Turner syndrome

123

Pathophysiology, Diagnosis

and Treatment

Patricia Y. Fechner

Editor

Turner Syndrome

Turner Syndrome

Patricia Y. Fechner

Editor

Turner Syndrome

Pathophysiology, Diagnosis and Treatment

ISBN 978-3-030-34148-0 ISBN 978-3-030-34150-3 (eBook)

https://doi.org/10.1007/978-3-030-34150-3

© Springer Nature Switzerland AG 2020

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of

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Editor

Patricia Y. Fechner

Division of Endocrinology

Seattle Children’s Hospital

University of Washington

Seattle, WA

USA

To my parents, thank you for all of your love

and support.

vii

Preface

The purpose of this book is to provide a resource for providers who care for girls

and women with Turner syndrome. Turner syndrome occurs in 1:1800–2000

females, yet many providers may not have a lot of experience caring for a female

with Turner syndrome. Patients with Turner syndrome have many of the same health

issues as other females, but some health issues are at a higher frequency that neces￾sitates more frequent and earlier screening.

Many contributors to this work are experts in the care of females with Turner

syndrome, while others are experts in their own field of medicine who can apply this

expertise to the care of individuals with Turner syndrome. They all have worked on

this project as a labor of love and for the benefit of the girl or woman with Turner

syndrome. I wish to thank each of them for their significant contributions to

this book.

The chapters in the book are organized by subspecialty and/or major health issue,

with the goal to provide in-depth coverage of the health issues faced by those with

Turner syndrome.

Seattle, WA, USA Patricia Y. Fechner, MD

ix

Contents

1 Description of Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Alissa J. Roberts and Patricia Y. Fechner

2 The Genetics of Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Margaret P. Adam and Melanie A. Manning

3 Pattern and Etiology of Growth Disturbance

in Turner Syndrome and Outcomes of Growth-Promoting

Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Charmian A. Quigley

4 Fertility Preservation for Turner Syndrome . . . . . . . . . . . . . . . . . . . . . 79

Courtney Finlayson, Lia Bernardi, and Reema Habiby

5 Estrogen Replacement in Turner Syndrome . . . . . . . . . . . . . . . . . . . . 93

Karen O. Klein, Robert L. Rosenfield, Richard J. Santen,

Aneta M. Gawlik, Philippe Backeljauw, Claus H. Gravholt,

Theo C. J. Sas, and Nelly Mauras

6 The Heart and Vasculature in Turner Syndrome:

Development, Surveillance, and Management . . . . . . . . . . . . . . . . . . . 123

Luciana T. Young and Michael Silberbach

7 Renal Disorders and Systemic Hypertension . . . . . . . . . . . . . . . . . . . . 139

Yosuke Miyashita and Joseph T. Flynn

8 Endocrine and Metabolic Consequences of Turner Syndrome . . . . . 157

Mette H. Viuff and Claus H. Gravholt

9 Care of Girls with Turner Syndrome: Beyond Growth

and Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Angel Siu Ying Nip and Darcy King

10 Ear and Hearing Problems in Turner Syndrome . . . . . . . . . . . . . . . . . 185

Åsa Bonnard and Malou Hultcrantz

x

11 Ocular Features in Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Erin P. Herlihy and Jolene C. Rudell

12 Gastrointestinal and Hepatic Issues in Women

with Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Ghassan T. Wahbeh, Amanda Bradshaw, Lauren White,

and Dale Lee

13 Dermatologic Conditions in Turner Syndrome . . . . . . . . . . . . . . . . . . 221

Alessandra Haskin and Eve Lowenstein

14 Orthopedic Manifestations in Turner Syndrome . . . . . . . . . . . . . . . . . 237

Anna M. Acosta, Suzanne E. Steinman, and Klane K. White

15 Oral Manifestations in Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . 249

Carolina Di Blasi and Harlyn Susarla

16 The Turner Syndrome Resource Center: An Interdisciplinary

Approach to the Care of Girls and Women

with Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

Philippe Backeljauw and Sarah Corathers

17 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

Patricia Y. Fechner

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

Contents

xi

Contributors

Anna  M.  Acosta, MD Memorial Care and Miller Children’s and Women’s

Hospital, Long Beach, CA, USA

Margaret P. Adam, MD Division of Genetic Medicine, Department of Pediatrics,

University of Washington School of Medicine and Seattle Children’s Hospital,

Seattle, WA, USA

Philippe Backeljauw, MD The Cincinnati Center for Pediatric and Adult Turner

Syndrome Care, Cincinnati Children’s Hospital Medical Center, University of

Cincinnati College of Medicine, Cincinnati, OH, USA

Lia Bernardi, MD, MSCI Division of Reproductive Endocrinology, Department

of Obstetrics and Gynecology, Northwestern University Feinberg School of

Medicine, Chicago, IL, USA

Carolina  Di Blasi, MD Seattle Childrens Hospital, University of Washington,

Seattle, WA, USA

Åsa  Bonnard, MD, PhD Department of Clinical Science, Intervention and

Technology, Division of Otorhinolaryngology, Karolinska Institutet, Stockholm,

Sweden

Department of Otorhinolaryngology, Karolinska University Hospital, Stockholm,

Sweden

Amanda Bradshaw, PA-C Gastroenterology, Seattle Children’s Hospital, Seattle,

WA, USA

Sarah  Corathers, MD The Cincinnati Center for Pediatric and Adult Turner

Syndrome Care, Cincinnati Children’s Hospital Medical Center, University of

Cincinnati College of Medicine, Cincinnati, OH, USA

Patricia Y. Fechner, MD Division of Endocrinology, Seattle Children’s Hospital,

University of Washington, Seattle, WA, USA

xii

Courtney Finlayson, MD Division of Endocrinology, Department of Pediatrics,

Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University

Feinberg School of Medicine, Chicago, IL, USA

Joseph T. Flynn, MD, MS University of Washington School of Medicine, Seattle,

WA, USA

Division of Nephrology, Seattle Children’s Hospital, Seattle, WA, USA

Aneta M. Gawlik, PhD Department of Pediatrics and Pediatric Endocrinology,

School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

Claus  H.  Gravholt, MD, PhD Department of Endocrinology and Internal

Medicine, Aarhus University Hospital, Aarhus, Denmark

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

Department of Endocrinology and Internal Medicine and Medical Research

Laboratories, Aarhus University Hospital, Aarhus, Denmark

Reema Habiby, MD Division of Endocrinology, Department of Pediatrics, Ann &

Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg

School of Medicine, Chicago, IL, USA

Alessandra  Haskin, BA Department of Dermatology, SUNY Health Science

Center at Brooklyn, Brooklyn, NY, USA

Erin  P.  Herlihy, MD Department of Ophthalmology, University of Washington

School of Medicine, Seattle, WA, USA

Division of Pediatric Ophthalmology, Seattle Children’s Hospital, Seattle, WA, USA

Malou  Hultcrantz, MD Department of Clinical Science, Intervention and

Technology, Division of Otorhinolaryngology, Karolinska Institutet, Stockholm,

Sweden

Department of Otorhinolaryngology, Karolinska University Hospital, Stockholm,

Sweden

Darcy King, ARNP University of Washington, Seattle, WA, USA

Karen  O.  Klein, MD University of California, San Diego & Rady Children’s

Hospital, San Diego, CA, USA

Dale Lee, MD Pediatrics-Gastroenterology, Clinical Nutrition & Celiac Program,

Seattle Children’s Hospital, University of Washington, Seattle, WA, USA

Eve Lowenstein, MD, PhD Department of Dermatology, SUNY Health Science

Center at Brooklyn, Brooklyn, NY, USA

Melanie  A.  Manning, MD Division of Medical Genetics, Department of

Pediatrics, Stanford University School of Medicine and Lucile Salter Packard

Children’s Hospital, Stanford, CA, USA

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

Nelly Mauras, MD Nemours Children’s Health System, Jacksonville, FL, USA

Contributors

xiii

Yosuke  Miyashita, MD, MPH University of Pittsburgh School of Medicine,

Pittsburgh, PA, USA

Angel Siu Ying Nip, MBChB University of Washington, Seattle, WA, USA

Charmian  A.  Quigley, MBBS Sydney Children’s Hospital, Randwick, NSW,

Australia

Alissa  J.  Roberts, MD Division of Endocrinology, Seattle Children’s Hospital,

University of Washington, Seattle, WA, USA

Robert L. Rosenfield, MD The University of Chicago Pritzker School of Medicine,

Chicago, IL, USA

Jolene  C.  Rudell, MD, PhD Department of Ophthalmology, University of

Washington School of Medicine, Seattle, WA, USA

Division of Pediatric Ophthalmology, Seattle Children’s Hospital, Seattle, WA,

USA

Richard J. Santen, MD University of Virginia, Charlottesville, VA, USA

Theo C. J. Sas, MD Albert Schweitzer Hospital Dordrecht and Sophia Children’s

Hospital Rotterdam, Rotterdam, The Netherlands

Michael  Silberbach, MD Doernbecher Children’s Hospital, Oregon Health &

Sciences University, Portland, OR, USA

Suzanne  E.  Steinman, MD Department of Orthopedics and Sports Medicine,

Seattle Children’s Hospital, Seattle, WA, USA

Department of Orthopaedics and Sports Medicine, University of Washington,

Seattle, WA, USA

Harlyn  Susarla, DMD Seattle Childrens Hospital, University of Washington,

Seattle, WA, USA

Mette  H.  Viuff, MD Department of Endocrinology and Medical Research

Laboratories, Aarhus University Hospital, Aarhus, Denmark

Ghassan  T.  Wahbeh, MD Pediatrics-Gastroenterology, Inflammatory Bowel

Disease Center, Seattle Children’s Hospital, University of Washington, Seattle, WA,

USA

Klane  K.  White, MD, MSc Department of Orthopedics and Sports Medicine,

Seattle Children’s Hospital, Seattle, WA, USA

Department of Orthopaedics and Sports Medicine, University of Washington,

Seattle, WA, USA

Lauren White, ARNP Gastroenterology, Seattle Children’s Hospital, Seattle, WA,

USA

Luciana  T.  Young, MD Seattle Children’s Hospital/University of Washington,

Division of Cardiology, Seattle, WA, USA

Contributors

© Springer Nature Switzerland AG 2020 1

P. Y. Fechner (ed.), Turner Syndrome,

https://doi.org/10.1007/978-3-030-34150-3_1

Chapter 1

Description of Turner Syndrome

Alissa J. Roberts and Patricia Y. Fechner

Introduction

Turner syndrome was defined in 1938 by Dr. Henry Turner who described a con￾stellation of findings in girls as “A Syndrome of Infantilism, Congenital Webbed

Neck and Cubitus Valgus.” This same syndrome had been previously described by

Otto Ullrich in 1930, thus, in some countries the term Ullrich-Turner syndrome is

used. As knowledge and the field of genetics progressed, Turner syndrome was

further defined as phenotypic features consistent with Turner syndrome (which

could be as subtle as isolated short stature) in a female along with complete or

partial absence of a second sex chromosome on 20–30-cell karyotype, which could

include cell line mosaicism [1]. There have been many advances in the diagnosis

and management of females with Turner syndrome, and this chapter serves as an

introductory overview of the incidence, karyotype findings, and phenotype of

Turner syndrome, most of which will be described in further detail in appropriate

chapters following. For a summary of overall screening recommendations in

Turner syndrome, see Table 1.1, which incorporates 2017 clinical practice guide￾lines from the 2016 Cincinnati International Turner Syndrome Meeting [2].

A. J. Roberts (*) ∙ P. Y. Fechner

Division of Endocrinology, Seattle Children’s Hospital,

University of Washington, Seattle, WA, USA

e-mail: [email protected]

2

Table 1.1 Screening recommendations in Turner syndrome

Screening

category Screening Frequency in childhood

Frequency in

adulthood

Metabolic BMI/weight At diagnosis, at least annually At least annually

Lipid panel Annually after age 10 years Annually

Liver function

(AST, ALT, GGT,

alkaline

phosphatase)

Annually after age 10 year Annually

Hemoglobin A1c Annually after age 10 years Annually

Skeletal

screening

Spine exam:

scoliosis/kyphosis

Every 6 months if on growth

hormone, annually if not on growth

hormone, screen until growth

complete

None

Growth Initiate growth hormone at age

5–6 years or when significant growth

failure occurs

None

Hip exam In infancy None

Bone density

(DEXA)

Baseline when completed puberty Every 5 years

25-Hydroxyvitamin

D level

Start at age 9–11 years, then every

2–3 years

Every 3–5 years

Orthodontic exam Age 7, then as recommended by

initial exam

As recommended

by initial exam

Puberty and

ovarian reserve

LH and

FSH ±AMH and

inhibin B

Age 11, then annually until initiate

estrogen

As needed

Cardiovascular Echocardiogram

with cardiology

evaluation

At diagnosis, every 3–5 years starting

at age 12 years, cardiac MRI once

Every 5–10 years

Cardiac MRI

once

Blood pressure At diagnosis, at least annually At least annually

Renal Renal ultrasound At diagnosis None

Autoimmunity Thyroid

(TSH and free T4)

At diagnosis, annually Annually

Celiac screen

(IgA level (once)

and tissue

transglutaminase

IgA level)

Starting at age 2–3 years, every

2 years thereafter

Every 5 years

HEENT Audiology screen Age 9–12 months or at diagnosis

whichever first, then every 3 years

Every 5 years

Ophthalmological

examination

Age 12–18 months or at diagnosis

whichever first, then annually

Annually

Skin Skin exam At diagnosis, annually Annually

Psychosocial Neurocognitive

evaluation

Preschool, school entry, transition to

high school or higher education

As indicated

A. J. Roberts and P. Y. Fechner

3

Incidence

The true incidence of Turner syndrome is unknown, given that the presentation can

be subtle and thus underdiagnosed, particularly in the mosaic forms. One large￾scale study in Denmark, which looked at the incidence of chromosome abnormali￾ties in almost 35,000 live births, found the incidence of Turner syndrome to be 1 per

1893 girls [3]. When looking at the presentation of phenotypic features in Turner

syndrome, there is thought to be an ascertainment bias [4]. In other words, because

the girls with milder phenotypes are less likely to be diagnosed with Turner syn￾drome, the distribution of features in those in whom the diagnosis is known tends to

lean toward the more moderately or severely affected. The incidence of Turner syn￾drome and the number of afflicted females who have very few signs or symptoms is

likely underrepresented in the medical literature.

As we move into a new era with the widely available cell-free fetal DNA prenatal

testing, we will likely see an increase in prenatally diagnosed Turner syndrome and

thus may have changes in the known incidence rate as well as a shift in the spectrum

of phenotypes and karyotypes. Cell-free fetal DNA is placental DNA found in mater￾nal blood, accessed by noninvasive venipuncture. This technology is becoming an

increasingly popular routine screening test in the first trimester of pregnancy for aneu￾ploidies—primarily trisomy 21 and 13 due to its noninvasive nature. However, with

the information on these aneuploidies, the consumer also acquires information on the

sex chromosomes of the fetus and sex chromosome differences such as 45,X. One

systemic review determined the current sensitivity of cell-free fetal DNA for mono￾somy X is 94.1% and false positive is 0.53% [5]. Others though have found higher

false positive rate. This demonstrates the limitations of this testing for diagnosis of

monosomy X and that either invasive prenatal or postnatal karyotype is far superior.

In addition, for any prenatal diagnosis of suspected monosomy X, a postnatal karyo￾type must be performed to confirm and establish a diagnosis of Turner syndrome. As

this field rapidly evolves, we expect to see a growing body of literature on this topic.

Table 1.1 (continued)

Screening

category Screening Frequency in childhood

Frequency in

adulthood

Occupational,

physical, and

speech therapy

evaluation

Preschool or school entry

Mental health

screening

Annually after age 10 Annually

Connect with social

supports

At diagnosis, annually Annually

Table 1.1 based on Gravholt et al. [2]

1 Description of Turner Syndrome

4

Karyotype

The distribution in karyotypes in girls identified with Turner syndrome is approxi￾mately half 45,X, 35% mosaic, and the rest structural abnormalities in the X chro￾mosome [6]. All these karyotypes have in common missing elements from the X

chromosome. The X chromosome contains over 1000 genes (as compared to the Y

chromosome which contains around 200 genes) [7]. In the case of the genetically

typical female, 46,XX, in every cell, one of the X chromosomes is inactivated via

lyonization. However, approximately 10–15% of the genes on the inactive X chro￾mosomes escape inactivation and therefore remain active. Most of these genes are

located on the tip of the short arm of the X chromosome in what is known as the

pseudoautosomal region and have corresponding homologous genes on the Y chro￾mosome. In the female with Turner syndrome, who lacks all or part of the inactive

X chromosome, she also lacks those pseudoautosomal genes and genes that would

continue to be expressed despite inactivation. Thus, she only has a “single dose” of

these genes with the one X chromosome, and many of the phenotypic features pres￾ent in Turner syndrome are from the haploinsufficiency or inadequate “dosing” of

these genes.

45,X is the classic karyotype of Turner syndrome but can lead to a wide array of

phenotypes, ranging from isolated short stature to multiple dysmorphic features and

congenital heart disease. Specific phenotypic features of Turner syndrome are out￾lined in the next section. Mosaicism, where only some cell lines are 45,X, can also

present in a variety of manners. Most common, 45,X/46,XX, is often the most subtle

phenotype, and some, which are incidentally diagnosed, may not even warrant a clin￾ical diagnosis of Turner syndrome. It must be cautioned that in mosaicism, karyotype

distribution of cell lines cannot predict phenotype in that a lymphocyte karyotype

may differ from the distribution of cell lines in other tissues [8].

Another mosaic form of Turner syndrome includes the presence of Y material,

such as 45,X/46,XY, and conveys an increased risk of gonadoblastoma. This mosaic

genotype can present with a variety of phenotypes, varying from typical appearing

male with normal testes to a female with Turner syndrome. There may be some

virilization of the patient with Turner syndrome with Y material, or there may not be

any depending on the presence or absence of functional testicular tissue. The

increased risk of gonadoblastoma in this population of females with Turner syn￾drome is notable and ranges from 12% to 60% risk depending on the cohort [9, 10].

Individuals with 45,X/46,XY karyotype who are phenotypically female have been

found to have the highest risk of gonadoblastoma due to the intra-abdominal loca￾tion of their gonads [11]. Standard of care remains prophylactic gonadectomy,

though some controversies may exist if there is no evidence of gonadal failure (i.e.,

streak gonads) thus indicating some potential fertility [8]. However, there have been

few reported cases in the literature of fertility with the 45,X/46,XY karyotype, and

these had almost exclusively been in phenotypically male individuals (hence with￾out intra-abdominal gonads) [12]. There is one case report of a successful pregnancy

in a Turner syndrome 45,X/46,XY individual [13]. In most cases, the high risk of

A. J. Roberts and P. Y. Fechner