First Aid - REPRODUCTIVE - Pathology - Part 1

Fetal alcohol syndrome - Major presentation

Developmental delay<br>Microcephaly<br>Characteristic facial abnormalities<br>± Limb dislocation<br>± Heart defects

What facial abnormalities are characteristic of fetal alcohol syndrome?

Smooth philtrum<br>Thin vermilion border<br>Small palpebral fissures<br>Flat nasal bridge

What severe CNS malformation can occur in fetal alcohol syndrome?

Holoprosencephaly

What is one proposed mechanism of fetal alcohol syndrome?

Alcohol exposure → impaired migration of neuronal + glial cells → abnormal CNS development

A newborn has developmental delay, microcephaly, small palpebral fissures, a smooth philtrum, and a thin vermilion border. What is the diagnosis?

Fetal alcohol syndrome

Fetal alcohol syndrome - Treatment

Supportive care

What is neonatal abstinence syndrome?

A neonatal withdrawal syndrome involving the CNS, autonomic nervous system, and GI tract, usually 2° to maternal substance use (especially opioids)

Neonatal abstinence syndrome - Presentation

• Uncoordinated sucking reflexes

• Irritability

• High-pitched crying

• Tremors

• Tachypnea

• Sneezing

• Diarrhea

• ± Seizures

Why does neonatal abstinence syndrome cause irritability, tremors, diarrhea, and autonomic symptoms?

Chronic in-utero drug exposure → neonatal drug withdrawal after delivery → CNS/autonomic hyperactivity + GI hypermotility

A newborn has a high-pitched cry, irritability, tremors, tachypnea, sneezing, diarrhea, and poor/uncoordinated sucking. Diagnosis?

Neonatal abstinence syndrome due to opioid withdrawl

Neonatal abstinence syndrome due to opioid withdrawal - Treatment

• Methadone

• Morphine

• Buprenorphine

How can Neonatal abstinence syndrome be prevented on a population or worldwide level

Universal screening for substance use in all pregnant patients

What is the main source of amniotic fluid?

Fetal urine (mainly) + fetal lung fluid

How is amniotic fluid mainly cleared?

Fetal swallowing + intramembranous absorption

Polyhydramnios - Major associations

Mechanical: Fetal malformations that impair swallowing:

• esophageal/duodenal atresia,

• anencephaly

Others:

• Maternal diabetes

• Fetal anemia

• Multifetal gestation

• May be idiopathic

Why can esophageal or duodenal atresia cause polyhydramnios?

Obstruction → fetus cannot effectively swallow amniotic fluid → ↓ fluid clearance → polyhydramnios

Why can anencephaly cause polyhydramnios?

Impaired fetal swallowing → ↓ amniotic fluid clearance → polyhydramnios

---

Anencephaly = Anencephaly is a fatal neural tube defect in which a baby is born without major parts of the brain and skull, occurring in about 1 in 4,762 U.S. births and resulting in death within hours or days.

Why can maternal diabetes cause polyhydramnios?

Maternal hyperglycemia → fetal hyperglycemia → osmotic diuresis → ↑ fetal urine production → polyhydramnios

Why can fetal anemia cause polyhydramnios?

Anemia → ↓ O₂-carrying capacity → compensatory ↑ cardiac output + renal perfusion → ↑ fetal urine production → polyhydramnios

---

Fetal anemia: a condition in which a fetus has an abnormally low number of red blood cells or hemoglobin, most commonly caused by Rh alloimmunization, infections such as parvovirus B19, or fetomaternal hemorrhage, and it is primarily diagnosed using middle cerebral artery (MCA) Doppler ultrasound.

Oligohydramnios - Major associations

• Placental insufficiency

• Bilateral renal agenesis (No urine production)

• Posterior urethral valves in males

Why can posterior urethral valves cause oligohydramnios?

Bladder outlet obstruction → impaired fetal urine excretion → ↓ amniotic fluid

Why can placental insufficiency cause oligohydramnios?

↓ Placental perfusion → ↓ fetal renal perfusion → ↓ fetal urine production → oligohydramnios

What can profound oligohydramnios cause?

Potter sequence

A fetus has bilateral renal agenesis and severe oligohydramnios. What complication should you think of?

Potter sequence

A fetus has severe oligohydramnios. Which broad mechanisms should you think of first?

↓ Fetal urine production/excretion or ↓ placental perfusion

Twin-twin transfusion syndrome (TTTS) occurs in what type of twin pregnancy?

Monochorionic twin gestations

Why does twin-twin transfusion syndrome occur only in monochorionic twins?

Monochorionic twins share a placenta → placental vascular connections can form between the twins → unbalanced blood flow may develop from one twin to the other

Twin-twin transfusion syndrome - Pathophysiology

Unbalanced arteriovenous anastomoses in a shared placenta → net blood flow from donor twin → recipient twin

Twin-twin transfusion syndrome - Donor twin findings

↓ Blood volume → hypovolemia + oligohydramnios<br>May appear "stuck" because the amniotic sac contains very little fluid

Why does the donor twin develop oligohydramnios in twin-twin transfusion syndrome?

Donor loses blood volume → ↓ renal perfusion → ↓ fetal urine production → oligohydramnios

Twin-twin transfusion syndrome - Recipient twin findings

↑ Blood volume → hypervolemia + polyhydramnios

Why does the recipient twin develop polyhydramnios in twin-twin transfusion syndrome?

Recipient gains blood volume → ↑ renal perfusion → ↑ fetal urine production → polyhydramnios

A monochorionic twin pregnancy shows one twin with oligohydramnios and a "stuck twin" appearance, while the other has polyhydramnios. What is the diagnosis?

Twin-twin transfusion syndrome

What placental abnormality underlies twin-twin transfusion syndrome?

Unbalanced vascular anastomoses between the twins within a shared placenta

How does the timing of monozygotic twin splitting affect chorionicity and amnionicity?

Splitting 0–4 days → dichorionic diamniotic<br>Splitting 4–8 days → monochorionic diamniotic<br>Splitting 8–12 days → monochorionic monoamniotic<br>Splitting ≥13 days → monochorionic monoamniotic with incomplete separation/conjoined twins

Why are monozygotic twins at risk for twin-twin transfusion syndrome only when splitting occurs after chorion formation?

Later splitting can produce a shared chorion/placenta → placental vascular anastomoses can connect the fetal circulations → risk of TTTS

What is the urachus?

Intra-abdominal remnant of the allantois that forms a duct between the fetal bladder and umbilicus

What happens to the urachus normally after birth?

It obliterates → becomes the median umbilical ligament, which is covered by the median umbilical fold of peritoneum

Why are persistent urachal anomalies clinically important?

Failure of urachal involution can predispose to infection and may increase risk of malignancy, especially adenocarcinoma, if untreated

Patent urachus - Defect

Total failure of the urachus to obliterate

Patent urachus - Classic presentation

Urine discharge from the umbilicus

A newborn has urine leaking from the umbilicus. What is the most likely diagnosis?

Patent urachus

Urachal cyst - Defect

Partial failure of urachal obliteration → persistent fluid-filled cavity between the umbilicus and bladder

What lines a urachal cyst?

Uroepithelium

How can a urachal cyst present clinically?

It may become infected → painful midline mass below the umbilicus

A child presents with fever and lower abdominal pain. Exam reveals a tender midline suprapubic mass without urinary symptoms. Imaging shows a fluid-filled structure between the bladder and umbilicus. What is the most likely diagnosis?

Urachal cyst

Vesicourachal diverticulum - Defect

Slight failure of urachal obliteration at the bladder end → outpouching of the bladder

Patent urachus vs urachal cyst vs vesicourachal diverticulum

Patent urachus → complete persistence, urine drains from umbilicus
Urachal cyst → central persistent cavity
Vesico-urachal diverticulum → persistence at bladder end causing bladder outpouching

A urachal abnormality communicates completely between the bladder and umbilicus. Which anomaly is this?

Patent urachus

A urachal remnant persists only in the middle, with both ends closed. Which anomaly is this?

Urachal cyst

A urachal remnant persists only near the bladder, producing a bladder outpouching. Which anomaly is this?

Vesicourachal diverticulum

What is the vitelline duct?

Also called the omphalomesenteric duct; connects the yolk sac to the midgut lumen during embryonic development

When does the vitelline duct normally obliterate?

Around week 7 of development

Patent vitelline duct - Defect

Total failure of the vitelline duct to obliterate

Patent vitelline duct - Classic presentation

Meconium discharge from the umbilicus

A newborn has meconium draining from the umbilicus. What is the most likely diagnosis?

Patent vitelline duct

Vitelline duct cyst - Defect

Partial failure of the vitelline duct to obliterate → persistent cyst along the tract

What complication is associated with a vitelline duct cyst?

↑ Risk of volvulus

Meckel diverticulum - Defect

Slight failure of vitelline duct obliteration → outpouching of the ileum

Why is Meckel diverticulum a true diverticulum?

It contains all layers of the intestinal wall

Meckel diverticulum - Typical clinical course

Usually asymptomatic

What heterotopic tissues may be found in Meckel diverticulum?

Gastric tissue and/or pancreatic tissue

How can Meckel diverticulum cause GI bleeding?

Ectopic gastric mucosa secretes acid → adjacent ileal mucosal injury/ulceration → melena or hematochezia

Meckel diverticulum - Possible presentation

Melena<br>Hematochezia<br>Abdominal pain

Patent vitelline duct vs vitelline duct cyst vs Meckel diverticulum

• Patent vitelline duct → complete persistence, meconium from umbilicus

• Vitelline duct cyst → central persistent cyst, ↑ volvulus risk

• Meckel diverticulum → persistence at ileal end, true diverticulum

What does the 1st pharyngeal cleft develop into?

External auditory meatus

What happens to the 2nd–4th pharyngeal clefts during normal development?

They form temporary cervical sinuses → normally obliterated by proliferation of 2nd arch mesenchyme

What is a pharyngeal cleft cyst?

Persistent cervical sinus due to failure of obliteration of the 2nd–4th pharyngeal clefts

Where does a pharyngeal cleft cyst classically present?

Lateral neck mass anterior to the sternocleidomastoid muscle

Does a pharyngeal cleft cyst move with swallowing?

No, unlike thyroglossal cysts

A young patient has a painless lateral neck mass along the anterior border of the sternocleidomastoid. The mass does not move with swallowing. What is the most likely diagnosis?

Pharyngeal cleft cyst

Pharyngeal cleft cyst vs thyroglossal duct cyst - key discriminator

• Pharyngeal cleft cyst → lateral neck, anterior to SCM, does not move with swallowing

• Thyroglossal duct cyst → midline and moves with swallowing

Pierre Robin sequence - Pathophysiology

Mandibular hypoplasia (micrognathia) → posterior displacement of tongue (glossoptosis) → cleft palate + airway compromise

Why can Pierre Robin sequence cause airway compromise?

Micrognathia → tongue is displaced posteriorly (glossoptosis) → upper-airway obstruction

Why are feeding difficulties common in Pierre Robin sequence?

Micrognathia + glossoptosis + cleft palate → impaired sucking/swallowing

A newborn has micrognathia, a posteriorly displaced tongue, cleft palate, and episodes of upper-airway obstruction. What is the most likely diagnosis?

Pierre Robin sequence

Treacher Collins syndrome - Inheritance

Autosomal dominant

Treacher Collins syndrome - Basic defect

Neural crest dysfunction → abnormal craniofacial development

Treacher Collins syndrome - Major findings

Craniofacial abnormalities (eg, zygomatic bone + mandibular hypoplasia)<br>Hearing loss<br>Airway compromise

Why can Treacher Collins syndrome cause hearing loss?

Craniofacial developmental abnormalities can involve structures of the ear → hearing impairment

A child has bilateral zygomatic hypoplasia, mandibular hypoplasia, hearing loss, and recurrent airway problems. What is the most likely diagnosis?

Treacher Collins syndrome

Pierre Robin sequence vs Treacher Collins syndrome - Key distinction

• Pierre Robin → micrognathia → glossoptosis → cleft palate

• Treacher Collins → Autosomal Dominant neural crest dysfunction with broader craniofacial abnormalities + hearing loss

A patient with mandibular hypoplasia also has prominent hearing loss and zygomatic hypoplasia. Which diagnosis is favored over Pierre Robin sequence?

Treacher Collins syndrome

What is the general relationship between cleft lip and cleft palate?

They have distinct, multifactorial etiologies but often occur together

Cleft lip - Embryologic defect

Failure of fusion of the intermaxillary segment (merged medial nasal processes) with the maxillary process → defective formation of the primary palate

Which embryologic structures fail to fuse in cleft lip?

Intermaxillary segment + maxillary process

What does the intermaxillary segment form in relation to the palate?

Primary (1°) palate

Cleft palate - Embryologic defect

Failure of fusion of the 2 lateral palatine shelves OR failure of a lateral palatine shelf to fuse with the nasal septum and/or primary palate → defective formation of the secondary palate

Which embryologic structures form the secondary (2°) palate?

Lateral palatine shelves

A newborn has a congenital defect of the upper lip extending toward the nostril. Which embryologic fusion failure most likely caused it?

Failure of fusion of the intermaxillary segment with the maxillary process → cleft lip

A newborn has an opening in the roof of the mouth that communicates with the nasal cavity. Which embryologic process most likely failed?

Fusion of the lateral palatine shelves with each other and/or with the nasal septum/primary palate → cleft palate

Cleft lip vs cleft palate - Key embryologic distinction

Cleft lip → failure of intermaxillary segment + maxillary process fusion → 1° palate defect<br>Cleft palate → failure of lateral palatine shelf fusion → 2° palate defect

What is Müllerian agenesis also called?

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome

Müllerian agenesis - Classic presentation

Primary amenorrhea with absent uterus and blind vaginal pouch

What are the external genitalia and secondary sexual characteristics like in Müllerian agenesis?

Normal female external genitalia<br>Normal secondary sexual characteristics

Why are secondary sexual characteristics normal in Müllerian agenesis?

Ovaries are functional → normal estrogen production → normal breast development and other 2° sexual characteristics

What reproductive organs are absent/abnormal in Müllerian agenesis?

Absent uterus + blind-ending vaginal pouch

What urinary tract anomaly is associated with Müllerian agenesis?

Renal anomalies, eg, renal agenesis

A teenage girl is evaluated for primary amenorrhea. She has normal breast development and normal external genitalia. Pelvic imaging shows no uterus, and examination reveals a shortened blind-ending vagina. What is the most likely diagnosis?

Müllerian agenesis (MRKH syndrome)

Primary amenorrhea with normal 2° sexual characteristics: what finding would favor Müllerian agenesis over a disorder with androgen insensitivity?

Absent uterus + blind vaginal pouch in Müllerian agenesis; ovaries are functional