HYDROPS FETALIS CAUSES

Causes:
• The heterogeneity of this collection of associations is bewildering at first glance. However, the common thread that runs through is useful for the clinician to understand. Thus, the same disturbed pathophysiology identified as causing hydrops in the animal studies is reflected in these conditions.

o Inheritance for most of these conditions (when known) is autosomal, most commonly recessive. Since a few of these conditions are X-linked recessive, slightly more males are affected among this particular set of causes. Gene therapy may hold therapeutic promise for the future; however, outcomes are generally grim for babies with hydrops related to these causes. Accurate diagnosis is particularly important in these babies, despite their poor prognosis, since parental counseling is of critical importance in the management of current and future pregnancies for these families.

o Fetal hydrops has been associated with approximately 10 of the approximately 50 lysosomal storage disorders. Little doubt appears to exist that hydrops will be linked with most such inborn errors of metabolism in the near future.

o Cystic hygroma is often found in several of these conditions. These vascular tumors are associated commonly with complex profound aberrations of lymphatic drainage. They are usually found in the neck but may also be present in the abdomen or thoracic cavity. Two thirds to three fourths of fetuses with this tumor have chromosomal abnormalities (most commonly 45,XO), and those fetuses with normal chromosomes often have major malformations. This association with Turner, Noonan, and lethal multiple pterygium syndromes is particularly notable. Mortality is extremely high (85-96%), but early precise diagnosis is important for purposes of genetic counseling and pregnancy management. The reports of spontaneous remissions with healthy long-term survival are important to note.

• Thoracic and abdominal tumors are common causes of fetal hydrops. This association makes physiologic sense because the location and size of these masses are likely to obstruct the return of venous or lymphatic fluids to the heart. Some are commonly associated with major malformations and/or chromosomal abnormalities and, consequently, have a poor long-term prognosis. For example, upper airway obstructions are associated with other major malformations in more than one half of the cases reported, and the association of fetal rhabdomyomas with tuberous sclerosis and complex cardiac malformations is well recognized.

• Venous return is directly impaired by such conditions as pericardial teratomas and cardiac rhabdomyosarcomas. Upper airway (laryngeal, tracheal) atresia or obstruction leads to massive pulmonary overdistention and, thus, to impaired cardiac filling. Cystic hygromas are mentioned again since they comprise an important and common example of mass compression with obstruction of venous-lymphatic return. This redundancy is excused by the fact that some observers have postulated an association with hydrops on the basis of mass effects on venous return; as noted earlier, the association is almost certainly one with fetal infection and consequent red cell aplasia.

o Some of these conditions may lead to fetal hydrops not because of mass compression effects but because their intense vascularization may lead to arteriovenous shunting and/or to massive fetal hemorrhage. Such consequences are especially common with sacrococcygeal teratomas and with placental chorioangiomas. In both instances, fetal high-output cardiac failure ultimately may lead to fetal hydrops and/or death. Sacrococcygeal teratoma is associated with hydrops in one fifth to one third of cases in several case series; fetal coagulopathy, most commonly thrombocytopenia, is found in approximately the same proportion of cases. Tumor size by sonography has not been demonstrated to be an independent prognostic factor; however, solid, highly vascular tumors lead to hydrops more often than those with a more cystic, less vascular structure.

o Since chromosomal abnormalities and life-threatening anomalies are rare with sacrococcygeal sequestration, early diagnosis and aggressive fetal treatment are particularly important with this condition. While bloody AF secondary to rupture of the highly vascular teratoma is not uncommon, diagnosis in most cases has been made only after hydrops has developed.

o Early routine fetal imaging may be the only way in which early diagnosis can be made in this condition; however, the low incidence of sacrococcygeal teratoma may preclude cost-effective screening for this condition. Elevated concentrations of alpha-fetoprotein (AFP) and/or acetylcholinesterase in AF have been found to accompany fetal sacrococcygeal teratoma, but the invasive sampling and low specificity appears to preclude these tests as routine screening procedures. While placental chorioangiomas are common (present in approximately 1% of pregnancies), large vascular tumors with cardiovascular and hematologic consequences are very uncommon. When present, the pathophysiology is remarkably similar to that found with fetal sacrococcygeal teratomas. Diagnosis and techniques for early intervention are also similar.

• Bronchopulmonary sequestration is a condition in which abnormal vascular supply and misplacement of a portion of the lung may lead to torsion of the affected lobes, profound obstruction of lymphatic and venous return, and tension hydrothorax. This sequence of events leads to fetal hydrops in perhaps one third of such cases. Although drainage of the hydrothorax, definitive diagnosis using color Doppler imaging, and fetal angiography have been described, and though fetal surgical excision of the affected portion of the lung may improve survival in this condition, nearly two thirds of these cases fail to be diagnosed before fetal death or birth occurs.

• Cystic adenomatoid malformation of the lung may also lead to hydrops by mass compression of venous return. Because this condition is seldom associated with other malformations or with chromosomal abnormalities and because fetal surgical maneuvers have demonstrated considerable promise with some forms of the disorder, early and precise diagnosis using fetal imaging techniques is of critical importance. Pulmonary capillary-alveolar development is abnormal in this condition, and 3 degrees of severity, described initially by Stocker, have been used to predict prognosis.

o Type I: The fetus with large (>2 mm), isolated cysts seldom develops hydrops, and spontaneous remissions have been reported. Drainage or excision of individual cysts has also been reported with generally favorable outcomes.

o Type II: Poorer prognosis is associated in the fetus with smaller (<2 mm) diffuse macrocysts, and isolated fetal pulmonary excisions have been proposed in those who develop hydrops.

o Type III: In the fetus with microcystic disease, the affected lung appears solid, hydrops is common, and outcome is generally unfavorable.

• Compression of fetal lung, not only impairs cardiac return but also has an additional particularly serious consequence. External compression of developing fetal lung is known to impair both anatomic and biochemical maturation. Pulmonary hypoplasia, with a profound reduction in the number of functional alveolar units, is a common finding when fetal hydrops accompanies these conditions. Delayed or impaired maturation of pulmonary surfactant production is another consequence of impaired expansion of the fetal lung, thus worsening the already serious compromise of extreme prematurity in these babies.

hydrops fetalis genetic causes :
Inborn errors of metabolism
o Glycogen-storage disease, type IV
o Lysosomal storage diseases
�� Gaucher disease, type II (glucocerebroside deficiency)
�� Morquio disease (mucopolysaccharidosis, type IV-A)
�� Hurler syndrome (mucopolysaccharidosis, type 1H; alpha1 - iduronidase deficiency)
�� Sly syndrome (mucopolysaccharidosis, type VII; beta-glucuronidase deficiency
�� Farber disease (disseminated lipogranulomatosis)
�� GM1 gangliosidosis, type I (beta-galactosidase deficiency)
�� Mucolipidosis I
�� I-cell disease (mucolipidosis II)
�� Niemann-Pick disease, type C
o Salla disease (infantile sialic acid storage disorder [ISSD] or sialic acid storage disease, neuroaminidase deficiency)
o Hypothyroidism and hyperthyroidism
o Carnitine deficiency

Chromosomal syndromes
o Beckwith-Wiedemann syndrome (trisomy 11p15)
o Cri-du-chat syndrome (chromosomes 4 and 5)
o Dehydrated hereditary stomatocytosis (16q23-qter)
o Opitz G syndrome (5p duplication)
o Pallister-Killian syndrome (isochrome 12p mosaicism)
o Trisomy 10, mosaic
o Trisomy 13
o Trisomy 15
o Trisomy 18
o Trisomy 21 (Down syndrome)
o Turner syndrome (45, X)

Genetic syndromes (autosomal recessive, unless otherwise noted)
o Achondrogenesis, type IB (Parenti-Fraccaro syndrome)
o Achondrogenesis, type II (Langer-Saldino syndrome)
o Arthrogryposis multiplex congenita, Toriello-Bauserman type
o Arthrogryposis multiplex congenita, with congenital muscular dystrophy
o Beemer-Langer (familial short-rib syndrome)
o Blomstrand chondrodysplasia
o Caffey disease (infantile cortical hyperostosis; uncertain inheritance)
o Coffin-Lowry syndrome (X-linked dominant)
o Cumming syndrome
o Eagle-Barrett syndrome (prune-belly syndrome; since 97% males, probably X-linked)
o Familial perinatal hemochromatosis
o Fraser syndrome
o Fryns syndrome
o Greenberg dysplasia
o Lethal congenital contracture syndrome
o Lethal multiple pterygium syndrome (excess of males, so probably X-linked)
o Lethal short-limbed dwarfism
o McKusick-Kaufman syndrome
o Myotonic dystrophy (autosomal dominant)
o Nemaline myopathy with fetal akinesia sequence
o Noonan syndrome (autosomal dominant with variable penetrance)
o Perlman/familial nephroblastomatosis syndrome (inheritance uncertain)
o Simpson-Golabi-Behmel syndrome (X-linked [Xp22 or Xp26])
o Sjögren syndrome A (uncertain inheritance)
o Smith-Lemli-Opitz syndrome
o Tuberous sclerosis (autosomal dominant)
o Yellow nail dystrophy with lymphedema syndrome (autosomal dominant)