What are the prenatal findings and management of Cornelia de Lange, Wolf-Hirschhorn, Goldenhar, Fryns, Neu-Laxova, Cri-du-chat, and Miller-Dieker syndromes?

Prenatal Findings and Management of Genetic Syndromes

Genetic testing is strongly recommended for definitive diagnosis of suspected genetic syndromes identified during prenatal screening, with molecular testing being the gold standard for confirmation.

Cornelia de Lange Syndrome (CdLS)

Prenatal Findings

• Intrauterine growth restriction (IUGR) - primary finding 1
• Characteristic facial profile detectable on ultrasound 1, 2
• Upper limb reduction defects/malformations 2
• Micrognathia 2
• Decreased PAPP-A (pregnancy-associated plasma protein A) 1
• Increased nuchal translucency 1, 2
• Possible associated structural defects 1

Management

• Serial ultrasound examinations for high-risk families 3
• NIPBL gene sequencing (detects ~75% of prenatal cases) 2
• Genetic counseling (autosomal dominant inheritance pattern)
• Detailed anatomical survey focusing on limbs and facial features

Wolf-Hirschhorn Syndrome (4p deletion syndrome)

Prenatal Findings

• Severe IUGR
• Microcephaly
• Facial dysmorphism ("Greek warrior helmet" appearance)
• Cardiac defects (especially atrial septal defects)
• Midline defects (cleft lip/palate)
• Renal anomalies

Management

• Chromosomal microarray analysis (CMA) recommended for definitive diagnosis 4
• Detailed fetal echocardiography
• Renal ultrasound assessment
• Genetic counseling (typically sporadic occurrence)

Goldenhar Syndrome (Oculoauriculovertebral spectrum)

Prenatal Findings

• Facial asymmetry
• Ear anomalies (microtia, anotia)
• Vertebral anomalies
• Ocular dermoids
• Cardiac defects in ~30% of cases
• Unilateral facial hypoplasia

Management

• Detailed anatomical survey with focus on craniofacial structures
• Fetal echocardiography
• Genetic testing (though etiology often multifactorial)
• Multidisciplinary team approach for delivery planning

Fryns Syndrome

Prenatal Findings

• Diaphragmatic hernia (most consistent finding)
• Distal limb hypoplasia
• Facial dysmorphism (coarse facies)
• Polyhydramnios
• Pulmonary hypoplasia
• IUGR

Management

• Detailed anatomical survey
• Assessment of diaphragmatic hernia and associated pulmonary development
• Genetic testing (autosomal recessive inheritance)
• Delivery planning at tertiary care center with pediatric surgery capability

Neu-Laxova Syndrome

Prenatal Findings

• Severe IUGR 5, 6
• Microcephaly with flat forehead 5
• Generalized edema of skin 5
• Joint contractures 5
• Hypoplastic chest 5
• Excessive soft tissue deposition of hands and feet 5
• Micrognathia 5
• Genital abnormalities 5

Management

• Early serial ultrasound examinations for at-risk families 5, 6
• Genetic counseling (autosomal recessive inheritance) 5, 6
• Molecular genetic testing when available
• Discussion of pregnancy options given the lethal nature of the condition 5

Cri-du-chat Syndrome (5p deletion syndrome)

Prenatal Findings

• IUGR
• Microcephaly
• Cerebellar hypoplasia
• Cardiac defects
• Hypertelorism
• Micrognathia
• Increased nuchal translucency

Management

• Chromosomal microarray analysis (CMA) for definitive diagnosis 4
• Detailed anatomical survey
• Fetal echocardiography
• Genetic counseling (typically sporadic occurrence)

Miller-Dieker Syndrome (17p13.3 deletion)

Prenatal Findings

• Lissencephaly (smooth brain) detectable on MRI
• Microcephaly
• IUGR
• Ventriculomegaly
• Facial dysmorphism
• Cardiac defects

Management

• Chromosomal microarray analysis (CMA) for definitive diagnosis 4
• Fetal MRI to assess brain development
• Fetal echocardiography
• Genetic counseling
• Delivery planning at tertiary care center with pediatric neurology capability

General Management Principles for Suspected Genetic Syndromes

1. Diagnostic Testing Recommendations:

   • Diagnostic testing is recommended for any suspected genetic syndrome identified on prenatal ultrasound 4
   • Chromosomal microarray analysis (CMA) is recommended for follow-up of smaller copy-number changes reported by NIPS 4
   • Molecular genetic testing should be applied for prenatal diagnosis when available 4

2. Genetic Counseling:

   • Preconception genetic counseling is recommended for individuals at increased risk of having a fetus with genetic syndromes 4
   • Posttest access to genetic counseling by trained genetics professionals is essential 4

3. Delivery Planning:

   • Management of delivery should be discussed early in pregnancy 4
   • Delivery at appropriate centers with specialized expertise 4
   • Newborns with genetic syndromes may require immediate specialized medical management 4

4. Follow-up Considerations:

   • Third-trimester ultrasound examination for reassessment and evaluation of fetal growth for many conditions 4
   • Postnatal confirmation of prenatal findings when diagnostic testing is declined 4

Important Caveats

• Prenatal ultrasound findings may not detect all features of these syndromes
• Some conditions have variable expressivity, making prenatal diagnosis challenging
• Cell-free DNA screening (NIPS) is not diagnostic and requires confirmation with invasive testing 4
• Sources of discordant results include confined placental mosaicism, maternal chromosome abnormalities, and technical limitations 4
• For high-risk pregnancies, serial ultrasound examinations are recommended rather than relying on a single assessment