Klippel‐Trénaunay‐Weber Syndrome: Prenatal Diagnosis and Review of the Literature

ABSTRACT

Klippel‐Trénaunay‐Weber syndrome (KTW) is a rare congenital disease, representing a challenge in prenatal diagnosis due to overlapping characteristics with other syndromes and no specific genetic markers known to date. We have collected all the cases present in the literature on the prenatal diagnosis of KTW, emphasizing common ultrasound findings that can guide the clinician and genetics to the prenatal counseling. Thus, we collected all the information about the postnatal prognosis and the necessity for treatment. Our review of 44 cases highlights the typical common features: hemihypertrophy, predominantly affecting the right leg, with cystic lesions extending to the trunk or upper limbs and rare internal organ involvement. Prenatal complications, including hydrops and polyhydramnios, emphasize the need for a careful ultrasound follow‐up. Despite no identified genetic mutation, genetic counseling and invasive testing are recommended. Mortality rate due to a severe complication known as Kasabach‐Merritt syndrome, underlines the importance of early diagnosis and accurate management strategies. Prenatal diagnosis of KTW, guided by ultrasound findings and genetic counseling, could help with informed decision‐making and optimal care planning.

This meta‐analysis demonstrates the high diagnostic accuracy of SZ‐CEUS for differentiating between malignant and benign focal liver lesions, as well as for HCC from non‐HCC lesions. The study shows better performance for smaller lesions and those with a higher proportion of malignancy.

1. Introduction

The Klippel‐Trénaunay‐Weber syndrome (KTW), also known as “hemangiectatic hypertrophy syndrome” and “angio‐osteohypertrophy syndrome”, is a rare and congenital disease, first described by Maurice Klippel and Paul Trénaunay in 1900. The incidence has been estimated at around 2–5:100000 [1]. This syndrome has a sporadic incidence without any racial or sex predilection [2] and it is characterized by typical features: port wine stains/capillary, venous malformation or varicosities, and limb hypertrophy [3].

Prenatal diagnosis can be challenging, due to the overlapping with other overgrowth syndromes; thus, a specific related genetic mutation has not been recognized, leading to a difficult genetic diagnosis [4].

Prenatal diagnosis can help the couple whether to continue the pregnancy and to program the birth and the successive follow‐up and surgical planning.

We report a review of the literature of prenatally diagnosed cases, to describe the most common ultrasound features, the risk of heart failure developing in utero, polyhydramnios and hydrops, and postnatal prognosis.

2. Material and Methods

The literature search was conducted using Web of Science, Scopus, MEDLINE, and Embase, as electronic databases from the inception of each database to February 2024, utilizing combinations of the relevant medical subject heading (MeSH) terms, key words, and word variants for: “Klippel–Trénaunay–Weber syndrome” and “prenatal diagnosis”. A review of articles also included the abstracts of all references retrieved from the search.

Inclusion criteria were prenatal diagnosis assessment of KTW cases. Only studies reporting the KTW description and the ultrasound features were eligible for the review. Two authors (GO and AA) reviewed all abstracts independently. Agreement regarding potential relevance was reached by consensus with authors. Full‐text copies of those articles were obtained, and the same two reviewers independently extracted relevant data. Inconsistencies were discussed and consensus was reached, or the dispute was resolved by discussion with the senior author (GMM). PRISMA guidelines were followed. Only full‐text and English‐written articles were considered eligible for inclusion.

3. Results

Thirty‐six articles of case reports of prenatal diagnosis of KTW syndrome were found, including 44 cases, eligible for inclusion in our review (Table 1—Figure 1) [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39].

TABLE 1.

Case reports of prenatal diagnosis of KTW.

Paper number	Year	Author	Age	G.A. at diagnosis	Fetal anemia	Limb involvement	Trunk involvement	Neck/head involvement	Upper arms	Extension	Internal organs involvement	Histologic diagnosis of the lesions
1	2023	GICA N.	NN	26	No	Left	Yes	No	No	Left buttock, pelvic area	—	Port wein stain
2	2023	SINGH (case 1)	26	39	No	Right	Yes	No	No	Glutall region	No	Low‐flow vascular malformation
		SINGH (case 2)	25	18	Yes	Right	No	No	No	No	No	Hemang‐ioma
		SINGH (case 3)	33	23	No	Left	No	No	No	No	No	NN
		SINGH (case 4)	36	31	Yes	Right	No	No	No	No	No	NN
3	2006	PENG (case 1)	22	28	No	Left	Yes	No	No	Left back		Port wein stain
		PENG (case 2)	26	35	Yes	Right	No	No	No	No		Hemangioma
4	2013	CAKIROGLU	27	26	No	Right	Yes	No	No	Scrotum, lower trunk		Port wein stain
5	2021	HOU‐QING	25	18	No	Right	No	No	No	No		NN
6	2014	TANAKA	27	25	Yes	Both legs	Yes	No	No	Chest, retroperitoneum		Hemangioma, port wein stains
7	2020	DONGMEI	26	17	No	Left	No	No	No	No		Port wein stains
8	1998	PALADINI (case1)	21	17	No	Right	Yes	No	No	Right iliac fossa	Hemangioma of bowel liver, kidneys	Hemangioma
		PALADINI (case2)	23	18	Yes	Right	Yes	No	Yes	abdomen, trunk (axillar mass)		NN
9	1992	HEYDANUS	34	20	No	Right	Yes	No	No	Right buttock, hip		Hemangioma
10	2006	Chih‐Ping	35	22	No	Right	Yes	No	No	Abdomen		Hemangioma
11	1994	Jorgenson	30	19	No	Left foot	No	No	No	No	Hepatic hemangioma	Hemangioma
12	2000	Goncalves	28	30	No	Right	Yes	No	No	Right buttock, flank		Port wein stains
13	2003	Sahinoglu	18	24	No	Left	No	No	No	No		Hemangioma
14	1991	Drose	24	29	No	Right	No	No	No	No		NN
15	1983	Warhit	30	20	No	Left	Yes	No	No	Buttock, foot		Varicous, hemangioma
16	2003	Assimakopoulos	36	22	No	Left	Yes	No	No	Abdome, thorax, gluteus	Bowel hemangioma	Port wein stains
17	2009	Coombs	32	24	No	Both legs	Yes	No	No	Retroperitoneum, pelvis	—	Bilaral agenesia of part femoral vein, popliteal veins
18	1981	Hatjis	34	30	No	Left	Yes	No	No	Thorax, abdomen	—	Cutaneous hemangioma
19	1993	Hayashi	26	19	No	NN	Yes	No	No	Buttock, lower abdomen	No	Hemangiolinfangioma
20	2019	Ivanitskaya (case1)	21	20	No	Left	Yes	No	Yes	Thorax, dorsum, abdomen, both buttock, axillary region	Right lung solid mass 15×12×12 mm, solid mass abdomen 6 mm	Port wine stains
		Ivanitskaya (case 2)	36	32	No	Left	Yes	No	No	Lumbar region, buttcock		Port wine stains
		Ivanitskaya (case 3)	31	24	No	Left	Yes	No	Yes	Left buttock, low abdomen		Port wine stains—vein varicose
		Ivanitskaya (case 4)	31	29	No	Right arm	Yes	No	Yes	Right thorax, right arm mixed cystic and solid structure, right shoulder and forearm	Right lung solid mass	NN
21	1986	Lewis	25	22	No	Both legs	Yes	No	Yes	Abdomen, chest wall, left forearm, buttocks thighs, retroperitoneum	Azygos vein, pericardium	Hemangiomas
22	1991	Meholic	28	23	No	Left arm	Yes	No	Yes	Chest wall, lower abdomen, pelvis	—	Hemangiomas
23	1994	Meizner	41	15	No	Right	Yes	No	No	Sacro coccigeal region, left chest wall	No	Hemangiomas, varicosities of abdominal wall
24	1988	Mor	31	30	Yes	Right	No	No	No	No	No	Port wine stains
25	1984	Seoud	36	17	No	NN	Yes	Yes	No	Upper abdomen and neck	No	Hemangiomas
26	1988	Shalev	28	33	No	Right	Yes	No	Yes	Abdomen, left arm	No	Hemangiomas
27	1993	Yancey	22	26	No	Left	Yes	Yes	No	Cystic and solid, multiloculated anterior neck mass	No	Hemangiomas
28	1994	Yancowitz	27	17	No	Right	Yes	Yes	Yes	Eedema of rigth body	No	NN
29	2001	Zoppi	28	28	Yes	Right	Yes	No	No	Hypoechoic and anechoic areas, right abdomen, sacral and perineal area	Bowel, right kidney involved	Hemangiomas, port wine stains
30	1998	Shih	32	15	No	Left	No	No	No	No		Hemangiomas
31	1999	Christenson	34	34	No	Right	Yes	No	No	Retroperitoneum		Port wein stains
32	1999	Roberts	26	19	No	Left	Yes	No	Yes	chest, right arm		Hemangiomas
33	2001	Martin	21	20	No	Left	Yes	Yes	No	Torax, neck, scalp, retroperitoneum		Hemangiomas
34	2000	Meja	NN	20	No	Right	Yes	No	No	No	Intestine	NN
35	2009	Volkow	NN	22	No	Arms	Yes	No	Yes	No	No	NN
36	2011	Al Asali	NN	22	No	Both legs	No	No	No	No	No	NN

Paper number	Hydrops	Polihydra mnios	Prenatal invasive diagnosis	Karyotype	Familiarity	G.A. at birth	Pregnancy outcome	Weight at birth	Associated anomalies	Neonatal outcome	Cause of death	Treatment
1	No	Yes	No	No	No	39	CS	3200	No	Normal at 6 months		NN
2	No	No	No	No	No	40	SD	2600	Fgr	Normal at 4 year		Scleroth‐erapy
	No	No	No	No	No		TOP		No
	No	No	No	No	No		TOP		No
	Yes	Yes	No	No	No	33	IUD	2400	No
3	No	Yes	Yes	46,XY	No	37	CS	2840	No	Death in 10 days of life	Kasabach‐Merrit syndrome
	Yes	No	No	46,XX	No	35	SD	3340	No	Death in 15 days of life	Cardiomegaly, thrombocitopenia
4	No	No	Yes	46,xy	No		TOP		No
5	No	No	Yes	46,XX	No		TOP		No
6	Yes	Yes	No	No	No	28	CS	1954	No	Death in first day	Kasabach‐Merrit syndrome
7	No	No	Yes	LOH for 1q21.2 q44	No		TOP		Umbilical cord hemangioma and cyst
8	No	No	No	No	No		TOP		No
	No	Yes	No	No	No		TOP		No
9	No	No	Yes	NORMAL	No		TOP		No
10	No	No	Yes	46,XY	No	36	SD	3268	No	Normal at 2 months		NN
11	No	No	Yes	NORMAL	Yes		TOP		No
12	No	Yes	No	No	No	37	CS	3210	No	Normal at 9 months		NN
13	No	No	Yes	46,XX	No	26	PS		Umbilical cord hemangioma	Death in first day	NRDS
14	No	Yes	Yes	46,XX	No	33	CS	3110	Macrosomia, cardiomegalia, Hepatomegaly, cisterna magna obliteration, mild ventriculomegaly	Death in first day
15	No	No	No	No	No	39	CS	4000	No	Normal at 3 years		NN
16	No	No	Yes	NORMAL	No	38	SD	3200	Bowel obstruction	Normal at 13 months		NN
17	No	No	Yes	46,xy	No	39	CS	—	Right foot syndactily, hypertrofy left hallux	Normal at 7 months		NN
18	No	Yes	Yes	NORMAL	No	37	SD	2470		Normal at 10 mesi		Spontaneous resolution
19	No	Yes	Yes	46,XY	No		TOP		No
20	No	Yes	No	No	No		TOP		Right diaphragmatic hernia, cystic hygroma
	No	No	No	No	No	39	SD	3750	Abnormal placement of toes	Death in 2 day	Kasabach‐Merrit syndrome
	No	No	No	No	No		TOP		No
	No	No	No	No	No		TOP		Ectrodactily right hand, hyoerechogenic bowel, ascites
21	No	No	Yes	NORMAL	No		TOP		Cataracts of both eyes
22	No	No	No	No		40	SD	3078	No	Alive at 4 months		NN
23	No	No	No	No	No		TOP		Absence of right foot
24	Yes	Yes	Yes	NORMAL	No	37	CS	3690	No	Normal at six months		NN
25	No	No	Yes	NORMAL	No		TOP		No
26	No	Yes	Yes	46,XX	No	33	SD	4200	Hypertrophy of right femur	Death in 4 day	Heart failure
27	No	Yes	Yes	NORMAL	No	35	SC	—	Bilateral syndactily	Death at 5 months
28	No	No	Yes	NORMAL	No	0	TOP		Hydrocephaly
29	No	No	No	No	No	32	CS	2740	Criptorchidism	Died after 8 h
30	No	No	No	No	No		TOP		No
31	no	no	no	no	yes	34	CS	3177	Hepatomegaly	Amputation right leg		Embolization, cardioovascular decompression, amputation right hip
32	No	No	No	No	No	37	CS	3385	No			Excision thoracic lesion
33	No	No	Yes	46, XY	No	0	TOP		No
34	No	No	No	No	No	NN	SD		No			NN
35	No	No	No	No	No	0	TOP
36	No	Yes	No	No	No	NN	SD	NN	Talipes equino‐varus,abductiont of the thumb and sindactil‐y right hand

FIGURE 1.

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only (n. 99 Embase; n. 44 Pubmed; n. 33 Web of Science).

General characteristics including family history, gestational age at diagnosis, familiarity, hemihypertrophy side, extension of the lesion (involvement of trunk, upper arms, and neck), the involvement of internal organs, presence of cardiac failure with hydrops and/or polyhydramnios, presence of associated anomalies, fetal karyotype, fetal and neonatal outcomes, treatment have been summarized in Table 1. The median maternal age was 28 years old and the median gestational age at diagnosis was 22 weeks. We found only one case with positive familiar history, where the mother was affected.

According to prenatal cases described in the literature, the lesion first involves the legs, predominantly the right side (n = 18) (40%), while the left side is the primary origin in 36% (n = 16).

In only three cases (6.8%), there was a primary lesion of other parts of the fetal body, not including the lower limbs (isolated involvement of left foot and upper limbs with thorax).

In 13 cases (29.5%), the lesion did not extend outside the leg. When the lesion extends outside the leg, it generally involves the trunk, and it can reach the upper arms. We found 11 cases of involvement of upper arms (25%). In 4 cases (9%), there were cystic lesions of the neck.

Internal organs were rarely involved: in fact, only in seven cases (15.9%), suspected hemangioma of the lungs, bowel, kidneys, and liver has been reported. In two cases, there was an association with umbilical cord hemangioma. Associated anomalies were found in 17 of 44 cases (38.6%); the most frequent were limb anomalies (7/17, 41% of cases), including ectrodactyly, femur hypertrophy, syndactyly, foot agenesia, and talipes equinovarus.

Fetal traditional karyotype was performed in 20 cases (45.4% of cases), and in only one case, a mutation was found with loss of heterozygosity (LOH) for 1q21.2 q44.

In four cases (9%), the fetus developed hydrops, which seemed not related to the extension of the lesion: in only one case of hydropic fetus, the lesion extended from the lower limb toward the thorax. Among the cases of fetal hydrops, one case had a stillbirth at 33 weeks; one had spontaneous vaginal delivery at 35 weeks, with neonatal death after 15 days for cardiac failure and thrombocytopenia; one case underwent urgent cesarean section at 28 weeks, and the neonate died in the first day of life because of Kasabach‐Merrit syndrome; in the fourth case, cesarean section was performed at 37 weeks for anasarca, and the neonatal outcome was regular at 6 months of life. Polyhydramnios developed in 31.8% of cases (14/44).

In 20 of 44 cases (47.7%), the couple opted for termination of pregnancy (TOP). In the remaining 24 cases, in which the couple was committed to the pregnancy, the median gestational age at birth was 36 weeks (range 28–40), with one intrauterine death at 33 weeks' gestation. The neonatal outcome was reported in 20 of 23 cases. Nine babies (37%) died in the first 5 months of life: four cases due to Kasabach‐Merrit syndrome, one case for heart failure, one case for respiratory distress, and in three cases, the cause of death is unknown.

In 11 of 24 newborns (45%), the outcome was good. In one case, spontaneous resolution of the hemangioma of the left leg and trunk is reported; in one case, sclerotherapy treatment of the lesion was performed and one case had amputation of the leg. In the other eight cases, the need for treatment is not reported, but the outcome reported is good.

4. Discussion

Prenatal diagnosis of KTW can be challenging, due to rarity of the pathology and its overlapping with other genetic syndromes. There is currently no such large collection of prenatal diagnosed cases of KTW in the literature. Our aim was to collect all case reports of prenatal diagnosis of KTW, confirmed after birth, to recognize common ultrasound signs and help clinicians with this complex prenatal diagnosis.

The KTW syndrome is a rare and congenital disease, with an incidence estimated at two to five per 100 000 [1].

This syndrome has a sporadic incidence without any racial or sex predilection, [2] and it is characterized by typical features: port wine stains/capillary hemangiomas due to abnormal ectasis capillaries in the papillary dermis (presenting as red or purple marks that are irregular but may have a comparatively linear border) (98%), venous malformation or varicosities (72%), and limb hypertrophy (67%) [3].

It belongs to a spectrum of limb overgrowth syndromes (PROS), with whose members it shares many similarities.

Differential diagnosis includes Proteus syndrome, which is a genetic mosaic overgrowth disorder characterized by progressive and segmental overgrowth of any affected body tissue. The syndrome is caused by a postzygotic, mosaic‐activating mutation in AKT1 [40], and in rare prenatal cases, it presents a focal overgrowth, without hemihypertrophy, but associated with skeletal and central nervous system anomalies. An exome sequencing can detect mosaic mutation of AKT1 gene [41].

Parkes‐Weber syndrome (PWS) is characterized by the same triad of malformations of KTS combined with arteriovenous fistula [42].

Postnatal KTS diagnosis is easy, and it generally depends on two of the following features of the classical triad of KTS. According to Oduber et al, [43] KTS diagnosis can be clinically diagnosed in postnatal life considering two groups of (symptoms: A) congenital vascular anomalies: capillary (port wine stains), venous (hypoplasia/aplasia of veins, persistent embryonic veins), and lymphatic and B. changing limb sizes (hypertrophy or hypotrophy). If at least one of the group A and one of the group B are present, diagnosis can be made.

In postnatal series, the lower limb is the site of malformations in approximately 95% of patients; lymphatic and venous malformations lead to an overgrowth of the affected limb, with hypertrophy. Enlargement of the extremity consists of bone elongation, circumferential soft‐tissue hypertrophy, or both [44].

Between varicosities, the pathognomonic sign is the persistence of lateral (embryonic) vein, which can be seen in 56% of patients affected [3]. Embryonic veins are easily recognized in postnatal life with MRI and venous doppler.

Bilateral and truncal involvement are rare [45]. Viscera can be affected, with genitourinary involvement in 30% of cases and gastrointestinal in 20% [46, 47]; other visceral vascular malformations can be seen in the liver, retroperitoneum, and pericardium, leading to hemorrhagic complications of the organs involved [45].

Craniofacial and brain anomalies can rarely occur [26, 48].

KTW syndrome can be associated with limb anomalies in about 29% of cases [2].

Redondo et al. described 51 patients with KTS, 17 of which had abnormalities of the hand and/or foot [49].

If large enough, the cutaneous lesions may sequester platelets, possibly leading to Kasabach‐Merritt syndrome, a type of consumptive coagulopathy [50].

The KTW has a sporadic occurrence, with mosaic distribution. It is mostly a sporadic disease with no distinct family history, and it arises from noninherited gene mutations, which are not germline, but somatic mutations [51]. This can be related to the model of autosomal dominant inheritance with incomplete penetrance [52]. Some cases of familiarity with venous malformations led Tian et al. to conduct a genetic analysis to recognize mutations related to KTW. They have demonstrated the involvement of a defect of an angiogenic factor, the VG5Q. The first mutation was a translocation t (5;11), which promotes the VG5Q transcription; the second was mutation E133K, which is a functional mutation that substantially enhances the angiogenic effect of VG5Q, the latter promoting the endothelial proliferation. This factor was found in 5 of 130 affected patients, but never in 200 controls [52].

Wang et al. found one case of KTW syndrome associated with translocation involving chromosomes 8q22.3 and 14q13 [52]. Puiu et al. [53] found a terminal deletion 2q37.3, associated with mental delay.

Prenatal diagnosis of KTW syndrome can be challenging, because ultrasound scans cannot recognize most of the typical anomalies. The hallmarks of the prenatal diagnosis of KTW are cutaneous or subcutaneous cystic areas and limb hypertrophy. Other features may be seen prenatally, such as complex soft‐tissue masses that affect unusual areas (e.g., head, neck, or trunk), nonimmune hydrops fetalis, cardiomegaly, and polyhydramnios [26, 27, 54]. Frequently, it presents in the second trimester, mostly unilateral (72%). When localized in the sacral region, the anomaly can be easily confused with a teratoma [26].

Less than 50 cases of prenatal diagnosis of KTW are described in the literature. While the syndrome can be easily diagnosed in the postnatal life with clinical criteria, skin manifestation (such as port wine stain) cannot be seen in prenatal life. Thus, lateral embryonic vein persistence, which is considered pathognomonic of the syndrome, cannot be diagnosed with fetal ultrasound.

According to prenatal series, our review confirmed the most typical ultrasound future, which is the soft‐tissue lesion (generally involving one leg, most frequently the right side), corresponding to hemangioma and/or lymphatic lesion, leading to isolated limb hypertrophy, with either no flow in case of lymphatic malformation or very low‐velocity blood flow in case of capillary and venous malformation. According to our review, in almost all cases (83%), a hemihypertrophy is found, with one leg site of anechoic and/or mixed lesion. Rarely, the lesion can extend toward the thorax and involve upper limbs and the neck.

In this case, an accurate ultrasound examination of the fetus is necessary to exclude associated anomalies. In fact, while the involvement of internal organs by the lymphovascular lesions was found in 15% of cases, in about 37% of cases, there is an association with other anomalies, first of all, limb anomalies.

Hydrops are not frequent but lead to a bad prognosis. Anyway, prenatal complications, such as hydrops, polyhydramnios, cardiac failure and anemia can appear later in pregnancy, which is why ultrasound follow‐up is necessary.

Although a specific genetic mutation has not been found, genetic counseling and prenatal invasive testing diagnosis should be offered to the couple. More studies are necessary to relate KTW syndrome to a specific mutation related to vascular growth factors, but prenatal diagnosis can be useful for differential diagnosis with Proteus syndrome.

The mortality rate is high (37%) and is mostly related to Kasabach‐Merritt syndrome development. Of the newborns survived, and in most cases, the need for treatment is not reported.

5. Conclusions

Prenatal manifestations of KTW are variable, but in the presence of cystic lesions of the legs, eventually extending toward the trunk or upper limbs, or involving internal organs, with no clear origin, this syndrome must be considered in differential diagnosis. Moreover, the association with limb anomalies, efforts the KTW suspicion.

Prenatal and genetic counseling is necessary to guide the couple in the decision whether to continue or not the pregnancy and, in the latter case, to program birth in a second‐ or third‐level center, and postnatal clinical and/or surgical follow‐up.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author uponreasonable request.