Severe aldosterone synthase deficiency in a nine-day old Lebanese boy: the importance of functional studies to establish pathogenicity of seemingly benign variants in CYP11B2.

Introduction Aldosterone synthase deficiency is a rare autosomal recessive disease characterized by vomiting, dehydration, salt wasting, life-threatening hyperkalemia in infancy, followed by failure to thrive. It results from pathogenic variants in CYP11B2. Case Presentation A boy, born in Montreal to Lebanese parents who are first cousins, was referred at nine days of life for severe dehydration. A diagnosis of primary adrenal insufficiency was made, and treatment was started with fludrocortisone and hydrocortisone. Exome sequencing revealed a homozygous variant p.(Asn201Asp)(N201D). In silico, this variant was considered benign, but in vitro functional expression studies established it caused the severe aldosterone deficiency. It ended the diagnostic odyssey and allowed to safely stop hydrocortisone replacement. Conclusion If a gene variant co-segregates with a phenotype, in vitro functional studies are required even if in silico studies are negative.

Thyrotropin Screening of Newborns: Before or After 72 Hours of Life? Before Discharge or at Home?

Objective: Until November 2019 in Belgium, dried blood spot (DBS) sampling was performed between 72 and 120 hours of life, when a majority of newborns had already been discharged from the maternity. In November 2019, the policy for newborn screening in South Belgium changed to allow sampling as soon as 48 hours of life, with the objective to accelerate the process and to allow more sampling during the hospital stay. Our objective was to evaluate the impact of this policy modification and, in particular, to assess the effectiveness of screening for hypothyroidism based on sampling before or after 72 hours of life, as well as to compare the effectiveness of DBS collection before discharge or at home. Methods: This retrospective study included live births ≥37 weeks of gestation, screened by the Université Libre de Bruxelles Newborn Screening Center between January 2019 and December 2021. To evaluate the efficiency of early sampling, we compared thyrotropin (TSH) results for screening <72 hours and screening ≥72 hours. We also compared TSH results of DBS performed before discharge with those performed at home. Results: A total of 53,794 newborns were included. The results of 24,816 healthy newborns screened before 72 hours of life and of 28,978 healthy newborns screened between 72 and 144 hours of life were compared. The median TSH level was similar (1.50 and 1.20 mU/L, respectively). The percentage of false positives was similar (0.08% and 0.07%, respectively). Earlier sampling, before 72 hours, allowed treatment of positive cases at 6 days rather than 8.5 days. DBS sampling at home resulted in longer delay for transferring the sample to the laboratory (a median of 3.0 days for hospital sampling vs. 5.0 days for home sampling). A poorer quality of home blood sampling was observed, with 0.27% unusable samples compared with 0.06% unusable samples for hospital sampling (p < 0.001). Conclusions: In term newborns, TSH screening before discharge, as early as 48 hours of life, is a valid strategy. It allows earlier treatment of positive cases, does not increase the percentage of false positives, and results in fewer unusable samples.

Why should orchidopexy be performed in congenital hypogonadotropic hypogonadism, and when?

BACKGROUND: In otherwise normal boys with undescended testes, early orchidopexy is recommended to preserve fertility, to decrease the risk of testicular cancer and to facilitate its detection. Indeed, compared to the general population, the risk of testicular cancer is increased two to eight-fold in isolated cryptorchidism and usually occurs before the age of 40 years. By contrast, when cryptorchidism is associated with congenital hypogonadotropic hypogonadism, the risk of testicular cancer is unknown. OBJECTIVE: To determine the characteristics of testicular cancer when cryptorchidism is associated with congenital hypogonadotropic hypogonadism. METHODS: PUBMED research without date limits including the following key words: hypogonadism, hypogonadotrophic hypogonadism, testicular cancer, testicular germ cell tumors, undescended testis, Kallmann syndrome, FSH, AFP (α foeto protein), ßHCG. RESULTS: Only three patients with testicular cancer and congenital hypogonadotropic hypogonadism have been published in the past four decades and cancer was diagnosed at 18.6, 50 and 64 years. CONCLUSION: Gonadotropin deficiency may protect against testicular cancer and orchidopexy in this context may be deferred.

Whole-Exome Sequencing in Congenital Hypothyroidism Due to Thyroid Dysgenesis.

Context: Congenital hypothyroidism due to thyroid dysgenesis (CHTD) is a predominantly sporadic and nonsyndromic (NS) condition of unknown etiology. NS-CHTD shows a 40-fold increase in relative risk among first-degree relatives (1 in 100 compared with a birth prevalence of 1 in 4000 in the general population), but a discordance rate between monozygotic (MZ) twins of 92%. This suggests a two-hit mechanism, combining a genetic predisposition (incomplete penetrance of inherited variants) with postzygotic events (accounting for MZ twin discordance). Objective: To evaluate whether whole-exome sequencing (WES) allows to identify new predisposing genes in NS-CHTD. Methods: We performed a case-control study by comparing the whole exome of 36 nonconsanguineous cases of NS-CHTD (33 with lingual thyroid ectopy and 3 with athyreosis, based on technetium pertechnetate scintigraphy at diagnosis) with that of 301 unaffected controls to assess for enrichment in rare protein-altering variants. We performed an unbiased approach using a gene-based burden with a false discovery rate correction. Moreover, we identified all rare pathogenic and likely pathogenic variants, based on in silico prediction tools, in 27 genes previously associated with congenital hypothyroidism (CH) (thyroid dysgenesis [TD] and dyshormonogenesis). Results: After correction for multiple testing, no enrichment in rare protein-altering variants was observed in NS-CHTD. Pathogenic or likely pathogenic variants (21 variants in 12 CH genes) were identified in 42% of cases. Eight percent of cases had variants in more than one gene (oligogenic group); these were not more severely affected than monogenic cases. Moreover, cases with protein-altering variants in dyshormonogenesis-related genes were not more severely affected than those without. Conclusions: No new predisposing genes were identified following an unbiased analysis of WES data in a well-characterized NS-CHTD cohort. Nonetheless, the discovery rate of rare pathogenic or likely pathogenic variants was 42%. Eight percent of the cases harbored multiple variants in genes associated with TD or dyshormonogenesis, but these variants did not explain the variability of hypothyroidism observed in dysgenesis. WES did not identify a genetic cause in NS-CHTD cases, confirming the complex etiology of this disease. Additional studies in larger cohorts and/or novel discovery approaches are required.

Transcriptomic Signature of Human Embryonic Thyroid Reveals Transition From Differentiation to Functional Maturation.

The human thyroid gland acquires a differentiation program as early as weeks 3-4 of embryonic development. The onset of functional differentiation, which manifests by the appearance of colloid in thyroid follicles, takes place during gestation weeks 10-11. By 12-13 weeks functional differentiation is accomplished and the thyroid is capable of producing thyroid hormones although at a low level. During maturation, thyroid hormones yield increases and physiological mechanisms of thyroid hormone synthesis regulation are established. In the present work we traced the process of thyroid functional differentiation and maturation in the course of human development by performing transcriptomic analysis of human thyroids covering the period of gestation weeks 7-11 and comparing it to adult human thyroid. We obtained specific transcriptomic signatures of embryonic and adult human thyroids by comparing them to non-thyroid tissues from human embryos and adults. We defined a non-TSH (thyroid stimulating hormone) dependent transition from differentiation to maturation of thyroid. The study also sought to shed light on possible factors that could replace TSH, which is absent in this window of gestational age, to trigger transition to the emergence of thyroid function. We propose a list of possible genes that may also be involved in abnormalities in thyroid differentiation and/or maturation, hence leading to congenital hypothyroidism. To our knowledge, this study represent the first transcriptomic analysis of human embryonic thyroid and its comparison to adult thyroid.

[Newborn screening for congenital hypothyroidism and congenital adrenal hyperplasia: Benefits and costs of a successful public health program]. / Dépistage néonatal de l'hypothyroïdie congénitale et de l'hyperplasie congénitale des surrénales - Bénéfices et coûts d'un programme de santé publique à succès.

Newborn screening is an important public health program and a triumph of preventive medicine. Economic analyses show that the benefits of newborn screening clearly outweigh the costs for certain diseases, but not necessarily for other ones. This is due to the great diversity of the natural history of the diseases detected, to the fact that each of these diseases considered individually is rare, and to differences in the effectiveness of interventions. In addition, the benefit-cost ratio of screening for a particular disorder may differ between countries, specifically between high-income and low- and middle-income countries. The burden of a disorder may also be alleviated by increased clinical awareness and effective clinical services, even in the absence of newborn screening. In this article, we focus on economic analyses of newborn screening for primary congenital hypothyroidism, which has been in place in high-income countries for roughly 40 years, and for classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Screening for the latter is not yet universal, even in high-income countries, although the lack of universal implementation may reflect factors other than economic considerations.

TITLE: Dépistage néonatal de l'hypothyroïdie congénitale et de l'hyperplasie congénitale des surrénales - Bénéfices et coûts d'un programme de santé publique à succès. ABSTRACT: Le dépistage néonatal est un important programme de santé publique et un triomphe de la médecine préventive. Les analyses économiques démontrent que les bienfaits de ce dépistage l'emportent sur les coûts pour certaines maladies, mais pas nécessairement pour toutes. Cela est dû à la grande diversité des maladies dépistées, au fait que chacune d'entre elles, considérée individuellement, est rare, et à des différences d'efficacité des interventions. En outre, le rapport entre les bénéfices et les coûts du dépistage d'une maladie donnée peut varier d'un pays à l'autre, en particulier entre les pays à revenus élevés et les pays à revenus faibles ou intermédiaires. Le fardeau d'une maladie peut être allégé, même en l'absence de dépistage néonatal, par une plus grande connaissance clinique et par des services cliniques efficients. Dans cet article, nous évaluons les arguments et les analyses économiques du dépistage de l'hypothyroïdie congénitale primaire, mis en place dans de nombreux pays depuis environ 40 ans, et celui de l'hyperplasie congénitale des surrénales due à une déficience en 21-hydroxylase. Le dépistage de cette dernière n'est pas encore universel, même dans les pays à revenus élevés, les décisions de sa mise en œuvre pouvant tenir compte de facteurs autres que des considérations économiques.

Severe Congenital Hypothyroidism Due to a Novel Deep Intronic Mutation in the TSH Receptor Gene Causing Intron Retention.

In 3 Somalian siblings with severe nongoitrous congenital hypothyroidism, exome sequencing identified a variant in TSHR predicted to be benign in isoform 3 but leading to an intronic mutation in isoform 1 (NM_00369:c.692 + 130C>A), which is the isoform expressed in the thyroid. This mutation creates a pseudoexon that results in a protein that, if transcribed, would lack the transmembrane domain, thereby hampering its expression at the cell surface. Our findings illustrate that the interpretation of exome analysis requires knowledge of the relevant isoform expression and of the biology of the disease. This is the first description of a deep intronic mutation creating a pseudoexon and inactivating the thyroid stimulating hormone (TSH) receptor.

Challenges in Assessing the Cost-Effectiveness of Newborn Screening: The Example of Congenital Adrenal Hyperplasia.

Generalizing about the cost-effectiveness of newborn screening (NBS) is difficult due to the heterogeneity of disorders included in NBS panels, along with data limitations. Furthermore, it is unclear to what extent evidence about cost-effectiveness should influence decisions to screen for specific disorders. Screening newborns for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency can serve as a useful test case, since there is no global consensus on whether CAH should be part of NBS panels. Published and unpublished cost-effectiveness analyses of CAH screening have yielded mixed findings, largely due to differences in methods and data sources for estimating health outcomes and associated costs of early versus late diagnosis as well as between-country differences. Understanding these methodological challenges can help inform future analyses and could also help interested policymakers interpret the results of economic evaluations.

Experience With Store-and-Forward Consultations in Providing Access to Pediatric Endocrine Consultations in Low- and Middle-Income Countries.

Pediatric specialists are often unavailable in low- and middle-income countries. As part of multiple professional associations' efforts to improve access to endocrine expertise globally, a pediatric endocrine teleconsultation network was established on a store-and-forward teleconsultation platform to facilitate focused, language-appropriate advice that can be kept for future reference while bypassing real-time video-conferencing, and obviating the need for a scheduled appointment. User information was recorded, and quality statistics on network performance and qualitative evaluation by referring physicians were analyzed. Over a 3-year period, 81 referrers (88% from Haiti) and 13 pediatric endocrinologists registered onto the network and discussed 47 pediatric endocrine cases, exchanging a total of 412 messages for a median of 7 messages (IQR 5, 11) per case. Diagnoses spanned the spectrum of pediatric endocrine disorders. According to referrers, an appropriate expert was consulted and an answer provided sufficiently quickly in 100% of cases. The answer was well-adapted to their environment in 86%, and referrers were able to follow the advice given in 72%. All but one referrer found the advice helpful, it clarified the diagnosis in 88%, assisted with management in 93%, improved patient's symptoms in 77%, improved function in 77%, and was considered cost-saving in 50%. Perceived benefits of the consultations were academic instruction, setting-adapted advice beyond the scope of guidelines or textbooks, and advancement in the diagnostic process. Pediatric endocrine remote store-and-forward consultations in low- and middle-income countries may provide a reasonable alternative to face-to-face visits, providing clinical and educational benefit, and a potential for cost-saving.

Growth Hormone Supplementation and Psychosocial Functioning to Adult Height in Turner Syndrome: A Questionnaire Study of Participants in the Canadian Randomized Trial.

Despite the long-held belief that growth hormone supplementation provides psychosocial benefits to patients with Turner syndrome (TS), this assumption has never been rigorously tested in a randomized control trial. As a sub-study of the Canadian growth-hormone trial, parent-, and patient-completed standardized questionnaires were used to compare 70 girls with TS who received injections (GH group) and 61 similarly followed untreated TS controls (C) on multiple facets of psychosocial functioning. Questionnaires were given (i) at baseline (session 1, mean age = 10.4 y), (ii) before estrogen therapy for puberty induction (session 2, mean age = 13.0 y), (iii) after 1 year of estrogen therapy (session 3, mean age = 14.4 y), and (iv) when growth stopped (session 4, mean age = 16.3 y). Groups were compared for multiple facets of psychosocial function within social, behavioral, self-esteem, and academic domains. Results were also correlated with indices of adult height. We found no global (i.e., across-session) group differences on any scales or subscales of the four domains. In both GH and C groups, age-related improvements were seen for social problems, externalizing behavior problems, and school functioning and age-related declines for social competence and social relations. Both parents and patients claimed GH received less teasing than C but C had more friends than GH. Results from analyses conducted within individual sessions showed that while GH at early sessions claimed to be more popular, more socially engaged, better adapted, and to have higher self-esteem than C, C was reported to be less anxious, depressed, and withdrawn than GH at adult height. The correlation analyses revealed different effects of adult height and height gain on outcome for the two groups. In GH, both height parameters were correlated with multiple parent- and/or self-reported indices from the four psychosocial domains, whereas in C, only adult height and two indices (viz., total self-concept and school functioning), were correlated. The observed modest gains in psychosocial functioning for patients with TS treated with GH highlight the need for alternative approaches to assist them in coping with the challenges of their condition.

Wide Spectrum of DUOX2 Deficiency: From Life-Threatening Compressive Goiter in Infancy to Lifelong Euthyroidism.

Six patients are described with bi-allelic DUOX2 variants and widely variable phenotypes. Patient 1 is an infant with a compressive hypothyroid goiter causing respiratory distress, which was promptly alleviated by levothyroxine (LT4). He was a compound heterozygote for DUOX2 variants, including a novel deletion of 540 base pairs. Patients 2 and 3 are siblings with the same compound heterozygous mutations of DUOX2, yet one had overt hypothyroidism at 14 months and the other lifelong euthyroidism. Patient 4 is a compound heterozygote individual and has mild persistent congenital hypothyroidism; his sister (patient 5) only had a borderline thyrotropin elevation at newborn screening, consistent with homozygous DUOX2 variants with a mild impact on enzyme activity. Their euthyroid mother (patient 6) is a compound heterozygote for the same DUOX2 mutations as her son. Targeted exome sequencing did not reveal any relevant modifiers. It is concluded that (i) prompt LT4 replacement in infants with respiratory distress due to a hypothyroid goiter makes surgery unnecessary; and (ii) the clinical expression of DUOX2 deficiency varies widely between individuals and over time, justifying periodic reevaluation of the need for LT4 replacement.

Are lower TSH cutoffs in neonatal screening for congenital hypothyroidism warranted?

When newborn screening (NBS) for congenital hypothyroidism (CH) using thyroid-stimulating hormone (TSH) as a primary screening test was introduced, typical TSH screening cutoffs were 20-50 U/L of whole blood. Over the years, lowering of TSH cutoffs has contributed to an increased prevalence of detected CH. However, a consensus on the benefit deriving from lowering TSH cutoffs at screening is lacking. The present paper outlines arguments both for and against the lowering of TSH cutoffs at NBS. It includes a review of recently published evidence from Australia, Belgium and Italy. A section focused on economic implications of lowering TSH cutoffs is also provided. One issue that bears further examination is the extent to which mild iodine deficiency at the population level might affect the association of neonatal TSH values with cognitive and developmental outcomes. A debate on TSH cutoffs provides the opportunity to reflect on how to make NBS for CH more effective and to guarantee optimum neurocognitive development and a good quality of life to babies with mild as well as with severe CH. All authors of this debate article agree on the need to establish optimal TSH cutoffs for screening programs in various settings and to ensure the benefits of screening and access to care for newborns worldwide.

Premature Ovarian Failure in French Canadian Leigh Syndrome.

In all surviving girls with Leigh syndrome, French Canadian variety, a mitochondrial disease, we detected premature ovarian failure, manifested as absent or arrested breast development, lack of menarche, high follicle-stimulating hormone, a prepubertal uterus, and small ovaries. Pubertal onset and progression should be evaluated in girls with mitochondrial diseases.