Publications by authors named "Kyriakie Sarafoglou"

61 Publications

Crinecerfont Lowers Elevated Hormone Markers in Adults with 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia.

J Clin Endocrinol Metab 2021 Oct 15. Epub 2021 Oct 15.

Neurocrine Biosciences, Inc.; El Camino Real, San Diego, CA.

Context: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production.

Objective: To evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD.

Design: Open-label, phase 2 study, with sequential cohort design (NCT03525886).

Setting: United States (6 centers).

Participants: Men and women, 18-50 years, with 21OHD.

Interventions: Four crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg oncedaily at bedtime (Cohorts 1 and 2, respectively); 100 mg once-daily in the evening (Cohort 3); 100 mg twice-daily (BID, Cohort 4). Participants could enroll in >1 cohort.

Main Outcomes: Changes from baseline to Day 14 in adrenocorticotropic hormone (ACTH), 17hydroxyprogesterone (17OHP), androstenedione, and testosterone.

Results: Eighteen participants (11 women, 7 men) were enrolled: Cohort 1 (n=8), Cohort 2 (n=7), Cohort 3 (n=8), Cohort 4 (n=8). Mean age was 31 years; 94% were white. Median percent reductions were >60% for ACTH (-66%), 17OHP (64%), and androstenedione (64%) with crinecerfont 100 mg BID. In female participants, 73% (8/11) had ≥50% reduction in testosterone levels; male participants had median 26-65% decreases in androstenedione/testosterone ratios.

Conclusions: Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical endpoints of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.
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http://dx.doi.org/10.1210/clinem/dgab749DOI Listing
October 2021

An endocrine perspective on menstrual suppression for adolescents: achieving good suppression while optimizing bone health.

J Pediatr Endocrinol Metab 2021 Nov 13;34(11):1355-1369. Epub 2021 Aug 13.

Pediatric Endocrine Unit and Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Suppression of menstruation and/or ovarian function in adolescent girls may be desired for a variety of reasons. Numerous medical options exist. The choice of the appropriate modality for an individual patient depends on several factors based on differences in the efficacy of achieving menstrual suppression as well as in their side effect profiles. Adolescence is also a period of bone mass accrual in girls, and several of these modalities may negatively influence peak bone mass. This review focuses on the efficacy of achieving menstrual suppression and the effect on bone health of the various options through an overview of the current literature and also highlights areas in need of further research.
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http://dx.doi.org/10.1515/jpem-2020-0539DOI Listing
November 2021

Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies.

J Clin Endocrinol Metab 2021 10;106(11):e4666-e4679

Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI and Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.

Context: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction.

Objective: Assess tildacerfont safety and efficacy.

Design And Setting: Two Phase 2 open-label studies.

Patients: Adults with 21OHD.

Intervention: Oral tildacerfont 200 to 1000 mg once daily (QD) (n = 10) or 100 to 200 mg twice daily (n = 9 and 7) for 2 weeks (Study 1), and 400 mg QD (n = 11) for 12 weeks (Study 2).

Main Outcome Measure: Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments.

Results: In Study 1, evaluable participants with baseline A4 > 2× ULN (n = 11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 > 2× ULN (n = 5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤ 2× ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%).

Conclusions: For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.
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http://dx.doi.org/10.1210/clinem/dgab438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530725PMC
October 2021

Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?

Mol Genet Metab 2021 08 11;133(4):397-399. Epub 2021 Jun 11.

Dept. of Pediatrics - Divisions of Endocrinology and Genetics & Metabolism, Dept. of Experimental & Clinical Pharmacology, University of Minnesota, USA.

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.
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http://dx.doi.org/10.1016/j.ymgme.2021.06.003DOI Listing
August 2021

Reply.

J Pediatr 2021 09 12;236:329-331. Epub 2021 Jun 12.

Division of Endocrinology, Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota.

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http://dx.doi.org/10.1016/j.jpeds.2021.06.013DOI Listing
September 2021

Application of Deep Neural Networks as a Prescreening Tool to Assign Individualized Absorption Models in Pharmacokinetic Analysis.

Pharmaceutics 2021 May 26;13(6). Epub 2021 May 26.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.

A specific model for drug absorption is necessarily assumed in pharmacokinetic (PK) analyses following extravascular dosing. Unfortunately, an inappropriate absorption model may force other model parameters to be poorly estimated. An added complexity arises in population PK analyses when different individuals appear to have different absorption patterns. The aim of this study is to demonstrate that a deep neural network (DNN) can be used to prescreen data and assign an individualized absorption model consistent with either a first-order, Erlang, or split-peak process. Ten thousand profiles were simulated for each of the three aforementioned shapes and used for training the DNN algorithm with a 30% hold-out validation set. During the training phase, a 99.7% accuracy was attained, with 99.4% accuracy during in the validation process. In testing the algorithm classification performance with external patient data, a 93.7% accuracy was reached. This algorithm was developed to prescreen individual data and assign a particular absorption model prior to a population PK analysis. We envision it being used as an efficient prescreening tool in other situations that involve a model component that appears to be variable across subjects. It has the potential to reduce the time needed to perform a manual visual assignment and eliminate inter-assessor variability and bias in assigning a sub-model.
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http://dx.doi.org/10.3390/pharmaceutics13060797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227048PMC
May 2021

Impact of pediatric hypophosphatasia on behavioral health and quality of life.

Orphanet J Rare Dis 2021 02 12;16(1):80. Epub 2021 Feb 12.

Department of Pediatrics, University of Minnesota Medical School, 2450 Riverside Avenue South, RPB 550, Minneapolis, MN, 55454, USA.

Background: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase. It is characterized by defective bone mineralization associated with low alkaline phosphatase activity. Clinical features of pediatric HPP are highly variable, and can include premature loss of teeth, musculoskeletal problems, and impaired mobility. The effects of pediatric HPP on sleep, mood, regulation of attention and behavior, and other aspects of behavioral health have not been comprehensively studied.

Methods: Parents of 30 children with HPP (14 females, 16 males) between the ages of 3 and 16 years (mean age = 8.0 years) enrolled in this cross-sectional survey-based study. Molecular genetic and biochemical testing as well as clinical records were reviewed to verify diagnosis of HPP. The cohort included 15 patients with a more clinically severe presentation of HPP who had received treatment with enzyme replacement therapy (asfotase alfa) and 15 children with less severe HPP who were treatment-naïve. Parents provided information regarding psychopathological comorbidity, emotional and behavioral well-being, and quality of life.

Results: Clinically significant behavioral health challenges were evident in 67% of children with HPP. The most common behavioral findings included sleep disturbance and symptoms of attention deficit hyperactivity disorder (ADHD), each of which were observed ≥ 50% of individuals. Sleep disturbance, pain interference, poor behavioral regulation, and mood/anxiety symptoms were associated with reduced physical and psychosocial quality of life. Behavioral concerns were evident among children with HPP receiving asfotase alfa treatment as well as among children with clinically less severe disease who had not initiated therapy. Although most children in the cohort (77%) had age-typical development of adaptive skills, emotional and behavioral challenges were associated with weaker adaptive function.

Conclusions: Children with HPP are at increased risk for ADHD symptoms and other behavioral health challenges. There is likely an under-recognition of these findings in clinical practice.
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http://dx.doi.org/10.1186/s13023-021-01722-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881480PMC
February 2021

Adjusting for Pubertal Status Reduces Overweight and Obesity Prevalence in the United States.

J Pediatr 2021 04 16;231:200-206.e1. Epub 2021 Jan 16.

Division of Endocrinology, Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, MN.

Objective: To compare pediatric overweight and obesity prevalence among non-Hispanic white, Mexican American, and non-Hispanic black US youths before and after adjusting body mass index (BMI) for pubertal status, as assessed by Tanner stage.

Study Design: We analyzed cross-sectional anthropometric and pubertal data from non-Hispanic white, Mexican American, and non-Hispanic black youths in the National Health and Nutrition Examination Survey (NHANES) III. We developed specialized Tanner stage and chronological age-adjusted models to establish Tanner-stage adjusted BMI z-scores, which were then used to determine adjusted overweight/obesity prevalence. We compared pediatric overweight/obesity prevalence before and after pubertal status adjustment.

Results: Among 3206 youths aged 8-18 years (50% male; 26% non-Hispanic white, 35% Mexican American, 39% non-Hispanic black), adjusting BMI for Tanner stage significantly reduced overweight (males, from 29% to 21%; females, from 29% to 17%) and obesity (males, from 14% to 7%; females, from 11% to 5%) prevalence across all races/ethnicities. The obesity prevalence reduction was more pronounced in Mexican Americans (males, 11% reduction; females, 9% reduction) and non-Hispanic blacks (males and females, 10% reduction) compared with non-Hispanic whites (males, 6% reduction; females, 5% reduction). Similar patterns were seen in overweight prevalence.

Conclusions: Adjusting for pubertal status reduced the prevalence of overweight/obesity in non-Hispanic white, Mexican American, and non-Hispanic black youth. This suggests that adjusting for puberty incorporates changes otherwise not captured when only considering the age of a child. Adjusting BMI for pubertal status may be important when interpreting a youth's weight status and consideration for obesity management, as well as when interpreting pediatric overweight/obesity prevalence data.
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http://dx.doi.org/10.1016/j.jpeds.2020.12.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005467PMC
April 2021

Nonvirilized Genitalia in 3 Female Newborns With the Salt-Wasting Congenital Adrenal Hyperplasia Phenotype.

J Endocr Soc 2021 Jan 5;5(1):bvaa169. Epub 2020 Nov 5.

Division of Endocrinology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a form of primary adrenal insufficiency characterized by impaired cortisol secretion and elevated androgen production, is the leading cause of atypical genitalia in the female newborn. Females with classic CAH, either salt-wasting or simple-virilizing form, usually present at birth with atypical genitalia ranging from clitoromegaly to male-appearing genitalia, due to in utero to elevated androgens (androstenedione and testosterone). Females with mild nonclassic CAH usually present with typical genitalia. Proving the importance of always keeping an open mind for exceptions to the rule, we report on 3 female newborns who presented with the nonvirilized genitalia, salt-wasting CAH phenotype and genotype most consistent with simple-virilizing CAH. It is only through a positive newborn screen identifying the females with CAH that they were diagnosed before developing adrenal and/or salt-wasting crisis.
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http://dx.doi.org/10.1210/jendso/bvaa169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684867PMC
January 2021

Attention-Deficit/Hyperactivity Disorder Among US Children and Adolescents With Congenital Adrenal Hyperplasia.

J Endocr Soc 2020 Dec 14;4(12):bvaa152. Epub 2020 Oct 14.

Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.

Background: Little is known regarding risk for co-occurring mental health conditions among pediatric patients with congenital adrenal hyperplasia (CAH). The objective of the current study was to investigate the prevalence of medically managed attention-deficit/hyperactivity disorder (ADHD) in 2 large administrative samples of insured children and adolescents with and without CAH in the United States.

Methods: We assessed the prevalence of CAH and of medically managed ADHD using algorithms defined from diagnosis codes and filled prescriptions data using the IBM MarketScan Commercial and Multi-State Medicaid claims databases. We evaluated subjects who were continuously enrolled for ≥ 12 months with a first claim during October 2015 through December 2017 when they were 5 to 18 years old.

Results: The administrative prevalence of CAH in the Commercial (N = 3 685 127) and Medicaid (N = 3 434 472) samples was 10.1 per 100 000 (n = 372) and 7.2 per 100 000 (n = 247), respectively. The prevalence of medically managed ADHD in the non-CAH population was 8.4% in the Commercial sample and 15.1% in the Medicaid sample. Among children with CAH, there was no increased prevalence of ADHD in the Commercial (9.2%, prevalence ratio [PR] = 1.1; 95% confidence interval [CI], 0.82-1.54; = 0.48) or Medicaid (13.8%; PR = 0.91; 95% CI, 0.67-1.24; = 0.55) samples compared with the general population.

Conclusions: Using 2 large samples of insured children and adolescents in the United States, we found similar prevalence of medically managed ADHD among those with CAH and the general population. Future research to assess the validity of our claims algorithm for identifying pediatric CAH cases is warranted.
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http://dx.doi.org/10.1210/jendso/bvaa152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648384PMC
December 2020

Hydrocortisone suspension formulations are not necessarily the same in the treatment of children with congenital adrenal hyperplasia.

Eur J Endocrinol 2020 Dec;183(6):L27-L28

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

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http://dx.doi.org/10.1530/EJE-20-0938DOI Listing
December 2020

Variation in early number skills and mathematics achievement: Implications from cognitive profiles of children with or without Turner syndrome.

PLoS One 2020 2;15(10):e0239224. Epub 2020 Oct 2.

Institute of Child Development, University of Minnesota, Minneapolis, Minnesota, United States of America.

Individuals with Mathematics Learning Disabilities have persistent mathematics underperformance but vary with respect to their cognitive profiles. The present study examined mathematics ability and achievement, and associated mathematics-specific numerical skills and domain-general cognitive abilities, in young children with Turner syndrome compared to their matched peers. We utilized two independent peer groups so that group comparisons would account for verbal skills, a hypothesized strength of girls with Turner syndrome, and nonsymbolic magnitude comparison skills, a hypothesized difference of girls with Turner syndrome. This individual matching approach afforded characterization of mathematics profiles of girls with Turner syndrome and girls without Turner syndrome that share potential key features of the Turner syndrome phenotype. Results indicated differences in mathematics ability and nonsymbolic magnitude comparison tasks between girls with Turner syndrome and peers with similar levels of verbal skill. Mathematics ability and mathematics achievement scores of girls with Turner syndrome did not differ significantly from their peers with similar levels of accuracy on a nonsymbolic magnitude comparison task. Cognitive correlates of mathematics outcomes showed disparate patterns across groups. These quantitative and qualitative differences across profiles enhance our understanding of variation in mathematics ability in early childhood and inform how mathematics skills develop in young children with or without Turner syndrome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239224PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531844PMC
November 2020

Development of Tanner Stage-Age Adjusted CDC Height Curves for Research and Clinical Applications.

J Endocr Soc 2020 Sep 17;4(9):bvaa098. Epub 2020 Jul 17.

Rollins School of Public Health, Emory University, Atlanta, Georgia.

Background And Objective: Variations in normal pubertal development, pubertal disorders, and race/ethnicity can lead to differences in growth patterns and timing that are not captured by the Centers for Disease Control and Prevention (CDC) height-for-chronological age (CA) charts. Therefore, we sought to develop new Tanner stage-adjusted height-for-age (TSA) charts accounting for these differences.

Study Design: Population-based Tanner staging and anthropometric data for 13 358 children age 8 to 18 years from 3 large US national surveys: National Health Examination Surveys (NHES cycle III); the Hispanic Health and Nutrition Examination Surveys (HHANES) and the third National Health and Nutrition Examination Surveys (NHANES III) were analyzed. TSA semi-parametric models with additive age splines were used to develop smoothed TSA curves accounting for maturation stage and calendar age.

Results: As expected, the TSA curves did not track along the respective percentile curves for the CDC 2000 CA curves. We generated race/ethnicity-nonspecific and race/ethnicity-specific TSA charts stratified by sex and plotted against the CDC 2000 CA curves to account for the pubertal status differences between these models. An online calculator to adjust height for pubertal status was created.

Conclusions: TSA charts provide a much-needed tool to assess and manage linear growth for US children over the course of puberty. These tools may be useful in clinical management of children with pubertal timing variations.
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http://dx.doi.org/10.1210/jendso/bvaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426000PMC
September 2020

Manipulation of Hydrocortisone Tablets Leads to Iatrogenic Cushing Syndrome in a 6-Year-Old Girl With CAH.

J Endocr Soc 2020 Aug 5;4(8):bvaa091. Epub 2020 Jul 5.

Department of Pediatrics, Division of Endocrinology, University of Minnesota, Minneapolis, Minnesota.

Currently there are no commercially available hydrocortisone formulations for the treatment of children with congenital adrenal hyperplasia (CAH) that allow for smaller doses (0.1-1.25 mg) and incremental adjustments needed to control excess androgen production and avoid the negative effects of overtreatment. This lack of availability has led physicians to recommend dividing hydrocortisone 5-mg tablets into 4 to 6 pieces, compounding capsules or hydrocortisone suspension, or crushing 5- or 10-mg tablets in 5 or 10 mL of water. We report a case of iatrogenic Cushing syndrome in a 6-year 11-month-old girl with salt-wasting CAH treated with hydrocortisone tablets that were administered after crushing and dispersing into water to obtain the prescribed dose. She presented with poor growth, increasing body mass index (BMI), excess downy hair, round facies, and gastric ulcers. Her hydrocortisone dose was 8.1 mg/m/day. Results for all adrenal steroid concentrations were undetectable at 8 am, 12 hours after her last dose. The year prior to presentation her parents began dissolving 10 mg of hydrocortisone in 10 mL of water and using this preparation over the course of 24 hours, which coincided with rapid increase of BMI. We switched her to a pharmacy-compounded alcohol-free hydrocortisone suspension with total daily doses ranging from 6.5 to 8.2 mg/m/day, which resulted in resolution of her cushingoid features, a decrease in BMI, and catch-up growth. Our case highlights that manipulation of hydrocortisone tablets by parents can result in great variability in dosing and the need for commercially available pediatric formulations allowing for smaller dosing required in young children.
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http://dx.doi.org/10.1210/jendso/bvaa091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417883PMC
August 2020

PMM2-CDG caused by uniparental disomy: Case report and literature review.

JIMD Rep 2020 Jul 28;54(1):16-21. Epub 2020 Apr 28.

Department of Clinical Genomics, and Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota USA.

Background: Phosphomannomutase 2 deficiency PMM2-CDG) affects glycosylation pathways such as the N-glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2-CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy.

Case Presentation: Our patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2-CDG.A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2-CDG.

Conclusion: Since the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2-CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counseling.
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http://dx.doi.org/10.1002/jmd2.12122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358672PMC
July 2020

Bone Health Management After Hematopoietic Cell Transplantation: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2020 10 9;26(10):1784-1802. Epub 2020 Jul 9.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.

Bone health disturbances commonly occur after hematopoietic cell transplantation (HCT) with loss of bone mineral density (BMD) and avascular necrosis (AVN) foremost among them. BMD loss is related to pretransplantation chemotherapy and radiation exposure and immunosuppressive therapy for graft-versus-host-disease (GVHD) and results from deficiencies in growth or gonadal hormones, disturbances in calcium and vitamin D homeostasis, as well as osteoblast and osteoclast dysfunction. Although the pathophysiology of AVN remains unclear, high-dose glucocorticoid exposure is the most frequent association. Various societal treatment guidelines for osteoporosis exist, but the focus is mainly on menopausal-associated osteoporosis. HCT survivors comprise a distinct population with unique comorbidities, making general approaches to bone health management inappropriate in some cases. To address a core set of 16 frequently asked questions (FAQs) relevant to bone health in HCT, the American Society of Transplant and Cellular Therapy Committee on Practice Guidelines convened a panel of experts in HCT, adult and pediatric endocrinology, orthopedics, and oral medicine. Owing to a lack of relevant prospective controlled clinical trials that specifically address bone health in HCT, the answers to the FAQs rely on evidence derived from retrospective HCT studies, results extrapolated from prospective studies in non-HCT settings, relevant societal guidelines, and expert panel opinion. Given the heterogenous comorbidities and needs of individual HCT recipients, answers to FAQs in this article should be considered general recommendations, with good medical practice and judgment ultimately dictating care of individual patients. Readers are referred to the Supplementary Material for answers to additional FAQs that did not make the core set.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.001DOI Listing
October 2020

An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia.

Br J Clin Pharmacol 2021 03 26;87(3):1098-1110. Epub 2020 Jul 26.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

Aims: The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17-hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH).

Methods: A nonlinear mixed-effect modelling approach was used to analyse cortisol, 17-hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an I model.

Results: Cortisol was characterized by a one-compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC values of cortisol concentrations for cortisol, 17-hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 μg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC values were higher in salt-wasting subjects than simple virilizers. Production rates of cortisol, 17-hydroxyprogesterone and androstenedione were higher in simple-virilizer subjects. Half-lives of cortisol, 17-hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively.

Conclusion: Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17-hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC-above-threshold, time-within-range, etc. Our long-range goal is to uncover dose-exposure-outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.
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http://dx.doi.org/10.1111/bcp.14470DOI Listing
March 2021

Individualized Absorption Models in Population Pharmacokinetic Analyses.

CPT Pharmacometrics Syst Pharmacol 2020 06 21;9(6):307-309. Epub 2020 May 21.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

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http://dx.doi.org/10.1002/psp4.12513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306615PMC
June 2020

Early characteristics of bone deficits in children with Fontan palliation.

Cardiol Young 2020 Apr 20;30(4):468-475. Epub 2020 Feb 20.

Department of Pediatrics, Emory University, Atlanta, GA, USA.

Background: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation.

Methods: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls.

Results: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex.

Conclusions: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.
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http://dx.doi.org/10.1017/S1047951120000293DOI Listing
April 2020

Partial gonadal dysgenesis associated with a pathogenic variant of transcription factor.

BMJ Case Rep 2019 Jul 12;12(7). Epub 2019 Jul 12.

Pediatrics, University of Minnesota Children's Hospital, Minneapolis, Minnesota, USA.

A term neonate was admitted to the Neonatal Intensive Care Unit for respiratory distress, hypotonia and atypical genitalia. Significant findings included a small phallic structure, labial folds, no palpable gonads and two perineal openings. Pelvic ultrasound showed uterine didelphys and a gonad in the right inguinal canal. The right gonad was removed during diagnostic laparoscopy with microscopic evaluation showing infantile testicular tissue and fluorescence in-situ hybridisation showed only XY signal suggesting that the removed gonad was a male-developed testis. Infant was 46,XY, SRY probe positive. The parents chose a female sex assignment prior to gonadectomy. The infant had respiratory insufficiency and central hypotonia that persisted on discharge. Whole exome sequencing showed a heterozygous pathogenic variant of the gene. This variant encodes the pre-B-cell leukaemia homeobox PBX transcription factor and has been associated with malformations and severe hypoplasia or aplasia of multiple organs including lungs and gonads. Whole exome sequencing was crucial in providing a unifying diagnosis for this patient.
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http://dx.doi.org/10.1136/bcr-2018-227986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626438PMC
July 2019

Use of an aromatase inhibitor in children with congenital adrenal hyperplasia: Impact of anastrozole on bone mineral density and visceral adipose tissue.

Clin Endocrinol (Oxf) 2019 07 15;91(1):124-130. Epub 2019 May 15.

University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota.

Objective: Anastrozole, an aromatase inhibitor, has been used off-label in males with short stature to delay bone maturation. No studies have examined anastrozole's effect on bone mineral density (BMD) or body composition in children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Our objective was to evaluate anastrozole's effect on BMD and visceral adipose tissue (VAT) in children with CAH.

Design: Total body BMD (TBMD) and L2-L4 BMD Z-scores were adjusted for height-for-age Z-scores (TBMD and L2-L4 ). Hydrocortisone doses (mg/m /d) were averaged over the previous year. Comparison of treated vs not treated with anastrozole used linear regression adjusting for age, pubertal status, sex, CAH type, years on hydrocortisone, BMI Z-scores and bone age Z-scores.

Patients: We compared 25 children with CAH treated with anastrozole (mean age 11.3 [SD 3.0] years, 56% males) vs 31 children with CAH not treated with anastrozole (13.5 [SD 4.6], 29%). Participants underwent a pubertal exam, bone age X-ray and dual X-ray absorptiometry (DXA) scan.

Results: Average bone age Z-score of 4.3 SDs on beginning anastrozole decreased to 1.9 SDs at time of DXA exam (P = 0.0004) 5.2 (SD 2.2) years later. TBMD Z-scores (P = 0.51), L2-L4 BMD Z-scores (P = 0.66), VAT (P = 0.38), TBMD Z-scores (P = 0.66) and L2-L4 Z-scores (P = 0.41) did not differ between children treated vs not treated with anastrozole.

Conclusion: Anastrozole significantly reduced bone age advancement in children with CAH and advanced bone age (>2SDs) without adverse effects on BMD or VAT. Longitudinal studies of anastrozole in children with CAH are needed to validate these findings.
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http://dx.doi.org/10.1111/cen.14009DOI Listing
July 2019

Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings.

J Investig Med 2020 01 28;68(1):16-25. Epub 2019 Feb 28.

Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA.

Adrenal insufficiency (AI) remains a significant cause of morbidity and mortality in children with 1 in 200 episodes of adrenal crisis resulting in death. The goal of this working group of the Pediatric Endocrine Society Drug and Therapeutics Committee was to raise awareness on the importance of early recognition of AI, to advocate for the availability of hydrocortisone sodium succinate (HSS) on emergency medical service (EMS) ambulances or allow EMS personnel to administer patient's HSS home supply to avoid delay in administration of life-saving stress dosing, and to provide guidance on the emergency management of children in adrenal crisis. Currently, hydrocortisone, or an equivalent synthetic glucocorticoid, is not available on most ambulances for emergency stress dose administration by EMS personnel to a child in adrenal crisis. At the same time, many States have regulations preventing the use of patient's home HSS supply to be used to treat acute adrenal crisis. In children with known AI, parents and care providers must be made familiar with the administration of maintenance and stress dose glucocorticoid therapy to prevent adrenal crises. Patients with known AI and their families should be provided an Adrenal Insufficiency Action Plan, including stress hydrocortisone dose (both oral and intramuscular/intravenous) to be provided immediately to EMS providers and triage personnel in urgent care and emergency departments. Advocacy efforts to increase the availability of stress dose HSS during EMS transport care and add HSS to weight-based dosing tapes are highly encouraged.
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http://dx.doi.org/10.1136/jim-2019-000999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996103PMC
January 2020

Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level.

JCI Insight 2018 11 2;3(21). Epub 2018 Nov 2.

Research Center of the University of Montreal Hospital Center (CRCHUM), Department of Neurosciences, Université de Montréal, Montreal, Quebec, Canada.

Glycine encephalopathy (GE), or nonketotic hyperglycinemia (NKH), is a rare recessive genetic disease caused by defective glycine cleavage and characterized by increased accumulation of glycine in all tissues. Here, based on new case reports of GLDC loss-of-function mutations in GE patients, we aimed to generate a zebrafish model of severe GE in order to unravel the molecular mechanism of the disease. Using CRISPR/Cas9, we knocked out the gldc gene and showed that gldc-/- fish recapitulate GE on a molecular level and present a motor phenotype reminiscent of severe GE symptoms. The molecular characterization of gldc-/- mutants showed a broad metabolic disturbance affecting amino acids and neurotransmitters other than glycine, with lactic acidosis at stages preceding death. Although a transient imbalance was found in cell proliferation in the brain of gldc-/- zebrafish, the main brain networks were not affected, thus suggesting that GE pathogenicity is mainly due to metabolic defects. We confirmed that the gldc-/- hypotonic phenotype is due to NMDA and glycine receptor overactivation, and demonstrated that gldc-/- larvae depict exacerbated hyperglycinemia at these synapses. Remarkably, we were able to rescue the motor dysfunction of gldc-/- larvae by counterbalancing pharmacologically or genetically the level of glycine at the synapse.
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http://dx.doi.org/10.1172/jci.insight.124642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238748PMC
November 2018

Adrenoleukodystrophy: Guidance for Adrenal Surveillance in Males Identified by Newborn Screen.

J Clin Endocrinol Metab 2018 11;103(11):4324-4331

Pediatric Endocrine Unit, Massachusetts General Hospital for Children and Harvard Medical School, Boston, Massachusetts.

Context: Adrenoleukodystrophy (ALD) is a peroxisomal disorder associated with neurologic decompensation and adrenal insufficiency. Newborn screening for ALD has recently been implemented in five states with plans to expand to all 50 states in the United States. Adrenal insufficiency ultimately develops in most males with ALD, but the earliest age of onset is not well established.

Objective: These clinical recommendations are intended to address screening for adrenal insufficiency in boys identified to have ALD by newborn screen.

Participants: Seven members of the Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee, with clinical experience treating children with ALD and adrenal insufficiency, and a pediatric endocrinologist and laboratory director were selected to be on the working committee.

Consensus Process: The authors comprised the working group and performed systematic reviews of the published literature regarding adrenal insufficiency and ALD. The recommendations were reviewed and approved by the larger Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee and then by the Pediatric Endocrine Society Board of Directors.

Conclusions: There is limited literature evidence regarding monitoring of evolving adrenal insufficiency in male infants and children with ALD. The recommendations suggest initiating assessment of adrenal function at diagnosis with ALD and regular monitoring to identify boys with adrenal insufficiency in a timely manner and prevent life-threatening adrenal crisis. These recommendations are intended to serve as an initial guide, with the understanding that additional experience will inform future guidelines.
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http://dx.doi.org/10.1210/jc.2018-00920DOI Listing
November 2018

Effect of Adjusting for Tanner Stage Age on Prevalence of Short and Tall Stature of Youths in the United States.

J Pediatr 2018 10 10;201:93-99.e4. Epub 2018 Jul 10.

Pediatric Endocrinology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN.

Objective: To evaluate the extent to which pubertal timing alters the classification of extremes of attained stature across race-ethnicity groups of youths in the US.

Study Design: We performed analyses of height and Tanner staging data of 3206 cross-sectional national sample of youths ages 8-18 years (53% male, n = 1606), 72% of whom were non-Hispanic white, 9% Mexican American, and 19% non-Hispanic black . Specialized growth models were used to derive Tanner-stage-age-adjusted z scores (TSA). The prevalence of shortness (<-1SD) and tallness (≥+1SD) status was quantified using TSA.

Results: Highly variable patterns of prevalence of shortness and tallness via chronologic age height z score (CA) were observed in results stratified by race-ethnicity and sex. Tallness CA prevalence was high among non-Hispanic white and non-Hispanic black male youths relative to Mexican American (40.0%-43.3% vs 20.5%) with a similar pattern in female youths. In both sexes, this pattern was eliminated with TSA, with Mexican American youth becoming statistically not different from their non-Hispanic white and non-Hispanic black peers.

Conclusions: Differences in timing of puberty between race-ethnicity groups affects estimated prevalence of shortness and tallness of attained height that remains uncaptured with CA. Adjustment for pubertal development might help isolate crucial determinants of attained stature and other aspects of body composition that may be most responsive to intervention programs in populations. The curves developed by adjusting for pubertal status may help the clinician avoid misclassification of children with early and late pubertal development.
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http://dx.doi.org/10.1016/j.jpeds.2018.05.051DOI Listing
October 2018

Mosaicism of the UDP-Galactose transporter SLC35A2 in a female causing a congenital disorder of glycosylation: a case report.

BMC Med Genet 2018 06 15;19(1):100. Epub 2018 Jun 15.

Division of Genetics & Metabolism, Department of Pediatrics and Ophthalmology, 2450 Riverside Avenue, Minneapolis, MN, 55454, USA.

Background: Congenital disorders of glycosylation are rare conditions caused by genetic defects in glycan synthesis, processing or transport. Most congenital disorders of glycosylation involve defects in the formation or transfer of the lipid-linked oligosaccharide precursor of N-linked glycans. SLC35A2-CDG (previously CDG-IIm) is caused by hemizygous or heterozygous mutations in the X-linked gene SLC35A2 that encodes a UDP-galactose transporter. To date there have only been 10 reported patients with SLC35A2 mutations. Importantly, the patient presented here was not identified in infancy by transferrin isoform analysis, the most common testing to identify patients with a congenital disorder of glycosylation.

Case Presentation: A 27 month old girl with developmental delay, central hypotonia, cerebral atrophy, and failure to thrive with growth retardation was identified by whole exome sequencing to have a mosaic missense variant in SLC35A2 (c.991G > A). This particular variant has been previously reported in a male as a mutation. Comparison of all clinical findings and new information on growth pattern, growth hormone testing and neurodevelopmental evaluation are detailed on the patient presented.

Conclusion: This patient report increases the clinical and scientific knowledge of SLC35A2-CDG, a rare condition. New information on reduced growth, growth hormone sufficiency, lack of seizures, and neurodevelopmental status are presented. This new information will be helpful to clinicians caring for individuals with SLC35A2-CDG. This report also alerts clinicians that transferrin isoform measurements do not identify all patients with congenital disorders of glycosylation.
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http://dx.doi.org/10.1186/s12881-018-0617-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003163PMC
June 2018

Lumbar spine bone mineral density Z-score discrepancies by dual X-ray absorptiometry do not predict vertebral fractures in children.

J Investig Med 2018 08 4;66(6):980-985. Epub 2018 Apr 4.

Division of Pediatric Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.

Dual X-ray absorptiometry (DXA) remains the most common mode of bone mineral density (BMD) evaluation. In adults, presence of a lumbar spine (LS) BMD T-score discrepancy (>1 SD difference between adjacent vertebrae) can indicate a vertebral fracture. In children, however, the clinical significance of such discrepancies is unknown. We conducted a retrospective study to evaluate the association between LS DXA and LS morphology to elucidate the clinical significance of an LS BMD Z-score discrepancy. We identified 360 DXA scans performed between September 2014 and May 2016 in patients 5-18 years of age. DXA scans were cross-referenced against available LS radiographs and vertebral fracture assessment (VFA) within the 6 months preceding or following a DXA scan. After excluding 44 DXA scans because of spinal hardware, incomplete DXA, or repeat scans, 316 DXA scans were included; 81 (25.6%) had either an LS radiograph or a VFA. Twenty-five of 81 patients (30.9%) had >1 SD difference between adjacent vertebrae in LS BMD Z-score. Two of these 25 patients (8%) had a lumbar vertebral fracture documented by a spine radiograph. Of the remaining 56 patients who did not have a discrepancy >1 SD, 6 patients (11%) had a lumbar vertebral fracture. Discrepancies in LS BMD Z-scores were not associated with lumbar vertebral fractures and, in the absence of fractures, likely represented vertebral developmental variants in children whose skeletons are still growing. Therefore, it does not appear justified to recommend further imaging based solely on the results of a DXA scan without clinically meaningful indications.
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http://dx.doi.org/10.1136/jim-2018-000738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062459PMC
August 2018

Bone mineral density and body composition in children with congenital adrenal hyperplasia.

Clin Endocrinol (Oxf) 2018 06 24;88(6):813-819. Epub 2018 Mar 24.

Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.

Objective: Children with congenital adrenal hyperplasia (CAH) are exposed to fluctuating cortisol and androgen levels. The effects these hormonal states have on bone mineral density (BMD) and body composition are not well studied. The study's objective was to compare BMD and body composition, including visceral adipose tissue (VAT) and Android:Gynoid (A:G) ratio, in children with CAH vs healthy age-matched, sex-matched and BMI-matched controls.

Design: Total body BMD (TBMD) Z-scores were adjusted for height-for-age Z-scores (TBMDHAZ). Hydrocortisone dose (mg/m2/d) was averaged over the past year. Bone age Z-scores were used as a surrogate for long-term androgen exposure in cases. Statistical analyses comparing cases and controls accounted for matched groups using mixed linear models.

Patients: Forty-two cases with CAH (average age 12.3 years [SE 3]; 17 males) and 101 controls underwent a dual-energy X-ray absorptiometry scan.

Results: Children with CAH had lower TBMD (0.81 vs 1.27, P = .003) and TBMD Z-scores (-0.51 vs -0.01, P = .001) than controls. In CAH cases, TBMD and TBMD Z-scores were positively correlated with bone age Z-scores (r = .63, P < .0001; r = .51, P = .001, respectively) but were not associated with HC dose. VAT and the A:G ratio did not differ significantly between children with CAH and controls and neither was associated with HC dose.VAT was not associated with bone age Z-score.

Conclusion: Lower BMD was observed in CAH cases compared with controls although no differences in body composition were identified. Among CAH cases, increased chronic androgen exposure, as measured by bone age Z-scores, was associated with higher BMD but was not associated with VAT.
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http://dx.doi.org/10.1111/cen.13580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980722PMC
June 2018

De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects.

Hum Mol Genet 2017 12;26(24):4849-4860

Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.

We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1-/-) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p.Arg184Pro, p.Met224Lys, and p.Arg227Pro) or within the homeodomain (p.Arg234Pro, and p.Arg235Gln), whereas p.Ser262Glnfs*2, and p.Arg288* yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species.
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http://dx.doi.org/10.1093/hmg/ddx363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455034PMC
December 2017
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