Popliteal Pterygium Syndrome

A number sign (#) is used with this entry because popliteal pterygium syndrome (PPS) is caused by heterozygous mutation in the gene encoding interferon regulatory factor-6 (IRF6; 607199) on chromosome 1q32. One patient with a homozygous mutation in the IRF6 gene has been reported.

Clinical Features

Lewis (1948) described brother and sister with cleft palate and webbing of the lower limbs whose father had harelip and cleft palate. The webbing extended from the region of the ischial tuberosities to the heels. Surgeons must be aware that the sciatic nerve may be situated in the web. The girl was said to have 'bilateral incomplete harelip.'

Pterygium of the neck and arms does not occur in this syndrome. An intercrural pterygium, if present, causes distortion of the genitalia. Bifid scrotum and cryptorchidism are the rule in males and hypoplasia of the labia majora in females. Congenital ankyloblepharon filiforme occurs in some cases. The epithelial strands connecting the eyelids in ankyloblepharon filiforme have their counterpart in symmetrical epithelial strands running from the maxilla, as pictured by Rintala et al. (1970). Pfeiffer et al. (1970) described affected father and 2 sons with predominantly unilateral popliteal pterygium, anomalies of the skin around the nails, syndactyly, abnormality of the scrotum or cryptorchidism, cleft lip and palate, congenital fistulae of the lower lip, congenital bands of mucous membranes between jaws, and ankyloblepharon filiforme adnatum. Kind (1970) described affected mother and daughter. In addition to bilateral popliteal pterygium, aplasia of the labia majora, ankyloblepharon filiforme, filiform bands between the jaws, lip pits and cleft palate were present. See Noonan syndrome (163950). Froster-Iskenius (1990) provided an extensive review.

Kopits (1937) described 4 cases, 3 of them belonging to the same family, and gave details of the operative techniques used. Cleft palate with or without cleft lip is found in 91 to 97% of cases. Paramedian sinuses or pits of the lower lip are said to occur in 45.6%. These are feature of the lip-pit or Van der Woude syndrome-1 (VWS; 119300), which had been mapped to 1q32. Over two-fifths of patients have intraoral tissue bands (syngnathia) impeding mouth opening. Ankyloblepharon filiforme adnatum occurs in about one-fifth of cases. About one-third of cases have a distinctive nail anomaly with a pyramidal skinfold extending from the base to the tip of the nails. Genital anomalies in females include hypoplastic labia majora as well as hypoplastic vagina and uterus. Males have cryptorchidism and bifid or absent scrotum; the penis is usually normal-sized.

Hunter (1990) described a family ascertained through an infant with most of the major signs of the popliteal pterygium syndrome. The mother, who had a repaired cleft palate and toe syndactyly, had been aware that her syndactyly was familial. She showed a hint of popliteal webbing. The infant proband showed ankyloblepharon, cleft lip, and oral synechiae, as well as lower lip pits, complete cleft palate, mild intracrural webbing and hypoplasia of the labia majora, popliteal webbing more marked on the right, and marked dimpling over the elbows and knees. Variable skin syndactyly involved the third and fourth fingers of both hands, fourth and fifth toes of both feet, and the second and third toes of the left foot.

Syndactyly is a useful diagnostic sign in PPS because it is not seen in most of the syndromes that should be considered in the differential diagnosis. In the reported cases reviewed by Hunter (1990), syndactyly of the toes was reported in 57% and of the hands in 16%; overall, 59% of patients had some form of syndactyly. In the hands, fusion of fingers 3 and 4 was the most common type of syndactyly. Thus, the syndactyly in PPS most closely resembles type I (185900).

Soekarman et al. (1995) described 2 families in which the popliteal pterygium syndrome occurred in 3 successive generations. While expression of the syndrome was relatively mild in the first and second generations, the patients in the third generation showed the full-blown syndrome. Differential diagnosis between mildly affected patients with the popliteal pterygium syndrome and those with Van der Woude syndrome is difficult and may even be impossible. Indeed, Soekarman et al. (1995) suggested that their observations support the hypothesis that the 2 syndromes are variants of the same disorder. Gorlin et al. (1990) suggested that a pathognomonic sign is a typical, triangular overgrowth of skin over the nail of the first toe. They suggested that if this sign is present in a patient in combination with cleft palate and/or lip, even without popliteal webbing, the diagnosis of PPS should be made.

Lees et al. (1999) reported clinical features in 3 families and 1 isolated individual with PPS. There was both intra- and interfamilial variation, with the severity of popliteal webbing varying from severe, causing a 90-degree flexion contracture, to a functionally insignificant fibrous cord. Clefting varied from submucous to bilateral cleft lip and palate. Severity of clefting did not correlate with the severity of popliteal webbing. Lip pits were absent in 1 family.

Matsuzawa et al. (2010) reported 2 unrelated Japanese families with genetically confirmed PPS. The proband in 1 family had lip pits, bilateral cleft lip and palate, syngnathia, syndactyly, popliteal webbing, and atrophic testes. His father, who also carried the mutation, had bilateral cleft lip and palate only. Family history revealed a paternal grandfather and aunt with bifid uvula and cleft palate. Thus, variable expressivity was clinically evident in this family. In the second family, a boy had cleft palate, syngnathia, unclear scrotum, syndactyly, and mild popliteal webbing, whereas his mother had cleft lip and palate, syngnathia, syndactyly, and hypoplasia of the labia majora.

Inheritance

Klein (1962) described a mother and a daughter with the features of this syndrome and suggested dominant inheritance. Gorlin et al. (1976) favored autosomal dominant inheritance with variable expressivity and incomplete penetrance; likewise, Escobar and Weaver (1978) concluded that autosomal dominant inheritance is usual.

Hecht and Jarvinen (1967) observed affected mother and 2 sons in one family and affected mother and son and daughter in a second. The observation of affected father and son by Lewis (1948) excludes X-linked inheritance.

Mapping

Lees et al. (1999) performed linkage analysis using the markers D1S205, D1S491, and D1S3753 in the critical region for the Van der Woude syndrome on chromosome 1q32. They obtained a multipoint lod score of 2.7 with no evidence of recombination, supporting the hypothesis that these 2 conditions are allelic.

Molecular Genetics

Kondo et al. (2002) carried out direct sequence analysis of genes and presumptive transcripts in the critical region for popliteal pterygium syndrome and van der Woude syndrome (VWS1; 119300) identified by linkage analysis on 1q32. They detected mutations in the IRF6 gene encoding interferon regulatory factor-6 (607199.0001-607199.0005) in both of these syndromes, which share phenotypic features.

In a 4-generation VWS family in which affected individuals carried an L22P mutation in the IRF6 gene (607199.0014), 2 of the patients displayed additional features: 1 had finger syndactyly, and the other had toe syndactyly and oral synechiae. Ghassibe et al. (2004) stated that because syndactyly and synechiae are major signs for PPS, these 2 patients were considered to have PPS, whereas the 6 other affected family members were classified as VWS, thus demonstrating that a single mutation could be responsible for both syndromes.

In affected members of 2 unrelated Japanese families with PPS, Matsuzawa et al. (2010) identified 2 different heterozygous mutation in the IRF6 gene (607199.0015 and 607199.0016, respectively).

In a neonate with a clinical diagnosis of PPS, Leslie et al. (2015) identified a homozygous mutation in the IRF6 gene (607199.0019). The unaffected consanguineous parents were heterozygous for the mutation.

Van der Woude Syndrome-Popliteal Pterygium Syndrome Spectrum

In a patient with overlapping features of VWS and PPS (unilateral cleft lip and palate, ankyloblepharon, paramedian lip pits) as well as unilateral renal aplasia and coronal hypospadias, de Medeiros et al. (2008) identified a novel mutation in the IRF6 gene (607199.0013). The patient and his brother, who had hypospadias and nephrocalcinosis but no IRF6 mutation, were both conceived by in vitro fertilization. De Medeiros et al. (2008) suggested that the hypospadias and renal aplasia may have been due to the method of fertilization rather than the IRF6 mutation. They noted that a lethal PPS syndrome (263650) has renal aplasia as a feature.