Cystic Hygroma

Nuchal cystic hygroma (CH) is an ultrasound anomaly defined after 14 weeks’ gestation as a sonolucent mass in the soft tissue of the occipital region with symmetrical cavities separated by a midline septum, with or without internal trabeculae (multiloculated cysts)(1). Before 14 weeks CH appears is equivalent to a very large septated nuchal translucency.

Lymphangioma, any site D18.1

The prevalence of first trimester cystic hygroma is 1 in 285 pregnancies in a general population of 38,000 unselected pregnancies undergoing first trimester ultrasonography(2). The incidence in the second trimester is much lower as early pregnancy losses may already have occurred. Incidence at birth is 1/6000.

Cystic hygroma is a malformation of the lymphatic system characterized by overdistention of the jugular lymphatic sacs as a consequence of failure of communication with the internal jugular vein (3). Secondary dilatation of the lymphatic channels draining the chest and limbs results in peripheral lymphedema and development of non-immune hydrops, which is found in about 75% of affected fetuses(3).
 

In view of the association with certain aneuploidies (trisomy 21, 18) the risk is increased in women of advanced maternal age (4). If cystic hygroma is part of a genetic syndrome the risk may be increased depending on the inheritance pattern or the type of syndrome. Turner syndrome, another commonly associated chromosomal anomaly does not occur more often in older women.

The ultrasound diagnosis of fetal cystic hygroma was described for the first time in 1983(5) and a later report in 1991 indicated the high association with chromosomal and structural anomalies (6).

In the first trimester CH can present itself as a very large septated nuchal translucency and sometimes the two terms are used interchangeably (2),(7). As both conditions carry the same prognosis in view of the high association with chromosomal anomalies, poor pregnancy outcome and because of the identical diagnostic approach, a distinction between a very thick NT and first trimester cystic hygroma seems unnecessary. In fact, in the first trimester, the prognosis is rather determined by the thickness of the nuchal translucency rather than by the presence or number of septations (7).
In the second trimester CH is defined as the macrocystic form of a lymphangioma and consists of large transonic areas with a midline septation best seen in transverse views of the fetal neck (8). Cystic hygroma is measured at its thickest part on a transverse view of the fetal neck. 

Color Doppler demonstrates no obvious internal flow in cystic hygromas, which helps distinguish them from hemangiomas (8).
Commonly associated findings include cardiac abnormalities, hydrothorax, ascites, generalized edema and hydropic changes (8) . 

Cystic hygroma is classified as a macrocystic lymphangioma, not to be confused with the cavernous lymphangioma a mass which is more commonly asymmetrical and consisting of a conglomerate of micro and microcystic lymphatic malformation with haemorrhagic fields. The cavernous lymphangioma usually originates from the oral cavity, face, neck with possible extension to the axilla and mediastinum.
 

Very thickened nuchal translucency in the first trimester, encephalocele, cavernous lymphangioma, hemangioma or cervical teratoma (4,9). 

Cystic hygroma is associated with abnormal karyotypes, genetic syndromes and structural abnormalities. These factors increase the risk of miscarriage, fetal demise, hydrops fetalis and neonatal death.

Karyotypic abnormalities occur more frequently when the anomaly is seen for the first time in the first trimester (60%) (10) rather than in the second (40%), with trisomies (trisomy 21) being more predominant in first trimester very thick NT and Turner syndrome in CH seen in the second trimester (11).
Other karyotype abnormalities include other trisomies (18,13), deletions, duplications, unbalanced translocations, inversions, and other types of sex chromosome abnormalities. (8)

Genetic syndromes can explain some of the cases with normal karyotype. The most common is Noonan syndrome, but cystic hygroma have also been described in fetuses with Cornelia de Lange, Fryns syndrome, multiple pterygium syndrome, and skeletal anomalies (8). 

Associated major congenital anomalies are found in 44% of fetuses with abnormal karyotypes (12) compared to 13-29% of those with normal karyotypes (10). Cardiac anomalies are the most common form of major congenital anomaly, followed by urinary, central nervous system, skeletal etc.(12). 

Spontaneous resolution is reported in 10% of the aneuploid cases and 18% of the euploid cases. In mild CH cases spontaneous resolution in the second/early third trimester is more likely to occur. This has also been described in some Turner syndrome (13) and some Noonan syndrome cases resulting in live births.

Cystic hygroma carries a poor prognosis in view of the high association with aneuploidies, genetic syndromes and cardiac or other defects. In the few (mild) cases with spontaneous prenatal resolution normal neonatal outcome is possible but extensive detailed diagnostic evaluation is crucial. 

Poor prognostic factors of cystic hygromas are: 1) deterioration of the initial finding with progressive growth of the cysts 2) progression towards hydrops and 3) association with other major anomalies. 

Although spontaneous resolution is more likely to be related to a better pregnancy outcome, the majority of studies concur that the prognosis is uniformly poor, with only 9% of babies with cystic hygroma surviving without major morbidity (11).

The finding of a CH prompts the offer of genetic investigations by CVS or amniocentesis, according to the moment of diagnosis.

If no numerical chromosomal anomaly is found genetic counselling and extended genetic investigations (arrays CGH, whole-exome sequencing) should be offered, taking into account the presence and sort of associated anomalies.

 An early anatomy scan may be of benefit to rule out major structural anomalies, in conjunction with a more detailed scan between 18-22 weeks.

A fetal Echocardiogram, performed as soon as possible in pregnancy, is advised, in order to rule out any major cardiac anomalies.
Termination of pregnancy should be offered to parents, particularly in cases where  aneuploidy or major structural anomalies are confirmed (14).

For patients opting to continue the pregnancy, an ultrasound follow up every 4 weeks is recommended to detect any hydropic changes in the fetus (15).

Delivery in a tertiary care facility is recommended and should be planned around 38 gestational age or earlier if hydrops develops. Vaginal delivery is not contraindicated unless there is hydrops or large cystic hygromas preventing flexion of the head (15).

No specific in utero fetal interventions are recommended following the diagnosis of cystic hygroma. However, in case of cavernous lymphangioma large cysts could compress the upper respiratory and GI tracts and result in polyhydramnios. Some reports described multiple cyst aspirations and a successful vaginal delivery after decompression (16).

EXIT procedure is an option for neonates who are expected to have obstructed airways (14).

The risk of recurrence mostly depends on the underlying cause. In cases with abnormal karyotyping, there may be a slightly increased risk of recurrence of the specific chromosomal abnormality, but this may not be necessarily accompanied by CH. The recurrence risk for Turner syndrome is not increased. 

In patients with a previous history of cystic hygroma in the setting of a genetic syndrome, the recurrence risk will depend on the inheritance pattern and type of genetic syndrome. A few cases of recurrent CH have been reported in the literature that were thought to be inherited as an autosomal recessive pattern (17).

1.     Ville Y, Lalondrelle C, Doumerc S, Daffos F, Frydman R, Oury JF, et al. First‐trimester diagnosis of nuchal anomalies: significance and fetal outcome. Ultrasound in Obstetrics and Gynecology. 1992;2(5):314–6.
2.     Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade GR, Berkowitz RL, et al. First-Trimester Septated Cystic Hygroma. Obstetrics & Gynecology. 2005;106(2):288–94. 
3.     SC  van der P. Lymphatic malformation in human fetuses. A study of fetuses with Turner’s syndrome or status Bonnevie-Ullrich. Virchows Archiv A, Pathological anatomy and histology. 1977 Sep;376(3):233–46. 
4.     Orgul G, Ozyuncu O, Oktem A, Beksac MS. Management and outcomes of cystic hygromas: experience of a tertiary center. Journal of Ultrasound. 2017. 
5.     Chervenak FA, Isaacson G, Blakemore KJ, Breg WR, Hobbins JC, Berkowitz RL, et al. Fetal Cystic Hygroma. New England Journal of Medicine. 1983 Oct 6;309(14):822–5. 
6.     Azar G.B., Snijders R.J.M., Gosden C., Nicolaides K.H. Fetal nuchal cystic hygromata: associated malformations and chromosomal defects. Fetal diagnosis and therapy. 1991;6(1–2):46–57. 
7.     Molina FS, Avgidou K, Kagan KO, Poggi S, Nicolaides KH. Cystic hygromas, nuchal edema, and nuchal translucency at 11-14 weeks of gestation. Obstetrics and Gynecology. 2006 Mar;107(3):678–83. 
8.     Chen YN, Chen CP, Lin CJ, Chen SW. Prenatal Ultrasound Evaluation and Outcome of Pregnancy with Fetal Cystic Hygromas and Lymphangiomas. Vol. 25, Journal of Medical Ultrasound. 2017. p. 12–5. 
9.     Dordea Leonte L. Fetology. Diagnosis and Management of the Fetal Patient. Vol. 9, Acta Endocrinologica (Bucharest). 2013. p. 657–657. 
10.     Malone CM, Mullers S, Kelliher N, Dalrymple J, O’Beirnes J, Flood K, et al. 1036: Euploid first trimester cystic hygroma - A more benign entity than previously thought? American Journal of Obstetrics and Gynecology. 2019; 
11.     Ganapathy R, Guven M, Sethna F, Vivekananda U, Thilaganathan B. Natural history and outcome of prenatally diagnosed cystic hygroma. Prenatal Diagnosis. 2004 Dec 15;24(12):965–8. 
12.     Scholl J, Durfee SM, Russell MA, Heard AJ, Iyer C, Alammari R, et al. First-trimester cystic hygroma: Relationship of nuchal translucency thickness and outcomes. Obstetrics and Gynecology. 2012; 
13.     Levy AT, Berghella V, Al-Kouatly HB. Outcome of 45,X fetuses with cystic hygroma: A systematic review. American Journal of Medical Genetics, Part A. 2021 Jan 1;185(1):26–32. 
14.     Tayyar A, Tayyar A, Tayyar M. Prenatal management of cystic hygroma and long term outcomes. Medicine Science | International Medical Journal. 2017; 
15.     Fetal Medicine Foundation. The Fetal Medicine Foundation. Accreditation in the 11-13+6 week scan. 2010; 
16.     Paladini D, Volpe P. Ultrasound of Congenital Fetal Anomalies. Ultrasound of Congenital Fetal Anomalies. 2018. 
17.     Dallapiccola B, Zelante L, Perla G, Villani G. Prenatal diagnosis of recurrence of cystic hygroma with normal chromosomes. Prenatal Diagnosis. 1984

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