Thyroid disease in children and adolescents with PTEN hamartoma tumor syndrome (PHTS).

Patients with PTEN hamartoma tumor syndrome (PHTS) are at increased risk of developing benign and malignant tumors, including thyroid carcinoma. Benign thyroid lesions and single cases of thyroid carcinoma have been reported in children with PHTS. We conducted a retrospective, single-centered study including children and adolescents with a molecularly proven diagnosis of PTEN. Our cohort consists of 16 patients, with a mean age at diagnosis PHTS of 5.7 years. Twelve of 16 cases exhibited thyroid abnormalities (75%). In seven patients, thyroid abnormalities were already present at first ultrasound screening, in five cases they occurred during follow-up. Eight patients underwent thyroidectomy. Histopathology included nodular goiter, follicular adenoma, papillary microcarcinoma in a boy of six and follicular carcinoma in a girl of 13 years. Two patients had autoimmune thyroid disease. CONCLUSION: Thyroid disease is common in children with PHTS. Physicians caring for patients with early thyroid abnormalities and additional syndromal features should be aware of PHTS as a potentially underlying disorder. Ultrasound screening should be performed immediately after diagnosis of PHTS and repeated yearly or more frequently. Because of possible early cancer development, we recommend early surgical intervention in the form of total thyroidectomy in cases of suspicious ultrasound findings. What is Known: • PHTS patients are at high risk of developing benign and malignant tumors. • Individual cases of thyroid carcinoma in children have been reported. What is New: • Thyroid disease is even more common in children with PHTS (75%) than previously expected. • Frequently thyroid disease is the first organ pathology requiring diagnostic workup and therefore children with PHTS should be examined for thyroid disease right after diagnosis and receive follow-up on a regular basis throughout life.

Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature.

Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson⁻Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections.

Factors contributing to partial remission in type 1 diabetes: analysis based on the insulin dose-adjusted HbA1c in 3657 children and adolescents from Germany and Austria.

OBJECTIVE: Insulin dose-adjusted hemoglobin A1c (HbA1C, IDAA1c) correlates well with stimulated C-peptide levels, but has not yet been evaluated in a large cohort of patients with Type 1 diabetes (T1D). METHODS: We investigated prevalence of partial remission (PREM) defined by IDAA1c ≤9 in 3657 in children with new-onset T1D who were continuously followed over 6 years. We evaluated the predictors of PREM using the multicenter database from the DPV (Diabetes Patienten Verlaufsdokumentation) registry. RESULTS: PREM occurred in 71% of patients. Median duration was 9 (0-21) months. Compared to children <5 years at T1D onset, those aged 5-10 and ≥10 years had twice the chance of developing PREM (OR: 2.08, CI: 1.67-2.60; P < .001 and OR: 2.16, CI: 1.70-2.75; P < .001). Boys were more likely to develop PREM than girls (OR 1.41, CI: 1.18-1.69; P = .0002). Further predictors for PREM were: ketoacidosis, autoantibodies, and HbA1c at T1D onset. These results were confirmed by quantile regression analysis with duration of PREM as dependent variable. CONCLUSION: This research on a large cohort provides insight into epidemiologic characteristics of PREM in T1D defined by IDAA1c. As IDAA1c does not discriminate between insulin sensitivity and secretion, available data cannot resolve whether the sex-difference in PREM reflects innate higher insulin resistance in girls, or better beta-cell recovery in boys. Further research is needed to clarify the usefulness and performance of IDAA1c in clinical practice.

Salivary Diurnal Glucocorticoid Profiles in Monozygotic Twins With Intratwin Birthweight Differences.

CONTEXT: Low birthweight (bw) and unfavorable intrauterine conditions have been associated with metabolic sequelae in later life, but little is known about their impact on glucocorticoid metabolism. OBJECTIVE: We studied monozygotic twins with intratwin bw differences to analyze the long-term impact of bw on glucocorticoid metabolism. METHODS: 46 monozygotic twin pairs with bw differences of <1 SDS (concordant; n = 29) and ≥1 SDS (discordant; n = 17) were recruited. At 6.9 years (mean age), saliva samples were collected (at 7 hours, 13 hours, 18 hours and 21 hour) and analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: We found significant or highly significant intratwin correlations in all twin pairs at 3 of 4 (cortisol), and 4 of 4 (cortisone) time points. Graphic evaluation of the diurnal cortisol patterns for each twin pair showed a distinct alignment in all groups. Analyses of the change of intratwin differences over the day by mixed linear modeling showed no intratwin differences in diurnal patterns. Regression analyses of intratwin differences at 7:00 hours showed a significant influence of catch-up growth, indicating lower cortisol concentrations in smaller twins with more catch-up growth (adj. R2 = 0.159, P = .014, ß = -3.71, F(1,42) = 9.15, f2 = 0.19). CONCLUSION: In monozygotic twins with intratwin bw differences, intratwin catch-up growth showed a moderate influence on intratwin differences in morning cortisol concentrations. We observed no differences regarding diurnal patterns. In contrast, in all groups, we found significant intratwin correlations for cortisol and cortisone over the day and a pronounced graphic alignment of cortisol diurnal patterns. We therefore suggest a predominant significance of the genetic background compared with bw differences on cortisol metabolism.

PTEN hamartoma tumor syndrome in childhood and adolescence-a comprehensive review and presentation of the German pediatric guideline.

BACKGROUND: The PTEN hamartoma tumor syndrome (PHTS) encompasses several different syndromes, which are linked to an autosomal-dominant mutation of the tumor suppressor PTEN gene on chromosome 10. Loss of PTEN activity leads to an increased phosphorylation of different cell proteins, which may have an influence on growth, migration, and apoptosis. Excessive activity of the PI3K/AKT/mTOR pathway due to PTEN deficiency may lead to the development of benign and malignant tumors and overgrowth. Diagnosis of PHTS in childhood can be even more challenging than in adulthood because of a lack of well-defined diagnostic criteria. So far, there are no official recommendations for cancer surveillance in affected children and adolescents. MAIN BODY: All individuals with PHTS are at high risk for tumor development and thus might benefit from cancer surveillance strategies. In childhood, macrocephaly may be the only evident symptom, but developmental delay, behavioral problems, dermatological features (e.g., penile freckling), vascular anomalies, lipoma, or enlarged perivascular spaces in cerebral magnetic resonance imaging (cMRI) may help to establish the diagnosis. Regular psychomotor assessment and assistance in subjects with neurological impairment play an important role in the management of affected children. Already in early childhood, affected patients bear a high risk to develop thyroid pathologies. For that reason, monitoring of thyroid morphology and function should be established right after diagnosis. We present a detailed description of affected organ systems, tools for initiation of molecular diagnostic and screening recommendations for patients < 18 years of age. CONCLUSION: Affected families frequently experience a long way until the correct diagnosis for their child's peculiarity is made. Even after diagnosis, it is not easy to find a physician who is familiar with this rare group of diseases. Because of a still-limited database, it is not easy to establish evidence-based (cancer) surveillance recommendations. The presented screening recommendation should thus be revised regularly according to the current state of knowledge.

Case Report: Extended Clinical Spectrum of the Neonatal Diabetes With Congenital Hypothyroidism Syndrome.

Background: Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3. Almost 20 patients have been reported to date, with significant phenotypic variability. Case presentation: We describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis. Conclusions: Our report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range.

Cerebral MRI and Clinical Findings in Children with PTEN Hamartoma Tumor Syndrome: Can Cerebral MRI Scan Help to Establish an Earlier Diagnosis of PHTS in Children?

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is caused by germline autosomal-dominant mutations of the tumor suppressor gene PTEN. Subjects harbour an increased risk for tumor development, with thyroid carcinoma occurring in young children. Establishing a diagnosis is challenging, since not all children fulfill diagnostic criteria established for adults. Macrocephaly is a common feature in childhood, with cerebral MRI being part of its diagnostic workup. We asked whether distinct cMRI features might facilitate an earlier diagnosis. METHODS: We retrospectively studied radiological and clinical data of pediatric patients who were presented in our hospital between 2013 and 2019 in whom PTEN gene mutations were identified. RESULTS: We included 27 pediatric patients (18 male) in the analysis. All patients were macrocephalic. Of these, 19 patients had received at least one cMRI scan. In 18 subjects variations were detected: enlarged perivascular spaces (EPVS; in 18), white matter abnormalities (in seven) and less frequently additional pathologies. Intellectual ability was variable. Most patients exhibited developmental delay in motor skills, but normal intelligence. CONCLUSION: cMRI elucidates EPVS and white matter abnormalities in a high prevalence in children with PHTS and might therefore aid as a diagnostic feature to establish an earlier diagnosis of PHTS in childhood.

Birthweight Differences in Adolescent Monozygotic Twins Influence Androgens, Psychological Morbidity, and Health-Related Quality of Life.

BACKGROUND: Adverse prenatal conditions can exert a long-lasting impact in later life. PATIENTS AND METHODS: Thirty-eight post-pubertal monozygotic twin pairs (16 female pairs) with divergent birthweight (bw) due to twin-to-twin transfusion syndrome were examined at a median of 15.1 years. Auxological and endocrine parameters were measured. To evaluate effects of intra-twin bw and hormone differences on mental health, adolescents and their parents completed the Strengths and Difficulties Questionnaire (SDQ), identifying psychological problems. Twins answered the questionnaire on health-related quality of life (HrQoL, KIDSCREEN-52). RESULTS: Parents attributed a higher number of psychological challenges to the formerly smaller twins, for example, total difficulties (8.8 vs. 6.5, p = 0.009). Differences in bw were associated with differences in parental evaluation of problems, for example, peer relationship problems (r = -0.57 and p = 0.0001). In contrast, bw differences did not affect subjects' self-assessment of psychological factors but on physical well-being (r = 0.42, p = 0.017). The formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being (24.9 vs. 26.6, T1,15 = -2.2, and p = 0.043) and moods and emotions (29.8 vs. 32.0, T1,15 = -2.3, p = 0.039). Higher concentrations of androstenedione were linked to greater psychological well-being (r = 0.39 and p = 0.036) in all twin pairs. CONCLUSION: Our results show that the prenatal environment leading to bw differences exerts a long-lasting impact on diverging parental evaluation of mental health. Formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being and moods and emotions. Higher androstenedione concentrations were linked to greater psychological well-being.

Influence of Prenatal Environment on Androgen Steroid Metabolism In Monozygotic Twins With Birthweight Differences.

OBJECTIVE: Although low birthweight (bw) and unfavorable intrauterine conditions have been associated with metabolic sequelae in later life, little is known about their impact on steroid metabolism. We studied genetically identical twins with intra-twin bw-differences from birth to adolescence to analyze the long-term impact of bw on steroid metabolism. METHODS: 68 monozygotic twin pairs with a bw-difference of <1 standard deviation score (SDS; concordant; n = 41) and ≥1 SDS (discordant; n = 27) were recruited. At 14.9 years (mean age), morning urine samples were collected and analyzed with gas chromatography-mass-spectrometry. RESULTS: No significant differences were detected in the concordant group. In contrast, in the smaller twins of the discordant group, we found significantly higher concentrations not only of the dehydroepiandrosterone sulfate (DHEAS) metabolite 16α-OH-DHEA (P = 0.001, 656.11 vs 465.82 µg/g creatinine) but also of cumulative dehydroepiandrosterone and downstream metabolites (P = 0.001, 1650.22 vs 1131.92 µg/g creatinine). Relative adrenal (P = 0.002, 0.25 vs 0.18) and overall androgen production (P = 0.001, 0.79 vs 0.65) were significantly higher in the formerly smaller discordant twins. All twin pairs exhibited significant intra-twin correlations for all individual steroid metabolites, sums of metabolites, indicators of androgen production, and enzyme activities. Multiple regression analyses of the smaller twins showed that individual steroid concentrations of the larger co-twin were the strongest influencing factor among nearly all parameters analyzed. CONCLUSION: In monozygotic twin pairs with greater intra-twin bw-differences (≥1 SDS), we found that bw had a long-lasting impact on steroid metabolism, with significant differences regarding DHEAS metabolites and relative androgen production. However, most parameters showed significant intra-twin correlations, suggesting a consistent interrelationship between prenatal environment, genetic background, and steroid metabolism.

Phenotype-Driven Diagnostic of PTEN Hamartoma Tumor Syndrome: Macrocephaly, But Neither Height nor Weight Development, Is the Important Trait in Children.

PTEN hamartoma tumor syndrome (PHTS) encompasses different syndromic disorders which are associated with autosomal-dominant mutations of the tumor suppressor gene PTEN. Patients are at high risk to develop benign and malignant tumors. Macrocephaly is a diagnostic feature, but there is a paucity of data on auxological development during childhood. Growth charts for height, weight and head circumference for PHTS do not exist yet. In this study, patient data for height, weight and head circumferences (HC) were collected from repeated medical exams or prevention check-up visits starting at birth. Growth charts were generated and compared to German reference data. Standard deviation scores (SDS) of HC, height and body mass index (BMI) were calculated. We included 23 pediatric patients (8 female, 15 male) with molecular proven PTEN gene mutation. Most male patients already demonstrated macrocephaly at birth (73%), whereas only one female patient had documented congenital macrocephaly. By the age of two years all patients exhibited a head circumference above the 97th percentile. Stratified for different age groups the median HC-SDSs were between +3.3 and +5.5 in male patients and between +2.9 and +4.1 in female patients. Height, weight and BMI measurements for both sexes were mostly within the normal range. We conclude that macrocephaly, but not height, weight or BMI, is useful in the identification of PHTS patients. The increased HC in PHTS patients develops early in life and is more pronounced in males than in females, which might explain the finding of a higher percentage of male PHTS patients diagnosed during childhood.

Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings With a Homozygous LRBA Mutation.

CONTEXT: Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic ß-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare. OBJECTIVE: Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing. CASE PRESENTATION: Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence-activated cell sorting analysis revealed B-cell deficiency. In addition, CD4(+)/CD25(+) and CD25(high)/FoxP3(+) cells were diminished, whereas an unusual CD25(-)/FoxP3(+) population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges. RESULTS: By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells. CONCLUSION: We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation.

20 Years of Pediatric Benchmarking in Germany and Austria: Age-Dependent Analysis of Longitudinal Follow-Up in 63,967 Children and Adolescents with Type 1 Diabetes.

BACKGROUND: To investigate changes in diabetes treatment over the last two decades in three age-groups of children and adolescents with type 1 diabetes (T1D) from Germany and Austria. METHODS: 63,967 subjects (<18yr) with T1D documented between 1995 and 2014 from the DPV-database were included and stratified according to age (0.5-<6, 6-<12, 12-<18yr). Regression models were applied for insulin regimens (<3 and ≥4 injection time points/day, or continuous subcutaneous insulin infusion (CSII)), use of rapid- and long acting insulin analogues, NPH insulin, and frequency of self-monitoring of blood glucose (SMBG)/day. Models were adjusted for sex, diabetes duration, and migration background. P-value for trend was given. FINDINGS: The number of subjects with <3 injection time points/day decreased from 1995 to 2014 to <5% in all age-groups (p<0.0001). Proportion of patients with ≥4 injections/day increased until the early 2000s, and then declined until 2014. This trend was not found in 6-<12yr olds (p = 0.3403). CSII increased in all age-groups (p<0.0001) with the highest increase in children <6 years (from 0.4% to 79.2%), and the lowest increase in 12-<18 year olds (from 1.0% to 38.9%). NPH insulin decreased in all age-groups (p<0.0001). Insulin analogues, especially rapid-acting, became more frequent in all age-groups (p<0.0001), accounting for 78.4% in 2014 for all subjects. The highest use was found in the youngest children (in 2014: 85.6%), the lowest use in 6-<12 year olds (in 2014: 72.9%). The number of SMBG/day increased from 2.2 to 6.4 with a similar rise in all age-groups (p<0.0001). Frequency was highest in subjects <6yr. CONCLUSIONS: In all age-groups, T1D treatment was intensified over the last 20 years. Age-specific differences in trends were particularly observed in the number of patients on CSII, in the number of patients with 4 or more injections/day, and in the frequency of SMBG/day.