenic ABCC8 mutation was identified in one of the 11 individuals. Of the remaining 10 individuals, five had non-genetic risk factors for hyperinsulinism resulting from the Down syndrome phenotype: intrauterine growth restriction, prematurity, gastric/oesophageal surgery, and asparaginase treatment for leukaemia. For five individuals no risk factors for hypoglycaemia were reported although two of these individuals had transient hyperinsulinism and one was lost to follow-up. CONCLUSIONS: Down syndrome is more common in patients with hyperinsulinism than in the population. This is likely due to an increased burden of non-genetic risk factors resulting from the Down syndrome phenotype. Down syndrome should not preclude genetic testing as coincidental monogenic hyperinsulinism and Down syndrome is possible.

Bone structure assessed with pQCT in prepubertal males with delayed puberty or congenital hypogonadotropic hypogonadism.

OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) is associated with impaired bone mineral density in adulthood, whereas the estimates on bone structure in adolescents with CHH has not been previously evaluated. This study describes bone structure in CHH patients and compares it to that in boys with constitutional delay of growth and puberty (CDGP). DESIGN: A cross-sectional study. METHODS: Peripheral quantitative computed tomography (pQCT) of non-dominant arm and left leg were performed. Volumetric bone mineral density (BMD), bone mineral content, and area in trabecular and cortical bone compartments were evaluated, and bone age-adjusted Z-scores for the bone parameters were determined. RESULTS: The participants with CHH had more advanced bone age and were older, taller and heavier than the CDGP boys, yet they had lower trabecular BMD in distal radius (147.7 mg/mm3 [95% CI, 128-168 mg/mm3 ] vs. 181.2 mg/mm3 [172-192 mg/mm3 ], p = .002) and distal tibia (167.6 mg/mm3 [145-190 mg/mm3 ] vs. 207.2 mg/mm3 [187-227 mg/mm3 ], p = .012), respectively. CHH males had lower cortical thickness at diaphyseal tibia than the participants with CDGP (p = .001). These between-group differences remained significant in corresponding Z-scores adjusted for bone age and height (p = .001). In CDGP group, serum testosterone correlated positively with trabecular BMD (r = 0.51, p = .013) at distal radius, and estradiol levels correlated positively with trabecular BMD at the distal site of tibia (r = 0.58, p = .004). CONCLUSIONS: Five treatment-naïve male patients with CHH exhibited poorer trabecular BMD than untreated males with CDGP. We speculate that timely low-dose sex steroid replacement in CHH males may benefit skeletal health in adulthood.

Treatment of gonadotropin deficiency during the first year of life: long-term observation and outcome in five boys.

STUDY QUESTION: What is the peripubertal outcome of recombinant human FSH (r-hFSH) treatment during minipuberty in boys with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Sertoli-cell response to r-hFSH, given during the minipuberty of infancy, appears insufficient to maintain Sertoli cell function throughout childhood, as evaluated by inhibin B measurements. WHAT IS KNOWN ALREADY: Severe CHH in boys can be diagnosed during the minipuberty of infancy. Combined gonadotropin treatment at that age is suggested to improve testicular endocrine function and future fertility, yet long-term evidence is lacking. STUDY DESIGN, SIZE, DURATION: In this retrospective cohort study, we describe five CHH boys treated with r-hFSH in Helsinki University Hospital or Kuopio University Hospital between 2004 and 2018. Immediate follow-up data (0.1-1.4 months after cessation of the gonadotropin therapy) was available for four boys and long-term observations (at the age of 10.0-12.8 years) was available for three boys. As a retrospective control cohort, we provide inhibin B values of eight untreated CHH boys at the age of 12.7-17.8 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Four patients had combined pituitary hormone deficiency, and one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7-4.2 months with r-hFSH (3.4 IU/kg-7.5 IU/kg per week in 2 or 3 s.c. doses for 3-4.5 months) combined with T (25 mg i.m. monthly for three months for the treatment of micropenis). Inhibin B was chosen as the primary outcome measure. MAIN RESULTS AND THE ROLE OF CHANCE: During the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/l to 176 ± 80 ng/l (P = 0.04) and penile length increased by 81 ± 50% (P = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: declining from 290 ng/l (4 months) to 16 ng/l (12.4 years), and from 207 ng/l (6 months) to 21 ng/l (12.8 years). All boys underwent orchiopexy at 2.0 ± 0.7 years of age. Inhibin B values in long-term follow-up, available for the three boys, did not significantly differ from the untreated CHH controls. LIMITATIONS, REASONS FOR CAUTION: Limitations of this retrospective study are the small number and heterogeneity of the patients and their treatment schemes. WIDER IMPLICATIONS OF THE FINDINGS: We describe the first long-term follow-up data on CHH boys treated with r-hFSH and T as infants. The results from this small patient series suggest that the effects of infant r-hFSH treatment may be transient, and further longitudinal studies are required to determine the efficacy of this treatment approach to optimise the fertility potential in this patient population. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Finnish foundation for Pediatric Research, the Academy of Finland and the Emil Aaltonen Foundation. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Non-applicable.

The effect of hypoglycaemia on neurocognitive outcome in children and adolescents with transient or persistent congenital hyperinsulinism.

AIM: To examine the hypoglycaemic effect on neurodevelopmental outcome in patients with transient and persistent congenital hyperinsulinism (CHI) born in the 21st century. METHOD: A cohort of 117 patients (66 males, 51 females) with CHI aged 5 to 16 years (mean age 8y 11mo, SD 2y 7mo) were selected from a Finnish nationwide registry to examine all the patients with similar methods. Neurodevelopment was first evaluated retrospectively. The 83 patients with no risk factors for neurological impairment other than hypoglycaemia were recruited and 44 participated (24 males, 20 females; mean age 9y 7mo, SD 3y 1mo) in neuropsychological assessment with the Wechsler Intelligence Scale for Children, Fourth Edition and the Finnish version of the Developmental Neuropsychological Assessment, Second Edition domains of attention, language, memory, sensorimotor, and visual functioning. RESULTS: In retrospective analysis, transient and persistent CHI groups had similar prevalences of mild (22% and 18% respectively) or severe (5% and 7% respectively) neurodevelopmental difficulties. In clinical assessment, the neurocognitive profile was within the average range in both groups, but children with persistent CHI showed significant but restricted deficits in attention, memory, visual, and sensorimotor functions compared with the general population. The transient CHI group did not differ from the standardization samples. INTERPRETATION: Besides the more apparent broader neurological deficits, children with persistent CHI have an increased risk for milder specific neurocognitive problems, which should be considered in the follow-up. WHAT THIS PAPER ADDS: Children with persistent congenital hyperinsulinism showed deficits in attention, memory, visual, and sensorimotor functions. The deficits were potentially of hypoglycaemic origin. Children with transient hyperinsulinism did not differ from the general population.

EL EFECTO DE LA HIPOGLUCEMIA SOBRE EL RESULTADO NEUROCOGNITIVO EN NIÑOS Y ADOLESCENTES CON HIPERINSULINISMO CONGÉNITO TRANSITORIO O PERSISTENTE: OBJETIVO: Examinar el efecto hipoglucémico sobre el resultado del neurodesarrollo en pacientes nacidos en el siglo XXI con hiperinsulinismo congénito (HIC) transitorio y persistente. MÉTODO: Una cohorte de 117 pacientes (66 varones, 51 mujeres) con HIC de 5 a 16 años de edad (media de 8 años 11 meses, DS 2 años 7 meses) fueron seleccionados de un registro nacional finlandés para examinar a todos los pacientes con métodos similares. El neurodesarrollo se evaluó por primera vez de forma retrospectiva. Los 83 pacientes sin factores de riesgo para el deterioro neurológico distintos de la hipoglucemia fueron reclutados y 44 de ellos participaron (24 varones, 20 mujeres; edad media 9 años 7 meses, DS 3 años 1mes) en la evaluación neuropsicológica con la Escala de Inteligencia de Wechsler y la versión finlandesa de la Evaluación Neuropsicológica del desarrollo, segunda edición, incluyendo los dominios de atención, lenguaje, memoria, sensoriomotor y funcionamiento visual. RESULTADOS: En el análisis retrospectivo, los grupos de HIC transitorios y persistentes tuvieron prevalencias similares de dificultades del neurodesarrollo leves (22% y 18% respectivamente) o graves (5% y 7% respectivamente). En la evaluación clínica, el perfil neurocognitivo estuvo dentro del rango promedio en ambos grupos, pero los niños con HIC persistente mostraron déficits significativos pero restringidos en la atención, memoria, funciones visuales y sensomotrices en comparación con la población general. El grupo de HIC transitorio no difirió de las muestras de estandarización. INTERPRETACIÓN: Además de los déficits neurológicos más aparentes generalizados, los niños con HIC persistente tienen un mayor riesgo de presentar problemas neurocognitivos específicos más leves, que deben ser considerados en el seguimiento.

O EFEITO DA HIPOGLICEMIA NO RESULTADO NEUROCOGNITIVO EM CRIANÇAS E ADOLESCENTES COM HIPERINSULINEMIA CONGÊNITA TRANSITÓRIA OU PERSISTENTE: OBJETIVO: Examinar o efeito hipoglicêmico no resultado neurodesenvolvimental em pacientes com hyperinsulinemia congênita (HIC) transitória ou persistente nascidas no século 21. MÉTODO: Uma coorte de 117 pacientes (66 do sexo masculino, 51 do sexo feminino) com HIC e idades de 5 a 16 anos (média de idade 8a 11m, DP 2a 7m) foram selecionados de um registro nacional finlandês para exame com métodos similares. Primeiramente, o neurodesenvolvimento foi avaliado retrospectivamente. Os 83 pacientes sem risco para deficiência neurológica além da hipoglicemia foram recrutados, e 44 participaram (24 do sexo masculino, 20 do sexo feminino; média de idade 9a 7m, DP 3a 1m) na avaliação neuropsicológica com a escala Wechsler de Inteligência, e a versão finlandesa da Avaliação Neuropsicológica Desenvolvimental, segunda edição, nos domínios de atenção, linguagem, memória, sensório-motor, e funcionamento visual. RESULTADOS: Na análise retrospective, os grupos com HIC transitória e persistente tiveram prevalências similares de dificuldades neurodesenvolvimentais leves (22% e 18% respectivamente) ou severa (5% e 7% respectivamente). Na avaliação clínica, o perfil neurocognitivo estava dentro da média para ambos os grupos, mas crianças com HIC persistente mostraram deficits significantes, mas restritos, nas funções de atenção, de memória, visuais e sensório-motoras comparado com a população em geral. O grupo com HIC transitória não diferiu das amostras padronizadas. INTERPRETAÇÃO: Além dos deficits neurológicos mais amplos e aparentes, crianças com HIC persistente têm risco aumentado de problemas neurocognitivos específicos leves, o que deve ser considerado no acompanhamento.

Future risk of metabolic syndrome in women with a previous LGA delivery stratified by gestational glucose tolerance: a prospective cohort study.

BACKGROUND: Whether the delivery of a large-for-gestational-age (LGA) infant predicts future maternal metabolic syndrome (MetS) is not known. To this aim, we investigated the incidence of MetS and its components in women with or without a history of gestational diabetes mellitus (GDM) with a view to the birth weight of the offspring. METHODS: Eight hundred seventy six women treated for their pregnancies in Kuopio University Hospital in 1989-2009 underwent a follow-up study (mean follow-up time 7.3 (SD 5.1) years), of whom 489 women with GDM and 385 normoglycemic controls. The women were stratified into two groups according to the newborn's birth weight: 10-90th percentile (appropriate-for-gestational-age; AGA) (n = 662) and > 90th percentile (LGA) (n = 116). MetS and its components were evaluated in the follow-up study according to the International Diabetes Federation criteria. RESULTS: LGA vs. AGA delivery was associated with a higher incidence of MetS at follow-up in women with a background of GDM (54.4% vs. 43.6%), but not in women without GDM. CONCLUSION: An LGA delivery in women with GDM is associated with a higher risk of future MetS and this group is optimal to study preventive measures for MetS. In contrast, an LGA delivery after a normoglycemic pregnancy was not associated with an increased future maternal MetS risk.

The risk of metabolic syndrome in women with previous GDM in a long-term follow-up.

The aim of this study was to evaluate the incidence of metabolic syndrome (MetS) during long-term follow-up of women with gestational diabetes (GDM). Furthermore, we evaluated the glycemic measures from an oral glucose tolerance test (OGTT) during pregnancy as predictors of incident MetS. Women diagnosed with GDM were divided into two groups according to the results of OGTT: one abnormal value = GDM1 (n = 338) and two abnormal values = GDM2 (n = 151), while women with normal glucose tolerance (n = 385) served as controls. MetS and its components were evaluated in a follow-up study (mean follow-up time 7.3 ± 5.1 years) according to the International Diabetes Federation (IDF) criteria. Fasting plasma glucose in OGTT was the best predictor of incident MetS in ROC (area under the curve) analysis. The incidence of MetS during a <5-year follow-up was 22.2% in controls, 39.3% in GDM1 and 60.4% in GDM2; and >10-year follow-up 24.2%, 46.2% and 62.5%, respectively. In controls and GDM2, the incidence of MetS remained nearly constant during the follow-up, whereas in GDM1 it increased. In conclusion, already mild gestational glucose intolerance may progress to MetS and therefore merits intervention measures to prevent future cardiovascular disease.

Post-challenge glycemia during pregnancy as a marker of future risk of type 2 diabetes: a prospective cohort study.

The aim of this study was to evaluate the glycemic measures from an oral glucose tolerance test (OGTT) during pregnancy as predictors of incident type 2 diabetes mellitus (T2DM). Patients diagnosed with gestational diabetes mellitus (GDM) were divided into two groups according to the results of OGTT: one abnormal value = GDM1 (n = 338) and two abnormal values = GDM2 (n = 151), while women with normal glucose tolerance served as controls (n = 385). Glucose tolerance was re-evaluated with an OGTT in a follow-up study (average follow-up time 7.3 ± 5.1 years). The incidence of T2DM after 10 years follow-up increased progressively by the degree of the glycemic abnormality during pregnancy: 0.8% in controls, 3.8% in GDM1 (adjusted HR 17.6, 95% CI 1.9-162.3) and 25.0% in GDM2 (adjusted HR 72.9, 95% CI 9.6-553.7), respectively (p = <0.0001). The risk of T2DM is significantly increased in women with two or more abnormal values in OGTT during pregnancy. Post-challenge glucose levels in OGTT were the best predictors of the incident T2DM in ROC analysis and they therefore identify the greatest risk group for targeted prevention of T2DM after GDM.

Long-term changes in glucose metabolism after gestational diabetes: a double cohort study.

BACKGROUND: Gestational diabetes (GDM) has been associated with an elevated risk of type 2 diabetes in women after the pregnancy. Recognition of the factors differentiating the women at highest risk of progression to overt disease from those who remain normoglycemic after gestational diabetes is of key importance for targeted prevention programmes. To this aim, we investigated the incidence and risk factors of prediabetes and type 2 diabetes with a view to the underlying pathophysiological mechanisms in a long-term follow-up of women with a history of gestational diabetes. METHODS: 489 women with GDM and 385 normoglycemic controls attended a follow-up study after pregnancy (mean follow-up time 7.3, SD 5.1 years) in Kuopio, Finland. Glucose tolerance was evaluated with an oral glucose tolerance test, insulin sensitivity by Matsuda insulin sensitivity index (ISI), and insulin secretion by Disposition Index 30 (DI30). RESULTS: GDM increased risk of pre-diabetes and diabetes (HR 3.7, 95% C.I. 2.8-4.7 and HR 40.7, 95% C.I. 5.3-310.1, respectively, after adjustment for confounding factors) and was associated with both increased fasting (P < 0.001) and 2-hour plasma glucose (P < 0.001) during OGTT at the follow-up study. This effect was attenuated when adjusted for Matsuda ISI but abolished after adjustments with DI30 suggesting insulin secretion is the key defect leading to type 2 diabetes after GDM pregnancy. Increase in waist circumference and weight after pregnancy predicted the development of hyperglycemic conditions in women with a history of GDM (P < 0.001, and P = 0.002, respectively). CONCLUSIONS: Pre-diabetic stages after GDM pregnancy are frequent and reflect the progressive risk of type 2 diabetes in long-term follow-up. Hyperglycemia after GDM pregnancy results from beta cell failure and inability to compensate the increased insulin resistance by insulin secretion. Importantly, increase in waist circumference and as well as weight gain during the follow-up is associated with progression to prediabetes and type 2 diabetes in women with a history GDM.

Treatment of Congenital Hypothyroidism: Impact of Secular Changes in Levothyroxine Initial Dose on Early Growth.

INTRODUCTION: Newborn screening of congenital hypothyroidism (CH) has enabled early treatment with levothyroxine (LT4), ensuring normal growth and development. The initial LT4 dose recommendation has increased over decades. We evaluated whether the increased LT4 dosing influenced thyroid-stimulating hormone (TSH) and thyroxine (fT4) concentrations, growth, or treatment-related symptoms. METHODS: LT4 doses, TSH, fT4, anthropometrics, and treatment-related symptoms until age 2 years were evaluated in 172 Finnish CH patients born between 1980 and 2018. The patients were grouped according to birth decade: 1980s (n = 19, mean LT4 starting dose 6.8 µg/kg/day), 1990s (n = 50, 7.4 µg/kg/day), 2000s (n = 59, 9.7 µg/kg/day), and 2010s (n = 44, 10.8 µg/kg/day). RESULTS: TSH concentrations were higher during the first 2 years of life in children born in the 1980s compared to children born later. TSH concentrations were often subnormal in children receiving higher LT4 doses (children born in the 2000s and 2010s). However, symptoms of overtreatment were uncommon. Linear or head growth showed no differences between the groups during the first 2 years of life. Although growth was within the normal spectrum, children in all groups were shorter than their target length at 2 years and their weight-for-length was above the mean through the first 2 years of life. DISCUSSION: Current treatment practice with higher LT4 dose normalizes TSH rapidly without significant increase in side effects. However, irrespective of initial LT4 dose, children were shorter than expected at 2 years of age. Effects of different initial LT4 dose on cognitive development urges further investigation.

Comorbidity in Congenital Hypothyroidism-A Nationwide, Population-based Cohort Study.

CONTEXT: Patients with congenital hypothyroidism (CH) are affected more often than the general population by other chronic diseases and neurological difficulties. OBJECTIVE: The aim of this nationwide population-based register study was to investigate the incidence of congenital malformations, comorbidities, and the use of prescribed drugs in patients with primary CH. METHODS: The study cohort and matched controls were identified from national population-based registers in Finland. All diagnoses from birth until the end of 2018 were collected from the Care Register, and subject-specific prescription drug purchases were identified from The Prescription Register from birth until the end of 2017. RESULTS: Diagnoses of neonatal and chronic diseases were collected for 438 full-term patients and 835 controls (median follow-up time 11.6 years; range, 0-23 years). Newborns with CH were more often found to have neonatal jaundice (11.2% and 2.0%; P < .001), hypoglycemia (8.9% and 2.8%; P < .001), metabolic acidemia (3.2% and 1.1%; P = .007), and respiratory distress (3.9% and 1.3%; P < .003) as compared to their matched controls.Congenital malformations were diagnosed in 66 of 438 (15.1%) CH patients and in 62 of 835 (7.4%) controls (P < .001). The most commonly affected extrathyroidal systems were the circulatory and musculoskeletal systems. The cumulative incidence of hearing loss and specific developmental disorders was higher among CH patients than controls. The use of antidepressant and antipsychotic drugs was similar in CH patients and their controls. CONCLUSION: CH patients have more neonatal morbidity and congenital malformations than their matched controls. The cumulative incidence of neurological disorders is higher in CH patients. However, our results do not support the existence of severe psychiatric comorbidity.

Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: A single center experience from over 30 years.

Background: Childhood-onset combined pituitary hormone deficiency (CPHD) has a wide spectrum of etiologies and genetic causes for congenital disease. We aimed to describe the clinical spectrum and genetic etiologies of CPHD in a single tertiary center and estimate the population-level incidence of congenital CPHD. Methods: The retrospective clinical cohort comprised 124 CPHD patients (48 with congenital CPHD) treated at the Helsinki University Hospital (HUH) Children's Hospital between 1985 and 2018. Clinical data were collected from the patient charts. Whole exome sequencing was performed in 21 patients with congenital CPHD of unknown etiology. Findings: The majority (61%;76/124) of the patients had acquired CPHD, most frequently due to craniopharyngiomas and gliomas. The estimated incidence of congenital CPHD was 1/16 000 (95%CI, 1/11 000-1/24 000). The clinical presentation of congenital CPHD in infancy included prolonged/severe neonatal hypoglycaemia, prolonged jaundice, and/or micropenis/bilateral cryptorchidism in 23 (66%) patients; despite these clinical cues, only 76% of them were referred to endocrine investigations during the first year of life. The median delay between the first violation of the growth screening rules and the initiation of GH Rx treatment among all congenital CPHD patients was 2·2 years, interquartile range 1·2-3·7 years. Seven patients harbored pathogenic variants in PROP1, SOX3, TBC1D32, OTX2, and SOX2, and one patient carried a likely pathogenic variant in SHH (c.676G>A, p.(Ala226Thr)). Interpretation: Our study suggests that congenital CPHD can occur in 1/16 000 children, and that patients frequently exhibit neonatal cues of hypopituitarism and early height growth deflection. These results need to be corroborated in future studies and might inform clinical practice. Funding: Päivikki and Sakari Sohlberg Foundation, Biomedicum Helsinki Foundation, and Emil Aaltonen Foundation research grants.

Circulating Liver-enriched Antimicrobial Peptide-2 Decreases During Male Puberty.

CONTEXT: Circulating levels of liver-enriched antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist, decrease under caloric restriction and increase in obesity. The role of LEAP2 in male puberty, a phase with accelerated energy demand, is unclear. OBJECTIVE: This work aimed to investigate whether circulating LEAP2 levels are downregulated in boys following the onset of puberty to respond to the energy need required for growth. METHODS: We determined circulating LEAP2 levels in 28 boys with constitutional delay of growth and puberty (CDGP) who participated in a randomized controlled trial (NCT01797718), and were treated with letrozole (n = 15) or intramuscular low-dose testosterone (T) (n = 13) for 6 months. Blood sampling and dual-energy x-ray absorptiometry-measured body composition were performed at 0-, 6-, and 12-month visits. RESULTS: Serum LEAP2 levels decreased statistically significantly during pubertal progression (0-6 months: mean decrease -4.3 [10.3] ng/mL, P = .036 and 0-12 months: -3.9 [9.3] ng/mL, P = .033). Between 0 and 6 months, the changes in serum LEAP2 levels correlated positively with changes in percentage of body fat (rs = 0.48, P = .011), and negatively with growth velocity and estradiol levels (rs = -0.43, P = .022, rs = -0.55, P = .003, respectively). In the T group only, the changes in serum LEAP2 correlated negatively with changes in T and estradiol levels. Between 0 and 12 months, the change in LEAP2 levels correlated negatively with the change in high-density lipoprotein levels (rs = -0.44, P = .022) and positively with the change in insulin (rs = 0.50, P = .009) and HOMA-IR (rs = 0.51, P = .007) levels. CONCLUSION: Circulating LEAP2 levels decreased after induction of puberty reciprocally with increased growth rate and energy demand, reflecting the metabolic state of the adolescent. Further, the results suggest that estradiol levels may have a permissive role in downregulating circulating LEAP2 levels.

Health-related quality of life in boys with constitutional delay of growth and puberty.

Introduction: Constitutional delay of growth and puberty (CDGP) is the most common reason for delayed puberty in healthy male adolescents. The main indication for medical treatment for this condition is psychosocial burden. However, to the best of our knowledge, no previous study has addressed the impact of puberty-promoting treatment on health-related quality of life (HRQoL) among boys with CDGP. Methods: We investigated HRQoL in 22 boys with CDGP, who participated in a randomized controlled trial in four Finnish pediatric endocrinology outpatient clinics between 2013 and 2017. The boys were randomized to receive either aromatase inhibitor letrozole (2.5mg/day; n=11) or intramuscular testosterone (1mg/kg/every 4 weeks; n=11) for 6 months and followed up to 12 months. HRQoL was assessed with a generic self-assessment 16D© instrument developed and validated for adolescents aged 12 to 15 years. The 16D includes 16 dimensions (vitality, sight, breathing, distress, hearing, sleeping, eating, discomfort and symptoms, speech, physical appearance, school and hobbies, mobility, friends, mental function, excretion and depression). The results were compared with an age-matched reference population that included 163 boys from the Finnish capital-city area. The study protocol is registered to ClinicalTrials.gov (registration number: NCT01797718). Results: At baseline, the mean 16D score of the CDGP boys was similar to the age-matched reference population (0.95 vs 0.96, p=0.838). However, the physical appearance score (satisfaction with general appearance, height and weight) was significantly lower in the CDGP boys (0.75 vs 0.92, p=0.004) than their peers. Twelve months after treatment, Appearance had improved significantly (0.75 vs 0.87, p=0.004) and no HRQoL dimension was inferior compared to the age-matched reference population. Discussion: In terms of HRQoL, the main impact of delayed puberty was dissatisfaction with physical appearance. Puberty promoting therapy was associated with a positive change in perceived appearance, with no clear difference between low-dose testosterone and letrozole treatments.

[Neonatal diabetes mellitus]. / Vastasyntyneen diabetes.

Instead of type 1 diabetes, the underlying cause in diabetes with an onset before the age of six months is more likely to be monogenic. Approximately half of the permanent cases of neonatal diabetes are due to mutations in genes coding for the potassium ATP channel proteins essential to insulin secretion. Identification of the cause of a monogenic form of diabetes is important, since it will affect the mode of treatment, prognosis and hereditability. It is especially important to detect neonatal diabetes caused by K-ATP channel genes, as insulin therapy can then usually be replaced by oral sulfonylurea medication.

[From injections to pills--neonatally diagnosed diabetes of mother and baby]. / Aidin ja vastasyntyneen diabetes-- pistoksista pillereihin.

The genetic background of neonatally diagnosed diabetes has begun to become clear only in the last few years. Recognition of the disease mechanism has often allowed the replacement of insulin therapy by sulfonylurea, which has improved the patients' quality of life and diabetes control. We describe a male infant diagnosed with neonatal diabetes, and his mother, who has had a disease considered to be type 1 diabetes since infancy. Both were diagnosed with a mutation in the KCNJ11 gene coding for the beta cell potassium channel and causing neonatal diabetes. The patients were treated with sylfonylurea.

Long-Term Outcome and Treatment in Persistent and Transient Congenital Hyperinsulinism: A Finnish Population-Based Study.

CONTEXT: The management of congenital hyperinsulinism (CHI) has improved. OBJECTIVE: To examine the treatment and long-term outcome of Finnish patients with persistent and transient CHI (P-CHI and T-CHI). DESIGN: A population-based retrospective study of CHI patients treated from 1972 to 2015. PATIENTS: 106 patients with P-CHI and 132 patients with T-CHI (in total, 42 diagnosed before and 196 after year 2000) with median follow-up durations of 12.5 and 6.2 years, respectively. MAIN OUTCOME MEASURES: Recovery, diabetes, pancreatic exocrine dysfunction, neurodevelopment. RESULTS: The overall incidence of CHI (n = 238) was 1:11 300 live births (1972-2015). From 2000 to 2015, the incidence of P-CHI (n = 69) was 1:13 500 and of T-CHI (n = 127) 1:7400 live births. In the 21st century P-CHI group, hyperinsulinemic medication was initiated and normoglycemia achieved faster relative to earlier. Of the 74 medically treated P-CHI patients, 68% had discontinued medication. Thirteen (12%) P-CHI patients had partial pancreatic resection and 19 (18%) underwent near-total pancreatectomy. Of these, 0% and 84% developed diabetes and 23% and 58% had clinical pancreatic exocrine dysfunction, respectively. Mild neurological difficulties (21% vs 16%, respectively) and intellectual disability (9% vs 5%, respectively) were as common in the P-CHI and T-CHI groups. However, the 21st century P-CHI patients had significantly more frequent normal neurodevelopment and significantly more infrequent diabetes and pancreatic exocrine dysfunction compared with those diagnosed earlier. CONCLUSIONS: Our results demonstrated improved treatment and long-term outcome in the 21st century P-CHI patients relative to earlier.

Boys but Not Girls Exposed to Maternal Gestational Diabetes Mellitus Have Unfavorable Fat Distribution.

BACKGROUND: Maternal gestational diabetes mellitus (GDM) and overweight are associated with an increased risk of obesity and the metabolic syndrome in the adult offspring. We studied the influence of maternal GDM on prepubertal children's body composition and bone mineral biochemistry. METHODS: A total of 134 prepubertal Caucasian children (age range 4.4-9.7 years) were studied in a controlled cross-sectional study. Seventy-six children had been exposed to maternal GDM and 58 children born after a normal pregnancy served as controls. The outcome variables were body fat %, android fat %, gynoid fat %, android/gynoid fat ratio, bone mineral density (BMD), bone mineral content (BMC), muscle mass, lean mass (LM) and serum 25-hydroxyvitamin D, ionized calcium, phosphate, and alkaline phosphatase concentrations. RESULTS: There were no differences in body fat %, android fat %, BMD, BMC, muscle mass, or LM between the study groups. Gynoid fat % was higher in the GDM than control children (p = 0.03). Android fat %, gynoid fat %, and android/gynoid fat ratio were higher in the GDM boys than control boys (p = 0.046, 0.037, and 0.038) respectively, but no differences were found between the GDM and control girls. CONCLUSIONS: Boys exposed to maternal GDM presented with more unfavorable fat distribution than their controls, whereas no difference was found between the girls. Otherwise, the differences in body composition were minimal between prepubertal GDM and control children.