A System-Based Approach to the Genetic Etiologies of Non-Immune Hydrops Fetalis

Abstract

A wide spectrum of genetic causes may lead to non-immune hydrops fetalis (NIHF), and a thorough phenotypic and genetic evaluation are essential to determine the underlying etiology, optimally manage these pregnancies, and inform discussions about anticipated prognosis. In this review, we outline the known genetic etiologies of NIHF by fetal organ system affected, and provide a systematic approach to the evaluation of NIHF. Some of the underlying genetic disorders are associated with characteristic phenotypic features that may be seen on prenatal ultrasound, such as hepatomegaly with lysosomal storage disorders, hyperechoic kidneys with congenital nephrosis, or pulmonary valve stenosis with RASopathies. However, this is not always the case, and the approach to evaluation must include prenatal ultrasound findings as well as genetic testing and many other factors. Genetic testing that has been utilized for NIHF ranges from standard chromosomal microarray or karyotype to gene panels and broad approaches such as whole exome sequencing. Family and obstetric history, as well as pathology examination, can yield additional clues that are helpful in establishing a diagnosis. A systematic approach to evaluation can guide a more targeted approach to genetic evaluation, diagnosis, and management of NIHF.

INTRODUCTION

Hydrops fetalis occurs in approximately 1 in 1700 to 1 in 3000 pregnancies, and is diagnosed by prenatal ultrasound when at least two abnormal fetal fluid collections are present, including ascites, pleural effusion, pericardial effusion, or skin edema.¹ The majority of cases are non-immune in nature when Rh(D) immune globulin is appropriately administered, and a wide variety of genetic causes are known to lead to non-immune hydrops fetalis (NIHF).¹ Significant perinatal risks accompany NIHF, ranging from stillbirth to preterm birth and neonatal death, and risks of these adverse outcomes vary by the underlying cause of hydrops.^1–6

An algorithm for the evaluation of NIHF has been published by the Society for Maternal-Fetal Medicine, which includes obstetric ultrasound with Doppler interrogation, fetal echocardiogram, fetal karyotype and/or chromosomal microarray analysis (CMA), and consideration of more targeted testing such as lysosomal enzyme assays.¹ However, nearly half of NIHF cases remain of unknown etiology following standard evaluation.⁷ Prenatal phenotyping, or characterization of the unique features associated with each case, can be helpful to developing an approach to the diagnosis of the chromosomal abnormalities and single gene disorders leading to the fetal structural anomalies, genetic syndromes, and inborn errors of metabolism seen with NIHF.^1,7,8

Understanding the etiology of NIHF is imperative in order to effectively manage these pregnancies, anticipate neonatal care requirements, implement time-sensitive treatments, and counsel families about prognosis and recurrence risk. While a number of non-genetic etiologies such as viruses may also lead to NIHF, we focus here on the genetic etiologies. This review provides a systematic approach to the genetic evaluation of NIHF, focusing on the etiologies by organ system affected. This framework allows providers to approach each NIHF case by considering the unique constellation of phenotypic features, and guides a more targeted approach to genetic evaluation, diagnosis, and management.

GENETIC CAUSES OF NIHF BY ORGAN SYSTEM

The presence of structural anomalies in the fetus, in addition to NIHF, may provide clues about the underlying genetic etiology. Both the constellation of findings as well as any unusual or uncommon features may be helpful in narrowing the differential diagnosis. While it can be difficult to detect subtle phenotypic features such as facial dysmorphism, defining the phenotype prenatally as much as possible can be helpful in the evaluation process.

Many genetic diseases and syndromes are difficult to classify into one primarily affected organ system, which highlights the importance of understanding the overall phenotypic picture for each case. The following sections take a practical approach by considering one organ system at a time, and reviewing considerations for underlying genetic etiologies when specific features are seen in addition to NIHF. Table 1 outlines genetic disorders and syndromes associated with NIHF by category, along with the major manifestations, associated genes, and prevalence.

Table 1.

Genetic disorders by organ system.

	Genetic disease or syndrome	Gene or Location	Prenatal Findings (in addition to NIHF)	Prevalence	References
Aneuploidies	Monosomy X (Turner syndrome)	Chromosome X	Cystic hygroma (often septated), increased NT, cardiac anomalies (aortic coarctation, HLHS), horseshoe kidney, short femur	1 in 2,000–2,500 female live births 10–20% of SABs	Papp 200653
	Trisomy 21 (Down syndrome)	Chromosome 21	Cardiac anomalies (especially endocardial cushion defects, septal defects), duodenal atresia, increased NT or NF, absent/short nasal bone, ventriculomegaly	1 in 800 live births	Smith Bindman 20019 Nyberg 199051
	Trisomy 18 (Edwards syndrome)	Chromosome 18	Cardiac defects (especially septal and valvular defects), skeletal anomalies (strawberry-shaped calvarium, clenched hands, rocker bottom feet), increased NT or cystic hygroma, CNS anomalies (abnormal cisterna magna, absent CC, NTDs, ventriculomegaly), facial anomalies (clefts, micrognathia), GI anomalies (omphalocele, CDH), GU (horseshoe kidney, hydronephrosis)	1 in 5500 live births	Bronsteen 200410
	Trisomy 13 (Patau syndrome)	Chromosome 13	CNS anomalies (increased NT, holoprosencephaly, posterior fossa abnormalities, absent CC, ventriculomegaly), midline defects (cyclopia, midline clefts, anophthalmia), cardiac defects (septal defects, TOF, HLHS), GI anomalies (omphalocele, CDH), polycystic kidneys, postaxial polydactyly, FGR	1 in 5,000–20,000 live births (but >75% die in utero)	Szigeti 200611
	Triploidy (partial mole)	69,XXX 69,XXY 69,XYY	CNS anomalies (ventriculomegaly, holoprosencephaly, Dandy Walker malformation, NTD), absent gallbladder, renal anomalies, syndactyly of 3rd and 4th digits, clubbed feet, clenched hands, 2 vessel umbilical cord Paternal (diandric, 75%): moderate, symmetric FGR; large, cystic placenta; increased NT Maternal (dyginic, 25%): asymmetric FGR; small, calcified placenta, oligohydramnios	1–3% of clinically recognized pregnancies; 20% of spontaneous abortions	Massalska 201712
Central nervous system	Meckel Gruber syndrome	B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TMEM67, TMEM216	Occipital encephalocele, bilateral large multicystic kidneys, fibrotic changes of the liver, polydactyly	1 in 13,250–140,000	Abrams 200722Barisic 201523
	Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome	FLVCR2	Hydranencephaly, cystic hygroma, arthrogrypsosis	Unknown	Petrovski 2019112
	Smith Lemli Opitz	DHCR7	Microcephaly, ventriculomegaly, FGR, CP, cryptorchidism, renal dysplasia, elevated NT, postaxial polydactyly, 2,3-syndactyly, cardiac defects	1 in 20,000 to 60,000 (higher in Caucasians)	Maymon 199924
	Zellweger syndrome	PEX1 (70%), PEX2, PEX3, PEX5, PEX6, PEX10, PEX11B, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26	Subependymal or periventricular pseudocysts, ventriculomegaly, increased NT, echogenic bowel, FGR, hypokinesia, hepatosplenomegaly, renal microcysts	1 in 50,000	Shen 2016127 Dursun 2009128
Cardiovascular	22q11 microdeletion syndrome	22q11.2	Conotruncal heart defects (truncus arteriosus, aortic arch abnormalities, TOF, left ventricular noncompaction), CP, micrognathia, hypertelorism, thymic hypoplasia, increased NT or NF	1 in 4,000	Dupont 2014129 Machlitt 200232
	9q duplication	9q	Congenital heart defects, microcephaly, contractures, urogenital malformations, FGR	Unknown	Amarillo 2015130
	ALPK3 related disorders	ALPK3	Cardiomegaly, severe biventricular hypertrophy and dilation	Unknown	Almomani 201631
	Barth syndrome	TAZ	Congenital heart disease (dilated cardiomyopathy, left ventricular noncompaction, endocardial fibroelastosis), X-linked	1 in 300,000–400,000	Steward 201028
	Congenital long QT syndrome	KCNQ1, KCNH2, SCN5A	Arrhythmia	1 in 2,000 live births	Komarlu 201136
	GATA-5 related disorders	GATA5	Congenital heart defects, genital anomalies	Unknown	Hempel 201730
	Kabuki syndrome	KMT2D, KDM6A	Cardiac anomalies (HLHS, coarctation of the aorta, bicuspid aortic valve, septal defects), increased NT, echogenic bowel, micrognathia, FGR, polyhydramnios	1 in 32,000	Long 2016131
	Klippel-Trenaunay-Weber syndorme	PIK3CA	Cardiomegaly, anemia, unilateral lower extremity hypertrophy, hemangiomas (placental, hepatic), polyhydramnios, cutaneous or subcutaneous cystic or multicystic lesions	1 in 100,000	Tanaka 201575
	McKusick-Kaufman syndrome	MKKS	Cardiac anomalies (atrioventricular canal, HLHS, single atria), hydrometrocolpos, polydactyly	1 in 10,000 of Old Order Amish population	Gaucherand 2002132 Tsai 2014133
	Opitz G/BBB syndrome, X-linked	MID1	Cardiac anomalies (VSD, ASD, aortic coarctation, persistent left SVC, PDA), hypertelorism, enlarged cisterna magna, polyhydramnios	1 in 50,000–100,000 males	Patton 1986134 Cheng 2014135
	PIK3CA-associated segmental overgrowth (including CLOVES and MCAP syndromes)	PIK3CA	CLOVES: lipomatous truncal masses, limb asymmetry, vascular or lymphatic malformations, polyhydramnios MCAP: macrocephaly, pleural effusion, ventriculomegaly, limb asymmetry, frontal bossing, polyhydramnios	Unknown	Nyberg 2005136 Mirzaa 2005137 Emrick 201413
	Capillary malformation-arterioveous malformation syndrome (RASA1-related disorders)	RASA1	Polyhydramnios, asymmetric MCA Dopplers, hyperechoic interventricular septum, arteriovenous malformations	1 in 100,000 people of northern European descent	Overcash 201538
	Tuberous sclerosis	TSC1, TSC2	Cardiac rhabdomyoma, arrhythmias, cerebral cortical tubers on MRI	1 in 6,000	Pruksanusak 201226
	Williams syndrome	7q11.23	Supravalvular aortic stenosis	1 in 7,500–10,000	Von Dadelszen 2000138
	Wolff-Parkinson-White syndrome	Most unknown; PRKAG2	Tachyarrhythmia	1–3 in 1,000	Abrams 200722 Hoeffler 201637
Pulmonary and thoracic	Cornelia de Lange Syndrome	NIPBL, SMC1A, HDAC8, RAD21, SMC3	CDH, sacrococcygeal teratoma, polyhydramnios, FGR	1 in 10,000–30,000	Toomayan 200883Banait 201582 Lord 2019113
	Fraser syndrome	FRAS1 (>50%), FREM2, GRIP1	Microphthalmia, cleft lip, renal agenesis or dysplastic kidneys, obstructive uropathy, CHAOS	1 in 200,000 live births; 1 in 10,000 fetal losses/spontaneous abortions	Tessier 201643
	Fryns syndrome	Unknown	CDH, distal limb hypoplasia, hypertelorism, broad nasal bridge, cleft lip and/or palate, micrognathia, polyhydramnios	Unknown; 1.3–10% of CDH cases	Ramsing 200141
	Pallister-Killian syndrome	Tetrasomy 12p (usually with isochromosome 12p)	Cardiac anomalies, CDH, rhizomelic micromelia, ventriculomegaly, flat nasal bridge	1 in 20,000 live births	Doray 200240
	VACTERL association	Unknown	Vertebral defects, anal atresia, cardiac defects, TEF, renal anomalies, limb abnormalities	1 in 10,000 to 40,000 newborns	Sanford 2012139
Gastrointestinal	Beckwith-Wiedemann syndrome	11p15.5	Omphalocele, placental cysts, macroglossia, enlarged kidneys, adrenal cysts, hepatosplenomegaly, polyhydramnios	1 in 13,700 live births	Hillstrom 199552
	Lysosomal Storage Disorders
	Galactosialidosis	CTSA	Hepatosplenomegaly, echogenic bowel	Unknown (100 reported cases)	Patel 1999140 Caciotti 2013141
	Gaucher disease	GBA	Arthrogryposis, ventriculomegaly, microcephaly, ichthyosis, hepatosplenomegaly	1:855 in Ashkenazi Jewish, 1:57,000 to 1.16:100,000 in general	Beaujot 201377
	Mucolipidosis I (Sialidosis)	NEU1	Hepatosplenomegaly	Unknown (1–4:200,000 to 1:4.2 million)	Gillan 198446
	Mucolipidosis II (I-cell disease)	GNPTAB	Skeletal dysplasia, FGR	1:640,000	Capobres 2015142 Heo 2012143
	Mucopolysaccharidosis IVa (Morquio syndrome)	GALNS	Isolated hydrops	1:250,000	Applegarth 1987144
	Mucopolysaccharidosis type IVB (GM1- gangliosidosis)	GLB1	Isolated or with hepatosplenomegaly	1:100,000–1:200,000	Sinelli 2005145 Gillan 198446
	Mucopolysaccharidosis VII (Slysyndrome)	GUSB	Short femurs, ventriculomegaly, increased nuchal translucency/nuchal fold, hydrothorax, echogenic bowel, myocardial hypertrophy, placentomegaly	1:250,000–1:<1,000,000	Cheng 2003 Hollander 2000 Geipel 2002146–148
	Niemann-Pick A	SMPD1	Placental thickening	1:40,000 in Ashkenazi Jewish, 1:250,000 in general populations	Schoenfeld 1985149
	Niemann-Pick C	NPC1, NPC2	Cystic hygroma, hepatosplenomegaly, echogenic bowel, placentomegaly	1:150,000	Ples 2018150
	Salla Disease	SLC17A5	Hepatosplenomegaly, clubbed feet, cardiomegaly, FGR, ventriculomegaly, brachycephaly, micromelia	Unknown, <1:1,000,00	Aula 2006151
	Mevalonate kinase deficiency	MVK	Hepatosplenomegaly, hypotonia	Unknown (200 reported worldwide)	Peciuliene 2016152
	Wolman Disease	LIPA	Hepatosplenomegaly, enlarged, calcified adrenal glands	1:350,000	Özmen 1992153 Blitz 2017154
Genitourinary and Renal	Bartter syndrome	SLC12A1, KCNJ1, CLCNKB, BSND, CLCNKA, CLCNKB	Large renal cysts	Unknown	Çetinkaya 201354
	Autosomal recessive polycystic kidney disease	PKHD1	Enlarged, echogenic kidneys with multiple cysts	1 in 20,000 to 40,000	Van Maldergam 199255
	Congenital nephrosis
	Pierson syndrome	LAMB2	Renal hyperechogenicity, pyelectasis, placentomegaly, oligohydramnios, anencephaly	Unknown	Mark 2006155
	Finnish nephrosis	NPHS1, NPHS2	Hyperechoic, enlarged kidneys, placentomegaly	1–3 in 100,000 worldwide 1 in 10,000 in Finland	Zenker 2004156
Musculoskeletal	Skeletal dysplasias
	Achondrogenesis	TRIP11, SLC26A2, COL2A1	Short, bent long bones, poor spine ossification, hydrocephalus, polyhydramnios	Unknown	Pretorius 198619 Heinrich 201556
	Achondroplasia	FGFR3	Short long bones with relative macrocephaly	1 in 15–40,000	Etches 1979157 Hatzaki 2011158
	Asphyxiating thoracic dystrophy (Jeune syndrome)	CEP120, CSPP1, DYNC2H1, IFT80, IFT140, IFT172, TTC21B, WDR19, WDR34, WDR35, WDR60	Bell-shaped thorax, short horizontal ribs, mesomelia, renal cysts	1–5 in 500,000 live births	Nakamura 1987159 Tonni 2013160
	Congenital disorders of glycosylation type I	PMM2, ALG1, ALG9	Short long bones, clubfeet, polyhydramnios, cardiomyopathy	800 cases reported	Kranz 200761
	Hydrops-ectopic calcification moth eaten (HEM) skeletal dysplasia (Greenberg dysplasia)	LBR	Severe shortening of all long bones, moth-eaten radiographic appearance, FGR, placentomegaly, rib fractures, narrow thorax, hepatomegaly	Unknown	Konstantinidou 200849
	Osteogenesis Imperfecta	COL1A1, COL1A2, CRTAP, P3H1	Reduced echogenicity of fetal bone; bowed, crumpled femurs; beaded ribs; evidence of fractures; markedly diminished calvarial mineralization	6–7 in 100,000	Nakamura 1987159 Steiner 2013161
	Osteopetrosis congenita	CLCN7 (75%), CA2, IKBKG, ITGB3, OSTM1, PLEKHM1, TCIRG1, TNFRSF11A, TNFSF11	Dense bones, macrocephaly, hydrocephaly, hepatosplenomegaly	1 in 20,000	Mathur 198448
	Roberts syndrome	ESCO2	Mesomelia, cleft lip/palate, oligodactyly	150 cases reported	Dalal 2006162
	Schneckenbecken dysplasia	SLC35D1	Hypoplastic iliac bones, oval-shaped vertebral bodies, short long bones	Unknown	Nikkels 2001163
	Short rib polydactyly, type I (Saldino-Noonan)	DYNC2H1	Short, horizontal ribs, small thorax, polydactyly, micromelia, pointed metaphyses, absent fibulae, delayed ossification, natal teeth; cardiac, pulmonary, GU, and GI anomalies; cleft palate; females more likely	1 in 200,000 live births	Badiner 2017 Montemarano 1995 Kumru 2005 Silveira 2017164–167
	Short rib polydactyly, type II (Majewski)	NEK1	Enlarged kidneys, oligohydramnios, micromelia
	Short rib polydactyly, type III (Verma-Naumoff)	DYNC2H1	Micromelia, narrow thorax (less severe than type 1), widened metaphyses, absent fibulae, arrhythmia, postaxial polydactyly, aortic coarctation, increased NT
	Short rib polydactyly, type IV (Beemer-Langer)	IFT122	Increased NF, micromelia, small thorax, postaxial polydactyly, hypoplastic clavicles
	Thanatophoric dysplasia	FGFR3	Hydrocephalus, absent CC, cloverleaf skull, bent long bones, normal spine ossification	1 in 20,000 to 50,000 newborns	Pretorius 198619
	Yunis-Varon syndrome	FIG4	Absent clavicles, ventriculomegaly, Dandy-Walker malformation, microcephaly, hypoplastic phalanges of fingers and toes	Unknown	Basel-Vanagaite 2008168
	Oral-facial-digital syndrome	OFD1	Polydactyly, short and low implanted thumbs, bifid tongue, CP, agenesis of the CC	1 in 50,000 to 250,000 newborns	Van Maldergam 199255 Alby 2018169
	Fetal akinesia
	Arthrogryposis multiplex congenita (Pena-Shokeir syndrome)	DOK7, MUSK, RAPSN	Multiple contractures, pulmonary hypoplasia, polyhydramnios, FGR, micrognathia, camptodactyly, reduced fetal movements	1 in 12,000	Gupta 201059
	Lethal multiple pterygium syndrome	CHRNG, CHRNA1, CHRND, RAPSN	Multiple contractures, pulmonary hypoplasia, cystic masses in neck, skin webs, reduced fetal movements, cystic hygroma or increased NT, pterygia	Unknown	Jauniaux 199057 Chen 201258
	Myotonic dystrophy	DMPK	Decreased fetal movements, bradycardia, tented mouth facies	1 in 8000	Stratton 199360
	Neu-Laxova syndrome	PHGDH, PSATI1, PSPH	FGR, contractures, distal hypoplasia, clubbed feet, microcephaly, microganthia, ichthyosis, scoliosis	Unknown	Jauniaux 199057 Mattos 201476
	IPEX syndrome	FOXP3	Echogenic bowel, skin desquamation, FGR, akinesia, echogenic kidneys, clubfeet, X-linked	n/a	Reichert 2015170 Shehab 2017171
Hematologic	Alpha thalassemia (HbH and Hb Barts)	HBA1, HBA2	Hydrocephaly, microcephaly, increased NT, placentomegaly, anemia, hepatomegaly	1 in 200–2,000 births in SE Asia	Chui 199862
	Congenital dyserythropoietic anemia	CDAN1, SEC23B	Anemia	Unknown	Tamary 199365
	Congenital erythropoietic porphyria	CEP, UROS	Cystic hygroma, hydropic placenta, FGR, hypoplasia of cerebellar vermis, echogenic dysplastic kidneys, echogenic bowel and kidneys; dark brown amniotic fluid	Unknown	Pannier 2002172
	Diamond Blackfan anemia	GATA1, RPL5, RPL11, RPL15, RPL26, RPL27, RPL31, RPL35A, RPL36, RPS7, RPS10, RPS15, RPS17, RPS19, RPS24, RPS26, RPS27, RPS28, RPS29, TSR2	Anemia, FGR, oligohydramnios	5–7 per 1 million	Dunbar 200364
	εγδβ-thalassemia	HBB, locus control region of beta-globin locus on 11p	Anemia, echogenic bowel	Unknown	Goel 2017173
	Glucose-6-phosphate dehydrogenase deficiency	G6PD	Anemia	400 million people worldwide	Arcasoy 199550
	Glucose phosphate isomerase deficiency	GPI	Anemia, hepatosplenomegaly	Unknown (~50 cases reported)	Arcasoy 199550
	Pyruvate kinase deficiency	PKLR	Anemia, multicystic encephalomalacia, hepatomegaly	1 in 20,000 people of European descent, especially Old Order Amish of Pennsylvania	Arcasoy 199550
Lymphatic	RASopathies
	Noonan syndrome	PTPN11, SOS1, RAF1, RIT1	Cardiac anomalies (hypertrophic cardiomyopathy, HLHS, valvular anomalies), hydrothorax, chylothorax, pyelectasis, increased NT, cystic hygroma	1:1,000–1:2,500	Croonen 201333
	Costello syndrome	HRAS	Increased NT, short long bones, abnormal hand posture, ventriculomegaly, large size, macrocephaly, atrial tachycardia	1:300,000–1:1,230,000	Lin 2002, 200914,35
	Cardiofaciocutaneous syndrome	MAP2K2	Increased NT, polyhydramnios	Unknown (200–300 worldwide)	Gos 2017174
	Casitas B-cell lymphoma syndrome	CBL	Pleural effusion, chylothorax	Unknown	Bülow 201434
	Noonan-like syndrome with loose anagen hair	SHOC2	Elevated nuchal fold, hypertelorism, low-set ears	Unknown	Gargano 2013178
	Generalized lymphedema
	ITGA9-associated fetal chylothorax	ITGA9	Chylothorax, polyhydramnios	1 in 12,000	Yang 201268
	Generalized lymphatic dysplasia	PIEZO1	Cystic hygroma	Unknown	Fotiou 201566
	Hennekam lymphangiectasia-lymphedema syndrome	CCBE1, FAT4	Polyhydramnios	<1:1,000,000	Bellini 200374
	Hereditary lymphedema (Nonne-Milroy disease)	VEGFR3	Leg edema, hydrothorax, lung hypoplasia	1 in 6,000	Gordon 201272 Lev-Sagie 2003175
	Hypotrichosis-lymphedema-telangiectasia syndrome	SOX18	Chylothorax	Unknown	Irrthum 200369
	Lymphedema-cholestasis syndrome (Aagenaes syndrome)	15q, gene unknown	Placentomegaly	<1:1,000,000	Shah 2013176
	Lymphedema-distichiasis	FOXC2	Cardiac anomalies, cleft palate, spinal extradural cysts, distichiasis, lymphedema, large NT	Unknown	Gulati 2018177
	Primary lymphedema (Emberger syndrome)	GATA2	Bilateral lower extremity and genitalia edema	<1:1,000,000	Ostergaard 201173
	Yellow Nail Syndrome	Unknown	Chylothorax, polyhydramnios	Unknown	Nanda 201067
Skin	Sphingosine-1-phosphate lyase deficiency	SGPL1	Ichthyosis, adrenal calcifications, gonadal defects, microcephaly, cerebellar hypoplasia	Unknown	Choi 201878

CC- corpus callosum, CDH- congenital diaphragmatic hernia, CNS- central nervous system, CP- cleft palate, FGR- fetal growth restriction, GI- gastrointestinal, GU- genitourinary, HLHS- hypoplastic left heart syndrome, NF- nuchal fold, NT- nuchal translucency, NTD- neural tube defect, TEF- tracheoesophageal fistula, TOF- tetralogy of Fallot

Central Nervous System

Many genetic etiologies of NIHF are associated with central nervous system (CNS) anomalies. The majority of these anomalies are not thought to be causative of NIHF; rather, they are more often a manifestation of the underlying etiology leading to hydrops. The majority of associated CNS anomalies are non-specific and are not pathognomonic for a particular genetic disorder. However, each anomaly may be part of an overall pattern of anomalies that is useful for identifying the underlying diagnosis.

Ventriculomegaly may be seen with NIHF in the setting of aneuploidy^9–12 as well as with genetic disorders such as Costello syndrome and PIK3CA-associated segmental overgrowth syndromes.^13,14 The presence of ventriculomegaly should also prompt the investigation of viral etiologies, which may also present with this feature.¹ Neural tube defects and strawberry-shaped calvarium may be seen with trisomy 18,^15,16 and posterior fossa abnormalities with trisomy 13,¹¹ trisomy 18,¹⁰ and triploidy.¹⁷ More rare CNS anomalies that have been reported in association with NIHF include hydrocephalus with Turner syndrome,¹⁸ achondrogenesis,¹⁹ and mucopolysaccharidosis type VII;²⁰ holoprosencephaly with trisomy 13¹¹ and short-rib thoracic dysplasia;²¹ occipital encephalocele with Meckel Gruber syndrome;^22,23 and microcephaly with Smith Lemli Opitz syndrome.²⁴ Additional features of genetic syndromes reported in association with NIHF are outlined in further detail in Table 1.

Cardiovascular

Cardiac anomalies are the most common type of structural anomaly seen with NIHF, present in about 17–35% of cases.^1,25 Structural cardiac abnormalities may lead to impaired venous return or other dysfunction, leading to NIHF. Associated cardiac anomalies may also be mild, and not necessarily the primary cause of the hydrops. It is particularly important to investigate for an underlying genetic abnormality that explains the presence of both the cardiac anomaly and the NIHF.

Cardiac rhabdomyomas are classically associated with tuberous sclerosis, and may present with NIHF.²⁶ Cardiomyopathy in association with NIHF has been reported with arthrogryposis,²⁷ mitochondrial disorders such as Barth syndrome,²⁸ RASopathies such as Noonan and Costello syndrome,²⁹ lysosomal storage disorders such as mucopolysaccharidosis type VII,²⁰ and other single gene disorders.^30,31 Truncus arteriosus and interrupted aortic arch can be seen with NIHF in the setting of 22q11 microdeletion syndrome.³² Pulmonary valve or supravalvular pulmonary stenosis have been well described with RASopathies, such as Noonan and Casitas B-cell lymphoma (CBL) syndrome, which are among the more common genetic syndromes underlying NIHF.^33,34 Cardiac arrhythmias may also lead to NIHF, with genetic etiologies including Costello, Barth, long QT, and Wolff-Parkinson White syndromes.^{22,28,35–37} More rarely reported vascular disorders associated with NIHF include: Klippel-Trenaunay-Weber syndrome,⁹³ RASA1-related disorders,³⁸ and PIK3CA-associated segmental overgrowth syndromes.¹³ Further details as well as other more rare genetic etiologies of cardiovascular anomalies and NIHF are listed in Table 1.

Pulmonary and Thoracic

Pulmonary and thoracic anomalies are seen in approximately 6% of NIHF cases.¹ Anomalies such as congenital pulmonary airway malformation (CPAM), congenital diaphragmatic hernia (CDH) or congenital highway airway obstruction syndrome (CHAOS), can obstruct blood flow or fetal swallowing of amniotic fluid. CPAMs have not been reported as part of specific genetic disorders, but the genes HOXB-5, FGF-7 and PDGFB have been implicated in their development.³⁹ CDH is associated with NIHF in a number of genetic disorders, including Pallister-Killian syndrome, Fryns syndrome, and deletions such as 1p21.1p12.^40–42 CHAOS has been reported with NIHF and an underlying diagnosis of VACTERL association (Vertebral defects, Anal atresia, Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities), as well as with several rare genetic disorders.^43,44 Pleural effusions are seen in association with a number of genetic etiologies, and are discussed further under the Lymphatic section below.

Gastrointestinal

Gastrointestinal (GI) anomalies are seen infrequently with NIHF, comprising 0.5–4% of cases.¹ Mechanisms suggested to lead to NIHF with GI anomalies include venous congestion, decreased hepatic function, hypoalbuminemia, and intrahepatic proliferation of metabolites.¹ Lysosomal storage disorders (LSD) are an increasingly recognized underlying etiology of NIHF, occurring in up to 29.6% of otherwise unexplained NIHF cases when a comprehensive work up is performed for these metabolic disorders.⁴⁵ LSDs may present with fetal hepatosplenomegaly due to accumulation of metabolites, and have been reported to present with isolated ascites as well.⁴⁶ Hepatomegaly has been also reported in association with NIHF and trisomy 21,⁴⁷ possibly due to transient myeloproliferative disorder, and has also been reported in association with skeletal and hematologic disorders (Table 1).^48–50 Duodenal atresia may be seen in trisomy 21,⁵¹ and fetal omphalocele with Beckwith Wiedemann syndrome⁵² or aneuploidy. Other more rarely reported GI anomalies in association with NIHF are listed in Table 1.

Genitourinary and Renal

Genitourinary (GU) and renal anomalies are seen infrequently with NIHF, reported in approximately 2–3% of cases.¹ Congenital nephrosis presents with enlarged, hyperechoic kidneys and an elevated maternal serum alpha feto-protein (MSAFP), and can lead to fetal hypoproteinemia, decreased oncotic pressure, and ultimately NIHF. Fraser syndrome may present with renal agenesis and NIHF.^10,43,53 NIHF has been described in association with Bartter syndrome,⁵⁴ in which renal cysts may be seen prenatally. Finally, enlarged, multicystic kidneys have been reported with NIHF in the setting of both Meckel Gruber syndrome^22,23 and infantile polycystic kidney disease.⁵⁵ Additional details are listed in Table 1.

Musculoskeletal

Musculoskeletal anomalies are present in approximately 3–4% of NIHF cases.¹ A variety of skeletal dysplasias and fetal movement disorders have been reported in association with NIHF, through hypothesized mechanisms including a small chest with increased intra-thoracic pressure and obstructed venous return, or intrahepatic proliferation of blood cell precursors due to small bone marrow volume leading to volume overload and heart failure.¹

A wide variety of skeletal dysplasias have been reported in the setting of NIHF, such as thanatophoric dysplasia and achondrogenesis.^19,56 Fetal movement disorders have also been associated with NIHF, including lethal multiple pterygium syndrome, fetal akinesia/hypokinesia sequence (Pena-Shokeir type I), and myotonic dystrophy.^57–60 Examples of specific abnormalities of the musculoskeletal system seen in disorders associated with NIHF are: rocker bottom feet and clenched hands with trisomy 18,¹⁰ undermineralization of bone and fractures with osteogenesis imperfecta,⁴⁸ shortened long bones with congenital disorders of glycosylation type 1,⁶¹ contractures with arthrogryposis,⁵⁹ and limb asymmetry with PIK3CA-associated segmental overgrowth syndromes.¹³ Table 1 lists further details of typical features associated with skeletal dysplasias and fetal akinesia sequences associated with NIHF.

Hematologic

Hematologic disorders are a more common cause of NIHF, implicated in approximately 4–12% of cases. Causes of anemia vary, and include genetic disorders, infections, vascular malformations, and fetomaternal hemorrhage. Anemia is suggested when the middle cerebral artery peak systolic velocity is elevated, reaching 1.5 multiples of the median or higher for the gestational age.

Alpha thalassemia is common worldwide, particularly in Southeast Asian populations. Hemoglobin Bart syndrome occurs with the loss of all 4 α-globin genes, and hemoglobin H disease occurs with the loss of 3 α-globin genes, leading to a greater proportion of ineffective hemoglobin in Bart form. NIHF may be seen with both hemoglobin Bart and hemoglobin H disease, although is more common with hemoglobin Bart.⁶² Transient abnormal myelopoeisis may present with fetal anemia and NIHF in the setting of trisomy 21.⁶³ Other genetic disorders that may lead to anemia and NIHF are listed in Table 1, such as Diamond Blackfan anemia,⁶⁴ pyruvate kinase deficiency,⁵⁰ and congenital dyserythropoietic anemias.⁶⁵

Lymphatic

Lymphatic vessel dysplasia or obstruction leads to NIHF in approximately 5–6% of cases.¹ Ultrasound findings may include increased nuchal translucency or nuchal fold, cystic hygroma, chylothorax, or NIHF. Cystic hygromas are particularly common in the setting of Turner syndrome,⁵³ but are also seen with other genetic syndromes including multiple pterygium syndrome,⁵⁸ generalized lymphatic dysplasia,⁶⁶ and RASopathies such as Noonan syndrome.³³

Another feature that is common among RASopathies is hydrothorax, chylothorax, or pleural effusion. Fetal chylothorax has also been observed with yellow nail syndrome,⁶⁷ ITGA9 variants,⁶⁸ and hypotrichosis-lymphedema-telangiectasia syndrome.⁶⁹ Recent studies have demonstrated PIEZO1 variants to be associated with generalized lymphatic dysplasia, likely resulting from abnormal electrical currents through ion channels on the plasma membrane.^66,70,71 Additional rare lymphedema syndromes reported to present with NIHF are listed in Table 1, such as hereditary lymphedema IA (Milroy disease),⁷² primary lymphedema (Emberger syndrome),⁷³ and Hennekam lymphangiectasia-lymphedema syndrome.⁷⁴

Skin

Although skin manifestations beyond edema are quite rare in cases of NIHF, there are several that should be mentioned. Enlargement of soft tissues in the limb as well as lipomatous truncal masses can be seen in PIK3CA-associated mutations,¹³ and cutaneous cystic lesions with multiple pterygium and Klippel-Trenaunay-Weber syndromes.⁷⁵ Severe cases of ichthyosis have been reported in the setting of NIHF with Neu-Laxova,^57,76 Gaucher,⁷⁷ and sphingosine-1-phosphate lyase deficiency syndromes.⁷⁸ Echogenic debris representing large sheets of sloughed skin cells may be observed on ultrasound in the amniotic fluid in these cases.

Fetal tumors

Fetal and placental tumors constitute approximately 2–7% of all NIHF cases.^1,79 These tumors are highly vascular, and can lead to shunting and sequestering of blood followed by high-output cardiac failure and NIHF. Fetal teratomas are the most commonly reported, occurring in the sacrococcygeal, mediastinal, cardiac, and intracranial regions. While many teratomas result from postzygotic somatic mutations, germline mutations have also been reported.

Sacrococcygeal teratomas are an especially common cause of NIHF, and reported genetic etiologies include MNX1 variants,⁸⁰ partial monosomy 7q/trisomy 2p,⁸¹ and Cornelia de Lange syndrome.^82,83 Other tumors occurring with NIHF include neuroblastomas, hemangiomas, fibrosarcomas, and rhabdomyosarcomas.⁷⁹ Examples of chromosome imbalances reported in association with fetal tumors and NIHF include a translocation between chromosomes 2q35 and 8q21.2 in a fetus with a cervical rhabdomyosarcoma,⁸⁴ a mosaic ring X chromosome in a fetus with an epignathus teratoma,⁸⁵ and a 22q11.2 deletion in a fetus with a rhabdoid tumor.⁸⁶

Placenta

Many cases of NIHF are associated with placentomegaly, likely resulting from intravillous edema. On the other hand, severe polyhydramnios may compress the placenta and cause it to appear thinned or compressed.

Fetal triploidy can be associated with placentomegaly when the extra chromosomal material is diandric, or paternally inherited.¹² Beckwith Wiedemann syndrome can present with NIHF and placental cysts, in addition to other structural anomalies.⁵² Klippel-Trenaunay-Weber syndrome may present with placental hemangiomas.⁷⁵ Other infrequent placental and umbilical cord lesions that have been associated with NIHF include chorioangioma, angiomyxoma of the umbilical cord, and aneurysm of the umbilical artery.¹

GENETIC EVALUATION OF NIHF

The morbidity, mortality, and recurrence risk for NIHF varies widely by underlying etiology.^1,3,6 Determining the specific cause is essential in order to counsel families about prognosis and recurrence risk, guide decision-making, provide targeted antenatal care, and anticipate neonatal needs. The genetic evaluation of NIHF includes a detailed family and obstetric history, imaging to identify additional phenotypic features, and step-wise laboratory evaluations to address the spectrum of genetic and structural etiologies that contribute to NIHF. The Society for Maternal-Fetal Medicine has published guidelines for the evaluation of NIHF cases to address the heterogeneous group of potential etiologies.¹ The approach to evaluation in this review is focused specifically on the range of genetic factors leading to NIHF.

Family and Obstetric History

A detailed family history is an essential component of the NIHF evaluation, and can yield important information to narrow the differential diagnosis. In particular, attention should be focused on a family history of recurrent pregnancy losses, stillbirths, hydrops, specific genetic diagnoses, developmental delay or regression, dysmorphic features, and early deaths. Detailed collection of information about prior pregnancies is also essential, with attention paid to similar details as well as imaging results and laboratory data. For living children that were affected by hydrops in utero, phenotypic data such as dysmorphic features, developmental progress, and comorbidities may also be informative. Finally, a pedigree is integral to understanding inheritance patterns of disease.

Imaging and Prenatal Phenotyping

Hydrops is formally diagnosed when at least two abnormal fetal fluid collections are present, including ascites, pleural effusion, pericardial effusion, or skin edema (skin thickness > 5mm) (Figure 1).¹ While polyhydramnios and placentomegaly (placental thickness ≥ 4cm in the second trimester, or ≥ 6cm in the third trimester) are often seen in conjunction with these abnormal fluid collections, they are not strictly part of the diagnostic criteria. NIHF can present at any point during pregnancy. In a recent review of 65 NIHF cases, the median gestational age at diagnosis was 22 weeks, ranging from 11 to 37 weeks.⁷ Early findings of NIHF may include cystic hygroma, which is commonly seen with aneuploidy. However, NIHF may occur at any point during pregnancy with a multitude of genetic disorders.

Figure 1.

Abnormal fetal fluid collections in hydrops.

(a) Pericardial effusion. (b) Pleural effusions. (c) Ascites. (d) Skin edema.

Hydrops is formally diagnosed when at least two abnormal fetal fluid collections are present, including ascites, pleural effusion, pericardial effusion, or skin edema (skin thickness > 5mm).

Obstetric ultrasound evaluation of the fetus with NIHF should be detailed and systematic, addressing each organ system, in order to detect any concurrent structural anomalies as discussed above. Because of the frequency with which cardiac anomalies are seen in conjunction with NIHF, fetal echocardiogram is additionally recommended.¹ In addition to identifying structural anomalies of the heart, fetal echocardiogram is useful for detecting cardiomyopathy, high output failure, arrhythmias, and other abnormalities that may lead to NIHF. Middle cerebral artery (MCA) Doppler assessment is a critical component of the ultrasound evaluation, as elevation suggests the presence of anemia and a different subset of etiologies.¹ The presence of appropriate fetal movements should be noted, to assure a fetal akinesia syndrome is not present.

As discussed above, NIHF is often not diagnosed until the second trimester of pregnancy or later.⁷ As a result, ultrasonographic evaluations are often performed during the second and third trimesters. However, hydrops can also be detected in the first trimester and early ultrasound can be helpful in situations where a prior pregnancy was affected with NIHF, when early evidence of hydrops is present such as with a cystic hygroma, or if structural anomalies are suspected.^87–89 Additional imaging modalities such as three- and four-dimensional ultrasound, as well as magnetic resonance imagining (MRI), have been investigated as potential ways to improve prenatal diagnosis of concurrent structural anomalies.^23,90,91 While the situations in which these modalities are most useful have not been defined, fetal MRI does appear promising in cases where intracranial anomalies are suspected, and may provide additional information about cortical sulcation, gyration, leukomalacia, vascular defects, and other differences.^90,91

Prenatal phenotyping is key in the evaluation, meaning the identification of prenatal features unique to each case that allows providers to narrow the differential diagnosis and target further testing. In addition to information gained from imaging, prenatal phenotyping may include maternal serum screening results that suggest a specific disorder or range of disorders, such as elevated MSAFP with congenital nephrosis or ichthyoses, or low maternal serum unconjugated estriol with metabolic disorders.^92,93 Accurate phenotyping can be more challenging in the prenatal setting though, and is sometimes limited to those features detectable through prenatal imaging. Subtle dysmorphic features and more minor fetal structural anomalies may be missed with standard prenatal ultrasound. Some anomalies become evident in later gestational ages, genetic disorders with variable expressivity or incomplete penetrance may present differently and thus be missed, and prenatal imaging cannot predict certain features such as developmental delay or intellectual disability.^8,94,95 Finally, an important component of phenotyping is fetal autopsy in cases for which a live birth is not the outcome. Fetal autopsy can supplement other diagnostic tests by confirming the presence of structural anomalies and other features, as well as by identifying additional anomalies that were not previously recognized on prenatal imaging.^96–98 Autopsy is further discussed in the Pathology section below.

Importantly, structural anomalies of the fetus are often cited as the underlying cause of the NIHF. However, in many cases where fetal structural anomalies are observed in conjunction with NIHF, it is unclear whether the structural anomaly itself is truly causative of the NIHF. Further, the genetic or environmental etiology of the structural anomaly itself remains unexplained in many of these cases.⁷ As a result, genetic testing is an essential component of the NIHF evaluation.

Biochemical, Cytogenetic and Molecular genetic testing

A thorough approach to genetic testing is integral to establishing a diagnosis in cases of NIHF. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recommend that chromosomal microarray (CMA) is offered in place of karyotype as the primary genetic test for patients undergoing prenatal diagnosis for a fetal structural abnormality seen on ultrasound examination.^99,100 CMA has greater resolution than karyotype, and is able to detect copy number variants (CNVs), submicroscopic deletions and duplications (as small as 50 – 100 kb), that are much smaller than seen with karyotype.⁹⁹ A large cohort study demonstrated an incremental yield of 6% when CMA was used for establishing a genetic diagnosis in cases of fetal structural anomalies.¹⁰¹

The yield of CMA for cases of NIHF, however, has not specifically been investigated, but may be in the range of 6 to 14% based on cohort studies of all anomalies.^7,107 Also unclear is how much CMA adds to the diagnostic yield of karyotype for NIHF cases beyond detection of aneuploidy.⁷ This likely reflects the heterogeneous group of genetic etiologies that underlie NIHF, including single gene disorders that CMA is not able to detect. For example, 19% of all NIHF cases have been attributed to rare genetic syndromes and nearly one-third of idiopathic NIHF cases to LSDs,^45,103 the vast majority of which are not detected by CMA. Despite these limitations, karyotype and CMA are still useful first-line tests for evaluation, given the 7–17% of NIHF cases that result from chromosomal abnormalities or copy number variants that are detectable with these tests.^1,7

As discussed above, the constellation of affected organ systems and other phenotypic data may suggest a more specific genetic disorder or category. In such situations, testing strategies may include single gene sequencing or genotyping, multiple gene sequencing or genotyping through panels, or testing for specific deletions or duplications as appropriate for the disorders under consideration. For example, RASopathies such as Noonan syndrome and Costello syndrome may present with NIHF and other lymphatic disturbances.¹⁰⁴ When features such as increased nuchal translucency, NIHF, polyhydramnios, and cardiac defects are seen, genetic sequencing for genes such as PTPN11, KRAS, and RIT1 associated with the RASopathies should be considered.^33,104,105 Occasionally, the family or obstetric history will include prior identification of a specific variant, in which case targeted genotyping for the familial variant may be performed if consistent with the presentation in the currently affected pregnancy.

Some commercial laboratories offer gene panels to analyze a group of genes implicated in NIHF development, although the yield of these panels has not been well-studied. In one retrospective review, next-generation sequencing was performed for 41 genes associated with inborn errors of metabolism and NIHF, which led to a diagnosis in 12.5% of cases sequenced.¹⁰⁶ Genes included on commercially available panels vary from one to the next, and additional research is needed to determine which genes should be included.

Enzyme assays and other biochemical tests to assess for LSDs are also available, although limitations include availability on a commercial basis for prenatal samples, standardized protocols for analysis, handling of isoenzymes, and prenatal reference ranges for interpretation.^107,108 A systematic review of NIHF publications from 1979 to 2014 found that LSDs were reported to underlie NIHF in 5.2% cases, but that when a comprehensive work up was completed for this category of disorders, 29.6% of idiopathic cases were attributable to a LSD.⁴⁵ LSDs are thus an important consideration in the differential diagnosis of NIHF, although the clinical availability of prenatal enzyme assays has decreased in lieu of molecular testing given the limitations noted above. However, it is important to note that enzyme assays may still provide important information to establish a diagnosis in situations such as when a variant of uncertain significance is identified in a gene of interest.

Whole exome sequencing (WES) has become more widely used in the prenatal setting in recent years, and has the potential to yield clinically useful information about underlying genetic variants. WES sequences the exome, or the protein-coding regions of the genome. Prenatal phenotyping is an essential component of WES interpretation, and availability of detailed phenotypic data significantly improves the diagnostic yield.^70,109,110 WES has not been applied specifically to a cohort of NIHF cases, although it has been used in studies considering a range of fetal anomalies including NIHF. In cohorts of all prenatal anomalies, WES has demonstrated a clear or likely diagnostic yield in 9 to 47% of cases when microarray and/or karyotype are normal.^{70,109,111–113} A recently published large prospective cohort study demonstrated a yield of 8.5% for diagnostic genetic variants in fetuses with a variety of structural anomalies, and the diagnostic yield specifically for the NIHF cases within this cohort was 9%.¹¹³ Finally, among a cohort of deceased fetuses with anomalies undergoing WES, 41% of cases with pathogenic variants and 31% of cases with variants in candidate genes had hydrops.¹¹⁴

For cases in which clinically relevant variants are not found, re-analysis is cost-effective at an interval of 12 months in postnatal settings,¹¹⁵ although the optimal interval for re-analysis based primarily on prenatal phenotypic data remains unclear. Limitations of WES include that it is not designed to detect CNVs or sequence intronic regions, and it relies on adequate probe density as well as accurate phenotypic data.¹¹⁶ While WES has not yet been studied specifically in a cohort of NIHF cases to determine its diagnostic utility or cost effectiveness, it should be considered for cases in which a genetic etiology is suspected but standard testing is unrevealing.¹¹⁷

Pathology

Evaluation of the placenta as well as fetal autopsy through detailed pathology examination may yield further important data for establishing a diagnosis in cases of NIHF. One study found that fetal autopsy identified a definitive cause in 58% of NIHF cases.⁹⁶ Chromosome abnormalities were the most frequent etiology, followed by single structural anomalies, multiple structural anomalies, and lysosomal storage disorders. Specialized techniques such as immunohistochemical staining to detect lymphatic dysplasia can significantly improve the ability of autopsy to establish a diagnosis.¹¹⁸ Detailed examination of the placenta may also identify changes that suggest a cause of the NIHF, such as placental chorioangioma, vacuolization of placental cells as seen with LSDs, or lymphedema of the villi associated with genetic abnormalities or congenital anomalies.^119–121

MANAGEMENT

Central to developing a management plan for pregnancies with NIHF is determining the underlying cause. For some genetic disorders, interventions to improve outcomes are not available either before or after birth. However, for others, antenatal or postnatal interventions are available, sometimes with greater effects on outcomes the earlier an intervention is initiated.

A discussion of the options for in utero intervention for the range of fetal anomalies associated with NIHF is beyond the scope of this paper. However, examples of situations in which in utero interventions may be applied include maternal antiarrhythmic medications for fetal arrhythmias, intrauterine transfusions for genetic disorders causing fetal anemia, and drainage or shunt placement for fetal pleural effusion or chylothorax. Further, in utero enzyme replacement therapy (ERT), as well as in utero stem cell transplantation and gene therapy, are active areas of research that have the potential to improve the in utero and neonatal course in cases of NIHF.^122–125

When determining an overall management plan for pregnancies with NIHF, it is essential to factor in the underlying cause and anticipated prognosis, so the options presented and decisions made are consistent with a realistic assessment of the outcome. Cases with a diagnosis of a serious or potentially lethal genetic syndrome should be offered termination, or a discussion of comfort care if termination is not pursued. For continuing pregnancies, cases in which in utero intervention is available and desired should be referred to an institution with appropriate expertise. More general recommendations for timing and mode of delivery with NIHF, as well as antenatal testing and other considerations, have been outlined in guidelines published by the Society for Maternal-Fetal Medicine.¹ Discussions for continuing pregnancies with NIHF should further include plans for monitoring during labor, location of delivery, mode of delivery, specialists needed at delivery, and neonatal resuscitation.

In some cases with identified genetic disorders, prompt initiation of an established treatment protocol, or enrollment in a research study protocol, may be beneficial for the outcomes of the affected neonate. For example, neonates with NIHF resulting from an arrhythmia can be managed medically and surveilled for cardiac events that impose risk. Protocols to screen for malignancies can be implemented early on for cases of NIHF resulting from PIK3CA-associated segmental overgrowth syndromes or other syndromes associated with greater risk of malignant transformation. Enzyme replacement therapy can be efficiently prepared and administered in neonates with NIHF resulting from a LSD such as mucopolysaccharidosis type VII, when a postnatal treatment is available. Individuals with LSDs in particular are known to benefit from early diagnosis and initiation of treatment after birth, in order to mitigate some of the more severe manifestations of disease.¹²⁶

CONCLUSION

It is well known that a heterogeneous group of underlying genetic disorders may lead to NIHF. A systematic approach is warranted for the evaluation of each case, considering personal and family history, concurrent structural anomalies, additional phenotypic features, and genetic testing as well as pathology examinations. Particularly important to consider are the unique phenotypic features of each case, as these may guide the approach to genetic testing and the interpretation of testing in many scenarios. Establishing a genetic diagnosis allows providers to improve the care for these fetuses and neonates by more accurately characterizing prognosis, anticipating neonatal needs, and implementing available treatments earlier. Moving forward, research to improve prenatal phenotyping, identify the underlying genetic cause in idiopathic cases, and revise the algorithm for genetic evaluation will be instrumental for better understanding and managing NIHF.

What is already known about this topic?

A wide spectrum of genetic etiologies may lead to non-immune hydrops fetalis. A thorough genetic evaluation is essential to determine the underlying etiology, optimally manage these pregnancies, and inform discussions about prognosis. Considering the unique phenotypic features in each case can aid in establishing the underlying genetic diagnosis.

What does this study add?

This review provides a systematic approach to the genetic evaluation of NIHF, focusing on structural anomalies by system and the genetic underpinnings of disease. This allows providers to approach each NIHF case in a way that considers the unique constellation of phenotypic features by organ system, and guides a targeted approach to genetic evaluation, diagnosis, and management.