Congenital Renal and Genital Abnormalities

Congenital Renal Abnormalities

Isolated Renal Agenesis Bilateral Renal Agenesis Hypoplastic Kidney Ectopic Ureter Bifid Ureter Megaureter Vesicourinary Reflux Hydronephrosis Cystic Kidney Renal Tubular Dysgenesis Accessory Renal Artery Ectopic (Pelvic) Kidney Horseshoe Kidney Mayer-Rokitansky-KusterHauser syndrome Gartners Cyst Epoophoron / Paroopheron Dysplastic Kidney

Renal Involvement in Multiple Congenital Anomaly Syndromes

Potters Syndrome RCS: Renal Coloboma Syndrome BOR: Brachio-oto-renal Syndrome TBS: Townes-Brocks Syndrome Nagar Syndrome CHARGE Syndrome VACTERL Syndrome DiGeorge Sequence

association with preauricular pits and tags? association with single umbilical artery?

Urogenital Development
Intermediate mesoderm
nephrotomes cervical, regress @ 4 wks

mesonephroi - Wolffian ducts - vas deferens - urogenital sinus - bladder, urethra thoracolumbar, regress @ 10 wks
metanephroi - ureteric buds & kidney blastema sacral, arise @ 4 wks

Urogenital Development
Metanephros induced by uteric buds
renal corpuscle induces Bowmans capsule as uteric bud branches, blastema bifurcates reciprocal induction of branching renal calyces form from 2o bud fusion uteric buds form collecting tubules blastema forms PCT, LoH, DCT DCT fuses with CD @ 10 wks

Kidneys ascend from sacral to lumbar

differential growth of segments new vessel growth from more proximal aorta

Molecular Genetics
PAX2 expressed in CNS, optic placode, kidney PAX2 prevents apoptosis, supporting proliferation PAX2 autophagy dependent on HSP73, LGP96 and inhibited by EGF receptor signalling PAX2 phosphorylated by MAPK pathway (JNK) PAX2 expressed in nephrogenic rests adjacent to Wilms tumors (WT1 inhibits Pax2 expression) PAX2 enhances transcription of WT1, E-cadherin, GDFa and several BMP and FGF genes PAX2 inhibits transcription of vimentin gene

Molecular Genetics
RET and GDFa involved in uteric bud growth and branching, and thus metanephric induction GDFa is absent in PAX2null mice BMP4 inhibits GDF EYA1 expressed in kidney blastema PAX8 expressed in early renal tubular epithelium called S-shaped body

Hereditary Urogenital Adysplasia

Isolated renal agenesis 1/2,000 Bilateral renal agenesis 1/3,000 Renal aplasia (non-functional tissue capping ureter)
true agenesis = absent ureter, bladder hemitrigone, and vas deferens

defects in mesonephric / paramesonephric ducts can get 2o regression of hypoplastic / dysplastic kidney nuclear medicine scan can rule out ectopic kidney autosomal dominant 50-90% penetrance, variable expression Vancouver family with 5q11.2 - q13.3 aberration

Renal Agenesis
Absence of kidneys
Unilateral (compatible with life)
Affects 1 in every 800-1500 people May occasionally present with genitalia anomolies Trisomy of 18 Addition or partial trisomy of 13 Prenatal rubella infection

Bilateral (incompatible with life)

40% stillborn Of those born alive 95% die within 24 hours of birth Potter syndrome and associated oligohydramnios

Renal hypoplasia
Incomplete development of kidneys
Unilateral (compatible with life) Bilateral (incompatible with life) if condition is severe

Kidneys are small

Decreased functional parenchyma

Hereditary Urogenital Adysplasia

10% incidence of asymptomatic renal anomalies found in parents / sibs of 41 index cases of B renal agenesis 8% incidence in sibs of 221 perinatal lethal renal dz Parental renal US does not predict recurrance risk

Recommendations:
prenatal US @ 15-18 weeks PMA no contact sports for ptns with unilateral renal agenesis increased risk for HTN, ESRD

Congenital Renal Abnormalities

Hypoplastic Kidney (paucity of uteric bud bifurcation, or renal vascular formation <brachyrrhine mouse>) Ectopic Ureter (formation 3 uteric buds) Bifid Ureter (premature uteric bud bifurcation) Hydronephrosis (failure of programmed cell death in blastema, spontaneously or 2o to obstruction) Megaureter Vesicourinary Reflux (familial, QTL at 1p13)

Cystic Kidney Diseases

Failure of collecting duct to fuse w/ metanephros Autosomal dominant polycystic kidney disease PKD1, mutant polycystin gene, 16p13.3 PKD2, polycystin interacting protein, 4q13-p23 PKD3, locus not mapped Autosomal recessive polycystic kidney disease disease gene maps to 6p, incidence 1/40,000 mouse model Pax2null in cpk background Multicystic dysplastic kidney multifocal microcystic tubular dilation (thickenned CD w/ undifferentiated renal blastema mouse model Pax2 transgenic

Congenital cystic kidneys

Type 1
Polycystic kidneys found in infants
Bilateral and results in early death AKA giant or sponge kidneys Large renal pelvis and calyces

Type 2
Cysts are variable in size and shape Usually unilateral Affected kidney non functional

Congenital cystic kidneys (cont.)

Type 3
Affected kidneys contain both normal and abnormal tissue Both kidneys involved Autosomal dominant gene
Trisomy of 13-15, 18, 21, 22

Type 4
Caused by urethral obstruction If severe early death

Type 5
Manifests during adult life, death by 50. Autosomal dominant

Renal Tubular Dysgenesis

Hereditary less common than acquired (ACEi) Hypoplasia of tubules, absense of PCTs Associated with paternal minimal change disease Normal amniotic fluid volume before 22 weeks (because of mesonephroi ?)

Congenital Renal Abnormalities

Accessory renal artery (no sacral vessel regression) Ectopic (Pelvic) Kidney (no migration of kidney) Horseshoe Kidney (fusion of inferior pole of kidneys) Gartners Cyst (mesonephric duct remnant near vagina) Mayer-Rokitansky-Kuster-Hauser syndrome (defect of metanephric and paramesonephric ducts) Epoophoron / Paroopheron (mesonephric duct remnant near oviduct)

Horseshoe (fused) kidney

Fusion of two kidneys at their lower end
Tissue that connects kidneys = isthmus

1:400 Trisomy 13-15; 18, 21, Turners syndrome, mosaicism In rats horseshoe kidney can be produced experimentally by creating vitamin A deficiency

Potters Syndrome
1946 Edith Potter - Chicago pathologist flattened ears & bilateral renal agenesis incompatible with life incidence 1/3,000 live births Potters facies only 20% Potters syndrome
wide set eyes, squashed nose, receding chin, large low set ears, deficiency of cartilage due to oligohydramnios of any cause

Eagle-Barrett Syndrome
More commonly known as Prune Belly Syndrome Characterized by:
deficiency of abdominal wall musculature a dilated, non-obstructed urinary tract bilateral cryptorchidism talipes equinovarus and hip dislocation

Incidence is 1/35-50,000 >95% occur in males

 Believed to be caused by in-utero urinary tract obstruction and a specific mesodermal injury between the 4th and 10th week of gestation. Associated with renal dysplasia or agenesis. Often presents with a large-capacity, poorly contractile bladder. Heart, pulmonary, GI and orthopedic anomalies occur in a large percentage of PBS patients.

Management:
Neonatal Period
Optimize urinary tract drainage Monitor and treat renal insufficiency Antibiotic prophylaxis if reflux is present

Children
Surgical repair of reflux Orchiopexy Reconstruction of the abdominal wall Renal transplant

Prune Belly Syndrome Prognosis

Prognosis varies from stillbirth to minimal abdominal laxity. Long-term prognosis depends on renal function and pulmonary status. Psychological issues stemming from abdominal wall laxity and infertility.

Renal Coloboma Syndrome

Renal failure, coloboma, high frequency hearing loss Extreme variability of phenotype: VU reflux only to oligomeganephronia (bilateral renal hypoplasia) Pax2 Gene Mutation on 10q22.1-q24.3 Two alternatively spliced transcripts known Multiple mutations / polymorphisms identified mouse model made by transgene insertion into Pax2 2nd mouse model Pax2(1Neu) frameshift mutant Zebrafish model no isthmus

Brachio-oto-renal Syndrome
Brachial cysts / fistulas Ear malformations (cup, lop, microtia) Preauricular pits Hearing loss Renal anomalies 60% 30% 70% 75% 15%

autosomal dominant, seen in 1/40,000 live births EYA1 gene mutation EYA1 expressed in condensing blastema prior to epithelialization

Townes-Brocks Syndrome
Ear defects (satyr, lop, cup, pits, tags)70% Hearing loss Hand malformation Imperforate anus / rectourinary fistula Renal anomalies
50% 50% 50% 25%

autosomal dominant transcription factor defect SALL1 gene mutation SALL1 expressed in excretory organs, ear, limbs

Nagar Syndrome
Craniofacial anomalies (mandibular hypoplasia) Preaxial limb defects (noradii, hypoplastic hallices) Hearing loss 95% Renal anomalies 10% unknown mode of inheritance

CHARGE Syndrome
Coloboma of iris / retina Heart defects Atresia of choanae Retarded growth Developmental delay Genital hypoplasia Ear Defects / hearing loss Renal abnormalities Cleft lip / palate Tracheo-esophageal fistula 80% 75% 50% 70% 100% 70% 90% 15% 20% 20%

VACTERL
Vertebral anomalies Anal atresia Cardiac abnormalities Tracheoesophageal fistula Esophageal dysmotility Renal anomalies Limb defects

DiGeorge Sequence
thymic aplasia / hypoplasia and immunodeficiency developmental delay cleft lip / palate colobomas parathyroid hypoplasia cardiac malformations renal agenesis
Autosomal dominant, recessive, or X-linked Microdeletion in 22q11 most common

Preauricular Pits and Tags

Incidence 5/1000 live births 2 studies: 4-9% associated w/ renal disease hydronephrosis, or undiagnosed MCA Mainz Congenital Birth Defect Monitoring System association with cup ears, preauricular pits no association with ear tags Embryology: Ear & Kidney Arise Separate Times UCLA recommendations for Renal US: FHx deafness, renal or auricular disease maternal gestational diabetes

 Makes its appearance during 5 & 6 week

Indifferent stage-sex cannot be determined

Development of the reproductive system th th

Gonads (testes & ovaries) develop from

Coelomic epithelium Inner mesenchyme tissue Primordial germ cells

Thickening of ventromedial surface of urogenital ridge forming genital ridge

Genital ridge
Covered by coelomic epithelium
Primary sex cords
Grow into underlying mesenchyme

Inner mass is composed of mesenchyme Outer layer called cortex Inner layer called medulla
Males- medulla differentiates, cortex regresses Females-cortex develops, medulla regresses

Primordial Germ Cells (PGC)

Differentiate in the neck of the yolk sac
Early in the 4th week

Migrate to genital ridge

Amoeboid movement By end of 6th week the PGC become incorporated into the primary sex cords
migration of primordial germ cells

Development of testes
Primary sex cords of testes containing the primordial germ cells = testes cords
Well defined cords within the medulla Contain two types of cells
Epithelial cells Sertoli cells Primordial germ cells spermatoblasts
development of testes

Testes cords remain solid until puberty

Canalize to form seminiferous tubules (ST), tubuli recti, rete testis
ST seperated from each other by mesenchyme that gives rise to interstitial cells (Cells of Leydig)

Development of the Ovaries

Primary sex cords are not well defined
Extend into the medulla but later dissappear

PGC migrate near the cortex (surface epithelium

Forms cortical cords At about 16th week cortical cords break up into isolated clusters called primordial follicles
development of ovary

Primordial Follicles
Follicle contains
Ooblast (oogonium)
Derived from the primordial germ cell Undergoes mitosis during fetal life
Results in development of primary oocyte

A number of follicular cells

Derived from the cortical cords

Each primary oocyte surrounded by follicular cells = primary follicle

follicular development

Development of Genital Ducts Indifferent stage

Both male and female genital ducts present
Male develop from mesonephric/wolffian ducts Female develop from paramesonephric/mullerian duct
Undifferentiated gonad

Males:Mesonephric ducts form epididymis, ductus deferens, ejaculatory duct

Cranial mesonephric tubules efferent ducts
Open into epididymis

Process begins about the 3rd month

Development of Genital Ducts

Females: Paramesonephric duct/Mullerian duct develops on each side of the body
Longitudinal invagination of coelomic epithelium on the lateral surface of mesonephros Ducts open into coelom Runs along side of mesonephric duct Fuse at caudal end
Y shaped uterovaginal complex uterus & vagina
uterovaginal complex

Fetal testes
Produce androgens
Stimulate development of mesonephric ducts Suppress formation of paramesonephric ducts

If testes fail to develop or removed

Paramesonephric ducts will develop

Removal of fetal ovaries

Has no effect on fetal sexual development

Development of external genitalia Indifferent stage

Genital tubercle
Develops at upper end of cloacal membrane Elongates to form the Phallus

Labioscrotal swellings appear Urogenital folds appear Cloacal membrane divided into two
Development of urorectal septum
Upper urogenital membrane Lower anal membrane These membranes rupture around week 7 forming urogenital and anal openings

Development of external genitalia

Male genitalia
Phallus elongates to form the penis
Enlongation pulls the urogenital folds together When folds start to fuse they enclose the urethra
Urethral opening moves progressively towards end of penis

Labioscrotal swellings fuse forming scrotum

Female genitalia
Phallus becomes clitoris (relatively small) Urogenital folds do not fuse labia minora Labioscrotal fuse only at ends labia majora

Accessory sex glands

Male
Highly developed
Seminal vesicles Prostate Bulbourethral glands

Female
Minimal
Major vestibular glands (homologous to bulbouretharal glands in male)

Congenital Malformations
Ovarian hypoplasia Pure gonadal dysgenesis Testicular feminization syndrome Hermaphroditism
true Female pseudohermaphroditism Male pseudohermaphroditism

Hypospadias Epispadia

Ovarian hypoplasia
Small overies Poor breast development Small uterus Found in Turners syndrome
Incomplete or partial X chromasome

Can be unilateral or bilateral

Unilateral fertile Bilateral infertile

Pure Gonadal Dysgenesis

Normal karyotypes (46, XX or 46, XY) Primordial germ cells do not migrate from the yolk sac
No development of the ovaries or testes

Jacobs syndrome
XYY No abnormal appearance/behavior fertile

Jacobs Syndrome
1 in 1,800 births
47 chromosomes XYY only 47XYY #23 Trisomy Nondisjunction

Jacobs Syndrome
Normal physically Normal mentally Increase in testosterone Perhaps more aggressive Normal lifespan

Testicular Feminization Syndrome

Occurs at rate of 1:50,000 Appears to be a normal female despite the presence of testes in either abdomen or inguinal region
Testes produce normal levels of testosterone
Tissues unresponsive to androgens

External genitalia are normal Shallow blind ending vagina

Hermaphroditism
True hermphrodite
Both ovaries and testicular tissue present
Masculine form Feminine form Intermediate form (more common)
46, XX/ 46, XY or 46, XX/ 47, XXY

Hermaphroditism
Female pseudohermaphroditism (46, XX)
AKA congenital adrenogenital syndrome
Masculinization due to high level of androgens from adrenal cortex

Male pseudohermaphroditism
Testes and ambiguous female genitalia
Many types, most common is of unknown etiology Often considered females at a young age because penis is absent
Raised as girls until puberty when male secondary sex characteristics appear via endocrine activities of testes

Klinefelters Syndrome
XXY, male

Klinefelters Syndrome
1 in 1,100 births 47 chromosomes XXY only 47, XXY #23 Trisomy Nondisjunction

Klinefelters Syndrome
Scarce beard Longer fingers and arms Sterile Delicate skin Low mental ability Normal lifespan

 47, XY, +21

Down Syndrome

Down Syndrome
1 in 1,250 births 47 chromosomes XY or XX

#21 Trisomy Nondisjunction

Down Syndrome
Short, broad hands Stubby fingers Rough skin Impotency in males Mentally retarded Small round face Protruding tongue Short lifespan

Turners Syndrome
45, X

 4p-

Wolf Hirshhorn Syndrome

Very rare. Affected children are small, with microcephaly and abnormal facies. There are cardiac, renal, and genital abnormalities. Most are stillborn or die in infancy.

Aniridia-Wilms Tumor Syndrome

1 in 50,000,000 births
46 chromosomes XY or XX #11 Deletion of upper arm

Aniridia-Wilms Tumor Syndrome

Mentally retarded Growth retarded Blindness Tumors on kidneys Short lifespan

Four-Ring Syndrome
Cleft palate Club feet Testes dont descend Short lifespan

Triple X Syndrome
1 in 2,500 births 47 chromosomes XXX only #23 Trisomy Nondisjunction

References:
1) Development of the Urogenital System. In Human Embryology 1st Ed. W.J. Larsen, Ed. Churchill Livingstone, New York, 1993. 2) Renal Agenesis. In Nelson Textbook of Pediatrics 16Ed., Behrman, Ed., W.B. Saunders Company, 2000.

3) R.Y. Wang et al. Syndromic Ear Anomalies & Renal Ultrasounds. Pedi. 108:e32, Aug 2001.
4) OMIM 191830, 267430.