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Objectives: Congenital adrenal hyperplasia (CAH) is a rare, inherited disorder of adrenal steroid synthesis. In many countries it is part of the neonatal screening program enabling early diagnosis and treatment. In case of an abnormal neonatal screening result or when other differences of sexual development (DSD) are suspected, measurement of serum steroid hormones using liquid chromatography coupled to mass spectrometry (LC-MS/MS) is needed for further diagnosis. However, reliable age- and sex-specific reference intervals (RIs) for serum steroid hormones during the neonatal period are missing. We therefore aimed to establish LC-MS/MS based RIs for serum steroid hormones in neonates., Methods: Serum was obtained from healthy term neonates at two time points: 130 samples at day 3-8 ( T1 , time of the neonatal screening) and 126 samples at day 13-15 ( T2,  two weeks old). Concentrations of cortisol, cortisone, corticosterone, 11-deoxycortisol, 21-deoxycortisol, 11-deoxycorticosterone, testosterone, androstenedione, and 17-hydroxyprogesterone (17-OHP) were measured using LC-MS/MS., Results: RIs (in nmol/L) were established for T1 and T2 : cortisone (19.3-215;18.0-212), cortisol (10.0-407;8.4-446), corticosterone (<31;<50), 11-deoxycortisol (0.73-4.6;0.70-3.6), 17-OHP (<4.9;<5.1), androstenedione (0.3-1.8;0.3-2.7), 11-deoxycorticosterone (<0.2;<0.2), and 21-deoxycortisol (<1;<1), respectively. Testosterone differed between boys and girls: RIs at T1 and T2 for boys were 0.27-4.3 and 0.63-13.9, and for girls<0.30 and <0.47, respectively., Conclusions: We established LC-MS/MS based RIs for cortisol, cortisone, corticosterone, 11-deoxycortisol, 21-deoxycortisol, 11-deoxycorticosterone, testosterone, androstenedione, and 17-OHP in neonates in the first and second week of life., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Context: Central congenital hypothyroidism (CH) requires lifelong medical treatment. The majority of children with central CH have multiple pituitary hormone deficiencies (MPHD), but in some cases central CH is isolated. Most pituitary hormone deficiencies are associated with impaired health-related quality of life (HRQoL). However, studies on HRQoL in central CH are lacking., Objective: To evaluate HRQoL and fatigue in children and young adults with central CH, as well as parent perspectives., Design: Nationwide cross-sectional study comparing HRQoL between early-detected central CH patients and unaffected siblings with the Pediatric Quality of Life inventory (PedsQL™) and PedsQL Multidimensional Fatigue Scale. Participants ≥ 8 years old filled in self-reports; parents of participants aged 3 to 18 years filled in parent reports. Isolated central CH patients, MPHD patients, and siblings were compared using a linear mixed model and Tukey's post hoc test., Results: Eighty-eight patients and 52 siblings participated, yielding 98 self-reports and 115 parent reports. Isolated central CH patients (n = 35) and siblings showed similar scores on all subscales, both in the self-reports and parent reports. For MPHD patients (n = 53), self-reported scores were similar to those of siblings. Parent reported total HRQoL and fatigue scores were significantly poorer in MPHD patients compared with siblings (mean differences -10.2 and -9.4 points; P < 0.01), as were scores for physical functioning, social functioning and general fatigue., Conclusion: Self-reported HRQoL scores in isolated central CH and MPHD patients were similar to siblings. However, parents reported significantly lower HRQoL and fatigue scores for MPHD patients, suggesting a difference in perceived limitations between MPHD patients and their parents., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Central congenital hypothyroidism (CH) is defined as thyroid hormone (TH) deficiency at birth due to insufficient stimulation by the pituitary of the thyroid gland. The incidence of central CH is currently estimated at around 1:13,000. Central CH may occur in isolation, but in the majority of cases (60%) it is part of combined pituitary hormone deficiencies (CPHD). In recent years several novel genetic causes of isolated central CH have been discovered ( IGSF1 , TBL1X , IRS4 ), and up to 90% of isolated central CH cases can be genetically explained. For CPHD the etiology usually remains unknown, although pituitary stalk interruption syndrome does seem to be the most common anatomic pituitary malformation associated with CPHD. Recent studies have shown that central CH is a more severe condition than previously thought, and that early detection and treatment leads to good neurodevelopmental outcome. However, in the neonatal period the clinical diagnosis is often missed despite hospital admission because of feeding problems, hypoglycemia and prolonged jaundice. This review provides an update on the etiology and prognosis of central CH, and a practical approach to diagnosis and management of this intriguing condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lauffer, Zwaveling-Soonawala, Naafs, Boelen and van Trotsenburg.)

Context: Early treatment of primary congenital hypothyroidism (CH) prevents irreversible brain damage. Contrary to primary CH, outcome studies on central CH are scarce. Most patients with central CH have multiple pituitary hormone deficiencies (MPHD); these patients are also at risk for neonatal hypoglycemia., Objective: To assess cognitive and motor outcome in patients with early-treated central CH detected by the Dutch neonatal screening., Methods: In this cross-sectional study, primary outcome full-scale intelligence quotient (FSIQ) was measured in patients with MPHD and patients with isolated central CH born between January 1, 1995, and January 1, 2015, with siblings as controls. Secondary outcomes were intelligence test subscales and motor function. Linear mixed models were used to compare both patient groups and siblings, followed by post hoc tests in case of significant differences., Results: Eighty-seven patients (52 MPHD; 35 isolated central CH) and 52 siblings were included. Estimated marginal means for FSIQ were 90.7 (95% CI 86.4-95.0) in patients with MPHD and 98.2 (95% CI 93.0-103.5) in patients with isolated central CH. While patients with MPHD scored lower FSIQs than siblings (mean difference -7.9 points, 95% CI -13.4 to -2.5; P = .002), patients with isolated central CH did not. Processing speed was lower in both patient groups than in siblings (mean differences -10.5 and -10.3 points). Motor difficulties occurred significantly more often in patients (33%) versus siblings (5%; P = .004)., Conclusion: In early-treated central CH, FSIQ is comparable with siblings in patients with isolated central CH, while patients with MPHD have a significantly lower FSIQ. This may be explained by disease-specific consequences of MPHD, such as neonatal hypoglycemia and more severe hypothyroidism., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To evaluate clinical characteristics of patients with central congenital hypothyroidism (CH), detected in the Dutch neonatal screening program. This included patients with isolated central CH but the majority have multiple pituitary hormone deficiencies (MPHD)., Design: Nationwide, cross-sectional study., Methods: Data was collected on clinical characteristics, endocrine tests and neuroimaging of central CH patients, detected by the Dutch neonatal screening and born between 1 January 1995 and 1 January 2015. Height and pubertal status were assessed during a study visit. Isolated central CH patients without a confirmed genetic diagnosis were offered genetic (re-)testing., Results: During the 20-year period 154 central CH patients were detected (incidence of permanent central CH 1:25 642). After excluding deceased (15), severe syndromic (7) and transient patients (6), 92 of 126 eligible patients were included (57 MPHD; 79% male). Sixty-one patients (50 MPHD) had been hospitalized before screening results were reported, but central CH was diagnosed on clinical grounds in only three of them (5%). MRI abnormalities consistent with pituitary stalk interruption syndrome were seen in 50 (93%) MPHD patients. Among isolated central CH patients, 27 (84%) had an IGSF1, TBL1X or IRS4 gene variant (53, 16 and 16%, respectively)., Conclusion: Many patients with central CH have neonatal health problems, especially MPHD patients. Despite hospital admission of two-thirds of patients, almost none were diagnosed clinically, but only after the notification of an abnormal screening result was received. This indicates that central CH, especially if isolated, is an easily missed clinical diagnosis.

Background: Congenital hypothyroidism (CH) is a common and preventable cause of mental retardation, which is detected in many neonatal screening programs. Upon suspicion of CH, plasma free thyroxine (fT4) and thyrotropin (TSH) concentrations are measured. CH can be of thyroidal or central origin (CH-T and CH-C, respectively). While CH-T diagnosis is based on an elevated TSH with a low fT4, CH-C diagnosis is based on a low fT4 without a clearly elevated TSH. Currently, reliable neonatal reference intervals (RIs) for plasma fT4 and TSH are lacking. Age-specific RIs would greatly improve the diagnostic process for CH, especially for CH-C. Our aim was to establish neonatal RIs for plasma fT4 and TSH in term neonates at day 3-7 ( t  = 1) and day 13-15 ( t  = 2). The study was particularly designed to provide a reliable fT4 lower limit of the RI to facilitate the diagnosis of CH-C. In the Netherlands, neonates are screened at day 3-7 of life. After a screening result suggestive for CH-C, pediatric consultation takes place on average at day 14. Thus, the time points were chosen accordingly. Methods: Venous blood was collected from 120 healthy neonates at each time point (94 participants provided blood samples at two time points; 52 participants provided a sample at t  = 1 or t  = 2). fT4 and TSH were measured using an immunoassay (Cobas; Roche Diagnostics). RIs were calculated using the 95% confidence interval for normally distributed data and the nonparametric percentile method if data were not normally distributed. Results: From 146 participants (49% female), ≥1 measurement was available. Ninety-five percent RIs for fT4 were 20.5-37.1 pmol/L (day 3-7) and 15.3-26.5 pmol/L (day 13-15). Ninety-five percent RIs for TSH were 1.0-8.4 mU/L (day 3-7) and 1.4-8.6 mU/L (day 13-15). Conclusions: Our results indicate an fT4 lower limit of the RI of 20.5 pmol/L at day 3-7 and 15.3 pmol/L at day 13-15. These lower limits are considerably higher than this assay's lower limit of the adult RI for fT4. In case CH is suspected, we recommend measuring fT4 and TSH using an assay with an established neonatal RI, taking into account the child's age in days.

Objective: To provide an overview of cognitive and motor outcome, and quality of life (QoL) in patients with congenital central hypothyroidism (CH-C)., Design: Systematic review with individual patient data (IPD) meta-analysis., Methods: OVID MEDLINE, EMBASE and PsycInfo were searched from inception to June 11th, 2019. Studies in patients with CH-C, either isolated or with multiple pituitary hormone deficiency (MPHD), were included if CH-C patients could be separated from any additional patient groups. Primary outcomes were full-scale intelligence quotient (FSIQ) and motor outcome; secondary outcome was QoL. Following data-extraction, one-stage IPD meta-analysis was performed, fitting a linear mixed model with FSIQ as dependent variable. Random intercepts were fitted for each study., Results: Six studies measuring FSIQ were eligible for meta-analysis, comprising 30 CH-C patients (20 males; 27 MPHD patients). FSIQ range was wide (64-123). Mean weighted FSIQ was 97 (95% CI: 88-105). Twenty-seven percent had an FSIQ below 85 (≥1 s.d. below norm score), and 10% below 70 (≥2 s.d. below norm score). There was no significant association between FSIQ and sex or age. Age at treatment initiation was available from three studies only, thus impeding a reliable analysis of this parameter. Motor outcome and QoL were each studied in one study; no quantitative analyses could be performed for these outcomes., Conclusion: A wide range in FSIQ scores was observed in CH-C patients. Results should be interpreted with caution, because included patients mainly had MPHD and age at treatment initiation was unknown for the majority of patients.

Context: Approximately 60% to 80% of patients with congenital central hypothyroidism (CH-C) have multiple pituitary hormone deficiencies (MPHDs), making CH-C a potentially life-threatening disease. Data on mortality in patients with CH-C are lacking., Objective: To study the mortality rate in pediatric patients with early-detected and treated CH-C in the Netherlands and to investigate whether causes of death were related to pituitary hormone deficiencies., Methods: Overall mortality rate, infant mortality rate (IMR), and under-5 mortality rate were calculated in all children with CH-C detected by neonatal screening between 1 January 1995 and 1 January 2013. Medical charts were reviewed to establish causes of death., Results: A total of 139 children with CH-C were identified, of which 138 could be traced (82 with MPHD, 56 with isolated CH-C). Total observation time was 1414 years with a median follow-up duration of 10.2 years. The overall mortality rate was 10.9% (15/138). IMR and under-5 mortality rate were 65.2/1000 (9/138) and 101.4/1000 (14/138), respectively, compared with an IMR of 4.7/1000 and under-5 mortality of 5.4/1000 live-born children in the Netherlands during the same time period (P < 0.0001). Main causes of death were severe congenital malformations in six patients, asphyxia in two patients, and congenital or early neonatal infection in two patients. Pituitary hormone deficiency was noted as cause of death in only one infant., Conclusion: We report an increased mortality rate in patients with early-detected CH-C that does not seem to be related to endocrine disease. This suggests that mortality due to pituitary insufficiency is low in patients with early-detected and early-treated CH-C.

Immediately after birth, a skin-covered mass with weak consistency was noted on the back of a full-term newborn boy. Ultrasound and MRI (performed to exclude spina bifida occulta) showed a multicystic venolymphatic malformation. Sclerotherapy or surgical excision are possible treatments. In asymptomatic patients, however, a watchful waiting approach is used.

Background and Objective: Advanced glycation end products (AGEs) are considered major contributors to microvascular and macrovascular complications in adult patients with diabetes mellitus. AGEs can be measured non-invasively with skin autofluorescence (sAF). The primary aim was to determine sAF values in children with type 1 diabetes mellitus and to study correlations between sAF values and HbA1c and mean HbA1c over the year prior to measurement, Research Design and Methods: In children with type 1 diabetes mellitus, sAF values were measured using the AGE Reader®. Laboratory and anthropometric values were extracted from medical charts. Correlations were studied using Pearson's correlation coefficient. Multivariable linear regression analysis was conducted to evaluate the effect of multiple study parameters on sAF values., Results: The mean sAF value was 1.33 ± 0.36 arbitrary units (AU) in children with type 1 diabetes mellitus (n = 144). sAF values correlated positively with HbA1c measured at the same time (r = 0.485; p < 0.001), mean HbA1c over the year prior to measurement (r = 0.578; p < 0.001), age (r = 0.337; p < 0.001), duration of type 1 diabetes mellitus (r = 0.277; p = 0.001), serum triglycerides (r = 0.399; p < 0.001), and total cholesterol (r = 0.352; p = 0.001). sAF values were significantly higher in patients with non-white skin (1.56 vs. 1.27 AU, respectively, p = 0.001)., Conclusions: In children with type 1 diabetes, sAF values correlate strongly with single HbA1c and mean HbA1c, making the non-invasive sAF measurement an interesting alternative to provide information about cumulative hyperglycemic states. To determine the value of sAF measurement in predicting long-term microvascular and macrovascular complications, further prospective follow-up studies are needed., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

General practitioners and paediatricians are frequently confronted with coughing infants. The age of the infant, the history of both mother and child, as well as the current maternal condition may provide important diagnostic information. A 4-week-old male infant was referred to the paediatrician with a persistent cough. He was admitted to hospital with dyspnoea and need for supplemental oxygen. Meanwhile, his mother was admitted with unexplained abdominal pain and elevated laboratory inflammation markers. Her history revealed an ectopic pregnancy. The infant's condition, for which the initial differential diagnosis was viral bronchiolitis or whooping cough, deteriorated. His medical history revealed a purulent conjunctivitis. Chlamydia trachomatis PCR turned out to be positive in both mother and child. C. trachomatis pneumonia is a common, yet often overlooked cause of cough in infants. This clinical lesson emphasises the importance of a complete history and efficient communication between medical specialists.