What are the inherited causes of fetal hydrops in a pregnant individual with a family history of genetic disorders?

Inherited Causes of Fetal Hydrops

Genetically transmitted disorders account for approximately one-third of nonimmune hydrops fetalis (NIHF) cases, with chromosomal abnormalities being the most common inherited cause (7-16% of all NIHF), followed by hemoglobinopathies (4-12%), skeletal dysplasias (3-4%), inborn errors of metabolism (1-2%), and other genetic syndromes. 1

Major Categories of Inherited Causes

Chromosomal Abnormalities (7-16% of NIHF cases)

• Turner syndrome (45,X) is the most common chromosomal cause, associated with 50-80% of cystic hygromas due to lymphatic dysplasia and impaired venous drainage 1
• Trisomy 21 (Down syndrome) is another frequent chromosomal cause, particularly when NIHF is identified early in gestation 1
• Trisomies 13 and 18, and triploidy are also associated with NIHF, often due to accompanying cardiovascular malformations 1
• Aneuploidy is the most common cause of NIHF in prenatal series, especially when diagnosed before 24 weeks gestation 1

Hemoglobinopathies (4-12% of NIHF cases)

• Alpha thalassemia is the most common hemoglobinopathy causing NIHF, accounting for 28-55% of cases in Southeast Asian populations and approximately 10% in other populations 1
• This autosomal recessive disorder causes anemia, high output cardiac failure, and hypoxia 1
• Parents can be screened by mean cell volume (MCV) <80 fL, which indicates thalassemia carrier status 1
• Other red cell disorders include glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency 1

Skeletal Dysplasias (3-4% of NIHF cases)

• These disorders cause hydrops through hepatomegaly, hypoproteinemia, and impaired venous return 1
• Multiple specific skeletal dysplasias have been associated with NIHF in the literature 2

Inborn Errors of Metabolism (1-2% of NIHF cases)

• Lysosomal storage disorders including mucopolysaccharidosis type VII, Niemann-Pick disease, Gaucher disease, and sialidosis cause hydrops through visceromegaly, obstruction of venous return, decreased erythropoiesis, and hypoproteinemia 1
• Multiple sulfatase deficiency has been identified as a cause in recent exome sequencing studies 3
• Lysosomal enzyme testing should be considered when no other etiology is identified 1

RASopathies and Genetic Syndromes (3-4% of NIHF cases)

• Noonan syndrome and related RASopathies (caused by mutations in PTPN11, RAF1, RIT1, RRAS2) account for approximately 30% of genetic diagnoses in recent exome sequencing studies 3, 4
• Kabuki syndrome has been identified through prenatal exome sequencing 3
• These disorders affect the RAS-MAPK cell-signaling pathway and have variable prognoses 4

Rare Inherited Anemias

• Diamond-Blackfan anemia is a rare inherited cause requiring detailed family history assessment and consideration of consanguinity 1, 5
• Fanconi anemia can present with fetal hydrops 1
• Congenital dyserythropoietic anemia (CDA) associated with KLF1 gene mutations can cause severe fetal anemia and hydrops, though this is extremely rare 6, 3

Other Genetic Disorders

• Musculoskeletal disorders caused by mutations in RYR1, AMER1, and BICD2 genes 3, 4
• Arthrogryposis multiplex syndromes (1.8% of cases) 2
• Multiple pterygium syndrome (1.5% of cases) 2
• Lymphatic dysplasia (5-6% of cases) causes impaired venous return 1

Diagnostic Approach for Inherited Causes

Essential Initial Workup

• Detailed family history is imperative to identify known inherited disorders and assess for consanguinity, which increases the likelihood of autosomal recessive disorders 1, 5
• Karyotype and/or chromosomal microarray analysis (CMA) should be offered with or without identified sonographic anomalies 1
• Parental mean cell volume (MCV) testing is essential; MCV <80 fL warrants DNA testing for alpha-thalassemia 1

Advanced Genetic Testing

• Exome sequencing provides a diagnostic yield of approximately 29-50% in cases of unexplained NIHF after standard workup, identifying both dominant (68% of genetic cases, mostly de novo) and recessive (27% of genetic cases, mostly inherited) disorders 3, 4
• Testing can be performed via amniocentesis or fetal blood sampling, with the latter allowing direct hematocrit analysis if anemia is suspected 1

Critical Clinical Considerations

Inheritance Patterns and Recurrence Risk

• Autosomal dominant disorders account for 68% of genetic diagnoses, with 88% being de novo mutations and only 12% inherited 4
• Autosomal recessive disorders account for 27% of genetic diagnoses, with 95% inherited from carrier parents 4
• Recurrence risk varies dramatically: idiopathic NIHF has low recurrence risk, but some genetic causes carry up to 25% recurrence risk, making genetic counseling integral to management 1

Prognostic Implications

• Aneuploidy confers extremely poor prognosis, with survival often <50% even in the absence of chromosomal abnormalities when diagnosed <24 weeks gestation 1
• Prognoses for genetic causes range from relatively mild outcomes to perinatal death depending on the specific disorder 4
• Early genetic diagnosis allows parents to make informed decisions about pregnancy management 7, 2

Common Pitfalls to Avoid

• Failure to obtain parental MCV can miss alpha-thalassemia, particularly in Southeast Asian populations where it accounts for the majority of NIHF cases 1
• Inadequate family history may miss recessive disorders, especially in consanguineous relationships 1
• Stopping workup after negative standard testing misses the 29-50% of cases diagnosable by exome sequencing 3, 4
• Assuming all genetic causes are lethal prevents appropriate counseling, as some disorders like certain RASopathies have favorable outcomes 4