Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Hematologic, Renal, and Immunologic Disorders

By Wayne W. Grody

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Hematologic, Renal, and Immunologic Disorders, Seventh Edition thoroughly examines medical genetics and genomics as applied to hematologic, immunologic and endocrinologic disorders, with an emphasis on understanding the genetic mechanisms underlying these conditions, diagnostic approaches, and treatment methods. Here, genetic researchers, students and health professionals will find new and fully revised chapters on the genetics of red blood cell diseases, rhesus and other fetomaternal incompatibilities, immunodeficiency disorders, inherited complement deficiencies, celiac disease, and diabetes mellitus, as well as thyroid, parathyroid and gonad disorders, among other conditions.

With regular advances in genomic technologies propelling precision medicine into the clinic, this book, which has served as the ultimate resource for clinicians integrating genetics into medical practice, continues to provide the most important information. With nearly 5,000 pages of detailed coverage, contributions from over 250 of the world’s most trusted authorities in medical genetics, and a series of 11 volumes available for individual sale, this updated edition includes the latest information on seminal topics such as prenatal diagnosis, genome and exome sequencing, public health genetics, genetic counseling, and management and treatment strategies.

• Fully addresses medical genetics and genomics as applied to hematologic, immunologic and endocrinologic disorders, with an emphasis on understanding the genetic mechanisms underlying these disorders, diagnostic approaches and treatment methods
• Provides genetic researchers, students and health professionals with new and updated chapters on the genetic basis of, and treatment pathways for, red blood cell disorders, rhesus and other fetomaternal incompatibilities, immunodeficiency disorders, inherited complement deficiencies, celiac disease, diabetes mellitus, as well as thyroid, parathyroid and gonad disorders, among other conditions
• Includes color images supporting identification, concept illustration and method processing
• Features contributions by leading international researchers and practitioners of medical genetics
• Includes a robust companion website that offers lecture slides, image banks and links to outside resources and articles to help readers stay up-to-date on the latest developments in the field

• Language: English
• Publisher: Academic Press
• Release date: Aug 26, 2022
• ISBN: 9780128126820

Book preview

Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics

Hematologic, Renal, and Immunologic Disorders

Seventh Edition

Editors

Reed E. Pyeritz

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Bruce R. Korf

University of Alabama at Birmingham, Birmingham, AL, United States

Wayne W. Grody

UCLA School of Medicine, Los Angeles, CA, United States

Table of Contents

Cover image

Title page

Copyright

List of contributors

Preface to the seventh edition of emery and Rimoin's principles and practice of medical genetics and genomics

Preface to hematologic, renal, and immunologic disorders

Part I. Renal Disorders

1. Congenital Anomalies of the Kidney and Urinary Tract

1.1. Introduction

1.2. Clinical Manifestations of CAKUT

1.3. Familial CAKUT

1.4. Spectrum of CAKUT Phenotypes

1.5. Syndromic CAKUT

1.6. Diagnosis of CAKUT

1.7. Embryonic Development of the Kidney and Urinary Tract

1.8. Pathogenesis of CAKUT

1.9. Disease Causation in CAKUT

1.10. Genetic Features Characteristic of CAKUT

1.11. Mouse Models of CAKUT

1.12. Molecular Pathways in CAKUT Pathogenesis

2. Cystic Diseases of the Kidney

2.1. Introduction

2.2. Autosomal Dominant Polycystic Kidney Disease (MIM 173900)

2.3. Autosomal Recessive Polycystic Kidney Disease (MIM 263200)

2.4. Familial Nephronophthisis

2.5. Autosomal Dominant Tubulointerstitial Kidney/Medullary Cystic Kidney Disease

2.6. Multicystic Dysplastic Kidney Disease (MCDK)

2.7. Genetic Syndromes with Cystic Renal Disease as a Major Component

2.8. Mechanisms of Cystogenesis

3. Nephrotic Disorders

3.1. Introduction

3.2. Glomerular Filtration Barrier

3.3. Nephrin Gene (NPHS1) Mutations

3.4. Podocin Gene (NPHS2) Pathogenic Variants

3.5. Wilms Tumor Suppressor Gene (WT1) Pathogenic Variants

3.6. Phospholipase ε1gene (PLCE1) Mutations

3.7. Laminin-β2 Gene (LAMB2) Mutations

3.8. Inverted Formin 2 Gene (INF2) Pathogenic Variants

3.9. Transient Receptor Potential C6 Ion Channel Gene (TRPC6) Pathogenic Variants

3.10. Type IV Collagen Gene (COL4A3-5) Pathogenic Variants

3.11. Mutations in Genes Encoding Mitochondrial Proteins

3.12. Rare Genetic Disorders of the SD Complex

3.13. Rare Genetic Disorders of the Actin Network

3.14. Mutations in Podocyte Nuclear Proteins

3.15. Polymorphic Gene Variants in NS

3.16. Diagnosis of NS

3.17. Management of Patients with Nephrotic Syndrome

3.18. Conclusions

4. Renal Tubular Disorders

4.1. Introduction

4.2. Generalized Disorders of Tubular Function (Fanconi Syndrome)

4.3. Disorders of Amino Acid Transport

4.4. Glycine and the Imino Acids

4.5. Dibasic Amino Acids and Cystine

4.6. Cystinosis

4.7. Other Forms of Dibasic Aminoaciduria

4.8. Neutral Amino Acids

4.9. Renal Tubular Acidosis

4.10. Proximal Renal Tubular Acidosis (Type 2 RTA)

4.11. Lowe Oculocerebrorenal Syndrome

4.12. Distal Renal Tubular Acidosis (Type I RTA)

4.13. Distal Renal Tubular Acidosis With Neural Hearing Loss (Type 2 RTA)

4.14. Distal Renal Tubular Acidosis With or Without Deafness (Type 3 DRTA)

4.15. Carbonic Anhydrase II Deficiency

4.16. Disorders of Sugar Transport

4.17. Renal Glycosuria

4.18. Fructosuria

4.19. Pentosuria

4.20. Hypophosphatemic Rickets

4.21. Important Areas of Current and Future Research

4.22. Conclusion

5. APOL1-Associated Kidney Disease

5.1. Introduction

5.2. APOL1-Associated Nephropathies

5.3. Human Genetics, Trypanolysis, and APOL1

5.4. The APOL1 Gene and Protein

5.5. APOL1 Function and Effect of Variants

5.6. Recessive but Gain of Function

5.7. Models of APOL1-Associated Disease

5.8. Nonkidney Phenotypes

5.9. APOL1 Second Hits: Genes and/or Environment

5.10. Clinical Implications

5.11. APOL1 and Kidney Transplantation

5.12. APOL1 in the Clinic

5.13. Racial Disparities in Kidney Disease

Part II. Hematologic Disorders

6. Hemoglobinopathies and Thalassemias

6.1. Introduction

6.2. Hemoglobin Genetics

6.3. Normal Human Hemoglobin

6.4. Human Hemoglobin Variants

6.5. Sickle Cell Disease and Related Disorders

6.6. Unstable Hemoglobin Variants

6.7. Hemoglobin Variants With Altered Oxygen Affinity

6.8. Thalassemias

7. Disorders of Hemostasis and Thrombosis

7.1. Overview of Hemostasis and Thrombosis

7.2. The Coagulation Cascade

7.3. Inherited Disorders Predisposing to Thrombosis

7.4. Interactions Among Multiple Genetic Defects

8. Amyloidosis and Other Protein Deposition Diseases

8.1. Introduction

8.2. Hereditary Systemic Amyloidosis

8.3. Clinical Variations in FAP

8.4. Genetics

8.5. Other Systemic Amyloidoses

8.6. Diagnosis

8.7. Management

8.8. Alzheimer Disease

8.9. Gerstmann–StrÄussler–Scheinker Disease

8.10. British Dementia

8.11. Corneal Dystrophies

8.12. Other Localized Amyloidoses

8.13. Conclusion

9. Leukemias, Lymphomas, and Plasma Cell Disorders

9.1. Introduction

9.2. Myeloproliferative Neoplasms

9.3. Myelodysplastic Syndromes

9.4. Acute Myeloid Leukemia

9.5. Therapy-Related Myeloid Neoplasms

9.6. Clonal Hematopoiesis

9.7. Acute Lymphoblastic Leukemia

9.8. Mature B Cell Neoplasms

Acknowledgments

Part III. Immunologic Disorders

10. Inherited Complement Deficiencies

10.1. Introduction

10.2. Introduction to the Complement System

10.3. The Classical Pathway

10.4. The Alternative Pathway

10.5. The Lectin Activation Pathway

10.6. The Membrane Attack Complex

10.7. Regulation of Complement Activation

10.8. Inherited Complement Deficiencies

10.9. Management of Complement Deficiencies

11. Heritable and Polygenic Inflammatory Disorders

11.1. Introduction

11.2. Autoimmunity

11.3. The Immune Response

11.4. Genetics of Autoimmune Diseases

11.5. HLA Allelic Diversity and Population Genetics

11.6. Genetic Susceptibility to Autoimmune Disease

11.7. HLA and Other Genotypes

11.8. Rheumatoid Arthritis

11.9. Seronegative Spondyloarthropathies

11.10. Spondyloarthritides

11.11. Ankylosing Spondylitis

11.12. Reactive Arthritis (Previously Reiter Syndrome)

11.13. Enteropathic Arthritis

11.14. Psoriasis and Psoriatic Arthritis

11.15. Juvenile Idiopathic Arthritis

11.16. Systemic-Onset JIA (Still Disease)

11.17. Oligoarticular JIA

11.18. Polyarticular JIA

Index

Copyright

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List of contributors

Merrill D. Benson,     Professor of Pathology and Laboratory Medicine, Professor of Medical and Molecular Genetics, and Professor of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States

Dervla M. Connaughton

Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada

Department of Medicine, Division of Nephrology, London Health Sciences Centre, London, ON, Canada

David J. Friedman,     Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

David Ginsburg,     Howard Hughes Medical Institute and Departments of Internal Medicine, Pediatrics, and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States

Friedhelm Hildebrandt,     Division of Nephrology, Professor of Pediatrics, Harvard Medical School, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States

Hannu Jalanko,     Children's Hospital, University of Helsinki, Helsinki, Finland

Helena Kääriäinen,     National Institute for Health and Welfare, Helsinki, Finland

Selina M. Luger,     Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Jennifer J.D. Morrissette,     Division of Precision and Computational Diagnostics, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Michal Mrug,     University of Alabama at Birmingham, Birmingham, AL, United States

Scott Peslak

Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States

Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, United States

Martin R. Pollak,     Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

Reed E. Pyeritz,     Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Frederic Rahbari Oskoui,     Emory University, Atlanta, GA, United States

Dana V. Rizk,     University of Alabama at Birmingham, Birmingham, AL, United States

Jacquelyn J. Roth,     Division of Precision and Computational Diagnostics, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Takamitsu Saigusa,     University of Alabama at Birmingham, Birmingham, AL, United States

Farzana Sayani,     Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States

Jordan A. Shavit,     Departments of Pediatrics and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States

Edward A. Stadtmauer,     Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Kathleen E. Sullivan,     Division of Allergy Immunology, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States

Angela C. Weyand,     Department of Pediatrics, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan, United States

Preface to the seventh edition of emery and Rimoin's principles and practice of medical genetics and genomics

The first edition of Emery and Rimoin's Principles and Practice of Medical Genetics appeared in 1983. This was several years prior to the start of the Human Genome Project in the early days of molecular genetic testing, a time when linkage analysis was often performed for diagnostic purposes. Medical genetics was not yet a recognized medical specialty in the United States, or anywhere else in the world. Therapy was mostly limited to a number of biochemical genetic conditions, and the underlying pathophysiology of most genetic disorders was unknown. The first edition was nevertheless published in two volumes, reflecting the fact that genetics was relevant to all areas of medical practice.

35 years later we are publishing the seventh edition of Principles and Practice of Medical Genetics and Genomics. Adding genomics to the title recognizes the pivotal role of genomic approaches in medicine, with the human genome sequence now in hand and exome/genome-level diagnostic sequencing becoming increasingly commonplace. Thousands of genetic disorders have been matched with the underlying genes, often illuminating pathophysiological mechanisms and in some cases enabling targeted therapies. Genetic testing is becoming increasingly incorporated into specialty medical care, though applications of adequate family history, genetic risk assessment, and pharmacogenetic testing are only gradually being integrated into routine medical practice. Sadly, this is the first edition of the book to be produced without the guidance of one of the founding coeditors, Dr. David Rimoin, who passed away just as the previous edition went to press.

The seventh edition incorporates two major changes from previous editions. The first is publication of the text in 11 separate volumes. Over the years, the book had grown from two to three massive volumes, until the electronic version was introduced in the previous edition. The decision to split the book into multiple smaller volumes represents an attempt to divide the content into smaller, more accessible units. Most of these are organized around a unifying theme, for the most part based on specific body systems. This may make the book more useful to specialists who are interested in the application of medical genetics to their area but do not wish to invest in a larger volume that covers all areas of medicine. It also reflects our recognition that genetic concepts and determinants now underpin all medical specialties and subspecialties. The second change might seem on the surface to be a regressive one in today's high-tech world—the publication of the 11 volumes in print rather than strictly electronic form. However, feedback from our readers, as well as the experience of the editors, indicated that access to the web version via a password-protected site was cumbersome and printing a smaller volume with two-page summaries was not useful. We have therefore returned to a full print version, although an eBook is available for those who prefer an electronic version.

One might ask whether there is a need for a comprehensive text in an era of instantaneous Internet searches for virtually any information, including authoritative open sources such as Online Mendelian Inheritance in Man and GeneReviews. We recognize the value of these and other online resources, but believe that there is still a place for the long-form prose approach of a textbook. Here the authors have the opportunity to tell the story of their area of medical genetics and genomics, including in-depth background about pathophysiology, as well as giving practical advice for medical practice. The willingness of our authors to embrace this approach indicates that there is still enthusiasm for a textbook on medical genetics; we will appreciate feedback from our readers as well.

The realities of editing an 11-volume set have become obvious to the three of us as editors. We are grateful to our authors, many of whom have contributed to multiple past volumes, including some who have updated their contributions from the first or second editions. We are also indebted to staff from Elsevier, particularly Peter Linsley and Pat Gonzalez, who have worked patiently with us in the conception and production of this large project. Finally, we thank our families, who have indulged our occasional disappearances into writing and editing. As always, we look forward to feedback from our readers, as this has played a critical role in shaping the evolution of Principles and Practice of Medical Genetics and Genomics in the face of the exponential changes that have occurred in the landscape of our discipline.

Preface to hematologic, renal, and immunologic disorders

This volume of Principles and Practice of Medical Genetics and Genomics presents topics focused on three organ systems, renal, immunologic, and hematologic. The latter two interact with each other intimately and both have positive and potentially negative effects on the kidney. Some of the authors have revised their chapters since much earlier editions of this treatise. New authors have brought fresh perspectives to the subjects introduced in the first edition in 1983. Several chapters are entirely original to this 7th edition. The explosive growth in genomics underlies enhanced comprehension of the normal, pathogenic, diagnostic, and therapeutic aspects of the topics in this volume. The fundamental and clinical perspectives discussed in the first two volumes of this 7th edition are well illustrated by the conditions in this volume.

Part I

Renal Disorders

Outline

1. Congenital Anomalies of the Kidney and Urinary Tract

2. Cystic Diseases of the Kidney

3. Nephrotic Disorders

4. Renal Tubular Disorders

5. APOL1-Associated Kidney Disease

1: Congenital Anomalies of the Kidney and Urinary Tract

Dervla M. Connaughton ¹ , ² , and Friedhelm Hildebrandt ³       ¹ Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada      ² Department of Medicine, Division of Nephrology, London Health Sciences Centre, London, ON, Canada      ³ Division of Nephrology, Professor of Pediatrics, Harvard Medical School, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States

Abstract

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genitourinary tract. CAKUT accounts for up to 50% of end-stage kidney disease (ESKD) in childhood and between 7% and 10% of adult-onset ESKD. CAKUT can occur in isolation or in association with extrarenal features of disease, which is sometimes referred to as syndromic CAKUT. The pathogenesis of CAKUT is due to disturbances in the various stages of the embryonic development of either the kidney or genitourinary tract, which can results in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin with studies demonstrating single gene defects in approximately 10–20% of patients with CAKUT. Multiple molecular pathways have been implicated in CAKUT including the RET tyrosine kinase signaling system, the Fraser complex and the extracellular matrix complex, and more recently, the vitamin A and retinoic acid signaling pathway.

Keywords

Congenital anomalies; Genetic kidney disease; Kidney development; Monogenic kidney disease; Renal developmental pathways

1.1. Introduction

Congenital anomalies of the kidney and urinary tract (CAKUT) are defined as any abnormality in structure or function of the kidneys, ureters, bladder, urethra, and/or distal genitourinary tract. CAKUT is a common disease entity detected at a frequency of one in 500 fetal ultrasound examinations [1]. CAKUT account for 20%–30% of all congenital malformations [2–4] and are frequently observed birth defects at a rate of ∼3–6/1000 live births [3,5].

CAKUT can have major health implications as they are the most common cause of chronic kidney disease in the first threedecades of life. Registry-based data from Europe and North America indicate that CAKUT account for 41% and 39% of pediatric onset end-stage renal disease, respectively [6,7]. The peak incidence of end-stage kidney disease (ESKD) in children with CAKUT is 15–19 years of age with a gradual decline throughout adulthood [8].

In adults, the prevalence of CAKUT is less clear. This is likely related to the fact that many individuals remain asymptomatic, with the diagnosis of CAKUT only made incidentally following routine imaging of the abdomen [9]. Based on epidemiological data, CAKUT has an estimated prevalence of 5%–10% in the general chronic kidney disease population and an estimated incidence of <5% in renal replacement therapy populations; however, these estimates are likely prone to underestimation [8,10–12].

1.2. Clinical Manifestations of CAKUT

CAKUT is defined as any abnormality in the number, size, shape, structure or function of the kidney and/or genitourinary tract. CAKUT can be categorized based on anatomical position into phenotypes that involve the upper urinary tract; renal agenesis, renal hypodysplasia and multicystic dysplastic kidney (MCDK), phenotypes involving the ureters; ureter duplication, hydronephrosis, hydroureter or megaureter, ectopic ureter or uretero-pelvic junction obstruction (UPJO) to phenotypes predominately affecting the lower urinary tract; vesico-urethral reflux (VUR), ureterovesical junction obstruction (UVJO), and posterior urethral valves (PUV) [2,5,13]. CAKUT can also encompass anomalies in kidney shape or position, namely horseshoe kidney or pelvic kidney, respectively. Pathologies involving bladder innervation resulting in discoordinated detrusor and urethral function can result in secondary urinary tract malformations [14]. For example, myelomeningocele, which can result in dysfunctional innervation of the bladder, can lead to hydronephrosis and secondary changes in the kidney due to obstruction and urinary reflux. Many of these conditions lead to an increased susceptibility to urinary tract infections due to stasis and obstruction of urine flow. This in turn can lead to parenchymal renal scarring and progressive renal impairment due to so-called reflux nephropathy [14].

Clinical heterogenicity is one of the hallmark features of the CAKUT phenotype since different phenotypes from the CAKUT spectrum can occur within the same individual [2,15]. In a study of over 200 families with CAKUT, a total of 546 pathologies were observed in 273 individuals. This included single unilateral pathologies (e.g., unilateral renal agenesis), bilateral concordant disease (e.g., bilateral VUR) to bilateral discordant disease (e.g., right side MCDK and left VUR) (Fig. 1.1) [16]. In a Japanese study, 26% of the study population with a single functioning kidney had a concurrent CAKUT phenotype [17]. Equally, unilateral disease such as single renal agenesis can occur in the setting of an entirely normal contralateral kidney and urinary tract [18].

Long-term renal outcomes are variable again depending on the number and type of CAKUT pathologies.

The median reported age of starting renal replacement therapy in all patients with CAKUT is 31 years, which is significantly younger than patients with other forms of kidney disease [8]. However, there is large variability, with sometimes conflicting data on disease progression and renal outcomes depending on the CAKUT subtype and the study population under study. For example, in a US study of over 300 patients with CAKUT, the presence of a solitary kidney or renal hypodysplasia associated with posterior urethral valves was associated with an increased risk of progression to ESKD, compared to patients with either unilateral or bilateral renal hypodysplasia, or dysplastic or horseshoe kidney [19]. In an European population, patients with isolated renal hypodysplasia required renal replacement therapy at an earlier age (median, 16 years) than those with renal hypoplasia and associated urinary tract disorders (median, 29.5–39.5 years) [8]. Therefore, further studies are required to determine the exact risk associated with each CAKUT subtype.

Interestingly, although many individuals remain asymptomatic, in the KIMONO study, it was found that 32% of children born with a single functioning kidney had evidence of renal injury by 10 years of age [17]. By adulthood (classified as 30 years of age), 18.5% (58 out of 312) of patients with either renal agenesis, renal hypodysplasia with or without posterior urethral valves, multicystic dysplastic kidney, or horseshoe kidney had reached end stage kidney disease requiring renal replacement therapy. This demonstrates that even in individuals with subclinical CAKUT, a poorer outcome in terms of maintaining long-term renal function may occur. Equally there is increasing evidence that even in the asymptomatic patients, a single functional kidney, either due to unilateral renal agenesis, MCDK, or renal hypodysplasia, can lead to glomerular damage with subsequent hypertension, albuminuria, and progression to end-stage renal disease in adulthood [20].

Figure 1.1  Heatmap comparing the distribution of the specific phenotypic pathologies in a cohort of individuals with congenital anomalies of the kidney and urinary tract (CAKUT).A study of 232 families with CAKUT. The absolute numbers of pathologies are graded according to the color chart displayed above on the right. Specific CAKUT phenotypic pathologies are listed from cranial to caudal positions in the y-axis. The x-axis is further subdivided into left and right pathologies. Note, 130 pathologies were present in 130 individuals with unilateral CAKUT. In the 143 individuals with bilateral CAKUT, a total of 286 pathologies were present. A total of 416 pathologies were present in 273 individuals with CAKUT. The bilateral renal pathologies consist of individuals with both bilateral concordant and bilateral discordant CAKUT. The total number of pathologies were calculated independent of both laterality and whether the bilateral pathologies were concordant or discordant in the same individual. Individuals with the CAKUT pathology of posterior urethral value (PUV) or epi/hypospadias (n =25) and individuals in whom the CAKUT phenotype is undefined (n =21) in this analysis, due to the lack and/or inability to determine laterality with these specific pathologies, were excluded from the above analysis.  Duplex, duplex collecting system, Ectopic/Horseshoe, ectopic or horseshoe kidney; MCDK, multicystic dysplastic kidney; RA, renal agenesis; RHD, renal hypoplasia/dysplasia; UPJO, ureteropelvic junction obstruction; UVJO, ureterovesical junction obstruction; VUR, vesicourethral reflux. (Adapted from van der Ven AT, Connaughton DM, Ityel H, Mann N, Nakayama M, Chen J, et al. Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol 2018;29(9):2348–2361.)

1.3. Familial CAKUT

Although routine screening in asymptomatic family members is not currently recommended, there is evidence of an increased incidence of CAKUT in first degree relatives of affected individuals. Epidemiological data have revealed that familial clustering occurs in patients with CAKUT with approximately 10%–15% of cases with CAKUT noted to have a familial component [10]. In a Turkish study of 145 families, screening of 412 asymptomatic first-degree relatives revealed a diagnosis of CAKUT in 23 individuals from 21 different families [21]. The most frequently observed phenotypes in asymptomatic family members were renal agenesis, renal hypodysplasia and hydronephrosis. It is important to note that wide variation can also occur within family members where in some, a single pathology is observed, and in others multiple different pathologies are evident. In parents or siblings of 41 patients with either bilateral or unilateral renal agenesis or dysgenesis, there was a 9% risk (10 of 111 asymptomatic family members) of detecting asymptomatic CAKUT by ultrasound examination. The most frequent CAKUT subtype observed in these asymptomatic individuals was again unilateral renal agenesis [22]. In patients with either, bilateral renal agenesis, or bilateral severe dysgenesis, or agenesis of one kidney and dysgenesis of the other kidney, 9% of either parents or siblings had asymptomatic urogenital malformations incidentally detected by ultrasonography. In patients with either unilateral or bilateral bifid or double ureters, there is also an increased incidence of duplex collecting system in first degree relatives of patients [23].

1.4. Spectrum of CAKUT Phenotypes

1.4.1. Renal Agenesis

Renal agenesis refers to congenital absence of one of both kidneys. In a study of more than 625,000 consecutive births in British Columbia, Canada, 92 cases of bilateral renal agenesis and 117 cases of unilateral renal agenesis were identified, with a male predominance of 2.45:1 [24]. Bilateral renal agenesis represents one of the most severe phenotypes in the CAKUT spectrum. Presentation generally occurs in utero with oligohydramnios evident as early as the second trimester. Owing to primary renal dysfunction, oligohydramnios occurs, leading to pulmonary hypodysplasia. Many infants perish in utero, with studies indicating a postnatal mortality of up to 100% [25]. The classic presentation includes a triad of club foot, respiratory compromise, and cranial anomalies referred to as the Potter sequence [26].

On the other hand, unilateral renal agenesis may be entirely subclinical only detected incidentally following routine imaging of the abdomen and pelvis.

Renal aplasia refers to the presence of renal parenchymal tissue without any function. After birth, involution of this rudimentary tissue can occur and often patients present with a clinical picture of renal agenesis.

1.4.2. Renal Hypodysplasia (RHD)

Renal hypodysplasia is characterized by under and/or abnormal development of the kidney usually resulting in reduced size of the kidney. Specifically, hypoplasia refers to small kidneys with reduced nephron numbers while dysplasia refers to abnormal kidney development. In reality, the two processes often occur together and can have a very similar clinical presentation. RHD is a common subtype within in the CAKUT disease spectrum with unilateral RHD occurring at a frequency of one in 1000 and bilateral RHD occurring at a frequency of one in 5000 in the general population [27].

1.4.3. Multicystic Dysplastic Kidney (MCDK)

Multicystic dysplastic kidney describes the condition of multiple irregular cysts of varying sizes that are surrounded by dysplastic renal tissue [28]. Ultrasonography at 20 weeks gestation has a high likelihood of diagnosis. Ultrasonography examination is characterized by multiple thin-walled cysts that do not connect and are randomly distributed throughout the kidney(s) [27].

Schreuder and colleagues performed a meta-analysis of 19 populations encompassing 2500 individuals with unilateral MCDK and demonstrated an incidence of one in 4300. There was a male predominance at 59% and MCDK was more commonly (53.1%) identified on the left side. In one-third of individuals, an additional subtype from the CAKUT spectrum was observed, most commonly vesico-urethral reflux (VUR) [29].

1.4.4. Horseshoe Kidney

Horseshoe kidney is a renal fusion defect that occurs when both kidneys fuse, usually at the upper pole, resulting in a horseshoe shape. Fusion results in the inability of the kidneys to ascend to the anatomically normal position, rather they remain in the embryonic pelvic position. Fusion therefore results in defects of not only position but also rotation and vascular supply; however, the functional mass of the kidney is generally intact, and the ureters remain uncrossed. The incidence in the general population is approximately one in 500 [30]; however, this may be subject to underestimation as it is believed that up to one-third of patients with a horseshoe kidney remain asymptomatic. Patients usually present if there is an associated CAKUT subtype such as UPJO, hydronephrosis, other genitourinary anomalies such as hypospadias and cryptorchidism or secondary complications related to urinary tract infections or renal stones.

1.4.5. Duplex Kidney

Duplex kidney occurs when more than one kidney forms. Duplex kidney is a common subtype of CAKUT, with an estimated incidence of approximately 1% [31]. In a study of 1716 children and 3480 adults, 79 cases of unilateral duplex and 16 cases of bilateral duplex kidneys were detected [32]. In individuals with unilateral duplex, the extra renal tissue can be partial, as seen in 10%, or complete duplication of the kidney resulting in a kidney of equal size in 39%. The duplex portion can be functionally normal but in up to 27%, the renal tissue is defective with evidence of impaired kidney function. In kidney duplication, there appears to be a slight female predominance, but there is no predilection to either the right or left side of the genitourinary tract [32]. Isolated duplex kidney can remain entirely asymptomatic. As with many of the CAKUT phenotypes, other subtypes of CAKUT may occur in conjunction with a duplex kidney such as ectopic ureter, ureterocele or most commonly VUR. When symptoms do occur, they usually result from the presence of these additional CAKUT phenotypes.

1.4.6. Duplex Ureter

Duplex ureter is the formation of more than one ureter, which are usually defective. Complete duplication of the ureters with separate insertion into the bladder is a rare phenomenon. More commonly partial duplication, also known as a bifid ureter, is observed; however, the exact prevalence is difficult to ascertain as many patients remain asymptomatic. The incidence of urinary tract duplication is estimated to be between 0.7% and 4% in the general population with a female predominance [32].

1.4.7. Obstructive Uropathy

Obstructive uropathy is an umbrella term for a diverse range of both acquired and inherited diseases that results in the impedance of normal urinary flow in either the upper or lower urinary tract. The obstruction can be secondary to either an intrinsic obstruction within the genitourinary tract or an extrinsic obstruction such as tumor compression. The clinical manifestation in most cases of obstructive uropathy is ultrasonographic evidence of either hydronephrosis or hydroureter.

1.4.8. Hydronephrosis and Hydroureter

Hydronephrosis is an abnormal distention of the pelvicalyceal region of the kidney, and hydroureter is abnormal distention of the ureter. Both occur usually secondary to distal obstruction and can occur in conjunction with each other. Megaureter is a subtype of hydroureter, where a large increase in ureter size is observed. In utero, hydronephrosis is a common clinical manifestation of obstructive uropathy, affecting between 1% and 4.5% of all pregnancies [33]. However, the definitive etiology of the obstruction is often not revealed until the postpartum period. Within the CAKUT spectrum, uretero-pelvic junction obstruction (UPJO) and vesicoureteral reflux (VUR) are the two most common postnatal causes of obstructive uropathy as well as any cause of lower urinary tract obstruction (please see below for further details).

1.4.9. Uretero-Pelvic Junction Obstruction (UPJO)

Uretero-pelvic junction obstruction is an abnormal constriction resulting in blockage of urine at the junction between the renal pelvis and the ureter. It has a reported incidence of one in 500 live births [34]. It occurs at higher frequency in males and has a predilection for the left side of the urinary tract, although can be bilateral. The most common clinical manifestation is ultrasonographic evidence of hydronephrosis without hydroureter [35].

1.4.10. Uretero-Vesical Junction Obstruction (UVJO)

Uretero-vesical junction obstruction is abnormal constriction resulting in blockage of urine at the junction between the ureter the bladder. UVJO is also a cause of antenatal hydronephrosis or megaureter and can occur in conjunction with other CAKUT phenotypes such as UPJO [36].

1.4.11. Vesico-Urethral Reflux (VUR)

Vesico-urethral reflux, also known as vesico-ureteric reflux, is the abnormal passage of urine from the bladder to the ureter or kidney in a retrograde direction. The primary etiology is dysfunction of the vesico-urethral value, which normally allows one-way flow of urine from the ureter to the bladder thus preventing back flow of urine during micturition. Normal valvular function is maintained through a number of coordinated processes and anatomical structures including the length of the submucosal ureter, the width of the ureteric opening, the muscles of the trigone and ureter, and coordinated ureteric peristalsis [37]. Value dysfunction is thought to occur due to a multitude of both genetic and environmental factors interfering with this process. VUR is predominately diagnosed based on voiding cystourography and is graded based on the International Reflux Study system, which is a scale grading system from I to V depending on findings on voiding cystourography [37]. The severity of VUR can range from mild disease that spontaneously resolves in childhood to progressive chronic kidney disease secondary to chronic infections and renal parenchymal scarring, which is commonly referred to as reflux nephropathy.

1.4.12. Lower Urinary Tract Obstruction (LUTO)

Posterior urethral valve (PUV), urethral anomalies including urethral atresia and the Prune Belly Syndrome (PBS) are the most common causes of LUTO with a combined incidence of 2.2 in 10,000 births [38]. Rarer causes of LUTO include anterior urethral valve, ureterocele, and other causes of external compression such as a urethral diverticulum or hydrocolpos due to cloacal anomalies [39].

1.4.13. Posterior Urethral Valve (PUV)

PUV occurs as a result of an obstructive membrane or valve in the posterior segment of the urethra resulting in blockage of urine flow from the bladder to the urethra. This subtype of CAKUT, also referred to as infra-vesical urinary tract obstruction, is the most common cause of lower urinary tract obstruction in childhood [40], with an estimated prevalence of three per 10,000 births [39]. PUV predominantly occurs in males and is a common cause of chronic kidney disease in this population. PUV can occur in isolation or conjunction with other CAKUT pathologies, including hydronephrosis, UVJO, VUR, and RHD. There is also an increased incidence of other genitourinary tract pathologies with an estimated incidence of PUV in male with hypospadias of 1% [41]. Long-term outcomes following PUV include bladder dysfunction in childhood with an elevated risk of lower urinary tract infections in adulthood and progressive kidney disease [42].

The initial presentation of PUV is usually within the first 12 months of life; however, presentation is variable depending on the degree and severity of the obstruction. With the widespread utilization of prenatal ultrasonography, up to 62% of cases are now diagnosed in utero [39]. The classic presentation in utero is ultrasonographic evidence of a dilated bladder with a thickened bladder wall, bilateral hydronephrosis, dilated ureters, and a dilated posterior urethra, which is commonly referred to as the keyhole sign [43]. If severe, oligohydramnios can ensue with subsequent pulmonary hypoplasia.

In the postnatal period, the clinical manifestations include a palpable abdominal mass secondary to a distended bladder, urinary tract infections, poor voiding pressure with a weak urinary stream, bladder dysfunction, and progressive renal impairment. Voiding cystourethrogram followed by urethral endoscopy is generally required to confirm the diagnosis. Endoscopic treatment with primary valve ablation through transurethral fulguration is the treatment of choice for most patients with PUV, although increasingly in utero interventions are being explored. For example, first trimester decompression by means of vesico-amniotic shunting or fetal cystoscopic ablation is currently being undertaken at a number of specialized centers [39].

1.4.14. Urethral Agenesis and Atresia

Urethral Agenesis and Atresia are rare subtypes of CAKUT occurring predominantly in males and occur when the urethra either fails to develop or there is abnormal development of the urethra.

1.4.15. Duplication of the Urethra

Duplication of the urethra is another rare subtype of CAKUT demonstrating a male predominance [44]. Urethral duplication is divided into four subclasses:

- Type 1 both bladder and urethral duplication

- Type 2 single bladder with urethral duplication

- Type 3 Y-type duplication, which is characterized by two limbs, a penile limb, which contains the urethral channel, and an ectopic limb, which tends to be a fistula tract to the perineum or anal cancel

- Type 4 miscellaneous type, which include urethral channels, spindle urethra, and other female forms

1.5. Syndromic CAKUT

CAKUT may occur in isolation as a monogenic disorder (Table 1.1) or as part of a syndromic disorder (Table 1.2). It may occur in conjunction with other structural defects (Table 1.3) or chromosomal anomalies (Table 1.4) [13,46–48].

1.6. Diagnosis of CAKUT

The widespread use of prenatal ultrasonography means than increasingly the diagnosis of CAKUT is established prenatally, with a diagnostic rate of over 85% following fetal screening during pregnancy ultrasonography. In the prenatal period, ultrasonography is the modality of choice for the diagnosis of most subtypes of CAKUT. In severe cases, CAKUT can often be suspected in the presence of oligohydramnios, which can be detected as early as the second trimester, usually at 14–16 weeks gestation. Renal agenesis can in some cases be detected as early as 15 weeks’ gestation, but usually a definitive diagnosis can only be confirmed on ultrasonography after 18–19 weeks of gestation.

Although not routinely performed, postnatal ultrasonography has a specificity of 100% and a sensitivity of 92.1% for the detection of single renal agenesis [49]. In a Japanese study of infants age 1 month old, routine screening with ultrasonography revealed a diagnosis of CAKUT in 3.5% (198 positive cases out of 5700 screened infants) [50]. However, not infrequently asymptomatic patients present in adulthood following an incidental finding on imaging of the abdomen or pelvis. Although ultrasonography is the standard method for the diagnosis of CAKUT, occasionally renal anomalies can also be detected following other modalities of abdominal or pelvic imaging such as computed tomography (CT) or magnetic resonance imaging (MRI).

In certain subtypes of CAKUT, additional imaging is required particularly in obstructive lesions or pathologies involving the distal genitourinary tract. Current recommendations from the American Academy of Pediatrics suggest ultrasonography and either voiding cystourethrography or radionuclide cystography for VUR and other potential causes of obstructive uropathy [51]. In lower urinary tract anomalies, ultrasound scanning is often of limited value as it will only reveal severe ureteral anomalies with significant dilatation. Therefore, further imaging modalities are generally warranted including, voiding cystourethrography (VCUG), intravenous pyelography (IVP), computed tomography (CT), dimercaptosuccinic acid (DMSA) renal cortical scintigraphy, ⁹⁹mtechnetium-mercaptoacetyltriglycine (⁹⁹mTc-MAG-3) renography, and magnetic resonance urography (MRU) [52].

1.7. Embryonic Development of the Kidney and Urinary Tract

Development of the kidney in humans occurs at day 35–37 of embryonic development. The genitourinary tract arises from two structures; the nephric ducts (also known as the mesonephric ducts or Wolffian ducts) and the nephric cord, both of which arise from the intermediate mesoderm (Fig. 1.2). The nephric duct (ND) is an epithelial tube from which the ureteric bud (UB) arises as an epithelial outgrowth. Ultimately the nephric duct fuses caudally with the cloacal epithelium, which is a precursor of the urinary bladder. The metanephric mesenchyme (MM) arises from mesenchymal cells in the posterior intermediate mesoderm. Renal morphogenesis is initiated and maintained by reciprocal interactions between the epithelial portion of the nephric duct and the MM. Nephrogenesis then arises from this structure due to reciprocal induction between the ureteric bud (UB) and the metanephric mesenchyme (MM). The portion of the MM that comes in closest proximity to the UB condenses and forms the cap mesenchyme (CM). Following induction from the UB, the CM then undergoes mesenchymal-to-epithelial transition (MET) with formation of the renal vesicle. This structure then forms the common-shaped body followed by the S-shaped body, which progressively invades endothelial cells. This is then followed by branching morphogenesis and nephrogenesis through a process called nephron patterning and elongation, which ultimately gives rise to the structures of the nephron (glomerulus, the proximal tubule, and the distal tubule) (Fig. 1.2).

Table 1.1

AD, autosomal dominant; AR, autosomal recessive; NA, not available; OMIM, online mendelian inheritance in man; XL, X-linked; #, phenotype MIM number; ∗ gene/locus MIM number if not phenotype MIM number available.

Adapted from Connaughton DM, Kennedy C, Shril S, Mann N, Murray SL, Williams PA, et al. Monogenic causes of chronic kidney disease in adults. Kidney Int 2019;95(4):914–928.

Table 1.2