Dagmar l’Allemand’s research while affiliated with Kantonsspital St. Gallen and other places

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Publications (27)


Fig. 2: Bar plot of the VarCoPP score of 64 rare gene variants found in oligogenic combinations with NR5A1/SF-1 variants in 22 cases with DSD. The pathogenicity score (VarCoPP score) generated by ORVAL's VarCoPP tool represents the probability (value between 0 and 1) that a variant combination belongs to the disease-causing class. If this score is above 0.4575 (hg38), the model predicts that the combination is disease-causing. For stricter analysis a pathogenicity score ≥0.85 (hg38) (dotted red line) was set as the threshold to include only gene pairs with combinations falling into the 99.9%-confidence zone. For one candidate variant (NR1H2, p.Arg171_Lys172insAsn) no prediction was found in ORVAL. Predicted digenic effect by ORVAL's digenic effect predictor tool 47,49 for the combination of NR5A1/SF-1 variants of each case with the additional variants are indicated by two colours: True digenic combination (blue), where the simultaneous presence of a pathogenic allele in each gene is necessary for the individual to express the disease phenotype. Monogenic and Modifier combination (violet), where a variant on the major gene induces a disease phenotype, while a mutation in the modifier gene modifies it.
Fig. 3: Stacked bar plot for 22 cases with DSD harbouring NR5A1/SF-1 variants showing the predicted pathogenicity of 65 variants based on Franklin (aqua green) and VarSome (blue) classifications. Clinical significance is given according to ACMG criteria for variants classification: 1 (Benign), 2 (Likely Benign), 3 (Variant of Uncertain Significance, VUS), 4 (Likely Pathogenic), 5 (Pathogenic). Note that none of the variants were predicted pathogenic or likely pathogenic, but need to be included when considering oligogenicity. Symbols indicate model cases that are described in detail in the text.
Fig. 4: Summary of common pathways identified between the NR5A1 gene and 14 other genes, in which additional variants were found in our study participants. The analysis was performed with Reactome and the visualisation with Cytoscape. 69
Fig. 5: Family trees showing the individual gene variants (left panel) and the predicted oligogenic network (right panel) in five model cases (a-e). The pedigrees depict the inheritance patterns of the identified variants. Note that all variants were observed in a heterozygous state. The networks created for each case by ORVAL inform on predicted gene interactions necessary to reveal a disease phenotype.
Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study
  • Article
  • Full-text available

March 2025

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54 Reads

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1 Citation

EBioMedicine

Chrysanthi Kouri

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Rawda Naamneh-Elzenaty

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[...]

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Background Oligogenic inheritance has been suggested as a possible mechanism to explain the broad phenotype observed in individuals with differences of sex development (DSD) harbouring NR5A1/SF-1 variants. Methods We investigated genetic patterns of possible oligogenicity in a cohort of 30 individuals with NR5A1/SF-1 variants and 46,XY DSD recruited from the international SF1next study, using whole exome sequencing (WES) on family trios whenever available. WES data were analysed using a tailored filtering algorithm designed to identify rare variants in DSD and SF-1-related genes. Identified variants were subsequently tested using the Oligogenic Resource for Variant Analysis (ORVAL) bioinformatics platform for a possible combined pathogenicity with the individual NR5A1/SF-1 variant. Findings In 73% (22/30) of the individuals with NR5A1/SF-1 related 46,XY DSD, we identified one to seven additional variants, predominantly in known DSD-related genes, that might contribute to the phenotype. We found identical variants in eight unrelated individuals with DSD in DSD-related genes (e.g., TBCE, FLNB, GLI3 and PDGFRA) and different variants in eight genes frequently associated with DSD (e.g., CDH23, FLNB, GLI2, KAT6B, MYO7A, PKD1, SPRY4 and ZFPM2) in 15 index cases. Our study also identified combinations with NR5A1/SF-1 variants and variants in novel candidate genes. Interpretation These findings highlight the complex genetic landscape of DSD associated with NR5A1/SF-1, where in several cases, the use of advanced genetic testing and filtering with specific algorithms and machine learning tools revealed additional genetic hits that may contribute to the phenotype. Funding 10.13039/501100001711Swiss National Science Foundation and Boveri Foundation Zurich.

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Figure 1. Scheme for steroid biosynthesis pathways in the adrenal cortex, testis, and peripheral tissues. In 3βHSD2 deficiency, conversion of Δ5 steroids (pregnenolone [P5], 17-hydroxypregnenolone [17OHP5], dehydroepiandrosterone [DHEA]) to corresponding Δ4 steroids (progesterone [P4], 17-hydroxyprogesterone [17OHP4], androstenedione [A4]) is affected; but unaffected 3βHSD1 activity may convert secreted precursors in the periphery.
Figure 2. Genetic analysis of the HSD3B2 gene (Chr 1:119, 415, 150-119, 423, 034) revealing the heterozygous variants (c.779C > T and c.307 + 1G > A) in the studied patient (boxes and arrows). The HSD3B2 gene consist of 4 exons, of which 3 are coding (highlighted in yellow). Whole-exome sequencing of patient DNA was performed using TWIST comprehensive exome (TWIST bioscience) on a NovaSeq 6000 sequencing system (Illumina). The following genes were subsequently analyzed: AAAS, ABCD1, AIRE, AMH, AMHR2, AR, ARX, ATRX, BMP4, BMP7, CDKN1C, CHD7, CTU2, CUL4B, CYB5A, CYP11A1, CYP11B1, CYP17A1, CYP19A1, CYP21A2, DHCR7, DHH, DHX37, GATA4, GPX1, HOXA13, HOXA4, HSD17B3, HSD3B2, LHCGR, MAMLD1, MAP3K1, MC2R, MCM4, MRAP, MYRF, NNT, NR0B1, NR2F2, NR3C1, NR5A1, POLE, POR, PPP1R12A, PRDX3, RPL10, RSPO1, SAMD9, SGPL1, SOX10, SOX9, SRD5A2, SRY, STAR, TOE1, TSPYL1, TXNRD2, WT1, and WTAP.
Figure 3. Functional characterization of the HSD3B2 variant p.(Pro260Leu) in vitro. Nonsteroidogenic HEK293T cells were transiently transfected (Lipofectamine 2000; 1 µg of DNA/well in 6-well plates) with wild-type (WT) and variant HSD3B2 expression vectors for 48 hours. Cell medium was enriched with a 3βHSD2 precursor steroid mixture in Dulbecco's modified Eagle's medium in 5 different concentrations. The activity of transfected cells to convert either pregnenolone (P5) to progesterone (P4), 17-hydroxypregnenolone (17OHP5) to 17-hydroxyprogesterone (17OHP4), or dehydroepiandrosterone (DHEA) to androstenedione (A4) at given substrate concentrations (x-axis) was assessed by measuring steroids in the supernatants after 24 hours' incubation by high-resolution LC-MS [12]. Conversion is given as µM/24 hours. Graphs were produced by GraphPad Prism from data of 3 independent experiments performed in triplicates. Equal expression of the WT and variant HSD3B2 was confirmed by RT-qPCR (data not shown; primer sequences are available on request).
Figure 4. Study of the HSD3B2 c.307 + 1g > a variant by minigene experiment. Human HSD3B2 wild-type (WT) minigene was designed to cover the end of the third and beginning of the fourth exon, and their in-between intron 3; it was cloned into pcDNA3 (GenScript). The mutant (Mut) c.307 + 1G > A minigene was then generated using site-directed mutagenesis following the QuikChange protocol by Stratagene (Agilent Technologies Inc). Correct sequences of plasmids were confirmed by direct sequencing (MicroSynth AG). HEK293T cells were transiently transfected with the WT and Mut minigenes (Lipofectamine 2000, 1 µg of DNA/well in 6-well plates). Total RNA was extracted and RT-PCR for HSD3B2 cDNA was performed. A shows the complementary DNA (cDNA) products in agarose gel. WT cDNA fragments were approximately 300 bp corresponding to the length of exons 3 and 4 in the WT minigene. Mut cDNA fragments were approximately 500 to 600 bp, indicating aberrant splicing. Both WT and Mut cDNA fragments were also subjected to direct sequencing (MicroSynth AG). B, Arrangement of the WT HSD3B2 minigene leading to normal splicing as seen in chromatogram of the WT cDNA fragment shown in A. C, Arrangement of the c.307 + 1G > A HSD3B2 minigene and chromatograms (separately with forward and reverse primers) of the mutant cDNA fragment shown in A. Forward strand of the c.307 + 1G > A fragment showed that this variant leads to continuation of the read frame into intron 3. Reverse strand of the sequenced c.307 + 1G > A shows that this variant leads to altered splicing in the predicted constitutive splicing donor site (in position c.307 + 214-233, highlighted with green boxes). Alternative splicing sites were predicted using the online tool Alternative Splice Site Predictor [13]. Variant in the donor splice site of intron 3 is highlighted by a gray box. Predicted STOP codon in c.307 + 1G > A variant is highlighted with red boxes, after 29 amino acids coded from the intronic site. Depicted in sequences of WT and c.307 + 1G > A are also their exon (black arrow) and intron (blue arrow) locations, exon-intron boundaries (dashed vertical line), and corresponding amino acid sequences with read frame 1.
Main biochemical findings in a child with a 46, XY difference of sexual development due to 3β-hydroxysteroid dehydrogenase 2 deficiency
Ambiguous Genitalia Due to 3β-Hydroxysteroid Dehydrogenase Type 2 Deficiency: Clinical, Genetic, and Functional Characterization of Two Novel HSD3B2 Variants

January 2025

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68 Reads

JCEM Case Reports

3β-Hydroxysteroid dehydrogenase 2 deficiency (3βHSD2D) is a rare form of congenital adrenal hyperplasia (CAH) with variable clinical presentation. We describe a 46, XY child with ambiguous genitalia and CAH without apparent adrenal insufficiency due to 2 novel heterozygous variants in the HSD3B2 gene (c.779C > T/p.Pro260Leu and c.307 + 1G > A/p.Gly103Asp,fs29X). The disease-causing effect of the novel variants was assessed by genetic and functional studies informing on positive genotype-phenotype correlation. Sex registration was female, and no gender dysphoria has been noted until the present age of 7 years, but psychological assessments have been difficult with a concomitant diagnosis of autism spectrum disorder. Virilization that already progresses prepubertally through peripheral conversion of androgen precursors by 3β-hydroxysteroid dehydrogenase 1 will pose an increasing challenge during puberty.


Fig. 1: Overview of the participants and summary of the NR5A1/SF-1 variants in the international SF1next study cohort. (a) Number of individuals collected from each country comprising the SF1next study cohort are shown (n = 197). (b and c) Identified variants in the NR5A1 gene are shown with respect to the gene and protein sequence. (b) Location of four intronic variants and one whole gene deletion of NR5A1/ SF-1 (NC_000009.11). (c) Location of 87 NR5A1/SF-1 variants identified in the SF1next cohort, shown at their protein level (NM_004959.5). Novel variants are shown in bold, while previously reported variants are shown in normal font. The SF-1 protein comprises the DNA-binding domain, which contains two zinc fingers (Zn1 and Zn2), a FTZ-F1 box, the accessory hinge region, and the ligand-binding domain. It harbors two activation functional domains, AF-1 and AF-2. NR5A1, nuclear receptor subfamily 5 group A member 1; UTR, untranslated region.
Fig. 2: Characterization of NR5A1/SF-1 variants identified in the SF1next study cohort. (a) Genotype-phenotype correlation. Each dot represents one individual (n = 197) with the corresponding DSD phenotype of the external genitalia and karyotype, stratified by karyotype and type of data. Filled dots show individuals who required medical care while white filled dots show individuals who came to medical attention because of the genetic workup of their NR5A1/SF-1 positive relatives (i.e., family members with basic data who did not require medical care because of DSD). NR5A1/SF-1 variants affecting the same amino acid residue/intronic region are highlighted in black, purple or blue colour, while others are shown in light grey. (b) Karyotype and DSD phenotype of individuals in the cohort. (c) Summary of the pathogenicity of the 93 different NR5A1/SF-1 variants according to ACMG classification, stratified by DSD phenotype of the identified individuals in the cohort. P, pathogenic, LP, likely pathogenic, VUS, variant of unknown significance, LB, likely benign, B, benign.
Fig. 3: Associated organ anomalies found in individuals with a DSD and NR5A1/SF-1 variants (n = 116). (a) Heatmap depicts frequency of organ anomalies found with specific NR5A1/SF-1 variants. Sufficient information on organ anomalies was available in 116 out of 131 individuals with a DSD. NR5A1/SF-1 variants affecting the same amino acid residue/intronic region are highlighted in blue or purple colour, while others are shown in light grey. The colour of a single cell provides the information on how many individuals are affected (light red to dark red (≥1)) or unaffected (green (≤−1)) by the specific organ anomaly (see value scale). Organ systems with reported anomalies are shown in bold. Number of individuals with reported anomaly divided by the number of individuals with sufficient information per organ system is shown on the right side of the heatmap. Individuals with organ anomalies and without DSD (n = 8) are not reported in the figure; in those, anomalies were found in the blood system and spleen (3/8), metabolism and homeostasis (2/8), endocrine system (1/8), head and neck (1/8), skeletal system (1/8), musculature (1/8), CNS (1/8), cardiovascular system (1/8), connective tissue (1/8), or abdomen (1/8). For white coloured cells no data were available. (b and c) Range of anomalies reported in each organ system according to karyotype (b) or (c) DSD phenotype (n = 38). CNS, Central nervous system; PNS, Peripheral nervous system.
Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development

January 2024

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305 Reads

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18 Citations

EBioMedicine

Background Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Findings Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. Interpretation The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. Funding 10.13039/100000001Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.


FRI478 Pharmacometrics-based Computer Model Utilizing Heart Rate To Monitor Thyroid Function In Children With Graves' Disease

October 2023

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28 Reads

Journal of the Endocrine Society

Disclosure: B. Steffens: None. G. Koch: None. F. Claude: None. F. Bachmann: None. J. Schropp: None. M. Janner: None. D. l'Allemand: None. D. Konrad: None. M. Pfister: None. G. Szinnai: None. Graves’ disease (GD) with onset in childhood or adolescence is a pediatric rare disease (ORPHA:525731) with a ten times lower incidence than in adults. Leading clinical signs of hyperthyroidism are sinus tachycardia, weight loss, tremor, and goiter. First-line treatment are anti-thyroid drugs in order to normalize thyroid function. However, dose finding in pediatric GD is complex due to a broad spectrum of disease severity at diagnosis, and highly variable disease activity during follow-up, especially during puberty. As thyroid hormones have a strong positive chronotropic effect, heart rate (HR) turns out to be a useful clinical marker to monitor thyroid activity under treatment. Our overall aim was to provide a practical pharmacometrics-based (PMX-based) computer model characterizing both, individual FT4 dynamics and the relation between FT4 and tachycardia in children with various disease severity of GD during the first 120 days of treatment. Development of the PMX computer model was based on the non-linear mixed effects approach (i) linking FT4 kinetics with HR dynamics, (ii) accounting for inter-individual variability, and (iii) incorporating individual patient characteristics. Retrospectively collected clinical (resting heart rate during consultation) and laboratory data (FT4) from 41 children and adolescents with GD at four pediatric hospitals in Switzerland (75% female, median age 11.2 [IQR 8.5, 13.5] years) with 187 FT4 measurements and 132 HR measurements, and 124 paired measurements, were available and used for model development. Pediatric patients showed median FT4 of 59.6 [IQR 44.5, 73.0] pmol/l and median HR of 112 [IQR 100, 128] bpm at diagnosis. GD severity groups were defined based on FT4 measurement at diagnosis, resulting in equal numbers of mild (13), moderate (14) and severe (14) GD. We observed a significant difference in HR at diagnosis (p < 0.01) between the three GD severity groups based on FT4 at diagnosis. The final PMX computer model accounted for inter-individual variability and clinically relevant covariate effects such as age, gender, and GD severity, and was able to accurately predict FT4 and HR dynamics for each individual patient during the first 120 days of treatment. A PMX-based computer model that leverages individual HR dynamics can be applied to facilitate personalized pharmacotherapy in pediatric GD and mitigate the risk for under- or overdosing of anti-thyroid drugs in these patients. Prospective randomized validation trials are warranted to further validate and fine-tune such computer-supported personalized dosing in children with Graves’ disease. Presentation: Friday, June 16, 2023


NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice

September 2023

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93 Reads

Yearbook of Paediatric Endocrinology



Schematic of the final PMX computer model, Equations (1)–(8). (A) Illustrates the schematic of the PK computer model, Equations (1)–(5), and (B) shows the schematic of the PD computer model, Equations (6)–(8).
FT4 measurements according to disease severity during follow-up. (A) Shows FT4 measurements during the whole follow-up (n = 494), and (B) displays FT4 measurements during the first 120 days (n = 129); circles correspond to FT4 measurements of patients with severe GD, triangles belong to patients with moderate GD, and crosses correspond to patients with mild GD.
Years of follow-up for each of the 44 individual patients with GD per severity group. The start of the line represents the age at the start of pharmacotherapy and the length of the line represents the duration of follow-up; solid lines correspond to patients with severe GD, dashed lines to patients with moderate GD, and dash-dotted lines to patients with mild GD.
Three simulations based on the developed PK computer model, Equations (1)–(5). MMZ measurements for (1) and (2) were obtained from Cooper et al. (48) with an oral dose of 30 and 60 mg, and MMZ measurements for (3) were obtained from Okamura et al. (39) with an oral dose of 10 mg.
Effect of age and disease severity on endogenous T4 production rate. For each disease severity group, the endogenous production rate (y-axis) is plotted as a function of age at diagnosis (x-axis); the solid line shows the production rate for patients with severe GD, the dashed line corresponds to patients with moderate GD, and the dashed-dotted line corresponds to patients with mild GD.
Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease

May 2023

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91 Reads

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2 Citations

Objectives Graves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy. Methods Retrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis. Results Data from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity. Discussion We present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases.


Figure 2: SOX10 protein domains and positions of SOX10 RSVs identified in IHH, WS and gnomAD. Heterozygous loss-of-function alleles are shown in red circles; heterozygous missense alleles are shown in black circles; homozygous missense alleles are shown in green circles. *Only single nucleotide variants associated with WS are shown and SOX10 structural variants are not depicted. DM, Dimerization Domain; HMG, High Mobility Group; Cons, Conserved in SOX-E Family; TA, Transactivation Domain
NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice

October 2022

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195 Reads

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36 Citations

Science Translational Medicine

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1 . The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1 -deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1 -deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.


Fig. 1 Non-normalized FT4 measurements (n = 505) are shown in panel a and b. TSH measurements (n = 510) are shown in panel c and d
Fig. 3 Change of distribution of the non-normalized FT4 measurements from a rightskewed distribution towards a normal distribution for increasing time of treatment. Panel a shows the distribution at start of treatment t = 0 of all available FT4 measurements, panel b and c show the distribution for later time intervals, whereas panel d shows the distribution based on the individual last measurement time point
Fig. 4 Visual predictive check based on normalized FT4 measurements modeled with Eqs. (4)-(7)
Presentation of all available laboratory reference ranges of FT4 measurements over time. Grey circles denote the upper limit and grey crosses the lower limit of each range. Black lines show the upper and lower limits of the target reference range (compare Table 2), where for simplicity in this Figure, individual PNA at start of treatment was neglected. The first 50 days are shown in panel a, and the total time interval is presented in panel b
Change of distribution of the non-normalized FT4 measurements from a right-skewed distribution towards a normal distribution for increasing time of treatment. Panel a shows the distribution at start of treatment t\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$t$$\end{document} = 0 of all available FT4 measurements, panel b and c show the distribution for later time intervals, whereas panel d shows the distribution based on the individual last measurement time point
Modeling of levothyroxine in newborns and infants with congenital hypothyroidism: challenges and opportunities of a rare disease multi-center study

October 2021

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89 Reads

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2 Citations

Journal of Pharmacokinetics and Pharmacodynamics

Modeling of retrospectively collected multi-center data of a rare disease in pediatrics is challenging because laboratory data can stem from several decades measured with different assays. Here we present a retrospective pharmacometrics (PMX) based data analysis of the rare disease congenital hypothyroidism (CH) in newborns and infants. Our overall aim is to develop a model that can be applied to optimize dosing in this pediatric patient population since suboptimal treatment of CH during the first 2 years of life is associated with a reduced intelligence quotient between 10 and 14 years. The first goal is to describe a retrospectively collected dataset consisting of 61 newborns and infants with CH up to 2 years of age. Overall, 505 measurements of free thyroxine (FT4) and 510 measurements of thyrotropin or thyroid-stimulating hormone were available from patients receiving substitution treatment with levothyroxine (LT4). The second goal is to introduce a scale/location-scale normalization method to merge available FT4 measurements since 34 different postnatal age- and assay-specific laboratory reference ranges were applied. This method takes into account the change of the distribution of FT4 values over time, i.e. a transformation from right-skewed towards normality during LT4 treatment. The third goal is to develop a practical and useful PMX model for LT4 treatment to characterize FT4 measurements, which is applicable within a clinical setting. In summary, a time-dependent normalization method and a practical PMX model are presented. Since there is no on-going or planned development of new pharmacological approaches for CH, PMX based modeling and simulation can be leveraged to personalize dosing with the goal to enhance longer-term neurological outcome in children with the rare disease CH.


MON-102 Serum Concentrations of FT4 and TSH in the First Six Months of L-Thyroxine Treatment in Infants with Congenital Hypothyroidism: Target Attainment Rates Should Be Improved

May 2020

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36 Reads

Journal of the Endocrine Society

Levo-Thyroxine (L-T4) is the medication of choice for treating congenital hypothyroidism (CH). Adequate L-T4 treatment is essential for early neurodevelopment in affected patients. Both under- and overtreatment with L-T4 were associated with long-term adverse neurological outcomes. Based on clinical experience, initial L-T4 dosing does not always result in optimal TSH and FT4 concentrations in all CH patients. The purposes of this study were 1) to quantify FT4 and TSH target attainment rates (TAR) in the first six months of L-T4 treatment in infants with CH, 2) to compare characteristics of patients with FT4 concentrations “OUT of” versus “IN” the target range at first time of monitoring. A multicenter retrospective analysis was conducted in infants born between 1995 and 2018. TSH and FT4 TARs were defined according to the most recent guidelines of the European Society for Paediatric Endocrinology (ESPE), as the percentage of concentrations “in” and “in the upper half” of the corresponding laboratory age-specific reference range for TSH and FT4, respectively. We analyzed a total of 208 TSH and 186 FT4 serum concentrations from 60 patients during the first 6 months of L-T4 treatment. The pretreatment FT4 and TSH serum concentrations (mean±SD) were 8.3±5.7 pmol/L and 338±248 mU/L, respectively. CH severity according to ESPE guidelines was severe, moderate and mild for 32%, 27% and 32% of the patients. Postnatal age (PNA) (mean±SD) at start of treatment was 10±12 days. Starting dose of L-T4 (mean±SD) for severe, moderate and mild CH were 10±4, 10±3, and 7±4 µg/kg/day, respectively. Over the study period, TSH TARs of 63% did not further improve between the first monitoring (mean at 17 days of treatment) and fourth monitoring (mean at 4 months of treatment), while FT4 TARs increased from 22% to 45% paralleled with a decrease of too high FT4 values from 55% to 21%. Comparing patients with FT4 concentrations “OUT of” versus “IN” the target range at first time monitoring (16 versus 18 days after starting treatment; p=0.45), they did not differ in pretreatment FT4 concentrations (p=0.2). In contrast, patients who had FT4 concentrations “OUT of” versus “IN” the target range received first dose of L-T4 at an earlier median PNA (7 versus 16 days; p=0.008), had higher pretreatment mean TSH concentrations (364 versus 181 mU/L; p=0.02) and received a higher mean initial L-T4 dose (10.3 versus 7.1 µg/kg/day; p=0.01). First, our results show that FT4 and TSH target ranges were not reached in all patients in the first six months of treatment. Second, our data suggest that TARs could be improved by individualizing initial L-T4 dosing not only according to pretreatment FT4 but also to pretreatment TSH concentrations. L-T4 dosing optimization is needed in this population.


Citations (9)


... [15][16][17]24 The oligogenic mode of inheritance has been proposed as a potential explanation for the broad spectrum of phenotypes observed in individuals with NR5A1/SF-1 variants encompassing healthy individuals, individuals with mild to severe or opposite sex DSD, male infertility, POI, and adrenal insufficiency. [24][25][26][27][28][29] So far, other mechanisms explaining the genotype-phenotype correlation associated with NR5A1/SF-1 have not been confirmed, ...

Reference:

Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study
Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development

EBioMedicine

... The study also revealed that the cornerstone of the treatment for juvenile GD is antithyroid medication, with long-term MMI therapy contributing to a higher rate of remission in children with GD [20]. Although both inferomedial and balanced OD effectively increased orbit capacity, the latter was more effective in lowering exophthalmos, most likely as a result of including the lateral wall. ...

Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease

... Further, studies on female mouse models suggest that during mini-puberty, gonadotropins are critical for early follicular development and may play additional roles, such as influencing sexual and maternal behaviors, and establishing coordinated GnRH pulsatility [62]. In addition, recent evidence suggests that the nitric oxide (NO) signaling pathway in hypothalamic neurons is essential for regulating the release of GnRH both in female and male humans and mice, and neuronal nitric oxide synthase deficiency can further lead to anosmia, hearing loss, and intellectual disability [63,64]. Despite these data, mini-puberty impact on female gonadal function and fertility remains incompletely understood. ...

NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice

Science Translational Medicine

... L-T4 is a synthetic tetraiodothyronine analog with a structure identical to that of human thyroid hormones, with the advantages of high purity, good absorption and homeostasis, low irritation, more stable biochemical activity, and a high safety profile for use in infants and the elderly. It is currently one of the drugs of choice for hormone replacement therapy in patients with thyroid disorders [23][24][25]. e results of this study showed that TSH levels were lower and FT4 levels were higher than before treatment in children with CH after 24 months of treatment, and the differences were statistically significant. ...

Modeling of levothyroxine in newborns and infants with congenital hypothyroidism: challenges and opportunities of a rare disease multi-center study

Journal of Pharmacokinetics and Pharmacodynamics

... Four trajectories showed significant enrichment: T-03 (P adj =2.3x10 -18 ), T09 (P adj =1.9x10 -11 ), T03 (P adj =3.7x10 -10 ), and T01 (P adj =1.0x10 -3 ) ( Figure 7B). Knowing the different genetic architecture of CHH relative to specific sub-phenotypes, we repeated the analysis separating KS and normosmic CHH (nCHH) diagnoses, which are preferentially associated with developmental and homeostatic pathogenic mechanisms [73,74]. In line with the hypothesis, the most significant enrichments were driven by PTVs found in KS patients, including T-03 (KS P adj =2.1x10 -13 nCHH P adj =10 -5 ) and T03 (KS P adj =2.9x10 -7 vs. nCHH P adj =1.6x10 -3 ) ( Figure 7B Table S8 and S9). ...

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures
  • Citing Article
  • September 2018

Yearbook of Paediatric Endocrinology

... When a variant in the candidate gene does not result in the expected phenotype in all family members carrying the variant, the finding of (an)other variant(s) in modifier genes, whose product interacts with the candidate gene, may explain the resulting phenotype in the affected individuals. This oligogenic model of inheritance has been proposed for CHH for almost 15 years and has been attributed as the underlying mechanism in up to 15% of cases in certain series (Cassatella et al., 2018). ...

Congenital Hypogonadotropic Hypogonadism and Constitutional Delay of Growth and Puberty Have Distinct Genetic Architectures

European Journal of Endocrinology

... Eighty-two patients with genotype-proven 3βHSD2 deficiency have been reported in the literature and 31 were female, of whom only one-third were reported to have ambiguous genitalia at birth, mostly having mild cliteromegaly. Twothirds of the reported female patients with 3βHSD2 deficiency had normal external genitalia, which may cause difficulty and delay in achieving a definitive diagnosis (21,22). In the present study, we provide further evidence that 3βHSD2 deficiency rarely causes ambiguous genitalia in females, even in cases with severely impaired 3βHSD2 activity. ...

Non-Virilizing Congenital Adrenal Hyperplasia in a Female Patient with a Novel HSD3B2 Mutation
  • Citing Article
  • September 2016

Sexual Development

... Raw scores of the parents of CCS sample were transformed to p-scores (percentage scores ranging from 0 to 100) for the health domain scale scores and to T-scores using norm-based scoring according to normative data from the Swiss general population [13]. Cronbach's alpha was considered good ranging from 0.76 (general health perceptions) to 0.94 (bodily pain) across the eight health domain scales in parents of CCS [22]. ...

Health-Related Quality of Life of Young Adults Treated with Recombinant Human Growth Hormone during Childhood

... 21 Investigation of the renin-aldosterone axis and use of USP in moderate or severe hyponatraemia and concurrent analysis of renin and aldosterone levels helps to confirm the diagnosis or exclude genetic causes of hyponatraemia such as aldosterone synthase deficiency. 22 Following restoration of normal electrolytes off treatment, USP can be used to demonstrate a return to normality. ...

The Aldosterone/Renin Ratio as a Diagnostic Tool for the Diagnosis of Primary Hypoaldosteronism in Newborns and Infants
  • Citing Article
  • May 2015

Hormone Research in Paediatrics