Klippel-Trenaunay-Weber Syndrome

Clinical Features

The features of Klippel-Trenaunay-Weber syndrome are large cutaneous hemangiomata with hypertrophy of the related bones and soft tissues. The disorder clinically resembles Sturge-Weber syndrome (185300), and indeed the 2 have been associated in some cases (Harper, 1971).

Lindenauer (1965) described a brother and sister with Klippel-Trenaunay syndrome. Both patients had varicosity, hypertrophy, and hemangioma, but no arteriovenous fistula. Lindenauer (1965) suggested that patients who also have arteriovenous fistula have a different disorder that might be called Parkes Weber syndrome, since Weber (1907) described cases of this type as well as cases seemingly identical to those of Klippel and Trenaunay (1900). Lindenauer (1965) also suggested that the deep venous system is atretic in KTW syndrome and, as a corollary, that stripping of varicose veins is unwise.

Campistol et al. (1988) described an affected 19-year-old woman who had multiple renal pelvic hemangiomas and renal artery aneurysm. Viljoen (1988) reviewed the clinical features of the syndrome. Lawlor and Charles-Holmes (1988) described a 25-year-old woman with KTW syndrome who had life-threatening menorrhagia due to uterine hemangioma. In an infant with this syndrome, Mor et al. (1988) observed hydrops fetalis (gross edema of the limbs, ascites, and palpable liver). The infant lost 520 gm of weight in the first 6 days of life without medication.

Muluk et al. (1995) described the case of a 32-year-old man in whom progressive pulmonary insufficiency was found to be due to repeated pulmonary emboli from the deep venous malformations associated with KTS.

Samuel and Spitz (1995) reviewed the clinical features and management of 47 children with KTS treated since 1970. Hemangiomas and soft tissue and/or skeletal hypertrophy were present in all 47 patients; venous varicosities developed in 37 (79%). None had clinical evidence of macrofistulous arteriovenous communications. Thromboembolic episodes occurred in 5 children (11%), and 25 (53%) experienced thrombophlebitis. The Kasabach-Merritt syndrome (141000) was observed in 21 (45%) children, and 6 (13%) presented with high-output heart failure. Other manifestations included hematuria in 5 (11%), rectal or colonic hemorrhage in 6 (13%), and vaginal, vulval, or penile bleeding in 6 (13%) children with visceral and pelvic hemangiomas. In 26 patients (55%), symptomatic treatment only was required. Surgery was undertaken in selected cases for complications of the hemangioma, for cosmetic reasons, and for chronic venous insufficiency. Only 1 of the 4 children who underwent resection of varicose veins improved.

Ceballos-Quintal et al. (1996) reported a family in which a child had large skin hemangiomata, overgrowth of the right leg, and severe heart defects (patent ductus arteriosus (see 607411), atrial septal defect, prolapsed tricuspid valve, and pulmonic stenosis). Her mother had a large capillary hemangioma on the left side of the back and developed severe varicosities in both legs. The maternal grandmother developed severe varicosities of the legs at a young age.

Cohen (2000) defined Klippel-Trenaunay syndrome and challenged 4 conceptions frequently found in the literature on this disorder. He considered it improper to add arteriovenous fistulas to the syndrome and on that basis to rename the disorder Klippel-Trenaunay-Weber syndrome. Although Parkes Weber syndrome (as Cohen called it) and Klippel-Trenaunay syndrome are similar, slow flow venous malformations are predominant in KTS, whereas arteriovenous fistulas are always found in Parkes Weber syndrome. Large series of patients with Parkes Weber syndrome were reported by Robertson (1956) and Young (1988). The involved limb is warm. The color of the cutaneous vascular malformation is usually more diffuse and pinker than that observed in KTS. Lymphatic malformations found in KTS do not occur in Parkes Weber syndrome. Cohen (2000) questioned whether Sturge-Weber syndrome and KTS are the same disorder. Cohen (2000) considered the affected brother and sister described by Lindenauer (1965) as the only well-documented examples of KTS in a family.

Hall et al. (2007) reported 6 patients with phakomatosis pigmentovascularis type II, consisting of nevus flammeus and mongolian spots; 2 patients were diagnosed with Klippel-Trenaunay syndrome, and 3 had features consistent with both Klippel-Trenaunay and Sturge-Weber syndromes. There were 4 patients with macrocephaly and 1 with microcephaly; 4 patients had CNS abnormalities, including 3 with hydrocephalus, 1 with Arnold-Chiari malformation, and 1 with polymicrogyria; 3 patients had mental retardation; and 1 patient had seizures. Hall et al. (2007) suggested that in the presence of persistent, extensive, and aberrant mongolian spots, the vascular abnormalities of Klippel-Trenaunay and Sturge-Weber syndromes carry a worse prognosis.

Inheritance

Aelvoet et al. (1992) provided evidence that Klippel-Trenaunay syndrome occasionally shows familial aggregation. In addition, they found isolated vascular nevi to be overrepresented in relatives of KTS patients.

Happle (1993) suggested that what he referred to as paradominant inheritance most satisfactorily explains the findings. According to this concept, KTS would be caused by a single gene defect. Heterozygous individuals would be, as a rule, phenotypically normal, and therefore the allele would be transmitted imperceptibly through many generations. The trait would only be expressed when a somatic mutation occurred in the normal allele at an early stage of embryogenesis, giving rise to a clonal population of cells either homozygous or hemizygous for the KTS mutation. One example of a genetic mechanism that might cause homozygosity of a cell population arranged in a mosaic pattern is somatic recombination. Presumably, diffuse involvement of the entire body would not be possible because of nonviability of embryos developing from a homozygous zygote.

Ceballos-Quintal et al. (1996) identified a family in which clinical signs in the mother and maternal grandmother were interpreted as mild expression of the KTW syndrome and the family tree was thought to support autosomal dominant inheritance.

Berry et al. (1998) reviewed 49 cases of KTS. All were sporadic. They speculated that the disorder may be due to a somatic mutation for a factor critical to vasculogenesis and angiogenesis in embryonic development.

Lorda-Sanchez et al. (1998) presented an epidemiologic analysis of a consecutive series of cases of KTW syndrome identified in the Spanish Collaborative Study of Congenital Malformations. They found an increase in parental age and in the number of pregnancies, as well as familial occurrence of hemangiomas. These observations suggested a genetic contribution to the occurrence of KTW syndrome. Although the effect of increased paternal age on the origin of spontaneous germline mutations is well documented for dominant conditions, sporadic conditions that are presumably caused by somatic mosaicism are not supposed to show advanced parental age. The increased parental age would be consistent with the model of paradominant inheritance. Epidemiologic studies of retinoblastoma, a classic example of the 2-hit model of Knudson, have shown an association of older parental age with the first mutation event in germinal cells in sporadic hereditary retinoblastoma (DerKinderen et al., 1990) but no evidence for risk factors related to the second somatic mutation (Matsunaga et al., 1990).

Cytogenetics

Whelan et al. (1995) reported the case of a girl with KTW syndrome associated with a reciprocal translocation: t(5;11)(q13.3;p15.1). This raised the possibility that this disorder is due to a single gene defect and that the gene is located on 5q or p11. At birth a capillary hemangioma of the right arm and a vascular anomaly of the left trunk with extension onto the left thigh was noted. At age 3 months, the patient's mother noted that the right second toe was larger than corresponding left toe. Subsequent progression to right leg hypertrophy was noted in the first 5 years of life.

Timur et al. (2004) identified a de novo supernumerary ring chromosome in a patient with mild mental retardation, long tapering fingers, elongated and thin feet, and KTS. The ring marker chromosome was found to be mosaic, present in 24% of cells, and was shown to be derived from chromosome 18, r(18). FISH was used to define the breakpoints involved in formation of the r(18). The 18p breakpoint was located less than 10 cM from the centromere; the 18q breakpoint was located between the centromere and BAC clone 666n19 (GenBank AC036178), representing a region of less than 40 kb. The data suggested that the r(18) mostly originated from 18p, with an estimated size of less than 10 cM.

The de novo translocation t(8;14)(q22.3;q13), reported by Timur et al. (2000) and Wang et al. (2001), points to a pair of chromosomes different from those focused on by Whelan et al. (1995) as the possible site of the Klippel-Trenaunay gene. Wang et al. (2001) used FISH to define the breakpoints on 8q22.3 and 14q13 in relation to specific markers and suggested that their study provided the basis for the fine mapping and ultimate cloning of a novel vascular gene at 8q22.3 or 14q13.

Tian et al. (2004) characterized the breakpoint of the translocation in a patient with Klippel-Trenaunay syndrome described by Whelan et al. (1995) and identified the VG5Q gene (608464). The chromosomal translocation resulted in 3-fold increased expression of VG5Q, suggesting that the t(5;11) translocation may be a functional genetic defect that can lead to overexpression of VG5Q and result in increased angiogenesis.

Diagnosis

By ultrasound examination, Christenson et al. (1997) made the prenatal diagnosis of KTW syndrome complicated by early fetal congestive heart failure. The postnatal course was complicated by Kasabach-Merritt syndrome (141000) of thrombocytopenia due to platelet consumption within the hemangioma. Neonatal cardiopulmonary resuscitation and limb amputation were required.

Molecular Genetics

Sperandeo et al. (2000) described a family in which 1 first cousin had KTW syndrome and the other had Beckwith-Wiedemann syndrome (BWS; 130650). The probands, sons of 2 sisters, showed relaxation of the maternal IGF2 (147470) imprinting, although they inherited different 11p15.5 alleles from their mothers and did not show any chromosome rearrangement. The patient with BWS also displayed hypomethylation of KvDMR1, a maternally methylated CpG island within an intron of the KvLQT1 gene (607542). The unaffected brother of the BWS proband shared the same maternal and paternal 11p15.5 haplotype with his brother, but the KvDMR1 locus was normally methylated. Methylation of the H19 gene (103280) was normal in both the BWS and KTW syndrome probands. Linkage between the IGF2 receptor gene (IGF2R; 147280) and the tissue overgrowth was excluded. These results raised the possibility that a defective modifier or regulatory gene unlinked to 11p15.5 caused a spectrum of epigenetic alterations in the germline or early development of both cousins, ranging from the relaxation of IGF2 imprinting in the KTW syndrome proband to disruption of both the imprinted expression of IGF2 and the imprinted methylation of KvDMR1 in the BWS proband. The data indicated that loss of IGF2 imprinting is not necessarily linked to alteration of methylation at the KvDMR1 or H19 loci and supports the notion that IGF2 overexpression is involved in the etiology of tissue hypertrophy observed in different overgrowth disorders, including KTW syndrome.

Tian et al. (2004) identified a heterozygous glu133-to-lys (E133K) nonconservative substitution in the VG5Q gene (AGGF1; 608464) in 5 of 130 unrelated individuals with Klippel-Trenaunay syndrome and none of 200 controls. In several in vitro assays, Tian et al. (2004) showed that VG5Q carrying the E133K mutation acted as a more potent angiogenic factor than wildtype protein, suggesting that it is a gain-of-function mutation. The authors suggested that VG5Q may be a susceptibility gene for KTS. In contrast, Barker et al. (2006) identified a heterozygous E133K change in 9 (3.3%) of 275 healthy controls. One of 24 patients with an asymmetric overgrowth syndrome, but not KTS, carried the E133K substitution, but the patient's unaffected mother also carried the substitution. Barker et al. (2006) concluded that E133K is a polymorphism and does not cause KTS. Gutierrez et al. (2006) identified a heterozygous E133K substitution in 17 (2.2%) of 768 unrelated Spanish control individuals and 3 (1.3%) of 223 patients or parents of patients with overgrowth syndromes, none of whom had Klippel-Trenaunay syndrome. The authors concluded that E133K is a polymorphism.

Kurek et al. (2012) found somatic mosaicism for a missense mutation in the PIK3CA gene (171834) in patients with CLOVE syndrome (612918), an overgrowth syndrome with features overlapping those of KTW syndrome. Analysis of lesional tissue from 15 patients who had been diagnosed with KTW syndrome revealed somatic mosaicism for a missense mutation in PIK3CA (H1047R; 171834.0001) in 3 of them.