The popliteal pterygium syndrome: Report of a new family and review of the literature

American Journal of Medical Genetics 36:196-208 (1990)

The Popliteal Pterygium Syndrome: Report of a New Family and Review of the Literature

Alasdair Hunter Division of Genetics, Children’s Hospital of Eastern Ontario, and Department of Paediatrics, University of Ottawa, Ontario, Canada.

This paper reports on a family with popliteal pterygium syndrome (PPS), which was ascertained through a baby with most of the major signs of the syndrome. The mother, who had a repaired cleft palate and toe syndactyly, had been aware that her syndactyly was familial, but her unpreparedness for the birth of a child with PPS led to interest in, and a subsequent review of, the differential diagnosis and the variable expression of the clinical manifestations of this syndrome. Upon review, some earlier reported cases were excluded as PPS, and certain ascertainment and reporting biases that could affect such an analysis were considered.

KEY WORDS: popliteal pterygium, cleft lip/ palate, ankyloblepharon, lip pits, syndactyly, autosomal- dominant inheritance

INTRODUCTION Trelat 118691 is generally credited with the first de-

scription of the popliteal pterygium syndrome (PPS). More than 60 cases have since been reported. The syndrome is characterized by marked variability in expression, while the occasional family history suggests the possibility of lack of penetrance [Kind, 19701. We have ascertained a family through a severely affected child and her less affected mother. Family history showed several other apparently mildly manifesting gene carriers. Evidence was sought as to whether sporadic cases represent new mutations of the autosomal-dominant PPS or are a closely related genocopy. The name pop- h e a l pterygium is used in preference to popliteal web simply to avoid confusion that might occur with the abbreviation PWS and Prader-Willi syndrome.

Received for publication April 11,1989; revision received August 25, 1989.

Address reprint requests to Alasdair Hunter, Division of Ge- netics, Children’s Hospital of Eastern Ontario Ottawa, Ontario. Canada K1H 8L1.

o 1990 Wiley-Liss, Inc.

CLINICAL REPORTS Pa tien t 1

The proposita KP (IV-1, Fig. 1) was the first pregnancy of her 34-year-old mother and 35-year-old father. The pregnancy was unremarkable save for first-trimes- ter nausea and a mild elevation in blood pressure during the last 2 weeks. At birth she weighed 2,620 g, was 48 cm long, and had an OFC of 33 cm. Neonatal cyanosis and grunting were treated with supplemental oxygen and resolved within 24 hr. A number of physical anomalies were immediately apparent.

Her skull was normocephalic with normal sutures and fontanelle. Hair pattern, structure and distribution were unremarkable. The ears were normal in position and shape. There was a slight downward slant of the palpebral fissures and bilateral ankyloblepharon from the midpoint of the lids to the temporal margins (Fig. 2). She had a right cleft lip, lower lip pits, a complete cleft palate, and multiple oral synechiae, which included a connection from the mucosal surface of the upper to the lower lip, from the anterior alveolar ridges to the buccal surfaces, and posteriorly from the upper to lower jaws. Tongue tie was noted. There was some redundant nuchal skin. There were no cardiovascular or abdominal anomalies. There was mild intracrural webbing and hypoplasia of the labia majora (Fig. 3 ) . Popliteal webbing was more marked on the right (Fig. 4). Variable skin syndactyly involved the 3rd and 4th fingers of both hands (Fig. 51, the 4th and 5th toes of both feet, and the 2nd and 3rd toes of the left foot (Fig. 6D). There was marked dimpling over the elbows and knees.

The oral and ocular synechiae were severed at 3 days; the cleft lip repaired a t 6 months and the palate a t 14 months. Active physiotherapy resulted in eventual full extension of both legs. Psychomotor development has been normal; some delay in speech noted a t 15 months was attributed to chronic otitis media, for which myr- ingotomy tubes were inserted. There was some early delay in weight gain.

Patient 2 The mother of the proposita (111-l), was a healthy 34-

year-old woman, who had been well aware of “the family’s webbed toes.” There was a minimal downslant of her palpebral fissures and absent canines. She had been

Popliteal Pterygium Syndrome 197

I

Ill

IV

9.” 41, I A

Fig. 1. Pedigree of the family showing distribution of anomalies. 0 Cleft lipipalate; 0 Cleft palate; 3 Toe syndactyly; @Mild or by history toe syndactyly; 0 Hand syndactyly; P = popliteal pterygium; A = Ankyloblepharon; S = Syngnathia; W = Excess oral frenula.

born with a cleft soft palate and abnormal gingival webs, which remained. Her feet showed bilateral variable syndactyly between the 2nd and 3rd and the 4th and 5th toes (Fig. 6A). The right 2nd and 3rd toenails were partially fused and dysplastic, and the left great toenail had a typical pyramidal skin bridge, which is seen in this syndrome. There was a suggestion of very mild popliteal involvement (Fig. 7). No other anomalies were noted.

Fig. 3. Genitalia of patient 1 showing labial hypoplasia. The mild crural web is not apparent on the photograph.

Patient 3 The maternal grandfather of the proposita (11-1) was a

58-year-old man with emphysema. He had bilateral metatarsus adductus, broad first toes, variable cutane- ous syndactyly of the 1st to 3rd toes and hypoplastic nails (Fig. 6B).

Patient 4 The maternal uncle of the proposita (111-2) had absent

canines, a slight downslant of his palpebral fissures, and abnormal feet (Fig. 6C). The forefoot was broad, with an increased space between the 1st and 2 4 extensive cuta- neous syndactyly of the 2nd and 3rd, and lateral deviation of the second toes.

Patients 5 and 6 The status of the 2 children (IV-2 and IV-3) of patient

4 remains uncertain. Both were thought to have mild syndactyly between the 2nd and 3rd fingers, but this was probably not of significance. IV-2 was noted to have

Fig. 2. Facial photograph of patient 1 showing ankyloblepharon, cleft lip and oral synechiae. Fig. 4. Right leg of patient 1 illustrating the popliteal web.

198 Hunter

Fig. 5. Hand of patient 1 showing the 3-4 syndactyly

excess gingival frenula, lateral deviation of the great toes, an increased space between the 1st and 2nd toes, very slight syndactyly of the 2nd and 3rd toes, and small toenails (Fig. 6E). IV-3 had no oral signs, while her feet showed similar, but more obvious, changes to those of her brother (Fig. 6F). The children were otherwise nor- Fig. 7. Legs of Patient 2 showing a hint of popliteal webbing

Fig. 6. A. Feet of patient 2 showing the variable 2-3, and 4-5 syndactyly and the typical skin pyramid on the left first toe. B. Feet of patient 3 showing variable 1-3 zygodactyly and broad first toe. C. Feet of patient 4 illustrating 2-3 syndactyly and increased 1-2 interdigital space. D. Feet of patient 1 showing variable bilateral 4-5, and left 2-3 syndactyly. E. Feet ofpatient 5 showing increased first interdigital space, valgus great toes and small nails. F. Feet ofpatient 6 showing increased first interdigital space, valgus great toes, 2-3 syndactyly (greater on right), and small nails.


mal, although there was some question as to the inter- pretation of palpable cords behind the knees; the conclusion was that they were normal hamstring tendons.

DISCUSSION Differential Diagnosis

While the fully expressed PPS consists of cleft lip and/ or palate, ankyloblepharon, syngnathia, lower lip pits, and syndactyly, the hallmark is clearly the popliteal pterygium. Unilateral or bilateral popliteal pterygium in the absence of additional anomalies would appear to be very uncommon and is unlikely to be the sole presenting sign in a patient with PPS. There was only one case of isolated popliteal web among the 56 cases reviewed from the literature (Appendix A). This retarded child was very briefly described and died a t age 6 years [Ko- pits, 19371. At the very least, additional signs may have gone unreported, and the atypical clinical course raises some question as to the actual diagnosis of PPS. Gener- ally, popliteal webbing will be found associated with other anomalies, and as part of one of a number of syndromes that can be readily distinguished.

The multiple pterygium syndromes, as their name implies, are associated with widespread pterygia involving the neck, axillae, elbows, intracrural area, knees, ankles, and fingers. They are generally divided into lethal and nonlethal forms; Hall [19841 has ten- atively subdivided the former into 4 subtypes.

The first lethal subtype [Bartsocas and Papas, 19721 includes ankyloblepharon, syngnathia, cleft lip and palate, thumb anomalies and osseous syndactyly. In the past, it has been confused with the PPS [Escobar and Weaver, 19781. However, it can be distinguished by its autosomal-recessive inheritance: generally lethal course, corneal changes, and marked anomalies of the distal limbs. Thus far, lower lip pits do not appear to have been reported, but Cheirif et al. [1985] reported a patient who was alive a t age 9 years. Unfortunately, no photographs were provided, although a similarly affected sib had died shortly after birth.

The remaining lethal subtypes exhibit more severe and diffuse involvement and are distinguished by the gestational stage of onset and degree of bony fusions [Hall, 19841. In addition to multiple contractures and skin webs, they have “apparent” hypertelorism, edema, cystic nuchal mass, loose skin, and lung hypoplasia.

Most nonlethal familial cases of multiple pterygium phenotype are autosomal-recessive [Jones, 19881, although many reported cases have been sporadic. The typical patient has ptosis, downslanting palpebral fissures, a “myopathic” face, pterygia, which may in- volve all the areas described above, camptodactyly and syndactyly. Cleft palate, rib and vertebral anomalies may also be seen, and intelligence is generally normal. There is significant intra- and interfamilial variation in expression, but in none of the sporadic or familial cases reviewed by Hall e t al. [19821 were popliteal webs the sole manifestation of pterygia. This, together with the absence of ankyloblepharon, cleft lip, and lip pits, makes confusion with the PPS unlikely. An autosomal dominant form of multiple pterygium syndrome has been

reported [Carnevale et al., 1973; Frias et al., 19731, and appears to have similar clinical signs but with a high rate of vertebral anomalies, pelvic dysplasia, tarsal fusions, and in some patients short stature and mental retardation [McKeown and Harris, 19881.

Similarly, the specific associated clinical signs facili- tate distinction from a number of other syndromes that may have associatedjoint webs [Hall et al., 1982; Happle et al., 1980; Herrmann et al., 19691.

In the absence of popliteal webs in the index patient or the family, specific diagnosis of the PPS becomes more problematic. The concurrence of cleft lip and/or cleft palate with pits or fistula of the lower lip that could occur as the only apparent manifestation of the gene in some patients with PPS may also be the result of an autosomal-dominant gene in the Van der Woude syndrome [Van der Woude, 19541. Associated hypodontia, which may also be present in PPS (Appendix A), is seen in 10-20% of patients [Schinzel and Klausler, 19861. Clefting and lower lip pits may also be seen in the type I oral-facial-digital syndrome (OFDS) [Gorlin and Psaume, 19621, but the associated manifestations facili- tate distinction of this syndrome.

Ankyloblepharon is a component of a number of syndromes, including the autosomal-dominant, ankyloblepharon-cleft lip andlor palate syndrome [Long and Blandford, 19621. It is of interest that the genetic distinction that is drawn between isolated cleft lip with or without palate and isolated cleft palate in genetic coun- seling is not apparent in the PPS, Van der Woude, or ankyloblepharon-clefting syndromes. All these syndromes, which have overlapping clinical signs, may exhibit cases with cleft lipipalate and cleft palate without cleft lip, within the same pedigree. HF Falls, in a per- sonal communication to Long and Blandsford [ 19621, reported that a patient in his family, which was reviewed by Van der Woude as an example of the cleftingl lower lip-pit syndrome, also had ankyloblepharon. A similar case reported by Oberst [19101 is cited by Cer- venka et al. [ 19671. Clinically insignificant ankyloblepharon might well be overlooked in studies whose primary interest was clefting and lower lip pits, and thus the distinction between the Van der Woude and ankyloblepharoniclefting syndromes may be blurred in some cases. The literature on PPS contains examples of patients whose manifestations consisted of various com- binations of ankyloblepharon, clefting and lower lip pits (Appendix A). In the absence of another relative with typical PPS, the distinction of such cases would be diffi- cult. Thus far, in contradistinction to the Van der Woude syndrome, lower lip pits in the absence of cleft lip or palate is unreported in PPS.

Hay and Wells [1976] reported on 3 families with parent-to-child transmission and one sporadic case of a syndrome that shared ankyloblepharon, clefting (mostly palate), and digit syndactyly with the PPS syndrome. However, their patients did not have lip pits, popliteal webbing or significant genital changes, and they had sparse, wiry hair, dental abnormalities, a true nail dysplasia, and palmariplantar hyperkeratosis. Fur- ther cases were reported by Spiegel and Colton [1985]. The Hay-Wells syndrome shares many characteristics

200 Hunter

with the probably autosomal-recessive syndrome reported in 3 sisters by Bowen and Armstrong 119761. Shared manifestations included clefting, ankyloblepharon, toe syndactyly, sparse, wiry hair, nail dysplasia, and abnormal teeth. Aside from the pattern of inheritance, differences included skin defects, hyperpig- mented areas, and mental retardation in the latter. Again, lack of webbing and lip pits, and the presence of the ectodermal changes permit distinction from the PPS syndrome. The Rapp-Hodgkin 119681 and lacrimo- auriculo-dental-digital [Hollister et al., 19731 syndromes bear some resemblance to these former 2 condi- tions, Ankyloblepharon in association with curly hair and hypoplastic (not truly dysplastic) nails was reported as the apparently autosomal-dominant curly hair- ankyloblepharon-nail dysplasia syndrome (CHANDS) by Baughman [1971]. More recent pedigree data on the original family showed that consanguinity had resulted in a pseudodominant pattern and that autosomal recessive inheritance was more likely [Toriello et al., 19791.

Oral synechiae, which commonly cause syngnathia and less often ankyloglossia in PPS, is an otherwise uncommon malformation. An excess of oral frenula may be a mild manifestation of the anomaly, and occurred in our family. The only syndrome that could cause confusion with PPS on the basis of oral synechiae is the cleft- palate lateral oral synechiae (CPLS) syndrome [Fuhr- mann et a]., 19721. The CPLS syndrome is usually sporadic but may show a dominant pattern with variable expression and lack of penetrance. Gassner et al. [19791, reported on a mother and son with syngnathia; the son had a bifid uvula attached to synechiae. Reus et al. [19741 commented on a particular face in the syndrome.

None of these syndromes discussed include the combi- nation of ankyloblepharon, syngnathia, oral clefting, and lower lip pits; yet this association occurs in PPS and may be seen in family members who lack popliteal webs. Thus, the sporadic male patient with this pattern of anomalies described by Neuman and Shulman 119611 may have had PPS. Similar reports of PPS, both sporadic and familial, reported by Leck and Aird 119841 and by Khan et a]. [1986l, respectively, as PPS without popliteal webs have been included in this analysis and are summarized in Appendix A.

Syndactyly is a useful diagnostic sign in PPS because it is not seen in most of the syndromes which may be considered in the differential diagnosis. The nosology with respect to 2 patients described briefly in the early French literature by Lannelongue [18791 and by Be- rauds [1861] [cited in Cervenka et al., 19671 is unclear. Both patients had lip pits, cleft lip and palate and finger syndactyly. Of potentially greater importance is the probability that toe syndactyly may be the only manifestation of the PPS gene. This was the case in our family. Three matrilineal relatives in the second family described by Escobar and Weaver [1978] had bilateral 4-5 toe syndactyly. These investigators considered i t “presumptive” to consider this evidence of the PPS gene because of the known autosomal-dominant inheritance of isolated syndactyly. By contrast, isolated 4-5 toe syndactyly is not typical of the recognized forms of isolated syndactyly [Temtamy and McKusick, 19781.

Syndactyly of the toes was reported in 57%, and of the hands in 16%, of patients summarized in Appendix A. Overall, 59% of patients had some form of syndactyly, and this rises to 61% if the relatives reported by Escobar and Weaver 119781 are included. The actual pattern of the syndactyly is extremely variable both between and within patients with respect to laterality and the digits involved. Among the toes, fusion of the 1st to the 2nd is uncommon; most often there is fusion in the pattern 2-3-4-5, 2-3 and 4-5, or 2-3 or 4-5 alone. However, isolated 3-4 fusion may be seen. In the hands, fusion of 3-4 is most common. Thus, the syndactyly in PPS most closely resembles type I zygodactyly which typically shows similar variability and involves syndactyly of toes 2-3 and fingers 3-4, but with occasionally other digits involved [Temtamy and McKusick, 19781.

Review of Previous Cases A major objective of this review was to look more

specifically a t the range of signs expressed in PPS, and some of the factors or biases that might influence that apparent variation. Nothwithstanding the risk of intro- ducing bias or circular reasoning, the cases previously reported were viewed as to whether they were actually likely to represent the PPS. Several cases that have been included in previous reviews were excluded. The sibs born of consanguineous parents, reported by Rosselli and Gulienetti [19611 were included by Gorlin et al. [19681, and Escobar and Weaver [19781, but are now, as reviewed by Hall et al. [1982], generally considered cases of the Bartsocas-Papas syndrome [Bartsocas and Papas, 19721. Similarly, 3 sibs reported by Kopits [19371, and included by Gorlin et al. [l968], and Escobar and Weaver [1978], are considered by Hall et al. [1982] to have the multiple pterygium syndrome. Gorlin et al. [19781 also included the cases of Matolcsy [1936], which are now accepted as multiple pterygium syndrome [Es- cobar and Weaver, 19781.

All 3 reviews included cases reported by Wolff [1889], Fischer 118931, and Schramm [1940], which I have excluded. Findings in the patient described by Wolff [l889] that seem out of keeping with PPS were a scar with a “tail” a t L2, and a bridge of skin running from there to the sternum, as well as absence of the tip of the left 2nd and 3rd digits. The popliteal web was unilateral and, in the absence of any facial anomalies, there seems the possibility of some unusual band condition with restriction of the left leg in utero. (It appears that Escobar and Weaver, who recorded facial anomalies for that patient, may have been misled by the photograph of another child on the same page.) The patient of Fischer [1893] had abnormalities limited to the left leg which had a popliteal web, and a complex duplication deficiency with an abnormal fibula, 8 toes, and 2-3 toe syndactyly. The patient of Schramm [19401 had anomalies confined to the legs. On the right, there was a scarred pterygium with a marked rotation of the foot against the pubis (photograph reversed?), while the left foot showed marked medial deviation of the great toe, fusion of toes 2-4, a long unusual cleft between the 4th and 5th toes, and a tibia1 defect. Finally, Negishi and Azuma [1981] reported a case of PPS that is not included in Appendix


A because the child had antecubital webbing and several signs not typical of PPS. This interesting patient lacked craniofacial manifestations of PPS, was short, retarded, had abnormal ears, unilteral ptosis, absent lateral clavicles and duplication of the medial portion of the right clavicle, dislocation of the radial head, and anomalous external genitalia. The child also had preax- ial polysyndactyly, and skin “pyramids,” usually limited to the great toe in PPS, on all fingers and toes. Some of the remaining cases are not well documented but at least do not have abnormalities that seem out of charac- ter for the PPS syndrome. (See Appendix A.)

Two issues that have been addressed to varying de- grees in previous reviews are the degree of variability seen in the syndrome and whether sporadic cases represent the same condition (new mutations) or a phenocopy. Several ascertainment and reporting biases may com- plicate such comparisons, especially for a syndrome in which the sine qua non has been a specific malformation-the popliteal web. In the absence of this specific malformation, there may be overlap with other syndromes. Thus, with the exception of the report by Leck and Aird [1984], all sporadic cases have a popliteal web (or in one case a scarlike streak), whereas in familial PPS only one member of the family need have the anomaly. This obvious bias might be avoided by simply ex- cluding the actual web from intergroup comparisons, but only if its presence has no association with the presence or absence of additional anomalies. However, such associations may well be present. For example, of patients with popliteal web, 59% (32/54) have genital anomalies, and 16% (8154) have crural web, as compared with 6% (1117) and 0% (0117), respectively, of patients without a popliteal web. Other forms of reporting bias might be less apparent but equally important. For example, familial cases might be more likely to be reported by geneticists who are interested in dysmorphogenic detail, while surgeons might report more sporadic cases and emphasize treatment of the web. If additional characteristics of the syndrome have been only recently recognized then early reports might lack these characteristics. I have attempted to examine some ofthese potential biases by summarizing the major signs of PPS in different ways in Table I.

For purposes of Table I and the summary of all cases in Appendix A, a manifestation was considered absent (N) unless i t was mentioned in the text or was clearly visible on a photograph.

While there is a slightly greater emphasis on familial reports in the nonsurgical literature, there is no system- atic difference in the number or pattern of anomalies reported in the different specialty journals. The literature before 1960 tends to report a somewhat lower rate of the clinically less important anomalies (lip pits, hypoplastic nails, and crural webs) or of those that are only present in the infant (ankyloblepharon, syngnathia). Males and females appear to show a similar pattern of malformations. Although the differences are not marked, overall the frequency of signs is lower among familial than among nonfamilial patients. Familial cases are more likely to mirror the true variation in gene expression but as a group are still likely to be biased

toward greater severity because of the requirement to ascertain a propositus. Thus, a comparison that elimi- nates the propositus might reflect the true behaviour of the gene more closely. Indeed a comparison of the rates of anomalies between propositus and nonpropositus familial cases shows a lower frequency of many traits among the latter group. These differences could be further exaggerated (not shown) by the inclusion as affected, of our cases IV-2 and IV-3, and the father with bifid uvula in case 1, and the relatives with toe syndactyly in case 2 of Escobar and Weaver [19781. Also, there were several patrilineal relatives with short stature and short hands and feet in the report of Hansson et al. [1976]. However, as argued by Escobar and Weaver [ 19781, the genital (and other) anomalies may result in a decreased fitness in carriers of the gene. Thus, affected parents would tend toward the mild spectrum of gene expression, and when included in the probandlnonpro- band comparison might result in an overly optimistic view of the average expression of the PPS gene. Perhaps the closest to actuality would be provided by examining the pattern of manifestations among sibs, uncles, and aunts ofthe propositus. These data are provided in Table I, but unfortunately the small number of cases precludes drawing any firm conclusions. However, allowing for the previously mentioned strong association between the presence of popliteal pterygium and genital anomalies, there is a generally lower rate of anomalies reported in this group. Further reports of PPS in this category of relative, together with the results of careful examina- tions of all close relatives of patients with PPS, will be of interest and may provide a solution to the genetic coun- seling problems posed by the presence of findings such as those in our patients IV-2 and IV-3.

An important question is whether sporadic cases of PPS simply represent new dominant mutations to the syndrome. Once those cases that I conclude do not represent true PPS are eliminated, comparison of the sporadic and familial cases does not provide evidence, based either on a specific anomaly, or a pattern, to distinguish the 2 groups. Paternal age data are available for 10 “nonfamilial” cases and provide an elevated mean paternal age of 34 years. If the families described by Escobar and Weaver [ 19781 are in reality familial then the mean paternal age of the remaining 8 cases is 37 years. There has been no suggestion of infertility in this syndrome and the genital anomalies are usually so mild as not to interfere with reproduction. However, therapy of the popliteal webs has historically not always been particularly successful, and together with the craniofacial signs, seem likely to result in a significantly reduced fitness, and a concomitant high proportion of new mutations. However, failure to examine and report affected relatives carefully may be an equally important deter- minant of this apparent high rate of sporadic cases.

The marked variation in expression and occasional documented lack of penetrance of PPS has already been alluded to, and it is of interest to examine whether the sex of the transmitting parent may influence the severity of manifestation in the offspring. A comparison was made (see Table I) between the offspring of affected fathers and mothers and no discernible trend was noted.

202 Hunter

TABLE I. Syndrome Manifestations*

Comparison groups . ~~~

1959 and before 1960 and after Surgical Non-surgical

Male Female Non familial Familial Propositi Non-propositi Sibs and uncle Offspring of

fathers Offspring

of mothers

Popliteal web

Number Number Ankylo- Cleft Lip Syn- Popliteal cases families blepharon lipipal pits gnathia web

15 12 2/15(13) 11/15(78) 4/15(27) 2/15(18) 14/15(93) 53 31 19/53(36) 50/53(94) 29/53(55) 28153i53) 38/53(72) 34 24 11134(32) 29/34(85) 13/34(38) 15/34(44) 27/34(79) 34 19 10/34(29) 32/34(94) 20/34(59) 16/34(47) 25/34(74)

~~~ _ _ -~

32 40 28 44 44 28 12 12

23 10/32(31) 27132i84) 30 12/40(30) 36140(90) - 12128(43) 23/28(82) - 10/44(23) 40/44(91) 44 19/44(43) 37/44(84) 16 3/28(11) 26/28(93) 12 1/12(8) 11/12(92)

7 3/12(25) 12/12(100)

15132(47) 19140i48) 13/28(46) 21/44(48) 22144i50) 12/28(43) 5/12(42) 4/12(33)

10/32(31) 23/40(58) 14/28(50) 19/44(43) 24/44(55)

9128(32) 4/12(33) 4/12i33)

11 7 5/11(45) 10111(90) 7/11(63) 8/11(72) 7/11(63)

Number’ Crural web Genital anomaly 54 8/54(15) 32/54(59)

Hand Hand syndact absence 5115i33) 2/15(18) 6/53(11) 4/53(8) 6/34(18) 5/34(15) 5/34(15) 1/34(3)

~~ __

4/32(13) 8/40(20) 8/28(29) 4/44(9)

10/44(23) 2/28(7) 0/12(0) 0/12(0)

4/32(13) 2/40(5) 3/28(11) 3144(7) 4/44(9) 2/28(7) 0/12(01 1/12(8)

No popliteal web 17 0.17(0) 1/17(6) *Percent in parenthesis. ‘Number will vary depending upon exclusion or inclusion of our family. ‘One ‘unaffected was a MZ twin who had a popliteal streak and twin with webs.

Embryogenesis

The pleiotropic PPS gene causes a broad array of malformations, some of which may be interrelated, and others of which seem to have no embryologic relationship. The embryogenesis of the various anomalies is unknown. It is well established that the popliteal web may contain vessels and nerves along its outer border [Champion and Cregan, 19591. Shved et al. [1983] car- ried out detailed anatomic studies of the lower limbs in a patient who had bilateral popliteal webs and apparently marked anomalies of the feet. Unfortunately clinical details were lacking. They found abnormalities of mus- cles, nerves, arteries, and bone, but considered the unex- plained muscle shortness, particularly that of the semi- tendinosus, to be the primary cause of the webs. No evidence was provided to support this hypothesis. The lethal multiple pterygium syndromes are associated with edema, and Hall [ 19841 has suggested that initial skin stretching and joint restriction due to edema, which subsequently may resorb would result in pterygia. This view has been promoted with respect to the pterygium colli in the Ullrich-Turner and Noonan syndromes, In case 5 of their report, Chen et al. [1980] observed promi- nent vascular channels in the web. Fitch et al. [1985] reported a macerated 16-week fetus with edema and a meshwork of dilated, thin walled vessels, lying in a loose edematous mesenchyme. This observation would support an hypothesis that localized development of abnormal and “leaky” vessels leads to edema, which sec- ondarily restricts the joint and leads to the pterygium. Hartwig et al. [19891 have recently suggested that

small, wrinkled reticular fibres, observed in a case of lethal multiple pterygium, evidence a weak connective tissue and abnormal collagen. They noted weak liga- ments and subcutis, and vessel walls could equally be affected.

Could a similar underlying mechanism involving microvascular anomalies and edema account for other manifestations in the PPS? Early in embryogenesis, the tongue lies in the nasal cavity, the future palatine process is below the tongue, and the upper and lower jaw surfaces are in contact. As the palatine process moves vertically it passes in contact with the lateral surface of the tongue, and thus, there is a t some point intimate contact between all the components which may ulti- mately be involved in oral synechiae. Gassner et al. [19791 cite Hochsletter and Mathis, [Mathis, 19621 and suggest that excessive epithelial growth leads to fusion and secondary mesenchymal involvement. However, it is not clear why epithelial hypertrophy should lead to fusion; underdevelopment or its breakdown would seem a more likely mechanism. During embryogenesis of the eyelid, there is a normal fusion of the epithelial surfaces of the opposing lids, but ankyloblepharon is not a simple persistence of this attachment because the adhesions contain a mesenchymal core [Long and Blandford, 19621. Loss of epithelial integrity with subsequent adhesions, much as has been suggested for amniotic bands [Hunter and Carpenter, 19861, and to explain the malformations in the Bartsocas-Papas syndrome [Opitz, 19881, could account for oral and ocular synechiae. In light of this hypothesis, the case of Wolff [18891, which was excluded from the review is interesting, in that the


Toe Toe Toe-skin Hypopl Crypt- Scro tum Penis Labia Clitor- Crural _ _ _ _ _ ~ _ _ _ _ _ _ ~ syndact absence pyramid nails orchid abn abn a b n omeg web - 8/15(53)

28/53(53) 16/34(47) 18/34(53)

14/32(44) 26/40(65) 12/28(61) 23/44(52) 30/44(68) 10/28(36) 5/12(42)

5/12(42)

8/11(72)

3/15(20) 14/53(26) 6/34(18)

11/34(32)

8/32(25) 10/40(25) 9/28(32) 9/44(20)

11 /44(25) 7/28(25) 2/12(17)

1/12(8)

3/11(27)

1/15(7) 16/53(30) 8/34(24)

10/34(29)

8/32(25) 10/40(25) 9/28(32) 9/44(20)

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scar from the back to the sternum is reminiscent of an amniotic band. Microvascular anomalies and secondary edema might account for the epithelial disturbance. A similar mechanism could be invoked to account for the syndactyly and less common absence deformities seen in PPS. Alternately, one could speculate about a disturbance of normal programmed cell death. The distribution of the anomalies in PPS follow the region of the embryonic Ektodermring [Opitz, 19881.

The lower lip pits presumably derive from the normal lateral sulci seen in the mandibular process of the 7.5- to 12.5-mm-stage embryo [Warbrick et al., 19521. These lateral sulci are obliterated, starting from their caudal end, and remain present longest in the area that forms the lower lip. Failure of obliteration will lead to their incorporation into the lip as growth continues. This could be due to an epithelial abnormality or failure of programmed cell death. Further studies of the type reported by Fitch et al. [1985] may shed further light on the embryopathology of PPS.

CONCLUSION With respect to the family reported in this paper, it is

clear that the child and mother had PPS, and i t is logical to conclude that the relatives with well-defined syndactyly also carry the gene. The status of IV-2 and IV-3, whose subtle findings are well within the range of normal variation, will await gene linkage studies and/or their future generations. The former will also be of interest with respect to the relationship of PPS to the various syndromes with which it shares overlapping manifestations.

ACKNOWLEDGMENTS I would like to thank Dr. Judith Hall and Dr. Stephen

Bamforth, who examined 11-2, 111-2, IV-2, and IV-3 in Vancouver, and Dr. Judith Hall for her encouragement and suggestions. Special thanks are due to Ms. Ute Portner, who worked to translate the original German literature, and to Dr. Toshikuni Yanagishita for his translations from Japanese. I would also like to thank Dr. J. Hamamoto for sending a copy of the paper by Dr. Hirakawa.

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Documents

The popliteal pterygium syndrome: Report of a new family and review of the literature